stanford md phd statistics

Doctoral Admissions

Use this page to explore admissions data for Stanford's research doctoral programs. While the most common doctoral degree across the university is the PhD, the JSD in Law and the DMA in Musical Arts are also included here. The MD and JD are considered to be professional degrees and are not included. Note that any year referenced in this dashboard refers to the academic year in which the applicant was intending to enroll. For example, an application submitted in September 2018 for the 2019-20 academic year would be counted under 2019-20. These data are limited to new, external applicants only. If you are interested in the Biosciences programs in the School of Medicine, please read the important note below the dashboard.

More information is available about  doctoral program enrollment and demographics , as well as  doctoral degree conferrals, time-to-degree, and graduation rates . Note that local variation in policy and practice regarding admission, matriculation, and degree conferral may affect the departmental and school-level metrics below.

Methodology & Definitions

Application counts.

Applicant counts are based on the number of applications to doctoral programs from new applicants only. Current students who are transferring into a doctoral program from another graduate program at Stanford without submitting a new application are not included. If an application was transferred between programs during the admission process, the application is counted under the final program for which it was considered, not the original program.

Application Years

Applications and offers of admission are counted in the year in which the applicant was intending to enroll. The year in this case encompasses the summer quarter through the following spring, so the 2018-2019 application year would include students who intended to matriculate in Summer 2018 through Spring 2019. If an applicant was admitted and decided to defer their enrollment, that application and offer of admission are counted in the later, deferred year instead of the original year. The majority of new doctoral students matriculate in either autumn or summer. As these dashboards are updated annually in the autumn, the data for the most recent year will not include applicants or admits for winter or spring.

Admit Rates

The admit rate is calculated by dividing the number of offers of admission by the total number of applications received.

An Important Note about Stanford Biosciences

Prospective students may only apply to a single doctoral program at a time, with the exception of the  14 programs in Stanford Biosciences . Beginning with the 2022-23 application period, prospective students in Biosciences are permitted to select up to two programs for consideration as part of their application. (Prior to the 2022-23 application cycle, students were able to and would commonly select up to three programs for consideration.) A successful applicant will only be offered admission to one of these programs, which may result in an artificially low admit rate for some of these programs.  These programs include:

• Biochemistry
• Biomedical Informatics
• Cancer Biology
• Chemical and Systems Biology
• Developmental Biology
• Microbiology and Immunology
• Molecular and Cellular Physiology
• Neurosciences
• Stem Cell Biology and Regenerative Medicine
• Structural Biology

Visit the  Graduate Admissions website  for more information about pursuing graduate study at Stanford.

The data are available for download in Google Drive .

• Data Source(s): PeopleSoft Campus Solutions, Institutional Research & Decision Support

Stanford University is committed to providing an online environment that is accessible to everyone, including individuals with disabilities. If you cannot access this content or use any features on this site, please contact  [email protected]  to obtain alternate formats.

You may submit feedback on this dashboard through the  feedback form .

• 2023 FACTS: Applicants and Matriculants Data

2023 FACTS: Enrollment, Graduates, and MD-PhD Data

• 2023 FACTS: Electronic Residency Application Service (ERAS) Data
• FACTS Glossary

By Institution

By gender and race/ethnicity, md-phd and other dual degrees, summary data, additional resources.

Graduation Rates and Attrition Rates of U.S. Medical Students (PDF) This AAMC Data Snapshot provides information on the graduation and attrition rates of U.S. Medical Students.

• Medical Education

PhD Students

Zhaomeng Chen

John Cherian

Apratim Dey

Kevin binh fry, paula gablenz.

Disha Ghandwani

Aditya Ghosh

Isaac Gibbs

Xavier gonzalez.

Dileka Gunawardana

Will hartog.

Michael Howes

Jayoon Jang

Yujin jeong.

Annette Jing

Rahul raphael kanekar, etaash katiyar, joshua leib kazdan.

Joonhyuk Lee

Harrison li.

Matthew MacKay

Tim Morrison

Michael david salerno.

Henry Smith

Asher Spector

Timothy sudijono.

Ian Christopher Tanoh

Nathan Tung

Zitong Yang

Julie Zhang

Kangjie zhou.

Yanxin Zhou

For Prospective Students

Introduction to the biomedical data science graduate program.

Biomedical Data Science is an interdisciplinary field that combines ideas from computer science and quantitative disciplines (statistics, data science, decision science) to solving challenging problems in biology and medicine. Applicants enter our program with many different backgrounds, so the program is designed to be flexible. Training in informatics and biocomputation is also available through other departments at Stanford, such as Bioengineering, Computer Science, Statistics, and Genetics. We recommend your explore the various options to find the best fit for you.

Important Dates:

Application Deadlines: December 5th for PhD and Academic MS; other MS applications accepted quarterly.

Mentoring and Info sessions : Faculty Online Information Sessions will be scheduled in the summer for the fall term, 2024. Meet-the-Students Online Panel will be scheduled in the summer for the fall term, 2024. Peer-to-Peer Application Mentoring Program registration deadline will be scheduled in the summer for the fall term, 2024.

What DBDS Offers

• The Academic (Research) MS, with NLM-funded positions for postdoctoral trainees; others may also apply, but are not guaranteed funding from DBDS.
• The Honors Cooperative Program (Professional Masters) MS, a part-time distance education program
• The Coterminal MS for Stanford undergraduates
• Certificate in Bioinformatics
• Individual courses
• Post-doctoral research training (not pursuing a degree)
• Scholarly Concentration and Med Scholars programs for Stanford Medical Students

Why apply here?

Prerequisites, diversity and inclusion, phd + masters of medicine, academic (research) ms, honors cooperative program (hcp) ms, coterminal ms, writing your personal statement, postdoctoral training, clinical informatics fellowship, distance education programs, for stanford medical students, for stanford mstp students, for stanford graduate students, for stanford undergraduates, for international applicants, why apply to this program.

• Reputation . Stanford is ranked #1 for graduate training in Biological Sciences (including  Genetics/Genomics ), Bioinformatics , Computer Science , and  Statistics . You will work with world-renown leaders in these areas.
• Interdisciplinary Research . DBDS is part of the Stanford Biosciences PhD program, and draws on faculty from research and clinical departments located throughout Stanford’s School of Medicine. We have access to the extensive research clinical database and clinical informatics expertise at Stanford Hospital and Lucile Packard Children’s Hospital. In addition, we have strong ties to Bioengineering, Computer Science and Statistics. All of these are in close physical proximity on Stanford’s main campus.
• History . Founded in 1982, our program is one of the oldest and most illustrious in the United States. Our graduates have gone on to become distinguished faculty at top universities and medical schools, industry leaders at major corporations and startups, or high-ranking positions in government.
• Curriculum . Our core courses span a wide array of topics, from the analysis of biological sequences and structures, to translational and imaging informatics, the use of clinical data to drive health care, and understanding the principles of developing models and representations of biomedical phenomena. Much of the course material is based on cutting-edge research conducted here at Stanford. Electives come from DBDS, Computer Science, Statistics, and other departments.
• Scientific Communication . We place a very high value on being able to present complex ideas to colleagues, collaborators, and the public in speech and in writing. Students present annually at our research seminar. All students make presentations regularly in their labs.
• Community . DBDS is a small, collegial, friendly program. We have an annual off-campus retreat, and a strong alumni network.
• Location . Stanford University’s campus occupies over 8000 acres, bordering Palo Alto, California. It has an ideal Mediterranean climate, is the heart of Silicon Valley, and provides easy access to the amenities of the San Francisco Bay Area.

Prerequisites for Graduate Degrees in Biomedical Data Science

Our program is quite quantitatively and computationally rigorous, and our students take graduate-level coursework in statistics and computer science at Stanford. Therefore, we expect strong preparation in these areas in order to make reasonable progress through our curriculum. All of our degree programs have the same prerequisites. Note that these are the minimum requirements, and that many applicants exceed them.

• Calculus: at least one year, preferrably the track taught for engineering or physical science. Additional coursework in multivariate calculus is  strongly  recommended
• Probability and statistics: at least one course, and preferably one course in both areas
• Linear algebra
• Computer science: one year, preferably the introductory sequence for CS majors. The focus should be fundamentals of computer science (data structures and algorithms) and software engineering principles (abstraction, modularity, object-oriented programming)
• Biology/Medicine: at least some coursework in this area, preferably the introductory sequence for biology majors

The Department of Biomedical Data Science recognizes that the Supreme Court issued a ruling in June 2023 about the consideration of certain types of demographic information as part of an admission review. All applications submitted during upcoming application cycles will be reviewed in conformance with that decision.  

The Department of Biomedical Data Science welcomes graduate applications from individuals with a broad range of life experiences, perspectives, and backgrounds who would contribute to our community of scholars. The review process is holistic and individualized, considering each applicant’s academic record and accomplishments, letters of recommendation, prior research experience, and admissions essays to understand how an applicant’s life experiences have shaped their past and potential contributions to their field and how they might enrich the learning community at Stanford.

We would like to make applicants aware of the following Stanford programs and resources:

DBDS Peer-to-Peer Application Mentoring Program

The DBDS Peer-to-Peer Application Mentoring Program is a student organized initiative that strives to assist individuals who:

• Identify as part of one or more groups that are historically underrepresented in STEM and
• Are applying to the DBDS PhD or MS program.

Participants may receive one round of feedback on their statements of purpose, up to the limit of our time and resources. Participation does not guarantee nor increase chance of admission.

The Peer-to-Peer application will be available in the fall term, 2024.

Meet the Students Panel

The Biomedical Informatics graduate students panel will be scheduled in the fall term, 2024.

Meet the Faculty Panel

Join our Meet the Faculty Panel will be held in the fall term, 2024.

Other Programs:

• SSRP-Amgen Scholars Program , an eight-week, residential, summer research program for current undergraduates, with a goal of bringing diversity to graduate study in the biomedical sciences, including Biomedical Data Science.
• Stanford’s Biosciences  ADVANCE Summer Institute  to prepare students for a successful graduate career.
• Stanford’s Biosciences Graduate Program  Diversity & Engagement  website.
• Stanford’s Vice Provost for Graduate Education  Diversity in Graduate Education  website.
• Stanford’s  Office of Accessible Education
• Stanford’s  SCRIBE  system to convert documents to Braille and audio formats.

We have admitted students who have previously studied at the following institutions across the world:

The PhD Degree in Biomedical Data Science

The PhD degree allows graduates to lead research in academic, industry, or government positions. All prospective applicants should note that the program in Biomedical Data Science is intellectually rigorous, and emphasizes research in novel computational methods aimed at advancing biology and medicine. You may also want to investigate degree programs from other computational and quantitative graduate programs (Bioengineering, Computer Science, Statistics) and other programs in the Biosciences Programs (such as Genetics, Chemical & Systems Biology, or Structural Biology). In contrast to the other computational/quantitative programs, DBDS focuses more on informatics issues of knowledge representation and reasoning, data mining and analysis, and machine learning, while in contrast to the Biosciences programs, DBDS places greater emphasis on method development and evaluation than on basic science. Faculty from many departments have research projects of a computational nature, and in some cases there is considerable overlap, but our applications committee evaluates the fit of your application to our program, so the choice of a home program is an important one.

Our students come from diverse backgrounds and training experiences. Some enter straight from baccalaureate training, while others have pursued advanced degrees, such as an MS, MPH, or MD, or worked in clinical medicine, bioengineering, biotechnology, or software engineering.

Please see the  prerequisites  page.

Degree Requirements

The curriculum is described on  Stanford ExploreDegrees .

The doctoral program is a full-time, residential, research-oriented program. DBDS does not offer part-time or distance education leading to the PhD. However, some students have applied to the part-time distance education MS program, completed that degree, and then submitted a separate application to the PhD program. There is no guarantee that Masters graduates will be accepted into the PhD program.

PhD students typically start in the fall quarter, but may begin in the preceding summer. They spend an average of about five years at Stanford.

Candidates are encouraged to explore the various research interests of the biomedical informatics core and participating faculty. Lab rotations during the first year expose students to different labs and faculty. Prior to being formally admitted to candidacy for the doctoral degree at the end of the second year of study, each student must demonstrate knowledge of informatics fundamentals and a potential for succeeding in research by passing a qualifying examination. Students later complete and defend a doctoral dissertation.

MDs interested in the PhD should contact us early, especially if you are coordinating the DBDS training with further medical residency or fellowship training. It is also important to ensure that sufficient math and computer science prerequisites are completed before applying.

BMI follows the same funding model as other programs in Biosciences: all of our PhD students are fully funded, and, at time of starting graduate school, your funding does not tie you to any particular lab, giving you the freedom to explore your research interests at Stanford. All funding sources cover tuition, a stipend, and health insurance. However, there are some restrictions:

US Citizens and permanent residents are eligible for our National Library of Medicine (NLM) Training Grant. They can also apply for National Science Foundation Graduate Fellowships, and other external fellowships; this is encouraged, but not required.

Join dozens of  Stanford Medicine students  who gain valuable leadership skills in a multidisciplinary, multicultural community as  Knight-Hennessy Scholars  (KHS). KHS admits up to 100 select applicants each year from across Stanford’s seven graduate schools, and delivers engaging experiences that prepare them to be visionary, courageous, and collaborative leaders ready to address complex global challenges. As a scholar, you join a distinguished cohort, participate in up to three years of leadership programming, and receive full funding for up to three years of your PhD studies at Stanford. Candidates of any country may apply. KHS applicants must have earned their first undergraduate degree within the last seven years, and must apply to both a Stanford graduate program and to KHS. Stanford PhD students may also apply to KHS during their first year of PhD enrollment. If you aspire to be a leader in your field, we invite you to apply. The KHS application deadline is October 11, 2023. Learn more about  KHS admission .

NSF Graduate Research Fellowship Program (GRFP) . Open to first  or  second year graduate students. Eligibility: No previous graduate training (e.g., masters degree), must be US citizen or permanent resident. Due date: late October.

We do not accept “self-pay” PhD students.

Application Instructions and Deadlines

Applications are due late November/early December each year. See details on the  Graduate Admissions webpage  and on the  Biosciences Application  website.

The Application Deadline: December 5, 2023 (11:59:59 pm PST).  

• Note that the Biosciences Program allows you to select two departments/programs from which you will receive simultaneous consideration. Also note that only one PhD application per academic year is allowed, and that Computer Science, Bioengineering, and Statistics are not part of the Biosciences Program.
• Submit scanned (unofficial) transcripts as part of the Biosciences application.  Graduate Admissions  only requires admitted applicants who accept the offer of admission to submit official transcripts that shows their degree conferral. Please do not send or have sent any official transcripts to us at this time.
• See our page about the  Personal Statement .
• Please include an up-to-date version of your CV.

The GRE General Test score is not required and will not be considered if submitted. We do not require any GRE Subject Test scores.

• Letters of recommendation cannot be mailed, emailed, faxed, or submitted through a letter service (with the exception of Interfolio). For letters submitted via Interfolio, please remember that letters written specifically for your Stanford graduate program tend to be stronger than letters written for general use purposes.
• For materials that are mailed, please use our  Contact Address .
• Please do NOT upload supporting materials, such as published papers, unpublished manuscripts, BS or MS theses, writing samples, posters, or class projects, with your application .
• To check your application status,  click here to Visit Your Status Page . Interview invitations go out in early January, and interviews are in late February or early March. Offers of admission are made on a rolling basis starting in March. Finals decisions from admitted candidates are due by April 15.
• The selection of PhD students admitted to DBDS is based on an individualized, holistic review of each application, including the applicant’s academic record, the letters of recommendation, the statement of purpose, personal qualities and characteristics, and past accomplishments.
• Deferral of admission: DBDS generally does not allow deferral of admission to the PhD program, and it is better for you to apply when you are ready to begin your graduate study following the normal timeline. However, sometimes one’s circumstances change; please contact us if that happens to you.

Frequently Asked Questions

It is highly recommended that you review our  Frequently Asked Questions  page.

The PhD with Masters of Medicine

The Masters of Medicine (MOM) is for students also pursuing the PhD. This combined degree program trains graduates who will conduct basic research with relevance to current problems in medicine. Candidates receive shared training with Stanford medical students and through seminars in translational medicine. The MOM program takes at least one additional year. Students interested in the MOM and PhD program must be accepted into the PhD program before they are eligible to apply for the MOM.

The MOM program supports students through a scholarship during their MOM training. The program does not accept candidates who do not qualify for the scholarship. The balance of the PhD training is funded through the usual DBDS mechanisms.

Application Instructions

See  Masters of Medicine  website for application instructions.

Combined MD/PhD

The MD and PhD degrees may be pursued jointly through the  Medical Scientist Training Program .

The PhD Minor in Biomedical Data Science

The PhD minor in Biomedical Data Science is designed for graduate students in allied departments to acquire specialization in biomedical informatics during their graduate studies. The PhD minor is open to Stanford graduate students only, and is not a formal degree. The minor may be of particular interest to those in Bioengineering, Computer Science, Electrical Engineering, Statistics, Biology, or any of the Bioscience Programs. Consider if the minor will advance your research career, and consult with your academic and research advisors in your home department.

Prerequisites depend on the classes you select for the minor but generally you should have completed at least most of what we have listed on our  Prerequisites page . Note that you cannot use any class numbered below 200 to contribute to the 20 units required for the minor.

Requirements

See the section on Biomedical Data Science  PhD Minor  in the Stanford Bulletin, especially the information about  not double counting course units .

The Biomedical Data Science Training Program is unable to fund the PhD minor.

You will need to submit the following three documents:

• The application form from the Registrar’s office. List the courses for your program of study that fulfill the University’s and DBDS program requirements.
• A copy of your unofficial transcript.
• A one-page statement of purpose.

You may submit your application any time during the academic year to our  Contact Address.

Academic MS in Biomedical Data Science

The Academic MS degree is a full-time, on-campus, research-oriented program, and is for candidates with an interest in academic or research positions. The MS requires 45 units taken at Stanford. Most will be taking 10 units per quarter, so this program typically lasts 1.5 to 2 years.

A research project is required for completion of the degree. Trainees are encouraged to participate in one or more research rotations during their first year.

All students are expected to participate fully in the program events including Journal Clubs, research presentations, orientations, retreats, and the National Library of Medicine’s Informatics Training Conference (if funded by NLM).

MDs interested in the Academic MS should contact us as early as possible, especially if you are coordinating the DBDS training with further medical residency or fellowship training. It is also important to ensure that sufficient math and computer science prerequisites are completed before applying. This degree program is not appropriate for those with little to no quantitative or computational skills; you might want to consider Health or Clinical Informatics masters programs elsewhere, or the Clinical Informatics Fellowship .

Clinicians who wish to maintain their clinical activities may do so, but should be aware that the NLM training grant restricts outside employment to eight hours per week. The DBDS program does not arrange appointments to clinical positions or to subspecialty fellowship training.

Our NLM funding for this degree is limited to post-doctoral scholars who are US citizens or permanent residents; others, including predoctoral or international candidates, will have to get external funding or pay themselves. In this context, postdoctoral means those holding one of these degrees: PhD, MD, DDS, DMD, DO, DVM, OD, DPM, ScD, EngD, Dr PH, DNSc, DPharm, DSW, or PsyD. Post-doctoral scholars are required under the terms of the funding to devote at least 50% time to research and 50% towards classes, and because of the terms of the NLM funding, we would prefer they remain in the program in increments of full years (typically, two). Note that there are limits on the number of years of NIH funding one may receive. The exact rule is: “No individual trainee may receive more than 5 years of aggregate Kirschstein-NRSA support at the predoctoral level and 3 years of aggregate Kirschstein-NRSA support at the postdoctoral level, including any combination of support from Kirschstein-NRSA institutional research training grants and individual fellowships.” ( National Institute of Health Grants Policy page )

Also, if you are currently pursuing a PhD degree (at Stanford, or elsewhere) you may apply for our postdoctoral MS funding. Note that we cannot appoint you to the NLM Training Grant until your PhD has been conferred, so it is important that your estimated graduation date be correct.

For applicants who are not postdoctoral, we do not guarantee funding, and you are responsible for arranging your own support. You can pursue external fellowships (although these are rarely available for MS students). If admitted, you can contact faculty in whose research you have interest, and see if they have research funds to support you. International applicants should read our  webpage .

Applications are due early December each year. Note: Applications should be submitted beginning mid-September and will not be considered before that. See details on the  Graduate Admissions webpage  and on the  Biosciences Application  website.

The Application Deadline: December 5, 2023 (11:59 pm PST)

• Application materials, including letters of recommendation, should be received by the deadline. We do review all applications, including incomplete ones.
• Please do NOT upload supporting materials, such as published or unpublished papers, posters, or class projects, with your application.
• If the application is incomplete, the Biomedical Data Science Admissions Officer will notify the applicant by February. For post-doctoral candidates, there is no special paperwork or application required to apply for NLM funding. There is no in-person interview for the Academic MS program. Offers of admission are made on a rolling basis starting in March. Finals decisions from admitted candidates are due by April 15.
• The selection of MS students admitted to DBDS is based on an individualized, holistic review of each application, including (but not limited to) the applicant’s academic record, the letters of recommendation, the statement of purpose, personal qualities and characteristics, and past accomplishments.

Distance Education MS in Biomedical Data Science

The Biomedical Data Science program offers a Honors Cooperative Program (HCP), a part-time, distance education Masters program. The HCP MS program is designed for working professionals, generally those employed in biomedical informatics or related fields. Other candidates may also apply. Note that the HCP MS is a regular MS degree awarded by Stanford University.

Students receive course content and interact via the Stanford Center for Professional Development (SCPD). It is  highly recommended  that candidates start by reviewing the information about this program on the  Stanford Online  website, especially their  HCP student handbook . Applicants are  strongly encouraged to consider starting as a Non-Degree Option student (either a single course, or a three course certificate). Taking at least one of the DBDS core courses before applying is recommended but not required.

Currently all of the curriculum content is available for fully-remote access. HCP MS students are allowed to attend class on campus if that is better for them. Remote access is not fully under DBDS’s control, and might change in the future; however, we would make every reasonable effort to accommodate alternatives if needed.

To learn more about our programs, consider attending the  Meet the Students Panel .

Our graduate curriculum is described  here . Candidates may wish to begin with SCPD Certificate program in Biomedical Data Science, or individual courses through the SCPD’s Non-Degree Option. Up to 18 units of academic credit from relevant Certificate programs may be transferred upon acceptance into the degree program. In addition, you can complete some prerequisite coursework through SCPD, such as a Computer Science Certificate.

Students spend on average of 3.5 years in the program. The program must be completed within five years.

Switching MS Programs

Requests to transfer from part-tIme (HCP) to full-time (Academic MS) are reviewed by the DBDS Executive Committee on a case-by-case basis. Final decisions are at DBDS’s discretion. Please note the following limitations (for students enrolling in the HCP program starting Fall 2020) :

• Students must  complete a minimum of two (2) quarters in the part-time program excluding summer quarter or enrollment as a non-degree option student, before requesting to transfer to full-time. Therefore, the soonest the transfer can be discussed and approved is during the first DBDS Exec meeting of the third quarter of the student in the HCP program
• Students must complete a minimum of 10 units of letter-graded courses that meet requirements for the DBDS MS degree before commencing their first full-time (Academic MS) quarter
• GPA will be considered as part of the request.
• Students can make a maximum of two (2) transfers during the program (e.g. transfer from part-time to full-time and back to part-time).
• Students should consider the availability of courses online before requesting to switch from full-time to part-time, especially if this may interfere with their ability to satisfy the requirements of the degree.

The Stanford Center for Professional Development sets the tuition for all of the Honors Cooperative Programs. There is a three unit minimum enrollment per academic quarter. Check the latest tuition and fees at the  Stanford Center for Professional Development website. The DBDS program does not set rates or policies or collect tuition.

Some employers will support tuition for students enrolled in graduate studies while employed. Check with your Human Resources department for programs and policies. Students in the HCP MS program are not eligible for funding from many US government fellowships and other scholarships due to the required research component of the awards. Many student loan programs require full-time registration status. DBDS does not provide financial aid for this program.

Review the information on the  Bioscience Application  website.

Complete the  Biosciences Application  (same as PhD) online. Applications are accepted most of the year, and students can start any quarter except Summer. The deadlines for HCP applications are specific to this degree program, and are listed  here .

Applications are accepted for admission each quarter except summer. The application deadlines are shown here:

Coterminal MS in Biomedical Data Science

The Biomedical Data Science program offers a coterminal Masters program for Stanford undergraduates.

Policies and Degree Requirements

The Registrar’s webpage on Coterminal Degree Programs is  here . Graduate Education website on coterminal degrees is  here .

The MS curriculum is described  here . Coterminal Masters students are not required to perform research rotations or submit a research project, although they are welcome to do so.

Please see the  prerequisites page. In addition, we recommend (but do not require) that you take at least one DBDS core course before applying.

We accept applications to the coterminal Masters program quarterly.  These application instructions are for the Coterminal Masters only.  The deadlines to submit your applications are listed in the table below. Letters of recommendation are required by the deadline.

If you lose your undergraduate status prior to the completion of the application for the coterminal MS, you must apply as a regular candidate to the DBDS program.

Application Procedure

Fill out the  Coterm on-line application . The application will ask you for:

• A Stanford Transcript
• GREs: Applicants to DBDS’s Coterminal MS program are not required to submit GRE scores.
• TOEFL:  The TOEFL is not required.
• Personal Statement (1-2 pages):  See  here .
• Enriching the Learning Community: Stanford University welcomes graduate applications from individuals with a broad range of experiences, interests, and backgrounds who would contribute to our community of scholars. We invite you to share the lived experiences, demonstrated values, perspectives, and/or activities that shape you as a scholar and would help you to make a distinctive contribution to Stanford University.
• Your Curriculum Vitae:  If you listed Awards and Publications on your CV, then you can skip the Awards and Publications question on the application.
• Two Letters of Recommendation:  You may submit more if you feel this enhances your chances of admission. The letters should come from faculty or others who are familiar with your academic/research activity.
• Prerequisites: We expect strong preparation of our prerequisites in order to make reasonable progress through our curriculum. Otherwise, please clearly indicate what your plan is to complete them, preferably prior to enrolling in DBDS. They will be reviewed on a case by case basis. The Registrar’s package contains the Preliminary Program Proposal Form; it is better to list all the proposed courses on the DBDS  Flow Sheet , and then just write “see flow sheet (attached)” on the Proposal Form. Please make sure you have a clear set of classes and schedule that will complete your prerequisites, your undergraduate degree requirements and graduate degree requirements. If you are uncertain, make your best estimate.  These instructions  (for current students) are also likely to be of use when applying.
• Additional Materials:  If you are submitting any additional materials, send them directly to the DBDS program at our Contact Address .
• Other:  Supplemental or additional department application requirements.

Decisions and Acceptance

In general, you will be notified by the end of the month in which you apply. If offered admission, you should reply by email to the offer.

Getting an Advisor

Upon acceptance into the program, you will be assigned a course advisor. You will revise your Program Proposal at this time. Please contact the DBDS program office if you need advice about coterminal status between acceptance and your first appointment with your course advisor.

Funding Sources

Access to financial aid and other options is very different for coterminal students and depends on the number of units and quarters as a registered student at Stanford.

Coterminal students have full access to undergraduate sources of financial aid until their twelfth quarter or four years of study. Coterminal students who have completed 180 units of are eligible for University fellowships and assistantships. However, many federal and private fellowships and assistantships are awarded only to students who have received the bachelors degree. Even after the conferral of the bachelors, there is no guarantee that a coterminal student will be awarded financial support via a RAship, TAship or fellowship.

Upon completion of the requirements for the bachelors, coterms may choose to obtain their bachelors degree early. However, all classes after conferral of the degree may only be counted towards the graduate degree. Please note, part of the strategy which allows coterms maximal flexibility in their course of study is their dual status as both undergraduates and graduate students.

You should definitely look at  our page for current coterm students . Also, it is highly recommended that you review our  Frequently Asked Questions  page

Personal Statement for applying in Biomedical Data Science

Instructions for writing your personal statement (statement of purpose).

You are required to submit a Personal Statement (Statement of Purpose) as part of the Graduate Application for either the MS or PhD degree.

Please note that the DBDS program focuses on the development  of novel computational and quantitative methods that can advance biomedicine. If your primary interest lies in the  application of such methods to pursue problems in a particular domain of biomedicine, then other Biosciences home programs are likely a better choice. The Admissions Committee will read your Personal Statement carefully to determine how well your aspirations align with the mission of the DBDS Training Program.

In your Personal Statement, please tell us how your schooling, work, research, and life experiences prepare you for study at DBDS, describe your current research interests and career goals, and explain how our training program will enable you to achieve them.

The Personal Statement should be 1-2 pages. Please do not append class projects, research proposals, draft manuscripts, published papers, posters, or other ancilliary materials.

Postdoctoral Training in Biomedical Data Science

Postdoctoral training is for those who already possess a doctoral level research degree (PhD, DSc), or professional degree (MD, DO, DDS).

• If you are interested in postdoctoral training which leads to an MS degree, then apply to our  Academic MS  program. (You could also apply to the PhD program if for some reason you wanted a second PhD, but we do not recommend this.)
• If you are looking for a postdoctoral research position without required classwork, then you should apply directly to the relevant faculty, generally in response to posted listings of postdoctoral positions. See the  general information  about postdoctoral training at Stanford. Also, see our  Resources for Postdocs page and our Faculty page.

Stanford offers an ACGME-approved fellowship in Clinical Informatics for board-eligible MDs. For more information, see the  main page for that fellowship .

Note that although there is some overlap in name, content, and personnel, the CI fellowship and DBDS graduate program are organizationally separate and serve different career goals. You may only apply to one of the two programs . The CI fellowship is for clinicians seeking further training in the broad area of applied clinical informatics; the DBDS program is for those seeking research training in quantitative and computational methods. Please review the materials for both programs and contact either program if you have questions.

Distance Education Programs in Biomedical Data Science including Certificate Program

In addition to the  distance education MS degree , DBDS offers a non-degree option of obtaining a certificate (three classes) or for taking individual classes. Students receive course content and interact via the Stanford Center for Professional Development (SCPD). All of the coursework is on-line; no time at Stanford is required. It is highly recommended that you start by reviewing the information on the SCPD  website, especially their  handbook  for non-degree option students. Information about any course can be found in Stanford’s  Explore Courses .

Certificate Program Eligibility and Prerequisites

The following are required for entry into the Certificate Program. Note that these prerequisite courses do not count towards the Certificate, even if taken at Stanford.

• A bachelor’s degree with a 3.0 (B) grade point average or better.
• One year of computer programming/software engineering coursework or equivalent experience. We recommend that students take the equivalent of Stanford’s CS 106A and CS 106B prior to entering the Certificate Program.
• One year of college biology.
• One year of calculus is required for some classes.
• Classwork in probability and statistics is a prerequisite for some classes.
• Some BIOMEDIN courses may have additional prerequisites. These are listed in Stanford’s catalog,  Explore Courses .

You need to achieve at least a B (3.0) in each Certificate class to continue in the program.

Student with good reasons may request waiver of these requirements through DBDS program staff.

Certificate in Biomedical Data Science: Data, Modeling and Analysis

Three courses are required for the Biomedical Data Science  Certificate . These courses are chosen from the following DBDS core courses.

• BIOMEDIN 210: Modeling Biomedical Systems: Ontology, Terminology, Problem Solving (Win quarter)
• BIOMEDIN 214: Representations and Algorithms for Computational Molecular Biology (Aut quarter)
• BIOMEDIN 215: Data Driven Medicine (Aut quarter)
• BIOMEDIN 217: Translational Bioinformatics (Win quarter)
• BIOMEDIN 260: Computational Methods for Biomedical Image Analysis (Spr quarter)

Individual Courses (Non-degree Option)

You can enroll in individual courses without pursuing a degree or certificate. You can use up to 18 Stanford units towards a degree (including those from a certificate) if you are later accepted into one of our degree programs.

You should apply directly through  SCPD , not DBDS or Biosciences.

See  here .

Biomedical Data Science for Stanford Medical Students

There several ways that Stanford medical students can be involved in DBDS-related activities. Some of these are integrated into the medical curriculum. Others involve applying to DBDS degree programs.

Scholarly Concentration

The Stanford medical curriculum provides medical training and an intellectual foundation to support future medical investigation through the required  Scholarly Concentrations . Stanford medical students interested in Biomedical Data Science can choose the Informatics and Data-Driven Medicine  concentration, one of the Foundation areas. These students take several classes in this area, including  BIOMEDIN 205 , where leading researchers from Stanford and the Bay Area present overviews of their work.

Medical Scholars

Medical students who want a more in-depth research experience are invited to participate in the  Medical Scholars  research program.

Graduate Programs (MS or PhD)

Medical students can apply to our MS or PhD programs. Follow  these procedures  for normal graduate applications and  these procedures  for MSTP students or applicants.

Postdoctoral Programs

Medical students can also apply to pursue either the MS or PhD degree after receiving their MD.

Biomedical Data Science for Stanford MSTP (Medical Scientist Training Program) students

For those already in the mstp program.

• You do rotations during the first two years (M1-2). When you join the DBDS PhD program during the Autumn quarter of your 3rd year, file a Graduate Authorization Petition (via Axess) by the second week of the quarter.
• You should request that the MSTP office send us a copy of your MSTP application.
• A unofficial copy of your Stanford transcript
• An up-to-date copy of your CV
• Your  personal statement (specifically for DBDS)
• One letter of recommendation from Stanford faculty
• The DBDS supplemental application form
• Note that GREs are not required, and there is no personal interview.

For current medical students applying to the MSTP program

• You can apply to the internal track of the MSTP and you also apply to DBDS through the standard Biosciences PhD procedure .
• MCATs can be supplied in place of the GREs (but strong performance on GRE could increase chance of acceptance in some cases).
• In-person interviews are typically early March.
• If you are not chosen by MSTP for funding, DBDS will consider you in the normal application pool with training grant funding through DBDS.

These instructions are for those currently enrolled in graduate study at Stanford (including medical students) who want to add our MS degree. However, if you are applying to DBDS for a degree to start after your current degree has been conferred, or if you are applying to DBDS to the PhD degree or the postdoctoral MS degree, then skip this page and follow the normal application instructions for the desired degree; note that generally you will have to apply in the Autumn to start in the following Autumn (or Summer).

You should submit  directly to us :

• A Graduate Authorization Petition (via Axess)
• Two letters of recommendation (have recommender send directly to us, or submit in sealed, signed envelope)
• An unofficial copy of your Stanford transcript and of any previous transcripts
• A 1-2 page  personal statement
• The DBDS  supplemental application form
• a DBDS  course flowsheet  with your proposed plan of study

Applications are accepted throughout the year. The deadlines to submit your applications are listed in the table below.

Biomedical Data Science for Stanford Undergraduates

The Biomedical Data Science Program does not offer an undergraduate major.

For students interested in an undergraduate major with an option to specialize in the area of Biomedical Data Science, see the Biomedical Computation  major.

Stanford undergraduates may choose to combine their major with the coterminal Masters degree. The Biomedical Data Science coterminal MS may be combined with many undergraduate majors; Computer Science, Biomedical Computation, Mathematical and Computational Science, Bioengineering, or any of the biological science programs offer the most efficient combination of the two degrees. See our webpage on the coterminal degree , and  the University rules .

Information for International Applicants

We welcome applications from international applicants. International applicants follow the same application process as other applicants, with additional rules and requirements listed here .

Required Academic Credentials

You need to hold a four-year bachelors degree in order to apply. The exact requirements vary by country and are listed on the Office of Graduate Admissions  International Applicants page .

Scores are required of all applicants whose first language is not English. Note that if  all  instruction for your bachelors or master degree program was in English, then the TOEFL is not required. See the  Biosciences Admissions page  for more details. Note that Stanford only accepts the TOEFL, not other tests of English.

We do not advise applicants about visas. The  Bechtel International Center  has information about how to maintain visas for international students. The US State Department has information about student and exchange visitor visas.

Please look at the webpage for the degree program (PhD or MS) to which you are applying. Unfortunately, funding for international students is quite limited, and you are encouraged to seek external funding. You should consider applying for Stanford’s  Knight-Hennessy Scholars program . Your home country may have programs to support study overseas. The  Fulbright program  funds international scholars. The Fogarty International Center maintains a  Directory of Funding Opportunities . The  Institute of International Education  has a search engine which will help you locate programs which fund international study.

For MS applicants: We have very occasionally had self-funded international MS students. You need to show funds equivalent to one year of tuition and board to meet the visa requirements.

Steven Goodman

Professor of epidemiology and population health, of medicine (primary care and population health) and, by courtesy, of health policy.

• Print Profile
• Email Profile
• View Stanford-only Profile
• Research & Scholarship
• Publications

Steven Goodman, MD, MHS, PhD is Associate Dean of Clinical and Translational Research and Professor of Epidemiology and Population Health, and Medicine. He is co-founder and co-director of the Meta-research innovation Center at Stanford (METRICS), a group dedicated to examining and improving the reproducibility and efficiency of biomedical research. He has since created and leads another initiative, the Stanford Program on Research Rigor and Reproducibility (SPORR), whose purpose is to teach and implement best practices in reproducible research in the School of Medicine. He led the Stanford CTSA KL2 and TL1 training programs from 2012-2019, and now leads the Translational Workforce Development components of the CTSA. Dr. Goodman's own research concerns the proper measurement, conceptualization and synthesis of research evidence, with particular emphasis on Bayesian approaches to quantitation, and qualitative approaches arising from the philosophy of science. He is also interested in developing methods to use shared data to confirm and extend published science. He also has worked on the connections between ethics and clinical research and policy making. Finally, he has a strong interest in developing curricula and new models for teaching the foundations of good scientific practice, from question development to proper study design, conduct, analysis and inference. He teaches courses on clinical research methods, foundations of scientific and statistical reasoning, and evaluation of diagnostic and predictive technologies. He has been a senior statistical editor of Annals of Internal Medicine since 1987 and was Editor of Clinical Trials: Journal of the Society for Clinical Trials from 2004-2013. He is Chair of the Methodology Committee of the Patient Centered Outcomes Research Institute (PCORI), where he led their open science and data sharing efforts, and is scientific advisor for the national Blue Cross–Blue Shield Technology Assessment Program. He has served on numerous Institute of Medicine committees since the mid 1990's, including one on vaccine safety, chairing a 2012 committee on drug safety, and a 2014 committee on sharing data from clinical trials. He was awarded the 2016 Spinoza Chair in Medicine from the University of Amsterdam for his work in scientific inference, received the 2019 Abraham Lilienfeld award from the American College of Epidemiology for his lifetime research and teaching contributions to the field, and was elected into the National Academy of Medicine in 2020. From 1989-2011, Steve served on the faculties of the Johns Hopkins Schools of Medicine and Public Health, where he was co-director of the doctoral program in Epidemiology and member (1989-2011) and then director (2007-2011) of the Johns Hopkins cancer center’s Division of Biostatistics and Bioinformatics. At Hopkins, he taught courses on Systematic reviews and Meta-analysis, Diagnostic and prognostic testing, and several courses on epidemiologic, clinical research and inferential methods. He received an AB from Harvard, majoring in Biochemistry and Applied Math, an MD from NYU, trained and was board-certified in pediatrics at Washington University in St. Louis, and received a master’s degree in Biostatistics and PhD in Epidemiology from Johns Hopkins.

Academic Appointments

• Professor, Epidemiology and Population Health
• Professor, Medicine - Primary Care and Population Health
• Professor (By courtesy), Health Policy
• Member, Stanford Cancer Institute

Administrative Appointments

• Associate Dean of Clinical and Translational Research, Stanford School of Medicine (2011 - Present)
• Director, Stanford Program on Research Rigor and Reproducibility (SPORR) (2020 - Present)
• Co-Director, Meta-research Innovation Center at Stanford (METRICS) (2013 - Present)
• Director of Graduate Studies, Dept. of Epidemiology and Population Health (2019 - Present)
• Co-Director, MedScholars Clinical Research Concentration, Stanford School of Medicine (2011 - Present)
• Director, Spectrum Research Education and Training, Stanford School of Medicine (2011 - 2019)
• Chief, DIvision of Epidemiology, Dept. of Health Research and Policy (2014 - 2019)
• Director, Division of Biostatistics and Bioinformatics, Department of Oncology, Johns Hopkins School of Medicine (2007 - 2010)
• Professor of Oncology, Pediatrics, Biostatistics and Epidemiology, Johns Hopkins Schools of Medicine and Public Health (1989 - 2011)

Honors & Awards

• Member, National Public Health Honor Society (1989)
• Myrto Lefkopoulou Distinguished Lecturer, Harvard Dept of Biostatistics (2000)
• Fellow, Society for Clinical Trials (2010)
• Spinoza Chair in Medicine, University of Amsterdam (2016)
• Abraham Lilienfeld Award, American College of Epidemiology (2019)
• Lifetime Fellow, American College of Epidemiology (2019)
• Elected Member, National Academy of Medicine (2020)
• Elected Fellow, Johns Hopkins Society of Scholars (2022)

Boards, Advisory Committees, Professional Organizations

• Member, Statistical review committee, PNAS (2022 - Present)
• Chair, Methodology Commitee, PCORI (2019 - Present)
• Scientific Advisor and member, Medical Advisory Panel, National Blue Cross-Blue Shield Technology Assessment Program (2001 - Present)
• Senior statistical editor, Annals of Internal Medicine (1987 - Present)
• Vice-chair, Methodology Committee, Patient Centered Outcomes Research Institute (PCORI) (2011 - 2019)
• Member, Advisory committee to the NIH director on the National Library of Medicine (2015 - 2015)
• Member, Committee on Responsible Sharing of Clinical Trial Data, Institute of Medicine (2013 - 2015)
• Co-chair, Committee on Drug Safety, Institute of Medicine (2010 - 2012)
• Editor in Chief, Clinical Trials: Journal of the Society for Clinical Trials (2004 - 2013)
• Member, Committee on Immunization Safety, Institute of Medicine (2001 - 2004)

Professional Education

• PhD, Johns Hopkins School of Public Health, Epidemiology (1989)
• MHS, Johns Hopkins School of Public Health, Biostatistics (1987)
• Board Certification, General Pediatrics, American Board of Pediatrics, Pediatrics (1985)
• Residency, St. Louis Children's Hospital, Washington University School of Medicine, Pediatrics (1984)
• MD, New York University, Medicine (1981)
• AB, Harvard College, Biochemistry, Applied Math (1976)
• 300 PASTEUR DR
• PALO ALTO,  California  94304 
• (650) 723-8524 (office)
• 650-497-2806 (office)

Additional Info

• Mail Code: 5405
• Other Names: Steve Goodman

Current Research and Scholarly Interests

I am interested in issues relating to the representation and measurement of evidence in medical research, and determinants of the truth of medical findings, using a Bayesian framework. I also do work in evidence synthesis, comparative effectiveness research, and the ethics of clinical research.

2023-24 Courses

• Epidemiology Research Seminar EPI 236 (Aut)
• Essentials of Clinical Research at Stanford EPI 273 (Win)
• Evaluating Technologies for Diagnosis, Prediction and Screening EPI 219 (Win)
• Foundations of Statistical and Scientific Inference EPI 264, STATS 264 (Aut)
• Foundations of statistics and reproducible research BIOS 217 (Aut)
• Intensive Course in Clinical Research EPI 245 (Aut)
• Stanford CTSA Scholars Seminar EPI 229 (Aut, Win, Spr)
• The Practice of Reproducible Research BIOS 216 (Win)
• Directed Reading in Epidemiology EPI 299 (Aut, Win, Spr, Sum)
• Directed Reading in Medicine MED 299 (Aut, Win, Spr, Sum)
• Early Clinical Experience in Medicine MED 280 (Aut, Win, Spr, Sum)
• Graduate Research EPI 399 (Aut, Win, Spr, Sum)
• Graduate Research MED 399 (Aut, Win, Spr, Sum)
• Medical Scholars Research EPI 370 (Aut, Win, Spr, Sum)
• Medical Scholars Research MED 370 (Aut, Win, Spr, Sum)
• Medical Scholars Research (Away) EPI 370W (Aut, Win, Spr, Sum)
• Undergraduate Research EPI 199 (Aut, Win, Spr, Sum)
• Undergraduate Research MED 199 (Aut, Win, Spr, Sum)

2022-23 Courses

2021-22 courses, 2020-21 courses.

• Cinematic Discoveries: A movie-based exploration of research rigor, communication and diversity BIOS 298 (Aut)
• Stanford CTSA Scholars Seminar EPI 229 (Aut, Win, Spr, Sum)
• The Practice of Reproducible Research BIOS 216 (Sum)

Stanford Advisees

• Doctoral Dissertation Reader (AC) Yan Min , Matthew Sigurdson , Parker Zhao
• Doctoral Dissertation Advisor (AC) Cesar Baeta, Catharine Bowman
• Master's Program Advisor Sanaa Alam , Catharine Bowman, Melissa Leeolou
• Doctoral (Program) Catharine Bowman

Graduate and Fellowship Programs

• Epidemiology (Phd Program)
• Epidemiology (Masters Program)

All Publications

A New Look at P Values for Randomized Clinical TrialsUsing the primary results of 23,551 randomized clinical trials from the Cochrane Database, van Zwet et al. provide an empirical guide for the interpretation of an observed P value from a "typical" clinical trial in terms of the degree of overestimation of the reported effect, the probability of the effect's sign being wrong, and the predictive power of the trial.

View details for DOI 10.1056/EVIDoa2300003

View details for PubMedID 38320512

We use information derived from over 40K trials in the Cochrane Collaboration database of systematic reviews (CDSR) to compute the replication probability, or predictive power of an experiment given its observed (two-sided) P $$ P $$ -value. We find that an exact replication of a marginally significant result with P = . 05 $$ P=.05 $$ has less than 30% chance of again reaching significance. Moreover, the replication of a result with P = . 005 $$ P=.005 $$ still has only 50% chance of significance. We also compute the probability that the direction (sign) of the estimated effect is correct, which is closely related to the type S error of Gelman and Tuerlinckx. We find that if an estimated effect has P = . 05 $$ P=.05 $$ , there is a 93% probability that its sign is correct. If P = . 005 $$ P=.005 $$ , then that probability is 99%. Finally, we compute the required sample size for a replication study to achieve some specified power conditional on the p $$ p $$ -value of the original study. We find that the replication of a result with P = . 05 $$ P=.05 $$ requires a sample size more than 16 times larger than the original study to achieve 80% power, while P = . 005 $$ P=.005 $$ requires at least 3.5 times larger sample size. These findings confirm that failure to replicate the statistical significance of a trial does not necessarily indicate that the original result was a fluke.

View details for DOI 10.1002/sim.9406

View details for PubMedID 35396714

Importance: Infection with COVID-19 has been associated with long-term symptoms, but the frequency, variety, and severity of these complications are not well understood. Many published commentaries have proposed plans for pandemic control that are primarily based on mortality rates among older individuals without considering long-term morbidity among individuals of all ages. Reliable estimates of such morbidity are important for patient care, prognosis, and development of public health policy.Objective: To conduct a systematic review of studies examining the frequency and variety of persistent symptoms after COVID-19 infection.Evidence Review: A search of PubMed and Web of Science was conducted to identify studies published from January 1, 2020, to March 11, 2021, that examined persistent symptoms after COVID-19 infection. Persistent symptoms were defined as those persisting for at least 60 days after diagnosis, symptom onset, or hospitalization or at least 30 days after recovery from the acute illness or hospital discharge. Search terms included COVID-19, SARS-CoV-2, coronavirus, 2019-nCoV, long-term, after recovery, long-haul, persistent, outcome, symptom, follow-up, and longitudinal. All English-language articles that presented primary data from cohort studies that reported the prevalence of persistent symptoms among individuals with SARS-CoV-2 infection and that had clearly defined and sufficient follow-up were included. Case reports, case series, and studies that described symptoms only at the time of infection and/or hospitalization were excluded. A structured framework was applied to appraise study quality.Findings: A total of 1974 records were identified; of those, 1247 article titles and abstracts were screened. After removal of duplicates and exclusions, 92 full-text articles were assessed for eligibility; 47 studies were deemed eligible, and 45 studies reporting 84 clinical signs or symptoms were included in the systematic review. Of 9751 total participants, 5266 (54.0%) were male; 30 of 45 studies reported mean or median ages younger than 60 years. Among 16 studies, most of which comprised participants who were previously hospitalized, the median proportion of individuals experiencing at least 1 persistent symptom was 72.5% (interquartile range [IQR], 55.0%-80.0%). Individual symptoms occurring most frequently included shortness of breath or dyspnea (26 studies; median frequency, 36.0%; IQR, 27.6%-50.0%), fatigue or exhaustion (25 studies; median frequency, 40.0%; IQR, 31.0%-57.0%), and sleep disorders or insomnia (8 studies; median 29.4%, IQR, 24.4%-33.0%). There were wide variations in the design and quality of the studies, which had implications for interpretation and often limited direct comparability and combinability. Major design differences included patient populations, definitions of time zero (ie, the beginning of the follow-up interval), follow-up lengths, and outcome definitions, including definitions of illness severity.Conclusions and Relevance: This systematic review found that COVID-19 symptoms commonly persisted beyond the acute phase of infection, with implications for health-associated functioning and quality of life. Current studies of symptom persistence are highly heterogeneous, and future studies need longer follow-up, improved quality, and more standardized designs to reliably quantify risks.

View details for DOI 10.1001/jamanetworkopen.2021.11417

View details for PubMedID 34037731

Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/ ). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is1.11 (95% CI: 1.02, 1.20; I=0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I=0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.

View details for DOI 10.1038/s41467-021-22446-z

View details for PubMedID 33859192

The U.S. Food and Drug Administration (FDA) has substantial flexibility in its approval criteria in the context of life-threatening disease and unmet therapeutic need.To understand the FDA's evidentiary standards when flexible criteria are employed.Case series.Applications submitted between 2013 and 2018 that went through multiple review cycles because the evidence for clinical efficacy was initially deemed insufficient.Information was obtained from the approval package (available on Drugs@FDA), including advisory committee minutes, FDA reviews, and complete response letters.Of 912 applications reviewed, 117 went through multiple review cycles; only 22 of these faced additional review primarily because of issues related to clinical efficacy. Concerns about the end point, the clinical meaningfulness of the observed effect, and inconsistent results were common bases for initial rejection. In 7 of the 22 cases, the approval did not require new evidence but rather new interpretations of the original evidence. No FDA decisions cited reasoning used in previous decisions.The conclusions rely on the authors' interpretation of the FDA statements and on a series of "close calls."The FDA has no mechanism to find or tradition to cite similar cases when weighing evidence for approvals, resulting in standalone, bespoke decisions. These decisions show highly variable criteria for "substantial evidence" when flexible evidential criteria are used, highlighted by the recent approval of aducanumab. A precedential tradition and suitable information system are required for the FDA to improve institutional memory and build upon past decisions. These would increase the FDA's decisional transparency, consistency, and predictability, which are critical to preserving the FDA's most valuable asset, the public's trust.U.S. Food and Drug Administration.

View details for DOI 10.7326/M21-2918

View details for PubMedID 34543584

View details for DOI 10.7326/M20-7448

View details for PubMedID 33205993

View details for DOI 10.7326/M20-2959

View details for PubMedID 32543881

View details for DOI 10.1001/jama.2019.9892

View details for PubMedID 31343666

Most research manuscripts are not accepted for publication on first submission. A major part of the resubmission process is reformatting to another journal's specific requirements, a process separate from revising the scientific content. There has been little research to understand the magnitude of the burden imposed by the current resubmission process.We analyzed original research article submission requirements from twelve randomly selected journals in each of eight scientific and clinical focus areas from the InCites Journal Citation Reports database. From the 96 journals selected, we randomly identified three recently published manuscripts and sent surveys to those first and/or corresponding authors (288 total) to solicit information on time spent reformatting resubmissions and opinions on the process.There was significant variation in manuscript submission requirements for journals within the same scientific focus and only 4% of journals offered a fully format-free initial submission. Of 203 authors responding (71.5% response rate), only 11.8% expressed satisfaction with the resubmission process and 91% desired reforming the current system. Time spent on reformatting delays most publications by at least two weeks and by over three months in about 20% of manuscripts. The effort to comply with submission requirements has significant global economic burden, estimated at over $1.1 billion dollars annually when accounting for a research team's time.We demonstrate that there is significant resource utilization associated with resubmitting manuscripts, heretofore not properly quantified. The vast majority of authors are not satisfied with the current process. Addressing these issues by reconciling reformatting requirements among journals or adopting a universal format-free initial submission policy would help resolve a major subject for the scientific research community and provide more efficient dissemination of findings.

View details for DOI 10.1371/journal.pone.0223976

View details for PubMedID 31665156

View details for PubMedID 30304363

Assessment of researchers is necessary for decisions of hiring, promotion, and tenure. A burgeoning number of scientific leaders believe the current system of faculty incentives and rewards is misaligned with the needs of society and disconnected from the evidence about the causes of the reproducibility crisis and suboptimal quality of the scientific publication record. To address this issue, particularly for the clinical and life sciences, we convened a 22-member expert panel workshop in Washington, DC, in January 2017. Twenty-two academic leaders, funders, and scientists participated in the meeting. As background for the meeting, we completed a selective literature review of 22 key documents critiquing the current incentive system. From each document, we extracted how the authors perceived the problems of assessing science and scientists, the unintended consequences of maintaining the status quo for assessing scientists, and details of their proposed solutions. The resulting table was used as a seed for participant discussion. This resulted in six principles for assessing scientists and associated research and policy implications. We hope the content of this paper will serve as a basis for establishing best practices and redesigning the current approaches to assessing scientists by the many players involved in that process.

View details for PubMedID 29596415

The language and conceptual framework of "research reproducibility" are nonstandard and unsettled across the sciences. In this Perspective, we review an array of explicit and implicit definitions of reproducibility and related terminology, and discuss how to avoid potential misunderstandings when these terms are used as a surrogate for "truth."

View details for DOI 10.1126/scitranslmed.aaf5027

View details for PubMedID 27252173

View details for DOI 10.1002/hast.133

View details for Web of Science ID 000313714600002

View details for PubMedID 23315895

View details for DOI 10.1002/hast.134

View details for Web of Science ID 000313714600003

View details for PubMedID 23315888

Causal inference has a central role in public health; the determination that an association is causal indicates the possibility for intervention. We review and comment on the long-used guidelines for interpreting evidence as supporting a causal association and contrast them with the potential outcomes framework that encourages thinking in terms of causes that are interventions. We argue that in public health this framework is more suitable, providing an estimate of an action's consequences rather than the less precise notion of a risk factor's causal effect. A variety of modern statistical methods adopt this approach. When an intervention cannot be specified, causal relations can still exist, but how to intervene to change the outcome will be unclear. In application, the often-complex structure of causal processes needs to be acknowledged and appropriate data collected to study them. These newer approaches need to be brought to bear on the increasingly complex public health challenges of our globalized world.

View details for DOI 10.1146/annurev-publhealth-031811-124606

View details for PubMedID 23297653

View details for DOI 10.1056/NEJMhle1207160

View details for Web of Science ID 000308343300017

View details for PubMedID 22913661

Comparative effectiveness research (CER) is still an evolving framework for which much needs to be done to improve the ability of randomized controlled trials (RCTs) to supply the necessary evidence. Perhaps, most important is to start with a clearly specified decision and decision maker in mind when the RCTs are designed. Second is to initiate RCTs with clinically relevant outcomes and comparators earlier in the evaluation process. Third is to specify and measure factors that might modify the intervention's effect, subject to logistical constraints of complexity and cost, so the trial is maximally informative, about how and to whom the intervention should be administered. It will be necessary to borrow observational methodologies and approaches to extract meaningful causal and subgroup inferences from such trials. Process variables should be seen as potentially part of that framework of effect-modifying factors, perhaps amenable to embedded experimental assessment with a trial. Perhaps most importantly, we need to improve the nationwide CER infrastructure to allow for rapid initiation and accrual for CER trials to reduce the trade-off that often exists between the speed of evidence development and its quality.

View details for DOI 10.1177/1740774511433285

View details for PubMedID 22334465

This review describes methods used in comparative effectiveness research (CER). The aim of CER is to improve decisions that affect medical care at the levels of both policy and the individual. The key elements of CER are (a) head-to-head comparisons of active treatments, (b) study populations typical of day-to-day clinical practice, and (c) a focus on evidence to inform care tailored to the characteristics of individual patients. These requirements will stress the principal methods of CER: observational research, randomized trials, and decision analysis. Observational studies are especially vulnerable because they use data that directly reflect the decisions made in usual practice. CER will challenge researchers and policy makers to think deeply about how to extract more actionable information from the vast enterprise of the daily practice of medicine. Fortunately, the methods are largely applicable to research in the public health system, which should therefore benefit from the intense interest in CER.

View details for DOI 10.1146/annurev-publhealth-031811-124610

View details for Web of Science ID 000304202700026

View details for PubMedID 22224891

View details for DOI 10.1059/0003-4819-155-1-201107050-00010

View details for Web of Science ID 000292447800008

View details for PubMedID 21727295

As a clinical trialist, I had thought that the methods I employed were far more challenging than those I had thought were needed for quality improvement. However, some personal experiences and participation in the Cliveden conference led me to a new appreciation of the methodological and conceptual challenges faced by those trying to improve medical systems.

View details for DOI 10.1136/bmjqs.2010.046623

View details for Web of Science ID 000289768600023

View details for PubMedID 21450783

View details for Web of Science ID 000268947800008

View details for PubMedID 19567619

The P value is a measure of statistical evidence that appears in virtually all medical research papers. Its interpretation is made extraordinarily difficult because it is not part of any formal system of statistical inference. As a result, the P value's inferential meaning is widely and often wildly misconstrued, a fact that has been pointed out in innumerable papers and books appearing since at least the 1940s. This commentary reviews a dozen of these common misinterpretations and explains why each is wrong. It also reviews the possible consequences of these improper understandings or representations of its meaning. Finally, it contrasts the P value with its Bayesian counterpart, the Bayes' factor, which has virtually all of the desirable properties of an evidential measure that the P value lacks, most notably interpretability. The most serious consequence of this array of P-value misconceptions is the false belief that the probability of a conclusion being in error can be calculated from the data in a single experiment without reference to external evidence or the plausibility of the underlying mechanism.

View details for DOI 10.1053/j.seminhematol.2008.04.003

View details for Web of Science ID 000257501600002

View details for PubMedID 18582619

This commentary reviews the argument that clinical trials with data monitoring committees that use statistical stopping guidelines should generally not be stopped early for large observed efficacy differences because efficacy estimates may be exaggerated and there is minimal information on treatment harms. Overall, the average of estimates from trials that use these boundaries differs minimally from the true value. Estimates from a given trial that seem implausibly high can be moderated by using Bayesian methods. Data monitoring committees are not ethically required to precisely estimate a large efficacy difference if that difference differs convincingly from zero, and the requirement to detect harms and balance efficacy against harm depends on whether the nature of the harm is known or unknown before the trial.

View details for Web of Science ID 000247347100007

View details for PubMedID 17577008

A community of scientists arrives at the truth by independently verifying new observations. In this time-honored process, journals serve 2 principal functions: evaluative and editorial. In their evaluative function, they winnow out research that is unlikely to stand up to independent verification; this task is accomplished by peer review. In their editorial function, they try to ensure transparent (by which we mean clear, complete, and unambiguous) and objective descriptions of the research. Both the evaluative and editorial functions go largely unnoticed by the public--the former only draws public attention when a journal publishes fraudulent research. However, both play a critical role in the progress of science. This paper is about both functions. We describe the evaluative processes we use and announce a new policy to help the scientific community evaluate, and build upon, the research findings that we publish.

View details for Web of Science ID 000245192200007

View details for PubMedID 17339612

• Assessing the unreliability of the medical literature: A response to ?Why most published research findings are false? www.bepress.com/jhubiostat/paper135 Goodman SN, Greenland S 2007

Bayesian inference is a formal method to combine evidence external to a study, represented by a prior probability curve, with the evidence generated by the study, represented by a likelihood function. Because Bayes theorem provides a proper way to measure and to combine study evidence, Bayesian methods can be viewed as a calculus of evidence, not just belief. In this introduction, we explore the properties and consequences of using the Bayesian measure of evidence, the Bayes factor (in its simplest form, the likelihood ratio). The Bayes factor compares the relative support given to two hypotheses by the data, in contrast to the P-value, which is calculated with reference only to the null hypothesis. This comparative property of the Bayes factor, combined with the need to explicitly predefine the alternative hypothesis, produces a different assessment of the strength of evidence against the null hypothesis than does the P-value, and it gives Bayesian procedures attractive frequency properties. However, the most important contribution of Bayesian methods is the way in which they affect both who participates in a scientific dialogue, and what is discussed. With the emphasis moved from "error rates" to evidence, content experts have an opportunity for their input to be meaningfully incorporated, making it easier for regulatory decisions to be made correctly.

View details for DOI 10.1191/1740774505cn098oa

View details for Web of Science ID 000232648100004

View details for PubMedID 16281426

Guillain-Barré syndrome (GBS) is a rare neurologic disease that occurs at all ages, causing a progressive, ascending paralysis that usually resolves over weeks or months. The disease appears to be identical in children and adults, except that children recover more quickly, with fewer residua. For patients who lose the ability to walk independently, the main treatment options are plasmapheresis or intravenous immune globulin (IVIg), treatments that have shown to have identical effectiveness in adults in two large RCTs involving 388 patients. The effectiveness of the treatments in children has only been studied in small, poorly controlled studies. If one could capture all eligible patients in the United States, only about 100-300 children would be available for a trial annually.The goal of this case was to demonstrate how Bayesian methods could be used to incorporate prior information on treatment efficacy from adults to design a randomized noninferiority trial of IVIg versus plasmapheresis in children. A Bayesian normal-normal model on the hazard ratio of time to independent walking was implemented.An evidence-based prior was constructed that was equivalent to 72 children showing exact equivalence between the therapies. A design was constructed based on a Bayesian normal-normal model on the hazard ratio, yielding a sample size of 160 children, with a preposterior analysis demonstrating a "Type I" error rate of 5% and a power of 77%.This case study illustrates a rational approach to constructing an evidence-based prior that would allow information from adults to formally augment data from children to minimize unnecessary pediatric experimentation. The frequentist properties of a Bayesian design can be evaluated and reported as they would be for a standard design. Discussion of the appropriate prior for such designs is both a necessary and desirable feature of Bayesian trials.

View details for DOI 10.1191/1740774505cn102oa

View details for Web of Science ID 000232648100008

View details for PubMedID 16281429

View details for Web of Science ID 000168367000006

View details for PubMedID 11337600

Bayesian inference is usually presented as a method for determining how scientific belief should be modified by data. Although Bayesian methodology has been one of the most active areas of statistical development in the past 20 years, medical researchers have been reluctant to embrace what they perceive as a subjective approach to data analysis. It is little understood that Bayesian methods have a data-based core, which can be used as a calculus of evidence. This core is the Bayes factor, which in its simplest form is also called a likelihood ratio. The minimum Bayes factor is objective and can be used in lieu of the P value as a measure of the evidential strength. Unlike P values, Bayes factors have a sound theoretical foundation and an interpretation that allows their use in both inference and decision making. Bayes factors show that P values greatly overstate the evidence against the null hypothesis. Most important, Bayes factors require the addition of background knowledge to be transformed into inferences--probabilities that a given conclusion is right or wrong. They make the distinction clear between experimental evidence and inferential conclusions while providing a framework in which to combine prior with current evidence.

View details for Web of Science ID 000080894700008

View details for PubMedID 10383350

An important problem exists in the interpretation of modern medical research data: Biological understanding and previous research play little formal role in the interpretation of quantitative results. This phenomenon is manifest in the discussion sections of research articles and ultimately can affect the reliability of conclusions. The standard statistical approach has created this situation by promoting the illusion that conclusions can be produced with certain "error rates," without consideration of information from outside the experiment. This statistical approach, the key components of which are P values and hypothesis tests, is widely perceived as a mathematically coherent approach to inference. There is little appreciation in the medical community that the methodology is an amalgam of incompatible elements, whose utility for scientific inference has been the subject of intense debate among statisticians for almost 70 years. This article introduces some of the key elements of that debate and traces the appeal and adverse impact of this methodology to the P value fallacy, the mistaken idea that a single number can capture both the long-run outcomes of an experiment and the evidential meaning of a single result. This argument is made as a prelude to the suggestion that another measure of evidence should be used--the Bayes factor, which properly separates issues of long-run behavior from evidential strength and allows the integration of background knowledge with statistical findings.

View details for Web of Science ID 000080894700007

View details for PubMedID 10383371

The Continual Reassessment Method (CRM) is a Bayesian phase I design whose purpose is to estimate the maximum tolerated dose of a drug that will be used in subsequent phase II and III studies. Its acceptance has been hindered by the greater duration of CRM designs compared to standard methods, as well as by concerns with excessive experimentation at high dosage levels, and with more frequent and severe toxicity. This paper presents the results of a simulation study in which one assigns more than one subject at a time to each dose level, and each dose increase is limited to one level. We show that these modifications address all of the most serious criticisms of the CRM, reducing the duration of the trial by 50-67 per cent, reducing toxicity incidence by 20-35 per cent, and lowering toxicity severity. These are achieved with minimal effects on accuracy. Most important, based on our experience at our institution, such modifications make the CRM acceptable to clinical investigators.

View details for Web of Science ID A1995RE49200001

View details for PubMedID 7667557

Although epidemiologic studies have long associated tobacco and alcohol use with the development of squamous-cell carcinoma of the head and neck, the molecular targets of these carcinogens have yet to be identified. We performed a molecular analysis to determine the pattern of mutations in the p53 gene in neoplasms from patients with squamous-cell carcinoma of the head and neck and a history of tobacco or alcohol use.Sequence analysis of the conserved regions of the p53 gene was performed in tumor samples from 129 patients with primary squamous-cell carcinoma of the head and neck. We then used statistical analysis to identify any patient characteristics associated with mutation of the p53 gene.We found p53 mutations in 42 percent of the patients (54 of 129). Fifty-eight percent of the patients who smoked cigarettes and used alcohol (37 of 64; 95 percent confidence interval, 45 to 70 percent), 33 percent of the patients who smoked but abstained from alcohol (13 of 39; 95 percent confidence interval, 19 to 50 percent), and 17 percent of the patients who neither smoked nor drank alcohol (4 of 24, 95 percent confidence interval, 5 to 37 percent) had p53 mutations (P = 0.001). (Two patients used alcohol but did not smoke, and neither had a p53 mutation.) Furthermore, 100 percent of the mutations in the patients who neither drank nor smoked occurred at sites containing cytidine phosphate guanosine dinucleotides (potentially representing endogenous mutations) within the p53 gene (5 of 5 mutations; 95 percent confidence interval, 48 to 100 percent), whereas only 23 percent of those in cigarette smokers consisted of such changes (12 of 53 mutations; 95 percent confidence interval, 12 to 36 percent; P = 0.001).In our study, a history of tobacco and alcohol use was associated with a high frequency of p53 mutations in patients with squamous-cell carcinoma of the head and neck. Preliminary evidence linked cigarette smoking to p53 mutations at nonendogenous mutation sites. Our findings suggest a role for tobacco in the molecular progression of squamous-cell carcinoma of the head and neck and support the epidemiologic evidence that abstinence from smoking is important to prevent head and neck cancer.

View details for Web of Science ID A1995QL78800004

View details for PubMedID 7854378

Although there is a growing understanding of the importance of statistical power considerations when designing studies and of the value of confidence intervals when interpreting data, confusion exists about the reverse arrangement: the role of confidence intervals in study design and of power in interpretation. Confidence intervals should play an important role when setting sample size, and power should play no role once the data have been collected, but exactly the opposite procedure is widely practiced. In this commentary, we present the reasons why the calculation of power after a study is over is inappropriate and how confidence intervals can be used during both study design and study interpretation.

View details for Web of Science ID A1994NY33800008

View details for PubMedID 8017747

It is not generally appreciated that the p value, as conceived by R. A. Fisher, is not compatible with the Neyman-Pearson hypothesis test in which it has become embedded. The p value was meant to be a flexible inferential measure, whereas the hypothesis test was a rule for behavior, not inference. The combination of the two methods has led to a reinterpretation of the p value simultaneously as an "observed error rate" and as a measure of evidence. Both of these interpretations are problematic, and their combination has obscured the important differences between Neyman and Fisher on the nature of the scientific method and inhibited our understanding of the philosophic implications of the basic methods in use today. An analysis using another method promoted by Fisher, mathematical likelihood, shows that the p value substantially overstates the evidence against the null hypothesis. Likelihood makes clearer the distinction between error rates and inferential evidence and is a quantitative tool for expressing evidential strength that is more appropriate for the purposes of epidemiology than the p value.

View details for Web of Science ID A1993KX52900001

View details for PubMedID 8465801

It is conventionally thought that a small p-value confers high credibility on the observed alternative hypothesis, and that a repetition of the same experiment will have a high probability of resulting again in statistical significance. It is shown that if the observed difference is the true one, the probability of repeating a statistically significant result, the 'replication probability', is substantially lower than expected. The reason for this is a mistake that generates other seeming paradoxes: the interpretation of the post-trial p-value in the same way as the pre-trial alpha error. The replication probability can be used as a frequentist counterpart of Bayesian and likelihood methods to show that p-values overstate the evidence against the null hypothesis.

View details for Web of Science ID A1992HU18300003

View details for PubMedID 1604067

Meta-analysis is the science of combining evidence from different studies, but traditional statistical techniques contain neither a formal definition nor a measure of evidence. It is argued in this paper that the log-likelihood ratio, as a measure of the "weight of evidence," can be a very useful tool in the meta-analysis. The mathematics and the philosophy behind the use of this index are introduced. The construction and interpretation of "support curves" in fixed and random-effects models are presented. The application of evidential techniques is illustrated on six trials of aspirin therapy previously presented by Canner. The possible dangers of focusing on statistical error rates instead of evidence are discussed.

View details for Web of Science ID A1989U775200005

View details for PubMedID 2666026

This commentary reviews the arguments for and against the use of p-values put forward in the Journal and other forums, and shows that they are all missing both a measure and concept of "evidence." The mathematics and logic of evidential theory are presented, with the log-likelihood ratio used as the measure of evidence. The profoundly different philosophy behind evidential methods (as compared to traditional ones) is presented, as well as a comparative example showing the difference between the two approaches. The reasons why we mistakenly ascribe evidential meaning to p-values and related measures are discussed. Unfamiliarity with the technology and philosophy of evidence is seen as the main reason why certain arguments about p-values persist, and why they are frequently contradictory and confusing.

View details for Web of Science ID A1988R635700013

View details for PubMedID 3189634

View details for DOI 10.1038/s41467-024-45360-6

View details for PubMedID 38316844

We assessed the rigor and reproducibility (R&R) activities of institutions funded by the National Center for Advancing Translational Sciences (NCTSA) through a survey and website search (N = 61). Of 50 institutional responses, 84% reported incorporating some form of R&R training, 68% reported devoted R&R training, 30% monitored R&R practices, and 10% incentivized them. Website searches revealed 9 (15%) freely available training curricula, and 7 (11%) institutional programs specifically created to enhance R&R. NCATS should formally integrate R&R principles into its translational science models and institutional requirements.

View details for DOI 10.1017/cts.2024.10

View details for PubMedID 38476247

View details for PubMedCentralID PMC10928701

In 2002, heterozygous suppressor of fused variants (SUFU+/- ) in the germline were described to have a tumor suppressor role in the development of pediatric medulloblastoma (MB). Other neoplasms associated with pathologic germline SUFU+/- variants have also been described among patients with basal cell nevus syndrome (BCNS; BCNS is also known as Gorlin syndrome, nevoid basal cell carcinoma [BCC] syndrome or Gorlin-Goltz syndrome; OMIM 109400), an autosomal-dominant cancer predisposition syndrome. The phenotype of patients with germline SUFU+/- variants is very poorly characterized due to a paucity of large studies with long-term follow-up. As such, there is a clinical need to better characterize the spectrum of neoplasms among patients with germline SUFU+/- variants so that clinicians can provide accurate counseling and optimize tumor surveillance strategies. The objective of this study is to perform a scoping review to map the evidence on the rate of medulloblastoma and to describe the spectrum of other neoplasms among patients with germline SUFU+/- variants. A review of all published literature in PubMed (MEDLINE), EMBASE, Cochrane, and Web of Science were searched from the beginning of each respective database until October 9, 2021. Studies of pediatric and adult patients with a confirmed germline SUFU+/- variant who were evaluated for the presence of any neoplasm (benign or malignant) were included. There were 176 patients (N = 30 studies) identified with a confirmed germline SUFU+/- variant who met inclusion criteria. Data were extracted from two cohort studies, two case-control studies, 18 case series, and eight case reports. The median age at diagnosis of a germline SUFU+/- variant was 4.5 years where 44.4% identified as female and 13.4% of variants were de novo. There were 34 different neoplasms (benign and malignant) documented among patients with confirmed germline SUFU+/- variants, and the most common were medulloblastoma (N = 59 patients), BCC (N = 21 patients), and meningioma (N = 19 patients). The median age at medulloblastoma diagnosis was 1.42 years (range 0.083-3; interquartile range 1.2). When data were available for these three most frequent neoplasms (N = 95 patients), 31 patients (32.6%) had neither MB, BCC nor meningioma; 51 patients (53.7%) had one of medulloblastoma or BCC or meningioma; eight patients (8.4%) had two of medulloblastoma or BCC or meningioma, and five patients (5.3%) had medulloblastoma and BCC and meningioma. This is the first study to synthesize the data on the frequency and spectrum of neoplasms specifically among patients with a confirmed germline SUFU+/- variant. This scoping review is a necessary step forward in optimizing evidence-based tumor surveillance strategies for medulloblastoma and estimating the risk of other neoplasms that could impact patient outcomes.

View details for DOI 10.1002/ajmg.a.63496

View details for PubMedID 38282294

View details for DOI 10.1073/pnas.2317870120

View details for PubMedID 37967219

SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis.RECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms.RECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options.NCT05172024.

View details for DOI 10.1371/journal.pone.0286297

View details for PubMedID 37352211

View details for PubMedCentralID PMC10289397

View details for DOI 10.7326/M23-0576

View details for PubMedID 36940441

BACKGROUND AND OBJECTIVES: Representative enrollment of racial and ethnic minoritized populations in biomedical research ensures the generalizability of results and equitable access to novel therapies. Previous studies on pediatric clinical trial diversity are limited to subsets of journals or disciplines. We aimed to evaluate race and ethnicity reporting and representation in all US pediatric clinical trials on ClinicalTrials.gov.METHODS: We performed a cross-sectional study of US-based clinical trials registered on ClinicalTrials.gov that enrolled participants aged <18 years old between October 2007 and March 2020. We used descriptive statistics, compound annual growth rates, and multivariable logistic regression for data analysis. Estimates of US population statistics and disease burden were calculated with the US Census, Kids' Inpatient Database, and National Survey of Children's Health.RESULTS: Among 1183 trials encompassing 405376 participants, race and ethnicity reporting significantly increased from 27% in 2007 to 87% in 2018 (P < .001). The median proportional enrollment of Asian American children was 0.6% (interquartile range [IQR], 0%-3.7%); American Indian, 0% (IQR, 0%-0%); Black, 12% (IQR, 2.9%-28.4%); Hispanic, 7.1% (IQR, 0%-18.6%); and white 66.4% (IQR, 41.5%-81.6%). Asian American, Black, and Hispanic participants were underrepresented relative to US population demographics. Compared with expected proportions based on disease prevalence and hospitalizations, Asian American and Hispanic participants were most consistently underrepresented across diagnoses.CONCLUSIONS: While race and ethnicity reporting in pediatric clinical trials has improved, the representative enrollment of minoritized participants remains an ongoing challenge. Evidence-based and policy solutions are needed to address these disparities to advance biomedical innovation for all children.

View details for DOI 10.1542/peds.2022-058552

View details for PubMedID 36916197

BACKGROUND: Most medical educational programs emphasize clinical observation or clinical skill acquisition, fewer focus upon research. The Danish-American Research Exchange (DARE) program, sponsored by the Lundbeck Foundation, is unique in that the medical student initiates biomedical research collaboration between Danish and US medical institutions. To achieve this, Danish medical students (DARE students) conduct binational mentored research projects while based in the United States for 10months. In addition, DARE students are introduced to interdisciplinary thinking about how to develop ultra-low-cost healthcare interventions through the '$10 Challenge'.METHODS: We conducted a cross-sectional study of DARE alumni over five consecutive years (2015-2020, n=24). Research metrics included completion of a research project, primary authorship, and co-authorship of publications. The number of publications, prior to and after the DARE program were enumerated. For the first four cohorts, graduation from medical school and acceptance or intention to enter a joint MD-PhD program also were assessed. Two focus groups were conducted using constructivist grounded theory. Discussions were transcribed, redacted, and coded using Dedoose software.RESULTS: DARE Medical students were 31.2years (range 24-35), the majority were women (67%;16/24). The majority (17/24;71%) completed a first author publication in a peer-reviewed journal with a median of 3.9 per DARE alumnus. DARE alumnus reported increased proficiency in biostatistics, epidemiology, coding and public speaking as well as stronger research qualities in creativity, critical thinking, comfort in approaching scientist in both the US and Denmark (p<0.001 for all). Qualitative key themes included: increased confidence, a deepening of research inquiry and linkage to a research network.CONCLUSIONS: Preliminarily, this study suggests that medical students can initiate binational collaboration in medicine. Benefits include research productivity, intention to pursue academic medical careers, as well as positive impacts on motivation. This medical student-initiated research model lays the groundwork for using this model across other country pairs to promote binational collaboration.

View details for DOI 10.1186/s12909-023-04002-z

View details for PubMedID 36747167

Importance: SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals.Objective: To develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections.Design, Setting, and Participants: Prospective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling.Exposure: SARS-CoV-2 infection.Main Outcomes and Measures: PASC and 44 participant-reported symptoms (with severity thresholds).Results: A total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months.Conclusions and Relevance: A definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC.

View details for DOI 10.1001/jama.2023.8823

View details for PubMedID 37278994

GOAL: The aim was to investigate the short-term impact of time restricted feeding on patients with suspected gastroesophageal reflux disease (GERD).BACKGROUND: Lifestyle modifications are often suggested, but the role of diet in GERD is unclear. Intermittent fasting is popular in the media and has demonstrated potential benefits with weight loss and inflammatory conditions as well as alterations in gastrointestinal hormones.STUDY: Patients who were referred for 96-hour ambulatory wireless pH monitoring off proton pump inhibitor to investigate GERD symptoms were screened for eligibility. Patients were instructed to maintain their baseline diet for the first 2 days of pH monitoring and switch to an intermittent fasting regimen (16 consecutive hour fast and 8h eating window) for the second 2 days. Objective measures of reflux and GERD symptom severity were collected and analyzed.RESULTS: A total of 25 participants were analyzed. 9/25 (36%) fully adhered to the intermittent fasting regimen, with 21/25 (84%) demonstrating at least partial compliance. Mean acid exposure time on fasting days was 3.5% versus 4.3% on nonfasting days. Intermittent fasting was associated with a 0.64 reduction in acid exposure time (95% CI: -2.32, 1.05). There was a reduction in GERD symptom scores of heartburn and regurgitation during periods of intermittent fasting (14.3 vs. 9.9; difference of -4.46, 95% CI: -7.6,-1.32).CONCLUSIONS: Initial adherence to time restricted eating may be difficult for patients. There is weak statistical evidence to suggest that intermittent fasting mildly reduces acid exposure. Our data show that short-term intermittent fasting improves symptoms of both regurgitation and heartburn.

View details for DOI 10.1097/MCG.0000000000001788

View details for PubMedID 36730832

To systematically assess the robustness of reported postacute SARS-CoV-2 infection health outcomes in children.A search on PubMed and Web of Science was conducted to identify studies published up to 22 January 2022 that reported on postacute SARS-CoV-2 infection health outcomes in children (<18 years) with follow-up of ≥2 months since detection of infection or ≥1 month since recovery from acute illness. We assessed the consideration of confounding bias and causality, as well as the risk of bias.21 studies including 81 896 children reported up to 97 symptoms with follow-up periods of 2.0-11.5 months. Fifteen studies had no control group. The reported proportion of children with post-COVID syndrome was between 0% and 66.5% in children with SARS-CoV-2 infection (n=16 986) and between 2.0% and 53.3% in children without SARS-CoV-2 infection (n=64 910). Only two studies made a clear causal interpretation of an association between SARS-CoV-2 infection and the main outcome of 'post-COVID syndrome' and provided recommendations regarding prevention measures. The robustness of all 21 studies was seriously limited due to an overall critical risk of bias.The robustness of reported postacute SARS-CoV-2 infection health outcomes in children is seriously limited, at least in all the published articles we could identify. None of the studies provided evidence with reasonable certainty on whether SARS-CoV-2 infection has an impact on postacute health outcomes, let alone to what extent. Children and their families urgently need much more reliable and methodologically robust evidence to address their concerns and improve care.

View details for DOI 10.1136/archdischild-2022-324455

View details for PubMedID 36719840

BACKGROUND AND OBJECTIVES: Unique ethical, epidemiological, and economic factors are barriers to performing research in children. The landscape of pediatric clinical trials, including drivers of completion and timely dissemination of results, is not well understood. We aimed to characterize the prevalence of and factors associated with early discontinuation, results reporting, and publication of pediatric clinical trials registered at ClinicalTrials.gov.METHODS: Cross-sectional analysis of clinical trials enrolling participants <18 years old registered at ClinicalTrials.gov from October 2007 to March 2020. Multivariable logistic regressions were performed to assess the association between trial characteristics and primary outcomes. Publication data were obtained through PubMed, ClinicalTrials.gov, Embase, and Scopus.RESULTS: Overall, 11.1% trials were stopped early, with recruitment failure being the predominant reason for discontinuation. Only 23.5% of completed trials reported results, and 38.8% were published within 3 years of completion. Rates of discontinuation and publication significantly improved over the study period. Among funding sources, government-sponsored trials (adjusted odds ratio [aOR], 0.72; 95% CI, 0.47-0.97) and academic trials (aOR, 0.64; 95% CI, 0.50-0.82) had lower odds of discontinuation compared with industry trials and were more likely to be published (government: aOR, 1.94 [95% CI, 1.52-2.48] academic: aOR, 1.61 [95% CI, 1.35-1.92). Academic trial investigators were the least likely to report results (aOR, 0.34; 95% CI, 0.31-0.52).CONCLUSIONS: Early discontinuation and nonreporting/nonpublication of findings remain common in registered pediatric clinical trials and were associated with funding source and other trial features. Targeted efforts are needed to support trial completion and timely results dissemination toward strengthening evidence-based pediatric medicine.

View details for DOI 10.1542/peds.2021-052557

View details for PubMedID 35314864

BACKGROUND: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX ).METHODS: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence.RESULTS: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2=0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis.CONCLUSIONS: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care.

View details for DOI 10.1186/s12879-021-06829-7

View details for PubMedID 34800996

View details for Web of Science ID 000717526100484

View details for DOI 10.1038/s41467-021-23559-1

View details for PubMedID 33990619

Importance: Convalescent plasma is a proposed treatment for COVID-19.Objective: To assess clinical outcomes with convalescent plasma treatment vs placebo or standard of care in peer-reviewed and preprint publications or press releases of randomized clinical trials (RCTs).Data Sources: PubMed, the Cochrane COVID-19 trial registry, and the Living Overview of Evidence platform were searched until January 29, 2021.Study Selection: The RCTs selected compared any type of convalescent plasma vs placebo or standard of care for patients with confirmed or suspected COVID-19 in any treatment setting.Data Extraction and Synthesis: Two reviewers independently extracted data on relevant clinical outcomes, trial characteristics, and patient characteristics and used the Cochrane Risk of Bias Assessment Tool. The primary analysis included peer-reviewed publications of RCTs only, whereas the secondary analysis included all publicly available RCT data (peer-reviewed publications, preprints, and press releases). Inverse variance-weighted meta-analyses were conducted to summarize the treatment effects. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation.Main Outcomes and Measures: All-cause mortality, length of hospital stay, clinical improvement, clinical deterioration, mechanical ventilation use, and serious adverse events.Results: A total of 1060 patients from 4 peer-reviewed RCTs and 10 722 patients from 6 other publicly available RCTs were included. The summary risk ratio (RR) for all-cause mortality with convalescent plasma in the 4 peer-reviewed RCTs was 0.93 (95% CI, 0.63 to 1.38), the absolute risk difference was -1.21% (95% CI, -5.29% to 2.88%), and there was low certainty of the evidence due to imprecision. Across all 10 RCTs, the summary RR was 1.02 (95% CI, 0.92 to 1.12) and there was moderate certainty of the evidence due to inclusion of unpublished data. Among the peer-reviewed RCTs, the summary hazard ratio was 1.17 (95% CI, 0.07 to 20.34) for length of hospital stay, the summary RR was 0.76 (95% CI, 0.20 to 2.87) for mechanical ventilation use (the absolute risk difference for mechanical ventilation use was -2.56% [95% CI, -13.16% to 8.05%]), and there was low certainty of the evidence due to imprecision for both outcomes. Limited data on clinical improvement, clinical deterioration, and serious adverse events showed no significant differences.Conclusions and Relevance: Treatment with convalescent plasma compared with placebo or standard of care was not significantly associated with a decrease in all-cause mortality or with any benefit for other clinical outcomes. The certainty of the evidence was low to moderate for all-cause mortality and low for other outcomes.

View details for DOI 10.1001/jama.2021.2747

View details for PubMedID 33635310

Vaccines are vital to control the Coronavirus disease 2019 (COVID-19) pandemic, but the pressure to quickly move from research to implementation in the context of a pandemic crisis raises concerns about benefits and harms, vaccine acceptance and fair access. Here we present a strategy for the COVID-19 vaccination rollout which can be rapidly embedded and would offer direct real-world evidence of vaccines on a large scale to generate otherwise unobtainable knowledge on the safety and perhaps efficacy of COVID-19 vaccines. Such strategic rollouts leveraging randomization can provide important evidence, for COVID-19 and in future occasions, for vaccines and beyond.

View details for DOI 10.1016/j.jclinepi.2021.05.014

View details for PubMedID 34048910

Importance: Rapid eye movement (REM) sleep has been linked with health outcomes, but little is known about the relationship between REM sleep and mortality.Objective: To investigate whether REM sleep is associated with greater risk of mortality in 2 independent cohorts and to explore whether another sleep stage could be driving the findings.Design, Setting, and Participants: This multicenter population-based cross-sectional study used data from the Outcomes of Sleep Disorders in Older Men (MrOS) Sleep Study and Wisconsin Sleep Cohort (WSC). MrOS participants were recruited from December 2003 to March 2005, and WSC began in 1988. MrOS and WSC participants who had REM sleep and mortality data were included. Analysis began May 2018 and ended December 2019.Main Outcomes and Measures: All-cause and cause-specific mortality confirmed with death certificates.Results: The MrOS cohort included 2675 individuals (2675 men [100%]; mean [SD] age, 76.3[5.5] years) and was followed up for a median (interquartile range) of 12.1 (7.8-13.2) years. The WSC cohort included 1386 individuals (753 men [54.3%]; mean [SD] age, 51.5[8.5] years) and was followed up for a median (interquartile range) of 20.8 (17.9-22.4) years. MrOS participants had a 13% higher mortality rate for every 5% reduction in REM sleep (percentage REM sleep SD=6.6%) after adjusting for multiple demographic, sleep, and health covariates (age-adjusted hazard ratio,1.12; fully adjusted hazard ratio,1.13; 95% CI, 1.08-1.19). Results were similar for cardiovascular and other causes of death. Possible threshold effects were seen on the Kaplan-Meier curves, particularly for cancer; individuals with less than 15% REM sleep had a higher mortality rate compared with individuals with 15% or more for each mortality outcome with odds ratios ranging from 1.20 to 1.35. Findings were replicated in the WSC cohort despite younger age, inclusion of women, and longer follow-up (hazard ratio,1.13; 95% CI, 1.08-1.19). A random forest model identified REM sleep as the most important sleep stage associated with survival.Conclusions and Relevance: Decreased percentage REM sleep was associated with greater risk of all-cause, cardiovascular, and other noncancer-related mortality in 2 independent cohorts.

View details for DOI 10.1001/jamaneurol.2020.2108

View details for PubMedID 32628261

View details for Web of Science ID 000554588500049

The PATH (Predictive Approaches to Treatment effect Heterogeneity) Statement was developed to promote the conduct of, and provide guidance for, predictive analyses of heterogeneity of treatment effects (HTE) in clinical trials. The goal of predictive HTE analysis is to provide patient-centered estimates of outcome risk with versus without the intervention, taking into account all relevant patient attributes simultaneously, to support more personalized clinical decision making than can be made on the basis of only an overall average treatment effect. The authors distinguished 2 categories of predictive HTE approaches (a "risk-modeling" and an "effect-modeling" approach) and developed 4 sets of guidance statements: criteria to determine when risk-modeling approaches are likely to identify clinically meaningful HTE, methodological aspects of risk-modeling methods, considerations for translation to clinical practice, and considerations and caveats in the use of effect-modeling approaches. They discuss limitations of these methods and enumerate research priorities for advancing methods designed to generate more personalized evidence. This explanation and elaboration document describes the intent and rationale of each recommendation and discusses related analytic considerations, caveats, and reservations.

View details for DOI 10.7326/M18-3668

View details for Web of Science ID 000506650200002

View details for PubMedID 31711094

Scientific claims in biomedical research are typically derived from statistical analyses. However, misuse or misunderstanding of statistical procedures and results permeate the biomedical literature, affecting the validity of those claims. One approach journals have taken to address this issue is to enlist expert statistical reviewers. How many journals do this, how statistical review is incorporated, and how its value is perceived by editors is of interest. Here we report an expanded version of a survey conducted more than 20 years ago by Goodman and colleagues (1998) with the intention of characterizing contemporary statistical review policies at leading biomedical journals. We received eligible responses from 107 of 364 (28%) journals surveyed, across 57 fields, mostly from editors in chief. 34% (36/107) rarely or never use specialized statistical review, 34% (36/107) used it for 10-50% of their articles and 23% used it for all articles. These numbers have changed little since 1998 in spite of dramatically increased concern about research validity. The vast majority of editors regarded statistical review as having substantial incremental value beyond regular peer review and expressed comparatively little concern about the potential increase in reviewing time, cost, and difficulty identifying suitable statistical reviewers. Improved statistical education of researchers and different ways of employing statistical expertise are needed. Several proposals are discussed.

View details for DOI 10.1371/journal.pone.0239598

View details for PubMedID 33002031

View details for DOI 10.1126/sciadv.aay5352

Background: Never before have clinical trials drawn as much public attention as those testing interventions for COVID-19. We aimed to describe the worldwide COVID-19 clinical research response and its evolution over the first 100 days of the pandemic. Methods: Descriptive analysis of planned, ongoing or completed trials by April 9, 2020 testing any intervention to treat or prevent COVID-19, systematically identified in trial registries, preprint servers, and literature databases. A survey was conducted of all trials to assess their recruitment status up to July 6, 2020. Results: Most of the 689 trials (overall target sample size 396,366) were small (median sample size 120; interquartile range [IQR] 60-300) but randomized (75.8%; n=522) and were often conducted in China (51.1%; n=352) or the USA (11%; n=76). 525 trials (76.2%) planned to include 155,571 hospitalized patients, and 25 (3.6%) planned to include 96,821 health-care workers. Treatments were evaluated in 607 trials (88.1%), frequently antivirals (n=144) or antimalarials (n=112); 78 trials (11.3%) focused on prevention, including 14 vaccine trials. No trial investigated social distancing. Interventions tested in 11 trials with >5,000 participants were also tested in 169 smaller trials (median sample size 273; IQR 90-700). Hydroxychloroquine alone was investigated in 110 trials. While 414 trials (60.0%) expected completion in 2020, only 35 trials (4.1%; 3,071 participants) were completed by July 6. Of 112 trials with detailed recruitment information, 55 had recruited <20% of the targeted sample; 27 between 20-50%; and 30 over 50% (median 14.8% [IQR 2.0-62.0%]). Conclusions: The size and speed of the COVID-19 clinical trials agenda is unprecedented. However, most trials were small investigating a small fraction of treatment options. The feasibility of this research agenda is questionable, and many trials may end in futility, wasting research resources. Much better coordination is needed to respond to global health threats.

View details for DOI 10.12688/f1000research.26707.1

View details for PubMedID 33082937

View details for DOI 10.1001/jama.2020.17195

View details for PubMedID 33170231

View details for DOI 10.1146/annurev-statistics-031219-041104

View details for Web of Science ID 000558768400594

View details for DOI 10.7326/M19-0440

View details for Web of Science ID 000481642800027

View details for DOI 10.1001/jama.2019.5447

View details for PubMedID 31265095

View details for DOI 10.1002/nau.23982

View details for Web of Science ID 000471901900016

View details for DOI 10.1016/j.biopsych.2018.11.012

View details for Web of Science ID 000460728200005

AIMS: To identify the clinical and urodynamic factors associated with the large capacity bladder and incomplete bladder emptying after prolapse repair.METHODS: We identified 592 women who underwent anterior and/or apical prolapse repair at our institution from 2009 to 2015. Women were stratified by urodynamic capacity. The primary outcome was incomplete emptying at the longest follow-up (postvoid residual [PVR]>200mL). Data were analyzed in the Statistical Analysis System software.RESULTS: Two hundred and sixty-six women (mean age, 61 years) had preoperative urodynamic tracings available for review. After surgery, there were 519 PVRs in 239 women recorded at up to 2949 days (mean, 396) and nine time points (median, 2; IQR, 1-3). The receiver operator curve for predicted probability of longest follow-up PVR greater than 200mL (area under curve=0.67) identified the 600mL cutpoint which defined large capacity bladder. Large capacity bladders (capacity, >600mL [n=79] vs ≤600mL, [n=160]) had a mean: detrusor pressure at maximum flow (21 vs 22cm H2 O; P=0.717), maximum flow rate (19 vs 17mL/s; P=0.148), significantly elevated PVR (202 vs 73mL; P 600mL] vs 4.1%-7.0% [capacity, ≤600mL]). VE was similar after surgery regardless of the capacity (87% vs 88%, P=0.772).CONCLUSIONS: The decision to pursue prolapse repair should be individualized and take into account, the bladder capacity and goals for PVR improvement after surgery.

View details for PubMedID 30912192

View details for DOI 10.1001/jama.2018.19684

View details for Web of Science ID 000456347000021

Heterogeneity of treatment effect (HTE) refers to the nonrandom variation in the magnitude or direction of a treatment effect across levels of a covariate, as measured on a selected scale, against a clinical outcome. In randomized controlled trials (RCTs), HTE is typically examined through a subgroup analysis that contrasts effects in groups of patients defined "1 variable at a time" (for example, male vs. female or old vs. young). The authors of this statement present guidance on an alternative approach to HTE analysis, "predictive HTE analysis." The goal of predictive HTE analysis is to provide patient-centered estimates of outcome risks with versus without the intervention, taking into account all relevant patient attributes simultaneously. The PATH (Predictive Approaches to Treatment effect Heterogeneity) Statement was developed using a multidisciplinary technical expert panel, targeted literature reviews, simulations to characterize potential problems with predictive approaches, and a deliberative process engaging the expert panel. The authors distinguish 2 categories of predictive HTE approaches: a "risk-modeling" approach, wherein a multivariable model predicts the risk for an outcome and is applied to disaggregate patients within RCTs to define risk-based variation in benefit, and an "effect-modeling" approach, wherein a model is developed on RCT data by incorporating a term for treatment assignment and interactions between treatment and baseline covariates. Both approaches can be used to predict differential absolute treatment effects, the most relevant scale for clinical decision making. The authors developed 4 sets of guidance: criteria to determine when risk-modeling approaches are likely to identify clinically important HTE, methodological aspects of risk-modeling methods, considerations for translation to clinical practice, and considerations and caveats in the use of effect-modeling approaches. The PATH Statement, together with its explanation and elaboration document, may guide future analyses and reporting of RCTs.

View details for DOI 10.7326/M18-3667

View details for PubMedID 31711134

View details for DOI 10.1080/00031305.2018.1558111

View details for Web of Science ID 000462083800003

View details for PubMedID 31060046

View details for PubMedID 30595232

View details for PubMedID 30566189

View details for DOI 10.7326/M18-3297

View details for Web of Science ID 000454061700024

View details for PubMedID 30508423

View details for DOI 10.7326/M18-2516

View details for Web of Science ID 000447340800025

View details for PubMedID 30208404

View details for DOI 10.1007/s12028-018-0543-7

View details for Web of Science ID 000448467900019

Rich literatures across multiple disciplines document the association between increased educational attainment and improved health. While quasi-experimental studies have exploited variation in educational policies to more rigorously estimate the health effects of education, there remains disagreement about whether education and health are causally linked. The aim of this study was to conduct a systematic review and meta-analysis to characterize this literature, with a focus on quasi-experimental studies of compulsory schooling laws (CSLs). Articles from 1990 to 2015 were obtained through electronic searches and manual searches of reference lists. We searched for English-language studies and included manuscripts if: (1) they involved original data analysis; (2) outcomes were health-related; and (3) the primary predictor utilized variation in CSLs. We identified 89 articles in 25 countries examining over 25 health outcomes, with over 600 individual point estimates. We systematically characterized heterogeneity on key study design features and conducted a meta-analysis of studies with comparable health outcome and exposure variables. Within countries, studies differed in terms of birth cohorts included, the measurement of health outcomes within a given category, and the type of CSL variation examined. Over 90% of manuscripts included multiple analytic techniques, such as econometric and standard regression methods, with as many as 31 "primary" models in a single study. A qualitative synthesis of study findings indicated that educational attainment has an effect on the majority of health outcomes-most beneficial, some negative-while the meta-analysis demonstrated small beneficial effects for mortality, smoking, and obesity. Future work could focus on inconsistent findings identified by this study, or review the health effects of other types of educational policies.

View details for PubMedID 30036767

View details for Web of Science ID 000447682000006

View details for Web of Science ID 000437692900216

BACKGROUND: Patients suffering from non-convulsive seizures experience delays in diagnosis and treatment due to limitations in acquiring and interpreting electroencephalography (EEG) data. The Ceribell EEG System offers rapid EEG acquisition and conversion of EEG signals to sound (sonification) using a proprietary algorithm. This study was designed to test the performance of this EEG system in an intensive care unit (ICU) setting and measure its impact on clinician treatment decision.METHODS: Encephalopathic ICU patients at Stanford University Hospital were enrolled if clinical suspicion for seizures warranted EEG monitoring. Treating physicians rated suspicion for seizure and decided if the patient needed antiepileptic drug (AED) treatment at the time of bedside evaluation. After listening to 30s of EEG from each hemisphere in each patient, they reevaluated their suspicion for seizure and decision for additional treatment. The EEG waveforms recorded with Ceribell EEG were subsequently analyzed by three blinded epileptologists to assess the presence or absence of seizures within and outside the sonification window. Study outcomes were EEG set up time, ease of use of the device, change in clinician seizure suspicion, and change in decision to treat with AED before and after sonification.RESULTS: Thirty-five cases of EEG sonification were performed. Mean EEG setup time was 6±3min, and time to obtain sonified EEG was significantly faster than conventional EEG (p<0.001). One patient had non-convulsive seizure during sonification and another had rhythmic activity that was followed by seizure shortly after sonification. Change in treatment decision after sonification occurred in approximately 40% of patients and resulted in a significant net reduction in unnecessary additional treatments (p=0.01). Ceribell EEG System was consistently rated easy to use.CONCLUSION: The Ceribell EEG System enabled rapid acquisition of EEG in patients at risk for non-convulsive seizures and aided clinicians in their evaluation of encephalopathic ICU patients. The ease of use and speed of EEG acquisition and interpretation by EEG-untrained individuals has the potential to improve emergent clinical decision making by quickly detecting non-convulsive seizures in the ICU.

View details for PubMedID 29923167

Background Sharing of participant-level clinical trial data has potential benefits, but concerns about potential harms to research participants have led some pharmaceutical sponsors and investigators to urge caution. Little is known about clinical trial participants' perceptions of the risks of data sharing. Methods We conducted a structured survey of 771 current and recent participants from a diverse sample of clinical trials at three academic medical centers in the United States. Surveys were distributed by mail (350 completed surveys) and in clinic waiting rooms (421 completed surveys) (overall response rate, 79%). Results Less than 8% of respondents felt that the potential negative consequences of data sharing outweighed the benefits. A total of 93% were very or somewhat likely to allow their own data to be shared with university scientists, and 82% were very or somewhat likely to share with scientists in for-profit companies. Willingness to share data did not vary appreciably with the purpose for which the data would be used, with the exception that fewer participants were willing to share their data for use in litigation. The respondents' greatest concerns were that data sharing might make others less willing to enroll in clinical trials (37% very or somewhat concerned), that data would be used for marketing purposes (34%), or that data could be stolen (30%). Less concern was expressed about discrimination (22%) and exploitation of data for profit (20%). Conclusions In our study, few clinical trial participants had strong concerns about the risks of data sharing. Provided that adequate security safeguards were in place, most participants were willing to share their data for a wide range of uses. (Funded by the Greenwall Foundation.).

View details for PubMedID 29874542

View details for PubMedID 29404564

View details for PubMedID 29369337

View details for Web of Science ID 000419794800020

View details for PubMedID 29323316

View details for DOI 10.1038/s41562-017-0189-z

View details for Web of Science ID 000428754400005

View details for PubMedID 30980045

View details for DOI 10.1016/j.pmcj.2017.06.013

View details for Web of Science ID 000415725100028

View details for DOI 10.1001/jamainternmed.2017.4609

View details for Web of Science ID 000410178900060

View details for PubMedID 29189798

View details for PubMedID 28241335

View details for PubMedID 28697249

View details for PubMedID 28715538

Despite the wide use of the design with statistical stopping guidelines to stop a randomized clinical trial early for efficacy, there are unsettled debates of potential harmful consequences of such designs. These concerns include the possible over-estimation of treatment effects in early stopped trials and a newer argument of a "freezing effect" that will halt future randomized clinical trials on the same comparison since an early stopped trial represents an effective declaration that randomization to the unfavored arm is unethical. The purpose of this study is to determine the degree of bias in designs that allow for early stopping and to assess the impact on estimation if indeed future experimentation is "frozen" by an early stopped trial.We perform simulations to study the effect of early stopping. We simulate a collection of trials and contrast the treatment-effect estimates (risk differences and ratios) with the simulation truth. Simulations consider various scenarios of between-study variation, including an empirically derived distribution of effects from the clinical literature.Across the trials whose true effects are sampled from a uniform distribution, estimates from trials that stop early for efficacy deviate minimally from the simulation truth (median bias of the estimate of risk difference is 0.005). Over-estimation becomes appreciable only when the true effect is close to the null value 0 (median bias of the risk difference estimate is 0.04) or when stopping happens with 40% information or less; however, stopping under these situations is rare. We also find slight reverse bias of the estimated treatment effect (median bias of the risk difference estimate is -0.002) among trials that do not cross the early stopping boundaries but continue to the final analysis. Similar results occur with relative risk estimates. In contrast, Bayesian estimation of the treatment effect shrinks the estimate from trials stopping early and pulls back under-estimation from completed trials, largely rectifying any over-estimation among trials that terminate early. Regarding the so-called freezing effect, the pooled effects from meta-analyses that include truncated randomized clinical trials show an unimportant deviation from the true value, even when no subsequent trials are conducted after a truncated randomized clinical trial.Group sequential designs with stopping rules seek to minimize exposure of patients to a disfavored therapy and speed dissemination of results, and such designs do not lead to materially biased estimates. The likelihood and magnitude of a "freezing effect" is minimal. Superiority demonstrated in a randomized clinical trial stopping early and designed with appropriate statistical stopping rules is likely a valid inference, even if the estimate may be slightly inflated.

View details for DOI 10.1177/1740774516649595

View details for PubMedID 27271682

View details for DOI 10.1126/science.aaf5406

View details for PubMedID 27257246

Misinterpretation and abuse of statistical tests, confidence intervals, and statistical power have been decried for decades, yet remain rampant. A key problem is that there are no interpretations of these concepts that are at once simple, intuitive, correct, and foolproof. Instead, correct use and interpretation of these statistics requires an attention to detail which seems to tax the patience of working scientists. This high cognitive demand has led to an epidemic of shortcut definitions and interpretations that are simply wrong, sometimes disastrously so-and yet these misinterpretations dominate much of the scientific literature. In light of this problem, we provide definitions and a discussion of basic statistics that are more general and critical than typically found in traditional introductory expositions. Our goal is to provide a resource for instructors, researchers, and consumers of statistics whose knowledge of statistical theory and technique may be limited but who wish to avoid and spot misinterpretations. We emphasize how violation of often unstated analysis protocols (such as selecting analyses for presentation based on the P values they produce) can lead to small P values even if the declared test hypothesis is correct, and can lead to large P values even if that hypothesis is incorrect. We then provide an explanatory list of 25 misinterpretations of P values, confidence intervals, and power. We conclude with guidelines for improving statistical interpretation and reporting.

View details for DOI 10.1007/s10654-016-0149-3

View details for PubMedID 27209009

It has been argued that incentive systems should be multi-dimensional, including productivity, quality, reproducibility, sharing, and translation potential ("PQRST"),(1) but many current systems weight productivity particularly heavily. These systems directly affect the volume, and indirectly the quality of the scientific publication record. This was recognized at least as far back as the 1980s, with a proposal that promotion committees consider only a handful of a scientist's publications, in the hopes of improving the quality of our "large and largely trivial" literature. This article is protected by copyright. All rights reserved.

View details for PubMedID 26924551

View details for PubMedID 26536942

In any clinical trial, it is essential to monitor the accumulating data to be sure that the trial continues to be safe for participants and that the trial is being conducted properly. Data monitoring committees, independent expert panels who undertake regular reviews of the data as the trial progresses, serve an important role in safeguarding the interests of research participants and ensuring trial integrity in many trials. Many pragmatic clinical trials, which aim to inform healthcare decisions by comparing alternate interventions in heterogeneous healthcare delivery settings, will warrant review by an independent data monitoring committee due to their potential impact on clinical practice. However, the very features that make a trial "pragmatic" may pose challenges in terms of which aspects of a trial to monitor and when it is appropriate for a data monitoring committee to intervene. Using the Pragmatic-Explanatory Continuum Indicator Summary tool that draws distinctions between pragmatic and explanatory clinical trials, we review characteristics of pragmatic clinical trials that may have implications for data monitoring committees and interim monitoring plans. These include broad eligibility criteria, a focus on subjective patient-centered outcomes, and in some cases a lack of standardized follow-up procedures across study sites. Additionally, protocol adherence is often purposefully not addressed in pragmatic trials in order to accurately represent the clinical practice setting and maintain practicability of implementation; there are differing viewpoints as to whether adherence should be assessed and acted upon by data monitoring committees in these trials. Some other issues not specifically related to the Pragmatic-Explanatory Continuum Indicator Summary criteria may also merit special consideration in pragmatic trials. Thresholds for early termination of a pragmatic clinical trial might be controversial. The distinguishing features of pragmatic clinical trials require careful consideration when developing interim data monitoring plans, and trial sponsors, investigators, and data monitoring committees should agree on a plan before trial inception. Finally, special expertise, such as an informatics, may be helpful on data monitoring committees for some pragmatic clinical trials. Patient representatives may provide particularly valuable insights in the monitoring process.

View details for PubMedID 26374679

View details for DOI 10.1177/1740774515597675

View details for Web of Science ID 000362450000001

View details for DOI 10.1177/1740774515597895

View details for PubMedID 26428470

As the scientific enterprise has grown in size and diversity, we need empirical evidence on the research process to test and apply interventions that make it more efficient and its results more reliable. Meta-research is an evolving scientific discipline that aims to evaluate and improve research practices. It includes thematic areas of methods, reporting, reproducibility, evaluation, and incentives (how to do, report, verify, correct, and reward science). Much work is already done in this growing field, but efforts to-date are fragmented. We provide a map of ongoing efforts and discuss plans for connecting the multiple meta-research efforts across science worldwide.

View details for DOI 10.1371/journal.pbio.1002264

View details for PubMedID 26431313

View details for DOI 10.7326/M15-0021

View details for Web of Science ID 000350232500023

View details for PubMedID 25621467

This article has an additional interactive example appended as a Supplement. Please visit the Supplement tab on this page to access the presentation. A primary goal of meta-analysis is to improve the estimation of treatment effects by pooling results of similar studies. This article explains how the most widely used method for pooling heterogeneous studies-the DerSimonian-Laird (DL) estimator-can produce biased estimates with falsely high precision. A classic example is presented to show that use of the DL estimator can lead to erroneous conclusions. Particular problems with the DL estimator are discussed, and several alternative methods for summarizing heterogeneous evidence are presented. The authors support replacing universal use of the DL estimator with analyses based on a critical synthesis that recognizes the uncertainty in the evidence, focuses on describing and explaining the probable sources of variation in the evidence, and uses random-effects estimates that provide more accurate confidence limits than the DL estimator.

View details for DOI 10.7326/M13-2886

View details for PubMedID 24727843

View details for PubMedID 24449313

View details for PubMedID 24068250

Making raw data from clinical trials widely publically available should reduce selective reporting biases and enhance the reproducibility of and trust in clinical research. The optimal procedures for data sharing are hotly debated. Some of the caveats and limitations in proposed data-sharing policies are potentially restrictive, and we argue in favor of more widespread availability of data from clinical research.

View details for DOI 10.1016/j.tips.2013.10.006

View details for PubMedID 24295825

Acknowledgment of all serious limitations to research evidence is important for patient care and scientific progress. Formal research on how biomedical authors acknowledge limitations is scarce.To assess the extent to which limitations are acknowledged in biomedical publications explicitly, and implicitly by investigating the use of phrases that express uncertainty, so-called hedges; to assess the association between industry support and the extent of hedging.We analyzed reporting of limitations and use of hedges in 300 biomedical publications published in 30 high and medium -ranked journals in 2007. Hedges were assessed using linguistic software that assigned weights between 1 and 5 to each expression of uncertainty.Twenty-seven percent of publications (81/300) did not mention any limitations, while 73% acknowledged a median of 3 (range 1-8) limitations. Five percent mentioned a limitation in the abstract. After controlling for confounders, publications on industry-supported studies used significantly fewer hedges than publications not so supported (p = 0.028).Detection and classification of limitations was--to some extent--subjective. The weighting scheme used by the hedging detection software has subjective elements.Reporting of limitations in biomedical publications is probably very incomplete. Transparent reporting of limitations may protect clinicians and guideline committees against overly confident beliefs and decisions and support scientific progress through better design, conduct or analysis of new studies.

View details for DOI 10.1371/journal.pone.0073623

View details for Web of Science ID 000327313100002

View details for PubMedID 24324540

View details for PubMedCentralID PMC3854521

Confidence in evidence summarized in meta-analyses depends on the strength of the underlying studies. This inherent limitation of syntheses appears in the case of a meta-analysis of sodium-glucose cotransporter 2 inhibitors for the treatment of type 2 diabetes because many of the pertinent randomized trials did not handle patient dropout and "rescue" medication properly. Repudiated statistical methods, such as last observation carried forward, and unsophisticated methods for handling postrescue data produce unreliable summary estimates. Future reports of randomized studies and meta-analyses of those studies must focus on posing precise questions about the treatment effect of interest and then implement appropriate statistical methods to account for missing data, patient dropout, and use of rescue medication.

View details for Web of Science ID 000323421700018

View details for PubMedID 24026261

The sensitivity of only a few tumors to anti-epidermal growth factor receptor EGFR tyrosine kinase inhibitors (TKIs) can be explained by the presence of EGFR tyrosine kinase (TK) domain mutations. In addition, such mutations were rarely found in tumor types other than lung, such as pancreatic and head and neck cancer. In this study we sought to elucidate mechanisms of resistance to EGFR-targeted therapies in tumors that do not harbor TK sensitizing mutations in order to identify markers capable of guiding the decision to incorporate these drugs into chemotherapeutic regimens. Here we show that EGFR activity was markedly decreased during the evolution of resistance to the EGFR tyrosine kinase inhibitor (TKI) erlotinib, with a concomitant increase of mitogen-inducible gene 6 (Mig6), a negative regulator of EGFR through the upregulation of the PI3K-AKT pathway. EGFR activity, which was more accurately predicted by the ratio of Mig6/EGFR, highly correlated with erlotinib sensitivity in panels of cancer cell lines of different tissue origins. Blinded testing and analysis in a prospectively followed cohort of lung cancer patients treated with gefitinib alone demonstrated higher response rates and a marked increased in progression free survival for patients with a low Mig6/EGFR ratio (approximately 100 days, P = 0.01).

View details for DOI 10.1371/journal.pone.0068966

View details for Web of Science ID 000322633700014

View details for PubMedID 23935914

View details for PubMedCentralID PMC3729565

View details for DOI 10.7326/0003-4819-158-12-201306180-00012

View details for PubMedID 23778911

"First they ignore you, then they laugh at you, then they fight you, then you win," a saying reportedly misattributed to Mahatma Ghandi(1), might apply to the use of Bayesian statistics in medical research. The idea that Bayesian approaches might be used to "affirm" findings derived from conventional methods, and thereby be regarded as more authoritative, is a dramatic turnabout from an era not very long ago when those embracing Bayesian ideas were considered barbarians at the gate. I remember my own initiation into the Bayesian fold, reading with a mixture of astonishment and subversive pleasure one of George Diamond's early pieces taking aim at conventional interpretations of large cardiovascular trials of the early 80's.(2) It is gratifying to see that the Bayesian approach, which saw negligible application in biomedical research in the 80's and began to get traction in the 90's, is now not just a respectable alternative to standard methods, but sometimes might be regarded as preferable. That said, it is premature to declare a "win," and the statistical lingua franca of biomedical research is still firmly frequentist, with P-values, confidence intervals and Type I and II errors dominating the journal landscape. It is helpful to use the thoughtful and thorough Bayesian exercise of Bittl et al.(3) to reflect on what Bayesian approaches give us, and what they don't.

View details for DOI 10.1161/CIRCULATIONAHA.113.003193

View details for PubMedID 23674396

View details for DOI 10.1001/jama.2013.4503

View details for PubMedID 23695478

View details for PubMedID 24287131

View details for Web of Science ID 000307813200022

View details for PubMedID 22910942

Our aim was to comprehensively analyze promoter hypermethylation of a panel of novel and known methylation markers for thyroid neoplasms and to establish their relationship with BRAF mutation and clinicopathologic parameters of thyroid cancer. A cohort of thyroid tumors, consisting of 44 cancers and 44 benign thyroid lesions, as well as 15 samples of adjacent normal thyroid tissue, was evaluated for BRAF mutation and promoter hypermethylation. Genes for quantitative methylation specific PCR (QMSP) were selected by a candidate gene approach. Twenty-two genes were tested: TSHR, RASSF1A, RARβ2, DAPK, hMLH1, ATM, S100, p16, CTNNB1, GSTP1, CALCA, TIMP3, TGFßR2, THBS1, MINT1, CTNNB1, MT1G, PAK3, NISCH, DCC, AIM1 and KIF1A. The PCR-based "mutector assay" was used to detect BRAF mutation. All p values reported are two sided. Considerable overlap was seen in the methylation markers among the different tissue groups. Significantly higher methylation frequency and level were observed for KIF1A and RARß2 in cancer samples compared with benign tumors. A negative correlation between BRAF mutation and RASSF1A methylation, and a positive correlation with RARß2 methylation were observed in accordance with previous results. In addition, positive correlation with TIMP3 and a marginal correlation with DCC methylation were observed. The present study constitutes a comprehensive promoter methylation profile of thyroid neoplasia and shows that results must be analyzed in a tissue-specific manner to identify clinically useful methylation markers. Integration of genetic and epigenetic changes in thyroid cancer will help identify relevant biologic pathways that drive its development.

View details for DOI 10.4161/epi.205248

View details for Web of Science ID 000306291900007

View details for PubMedID 22694820

Rigorous methodological standards help to ensure that medical research produces information that is valid and generalizable, and are essential in patient-centered outcomes research (PCOR). Patient-centeredness refers to the extent to which the preferences, decision-making needs, and characteristics of patients are addressed, and is the key characteristic differentiating PCOR from comparative effectiveness research. The Patient Protection and Affordable Care Act signed into law in 2010 created the Patient-Centered Outcomes Research Institute (PCORI), which includes an independent, federally appointed Methodology Committee. The Methodology Committee is charged to develop methodological standards for PCOR. The 4 general areas identified by the committee in which standards will be developed are (1) prioritizing research questions, (2) using appropriate study designs and analyses, (3) incorporating patient perspectives throughout the research continuum, and (4) fostering efficient dissemination and implementation of results. A Congressionally mandated PCORI methodology report (to be issued in its first iteration in May 2012) will begin to provide standards in each of these areas, and will inform future PCORI funding announcements and review criteria. The work of the Methodology Committee is intended to enable generation of information that is relevant and trustworthy for patients, and to enable decisions that improve patient-centered outcomes.

View details for Web of Science ID 000302896100026

View details for DOI 10.1177/1740774511402750

View details for Web of Science ID 000289892600001

View details for PubMedID 21478326

View details for DOI 10.1177/1740774511400454

View details for PubMedID 21478325

The optimal blood pressure level to minimize the risk of ischemic stroke (IS) in older adults is undetermined. Cerebral white matter lesions (WML), prevalent in older adults, may be a marker for vulnerability to IS. We aimed at determining the relationship between diastolic blood pressure (DBP) levels and IS in the presence of WML.The Cardiovascular Health Study population (N = 3,345, age ≥ 65 years, N = 3,345) was followed between 1989 and 2002 for IS incidence. Survival analysis included quintiles of DBP analyzed within WML levels controlling for age and cardiovascular disease.DBP had no effect on IS incidence in low WML levels but had a marginally significant J-curve relationship with IS in high WML levels: the adjusted hazard ratio for IS in the lowest (<63 mmHg) and highest (≥ 80) DBP quintiles compared with the third (nadir, 69-73 mmHg) was 1.64 (95% confidence interval: 0.93-2.9) and 1.83 (95% confidence interval: 1.06-3.15), respectively.In older adults with low-grade WML, low DBP may not pose a risk for IS. However, in high-grade WML, IS risk may increase in DBP less than 69 mmHg but is highest more than 80 mmHg. People with high-grade WML may be at risk of IS in high and low DBP.

View details for DOI 10.1093/gerona/glq166

View details for Web of Science ID 000286655300011

View details for PubMedID 21030465

View details for DOI 10.1177/1740774510389124

View details for Web of Science ID 000285095100001

View details for PubMedID 21138919

Overwhelming evidence shows the quality of reporting of randomised controlled trials (RCTs) is not optimal. Without transparent reporting, readers cannot judge the reliability and validity of trial findings nor extract information for systematic reviews. Recent methodological analyses indicate that inadequate reporting and design are associated with biased estimates of treatment effects. Such systematic error is seriously damaging to RCTs, which are considered the gold standard for evaluating interventions because of their ability to minimise or avoid bias. A group of scientists and editors developed the CONSORT (Consolidated Standards of Reporting Trials) statement to improve the quality of reporting of RCTs. It was first published in 1996 and updated in 2001. The statement consists of a checklist and flow diagram that authors can use for reporting an RCT. Many leading medical journals and major international editorial groups have endorsed the CONSORT statement. The statement facilitates critical appraisal and interpretation of RCTs. During the 2001 CONSORT revision, it became clear that explanation and elaboration of the principles underlying the CONSORT statement would help investigators and others to write or appraise trial reports. A CONSORT explanation and elaboration article was published in 2001 alongside the 2001 version of the CONSORT statement. After an expert meeting in January 2007, the CONSORT statement has been further revised and is published as the CONSORT 2010 Statement. This update improves the wording and clarity of the previous checklist and incorporates recommendations related to topics that have only recently received recognition, such as selective outcome reporting bias. This explanatory and elaboration document-intended to enhance the use, understanding, and dissemination of the CONSORT statement-has also been extensively revised. It presents the meaning and rationale for each new and updated checklist item providing examples of good reporting and, where possible, references to relevant empirical studies. Several examples of flow diagrams are included. The CONSORT 2010 Statement, this revised explanatory and elaboration document, and the associated website (www.consort-statement.org) should be helpful resources to improve reporting of randomised trials.

View details for DOI 10.1016/j.jclinepi.2010.03.004

View details for PubMedID 20346624

View details for Web of Science ID 000279811000016

View details for PubMedID 20628126

View details for DOI 10.1093/biostatistics/kxq030

View details for Web of Science ID 000278689300007

View details for PubMedID 20538874

View details for DOI 10.4103/0976-500X.72352

View details for Web of Science ID 000215864800007

View details for PubMedID 20332511

View details for PubMedCentralID PMC2844943

View details for DOI 10.1097/AOG.0b013e3181d9d421

View details for Web of Science ID 000277185800026

View details for PubMedID 20410783

Because of its potent immunosuppressive yet stem cell-sparing activity, high-dose cyclophosphamide was tested as sole prophylaxis of graft-versus-host disease (GVHD) after myeloablative allogeneic bone marrow transplantation (alloBMT). We treated 117 patients (median age, 50 years; range, 21-66 years) with advanced hematologic malignancies; 78 had human leukocyte antigen (HLA)-matched related donors and 39 had HLA-matched unrelated donors. All patients received conventional myeloablation with busulfan/cyclophosphamide (BuCy) and T cell-replete bone marrow followed by 50 mg/kg/d of cyclophosphamide on days 3 and 4 after transplantation. The incidences of acute grades II through IV and grades III through IV GVHD for all patients were 43% and 10%, respectively. The nonrelapse mortality at day 100 and 2 years after transplantation were 9% and 17%, respectively. The actuarial overall survival and event-free survivals at 2 years after transplantation were 55% and 39%, respectively, for all patients and 63% and 54%, respectively, for patients who underwent transplantation while in remission. With a median follow-up of 26.3 months among surviving patients, the cumulative incidence of chronic GVHD is 10%. These results suggest that high-dose posttransplantation cyclophosphamide is an effective single-agent prophylaxis of acute and chronic GVHD after BuCy conditioning and HLA-matched BMT (clinicaltrials.gov no. NCT00134017).

View details for DOI 10.1182/blood-2009-11-251595

View details for Web of Science ID 000276956500008

View details for PubMedID 20124511

Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder that can be treated with bone marrow transplantation, immunosuppressive therapy, and high-dose cyclophosphamide. Here, we report long-term follow-up on 67 SAA patients (44 treatment-naive and 23 refractory) treated with high-dose cyclophosphamide. At 10 years, the overall actuarial survival was 88%, the response rate was 71% with the majority being complete, and the actuarial event-free survival was 58% in 44 treatment-naive SAA patients. Patients with refractory SAA fared less well after high-dose cyclophosphamide therapy; at 10 years, overall actuarial survival, response, and actuarial event-free survival rates were 62%, 48%, and 27%, respectively. High-dose cyclophosphamide is highly effective therapy for severe aplastic anemia. Large randomized controlled trials will be necessary to establish how results of high-dose cyclophosphamide compare with either bone marrow transplantation or standard immunosuppressive regimens, such as antithymocyte globulin and cyclosporine.

View details for DOI 10.1182/blood-2009-06-225375

View details for Web of Science ID 000275751400008

View details for PubMedID 20018919

View details for Web of Science ID 000278447300009

View details for PubMedID 20526964

View details for DOI 10.1371/journal.pmed.1000111

View details for Web of Science ID 000270818100004

View details for PubMedID 19787044

Analysis of abnormally methylated genes is increasingly important in basic research and in the development of cancer biomarkers. We have developed methyl-BEAMing technology to enable absolute quantification of the number of methylated molecules in a sample. Individual DNA fragments are amplified and analyzed either by flow cytometry or next-generation sequencing. We demonstrate enumeration of as few as one methylated molecule in approximately 5,000 unmethylated molecules in DNA from plasma or fecal samples. Using methylated vimentin as a biomarker in plasma samples, methyl-BEAMing detected 59% of cancer cases. In early-stage colorectal cancers, this sensitivity was four times more than that obtained by assaying serum-carcinoembryonic antigen (CEA). With stool samples, methyl-BEAMing detected 41% of cancers and 45% of advanced adenomas. In addition to diagnostic and prognostic applications, this digital quantification of rare methylation events should be applicable to preclinical assessment of new epigenetic biomarkers and quantitative analyses in epigenetic research.

View details for DOI 10.1038/nbt.1559

View details for Web of Science ID 000269751400029

View details for PubMedID 19684580

View details for Web of Science ID 000268798100017

View details for PubMedID 19667309

View details for PubMedID 19552233

View details for DOI 10.1177/1740774509103609

View details for Web of Science ID 000265756200004

View details for PubMedID 19342465

In newly diagnosed aggressive non-Hodgkin lymphoma (NHL), a positive midtreatment fluorine-18 fluorodeoxyglucose positron emission tomography (PET) scan often carries a poor prognosis, with reported 2-year event-free survival (EFS) rates of 0% to 30% after standard therapy. To determine the outcome of early treatment intensification for midtreatment PET-positive disease, a phase II trial of risk-adapted therapy was conducted. Fifty-nine newly diagnosed patients, 98% with B cell lymphoma, had PET/CT performed after 2 or 3 cycles of first-line chemotherapy. Those with negative PET on semiquantitative visual interpretation completed standard therapy. Those with positive PET received platinum-based salvage chemotherapy, high-dose therapy, and autologous stem cell transplantation (ASCT). Midtreatment PET was positive in 33 (56%); 28 received ASCT with an actuarial 2-year EFS of 75% (95% confidence interval, 60%-93%). On intention-to-treat analysis, 2-year EFS was 67% (53%-86%) in all PET-positive patients and 89% (77%-100%) in PET-negative patients. No association was found between the International Prognostic Index category and the midtreatment PET result. The favorable outcome achieved here in historically poor-risk patients warrants further, more definitive investigation of treatment modification based on early PET scanning.

View details for DOI 10.1016/j.bbmt.2008.11.026

View details for Web of Science ID 000263016600010

View details for PubMedID 19167684

Despite over 80 years of use, the ketogenic diet (KD) has never been tested in a blinded manner. Twenty children with intractable Lennox-Gastaut syndrome (LGS) were fasted 36 h and then randomized to receive the classic KD in conjunction with a solution containing either 60 g/day of glucose or saccharin. Parents and physicians were blinded to both the solution composition and level of ketosis. A crossover to the KD with the alternate solution occurred following the sixth day and a repeat fast. A 24-h electroencephalography (EEG) was obtained at baseline and after each arm. After administration of the solution, there was moderate evidence of a reduction in parent-reported seizures between the glucose and saccharin arms, with a median difference of 1.5 seizures per day (p = 0.07). There was no reduction in the number of EEG-identified events, with a median reduction of 7 events per day (p = 0.33). Ketosis was not completely eliminated in the glucose-added arm.

View details for DOI 10.1111/j.1528-1167.2008.01740.x

View details for Web of Science ID 000262781800018

View details for PubMedID 18717710

Nuclear factor erythroid-2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that regulates the expression of electrophile and xenobiotic detoxification enzymes and efflux proteins, which confer cytoprotection against oxidative stress and apoptosis in normal cells. Loss of function mutations in the Nrf2 inhibitor, Kelch-like ECH-associated protein (Keap1), results in constitutive activation of Nrf2 function in non-small cell lung cancer. In this study, we show that constitutive activation of Nrf2 in lung cancer cells promotes tumorigenicity and contributes to chemoresistance by up-regulation of glutathione, thioredoxin, and the drug efflux pathways involved in detoxification of electrophiles and broad spectrum of drugs. RNAi-mediated reduction of Nrf2 expression in lung cancer cells induces generation of reactive oxygen species, suppresses tumor growth, and results in increased sensitivity to chemotherapeutic drug-induced cell death in vitro and in vivo. Inhibiting Nrf2 expression using naked siRNA duplexes in combination with carboplatin significantly inhibits tumor growth in a subcutaneous model of lung cancer. Thus, targeting Nrf2 activity in lung cancers, particularly those with Keap1 mutations, could be a promising strategy to inhibit tumor growth and circumvent chemoresistance.

View details for DOI 10.1158/0008-5472.CAN-08-1401

View details for Web of Science ID 000260029900035

View details for PubMedID 18829555

The measurement of circulating nucleic acids has transformed the management of chronic viral infections such as HIV. The development of analogous markers for individuals with cancer could similarly enhance the management of their disease. DNA containing somatic mutations is highly tumor specific and thus, in theory, can provide optimum markers. However, the number of circulating mutant gene fragments is small compared to the number of normal circulating DNA fragments, making it difficult to detect and quantify them with the sensitivity required for meaningful clinical use. In this study, we applied a highly sensitive approach to quantify circulating tumor DNA (ctDNA) in 162 plasma samples from 18 subjects undergoing multimodality therapy for colorectal cancer. We found that ctDNA measurements could be used to reliably monitor tumor dynamics in subjects with cancer who were undergoing surgery or chemotherapy. We suggest that this personalized genetic approach could be generally applied to individuals with other types of cancer.

View details for DOI 10.1038/nm.1789

View details for Web of Science ID 000258988600033

View details for PubMedID 18670422

CANCER PATIENTS OVERESTIMATE BENEFITS of early phase trials but studies have not reported what oncologists say to patients about trials. We audiotaped oncologists talking to cancer patients about Phase I or II trials and interviewed patients about the purpose and expected outcomes of trials presented to them. Oncologists gave mixed messages, saying Phase I trials measure safety and dosing, yet referring to trials as treatment with uncertain therapeutic effects. Seventeen percent of Phase I respondents said the trial's purpose related to safety/dosing (p = 0.017); 17% of Phase I respondents said the purpose was "to cure my cancer." Patients may find it important to believe trials offer significant benefit. Oncologists, while respecting patients' hopes, should be precise in their language, particularly regarding Phase I trials, distinguishing early stages of research from treatment.

View details for DOI 10.1525/jer.2008.3.3.57

View details for Web of Science ID 000259994900008

View details for PubMedID 19385771

Somatic mutations provide uniquely specific markers for the early detection of neoplasia that can be detected in DNA purified from plasma or stool of patients with colorectal cancer. The primary purpose of the present investigation was to determine the parameters that were critical for detecting mutations using a quantitative assay. A secondary purpose was to compare the results of plasma and stool DNA testing using the same technology.We examined DNA purified from the stool of 25 patients with colorectal cancers before surgery. In 16 of these cases, plasma samples also were available. Mutations in stool or plasma were assessed with an improved version of the BEAMing technology.Of the 25 stool DNA samples analyzed, 23 (92%) contained mutations that were present in the corresponding tumors from the same patients. In contrast, only 8 of the 16 (50%) plasma DNA samples analyzed had detectable levels of mutated DNA. We found that the DNA fragments containing mutations in both stool and plasma DNA typically were smaller than 150 bases in size. The sensitivity of the new method was superior to a widely used technique for detecting mutations, using single base extension and sequencing, when assessed on the same samples (92% vs 60%; P = .008, exact McNemar test).When assessed with sufficiently sensitive methods, mutant DNA fragments are detectable in the stool of more than 90% of colorectal cancer patients. DNA purified from stool provides a better template for mutation testing than plasma.

View details for DOI 10.1053/j.gastro.2008.05.039

View details for Web of Science ID 000258439900026

View details for PubMedID 18602395

Three gene expression-based prognostic breast cancer tests have been licensed for use.To summarize evidence on the validity and utility of 3 gene expression-based prognostic breast cancer tests: Oncotype DX (Genomic Health, Redwood City, California), MammaPrint (Agendia BV, Amsterdam, the Netherlands), and H/I (AvariaDX, Carlsbad, California).MEDLINE, EMBASE, and Cochrane databases (from 1990 through January 2007), Web sites of test manufacturers, and discussion with the manufacturers.Original data studies published in English that addressed prognostic accuracy and discrimination or treatment benefit prediction of any of the 3 tests in women with breast cancer.Information was extracted about the clinical characteristics of the study population (particularly clinical and therapeutic homogeneity), tumor characteristics, and whether the marketed test or underlying signature was evaluated.The tests are based on distinct gene lists, using 2 different technologies. Overall, the body of evidence showed that this new generation of tests may improve prognostic and therapeutic prediction, but the tests are at different stages of development. Evidence shows that the tests offer clinically relevant, improved risk stratification over standard predictors. Oncotype DX has the strongest evidence, closely followed by MammaPrint and H/I (which is still maturing).For all tests, the relationship of predicted to observed risk in different populations and their incremental contribution over conventional predictors, optimal implementation, and relevance to patients receiving current therapies need further study.Gene expression technologies show great promise to improve predictions of prognosis and treatment benefit for women with early-stage breast cancer. More information is needed on the extent of improvement in prediction, characteristics of women in whom the tests should be used, and how best to incorporate test results into decision making about breast cancer treatment.

View details for Web of Science ID 000253600800005

View details for PubMedID 18252678

TIMP-3 (tissue inhibitor of metalloproteinases-3) is 1 of 4 members of a family of proteins that were originally classified according to their ability to inhibit matrix metalloproteinases. We analyzed TIMP-3 methylation in 175 urine sediment DNA samples from patients with bladder cancer with well characterized clinicopathological parameters, including patient outcome.We examined urine sediment DNA for aberrant methylation of 9 genes, including TIMP-3, by quantitative fluorogenic real-time polymerase chain reaction.Using an optimal cutoff value by TaqMan(R) quantitation we found that the risk of death was statistically significantly higher in patients with higher TIMP-3 and ARF methylation (HR 1.99, 95% CI 1.12 to 3.27, p = 0.01 and HR 1.66, 95% CI 1.00 to 2.76, p = 0.05, respectively) than in patients without/lower TIMP3 and ARF methylation in urine. A significant correlation was also seen between the risk of death and stage 3 tumor (HR 2.73, 95% CI 1.58 to 4.72, p = 0.003) and metastasis (HR 3.32, 95% CI 1.98 to 5.57, p = 0.0001). Multivariate analysis subsequently revealed that TIMP-3 methylation was an independent prognostic factor for bladder cancer survival with stage and metastasis (p = 0.001 and 0.02, respectively).These results suggest that TIMP-3 promoter methylation could be a clinically applicable marker for bladder cancer progression.

View details for DOI 10.1016/j.juro.2007.09.019

View details for Web of Science ID 000252369600091

View details for PubMedID 18082200

View details for DOI 10.1016/j.jclinepi.2007.06.012

View details for Web of Science ID 000252044900011

View details for PubMedID 18083466

To assess the evidence that three marketed gene expression-based assays improve prognostic accuracy, treatment choice, and health outcomes in women diagnosed with early stage breast cancer.We evaluated the evidence for three gene expression assays on the market; Oncotype DX, MammaPrint and the Breast Cancer Profiling (BCP or H/I ratio) test, and for gene expression signatures underlying the assays. We sought evidence on: analytic performance of tests, clinical validity (i.e., prognostic accuracy and discrimination), clinical utility (i.e., prediction of treatment benefit), harms, impact on clinical decision making and health care costs.Few papers were found on the analytic validity of the Oncotype DX and MammaPrint tests, but these showed reasonable within-laboratory replicability. Pre-analytic issues related to sample storage and preparation may play a larger role than within-laboratory variation. For clinical validity, studies differed according to whether they examined the actual test that is currently being offered to patients or the underlying gene signature. Almost all of the Oncotype DX evidence was for the marketed test, the strongest validation study being from one arm of a randomized controlled trial (NSABP-14) with a clinically homogeneous population. This study showed that the test, added in a clinically meaningful manner to standard prognostic indices. The MammaPrint signature and test itself was examined in studies with clinically heterogeneous populations (e.g., mix of ER positivity and tamoxifen treatment) and showed a clinically relevant separation of patients into risk categories, but it was not clear exactly how many predictions would be shifted across decision thresholds if this were used in combination with traditional indices. The BCP test itself was examined in one study, and the signature was tested in a variety of formulations in several studies. One randomized controlled trial provided high quality retrospective evidence of the clinical utility of Oncotype DX to predict chemotherapy treatment benefit, but evidence for clinical utility was not found for MammaPrint or the H/I ratio. Three decision analyses examined the cost-effectiveness of breast cancer gene expression assays, and overall were inconclusive.Oncotype DX is furthest along the validation pathway, with strong retrospective evidence that it predicts distant spread and chemotherapy benefit to a clinically relevant extent over standard predictors, in a well-defined clinical subgroup with clear treatment implications. The evidence for clinical implications of using MammaPrint was not as clear as with Oncotype DX, and the ability to predict chemotherapy benefit does not yet exist. The H/I ratio test requires further validation. For all tests, the relationship of predicted to observed risk in different populations still needs further study, as does their incremental contribution, optimal implementation, and relevance to patients on current therapies.

View details for PubMedID 18457476

View details for DOI 10.1371/journal.pmed.0040168

View details for Web of Science ID 000245947000031

View details for PubMedID 17456002

The purpose of the paper is to examine the ethical arguments for and against disclosing surgeon-specific performance rates to patients during informed consent, and to examine the challenges that generating and using performance rates entail.Ethical, legal, and statistical theory is explored to approach the question of whether, when, and how surgeons should disclosure their personal performance rates to patients. The main ethical question addressed is what type of information surgeons owe their patients during informed consent. This question comprises 3 related, ethically relevant considerations that are explored in detail: 1) Does surgeon-specific performance information enhance patient decision-making? 2) Do patients want this type of information? 3) How do the potential benefits of disclosure balance against the risks?Calculating individual performance measures requires tradeoffs and involves inherent uncertainty. There is a lack of evidence regarding whether patients want this information, whether it facilitates their decision-making for surgery, and how it is best communicated to them. Disclosure of personal performance rates during informed consent has the potential benefits of enhancing patient autonomy, improving patient decision-making, and improving quality of care. The major risks of disclosure include inaccurate and misleading performance rates, avoidance of high-risk cases, unjust damage to surgeon's reputations, and jeopardized patient trust.At this time, we think that, for most conditions, surgical procedures, and outcomes, the accuracy of surgeon- and patient-specific performance rates is illusory, obviating the ethical obligation to communicate them as part of the informed consent process. Nonetheless, the surgical profession has the duty to develop information systems that allow for performance to be evaluated to a high degree of accuracy. In the meantime, patients should be informed of the quantity of procedures their surgeons have performed, providing an idea of the surgeon's experience and qualitative idea of potential risk.

View details for DOI 10.1097/01.sla.0000242713.82125.d1

View details for Web of Science ID 000245232900002

View details for PubMedID 17414595

View details for DOI 10.1177/1740774507079655

View details for Web of Science ID 000249489200001

View details for PubMedID 17715245

View details for Web of Science ID 000240255900011

View details for PubMedID 16954364

View details for Web of Science ID 000240255900012

The noninvasive identification of bladder tumors may improve disease control and prevent disease progression. Aberrant promoter methylation (i.e., hypermethylation) is a major mechanism for silencing tumor suppressor genes and other cancer-associated genes in many human cancers, including bladder cancer.A quantitative fluorogenic real-time polymerase chain reaction (PCR) assay was used to examine primary tumor DNA and urine sediment DNA from 15 patients with bladder cancer and 25 control subjects for promoter hypermethylation of nine genes (APC, ARF, CDH1, GSTP1, MGMT, CDKN2A, RARbeta2, RASSF1A, and TIMP3) to identify potential biomarkers for bladder cancer. We then used these markers to examine urine sediment DNA samples from an additional 160 patients with bladder cancers of various stages and grades and from an additional 69 age-matched control subjects. Data were analyzed on the basis of a prediction model and were internally validated using a jacknife procedure. All statistical tests were two-sided.For all 15 patients with paired DNA samples, the promoter methylation pattern in urine matched that in the primary tumors. Four genes displayed 100% specificity. Of the 175 bladder cancer patients, 121 (69%, 95% confidence interval [CI] = 62% to 76%) displayed promoter methylation in at least one of these genes (CDKN2A, ARF, MGMT, and GSTP1), whereas all control subjects were negative for such methylation (100% specificity, 95% CI = 96% to 100%). A logistic prediction model using the methylation levels of all remaining five genes was developed and internally validated for subjects who were negative on the four-gene panel. This combined, two-stage predictor produced an internally validated ROC curve with an overall sensitivity of 82% (95% CI = 75 % to 87%) and specificity of 96% (95% CI = 90% to 99%).Testing a small panel of genes with the quantitative methylation-specific PCR assay in urine sediment DNA is a powerful noninvasive approach for the detection of bladder cancer. Larger independent confirmatory cohorts with longitudinal follow-up will be required in future studies to define the impact of this technology on early detection, prognosis, and disease monitoring before clinical application.

View details for DOI 10.1093/jnci/djj265

View details for Web of Science ID 000239279000013

View details for PubMedID 16849682

After stroke, 10% of patients have adverse cardiac outcomes. Left insular damage may contribute to this by impairing sympathovagal balance (associated with cardiac structural damage and arrhythmias).The authors conducted a prospective study of 32 patients with left insular stroke (Group 1) and 84 patients with non-insular stroke/TIA (Group 2). Adverse cardiac outcomes (cardiac death, myocardial infarction, angina, and heart failure) were assessed over 1 year. Myocardial wall motion was investigated with transesophageal echocardiography.Group 1's cardiac outcome relative risk (RR) compared with Group 2 was 1.75 (95% CI: 1.02, 3.00, p = 0.05). Left insular stroke remained an independent predictor of cardiac outcome in multivariate analyses. Sensitivity analysis excluding TIA and angina showed similar results. For Group 1 patients without symptomatic coronary artery disease (SCAD), cardiac outcome RR = 4.06 (95% CI: 1.83, 9.01, p = 0.002). For Group 1 with SCAD, RR = 0.36 (95% CI: 0.06, 2.13, p = 0.14). Cardiac wall motion impairment was also associated with left insular stroke independent of CAD or nonischemic heart disease. Right insular stroke was not associated with adverse cardiac outcomes or cardiac wall motion impairment.Left insular stroke is associated with an increased risk of adverse cardiac outcome and decreased cardiac wall motion compared to stroke in other locations and TIA. This was particularly marked in patients without symptomatic coronary artery disease (SCAD). In patients with SCAD, the cardioprotective effect of medications, especially beta-blockers alone or combined with ischemic preconditioning, may explain the lack of association in this subgroup.

View details for Web of Science ID 000235645200008

View details for PubMedID 16505298

View details for Web of Science ID 000235543100010

View details for PubMedID 16490917

Evidence-based medicine, although ostensibly concerned with the research evidence underlying claims of efficacy for surgical procedures,has a direct connection with the ethics of surgical decision making. Questions of whether new procedures should ever be performed on patients outside of a formal research protocol, what the patient should be told about the uncertainties inherent in the use of nonvalidated innovative procedures, when formal evaluation is necessary, what form that evaluation should take, and how the burdens and results of such research can be distributed fairly all involve balancing competing ethical principles. Good ethics requires good facts, and evidence from well-controlled experiments provides best information upon which to base decisions in these areas and to build ethical surgical practice.

View details for DOI 10.1016/j.suc.2005.10.003

View details for Web of Science ID 000235522200012

View details for PubMedID 16442426

Fludarabine and cyclophosphamide is an effective combination but increases the risk of opportunistic infections due to depressed lymphocyte counts. In an attempt to preserve CD4 counts, we conducted a phase I, double-blind, placebo-controlled trial of recombinant interleukin-2 (IL-2) added to fludarabine and cyclophosphamide in patients with treatment-naive indolent lymphomas or chronic lymphocytic leukemia.Subcutaneous IL-2 (days 1-21 of each 28-day cycle) was combined with cyclophosphamide (600 mg/m2, day 8) and fludarabine (20 mg/m2, days 8-12) at four dose levels: 0.8, 1.0, 1.2, and 1.4 x 10(6) IU/m2/d. IL-2 dose was escalated in cohorts of four to six patients, with one patient per cohort receiving placebo.Twenty-three patients, median age 50, were enrolled, of whom 30% had chronic lymphocytic leukemia/small lymphocytic lymphoma and 52% had follicular lymphomas. The combination was generally well tolerated, with mainly hematologic toxicities. CD4 counts typically declined substantially during the early weeks of treatment and remained suppressed for months afterward. In the 18 evaluable patients who received IL-2, the mean absolute CD4 count was 999 cells/microL (range, 97-3,776) pretreatment, 379 cells/microL (range, 54-2,599) at day 14, and 98 cells/microL (range, 17-291) at end of treatment. In longitudinal linear models, the changes in CD4 counts were not significantly different across IL-2 dose levels.The addition of low-dose IL-2 to fludarabine and cyclophosphamide does not seem immunoprotective. New approaches are needed to reduce the cellular immunosuppression and infectious complications associated with purine analogues.

View details for DOI 10.1158/1078-0432.CCR-05-1612

View details for Web of Science ID 000233701300027

View details for PubMedID 16322303

The early detection of cancers through analysis of circulating DNA could have a substantial impact on morbidity and mortality. To achieve this goal, it is essential to determine the number of mutant molecules present in the circulation of cancer patients and to develop methods that are sufficiently sensitive to detect these mutations. Using a modified version of a recently developed assay for this purpose, we found that patients with advanced colorectal cancers consistently contained mutant adenomatous polyposis coli (APC) DNA molecules in their plasma. The median number of APC DNA fragments in such patients was 47,800 per ml of plasma, of which 8% were mutant. Mutant APC molecules were also detected in >60% of patients with early, presumably curable colorectal cancers, at levels ranging from 0.01% to 1.7% of the total APC molecules. These results have implications for the mechanisms through which tumor DNA is released into the circulation and for diagnostic tests based on this phenomenon.

View details for Web of Science ID 000233283700044

View details for PubMedID 16258065

View details for DOI 10.1097/01.ede.0000165813.07327.35

View details for Web of Science ID 000230068000003

View details for PubMedID 15951660

View details for Web of Science ID 000227096800020

View details for PubMedID 15721469

View details for DOI 10.1191/1740774505cn083ed

View details for Web of Science ID 000232647900001

View details for PubMedID 16279142

Cancer risk assessment is one of the most visible and controversial endeavors of epidemiology. Epidemiologic approaches are among the most influential of all disciplines that inform policy decisions to reduce cancer risk. The adoption of epidemiologic reasoning to define causal criteria beyond the realm of mechanistic concepts of cause-effect relationships in disease etiology has placed greater reliance on controlled observations of cancer risk as a function of putative exposures in populations. The advent of molecular epidemiology further expanded the field to allow more accurate exposure assessment, improved understanding of intermediate endpoints, and enhanced risk prediction by incorporating the knowledge on genetic susceptibility. We examine herein the role and limitations of epidemiology as a discipline concerned with the identification of carcinogens in the physical, chemical, and biological environment. We reviewed two examples of the application of epidemiologic approaches to aid in the discovery of the causative factors of two very important malignant diseases worldwide, stomach and cervical cancers. Both examples serve as paradigms of successful cooperation between epidemiologists and laboratory scientists in the pursuit of the understanding of cancer etiology.

View details for DOI 10.1016/j.semcancer.2004.06.004

View details for Web of Science ID 000224847300004

View details for PubMedID 15489134

Patients with a preoperative cytologic diagnosis of a suspicious thyroid nodule present a therapeutic dilemma because surgery differs for benign and malignant lesions. To address this issue, several molecular markers, including human telomerase reverse transcriptase (TERT), have been tested as markers of thyroid cancer. Because most studies select cases falling into well-defined categories to test new markers, they may overestimate their discriminatory power when applied to samples that are difficult to classify. Fine-needle aspirates (FNAs) of the thyroid with indeterminate cytology are an example of such cases.We examined whether assessing TERT mRNA by reverse transcription-PCR could have improved the surgical management in a cohort of 100 patients undergoing thyroidectomy for indeterminate FNA results.Ninety percent of 48 cancers were TERT positive, as were 35% of 52 benign lesions. When 10 cases with concomitant lymphocytic thyroiditis were excluded, the overall sensitivity of TERT was 91% (95% confidence interval, 80-98%) and specificity was 79% (64-90%). No clinical or tumor variable contributed to the predictive ability of TERT except for tumor size, which added only marginally. Basing the surgical approach on the TERT assay alone would have reduced lobectomies performed for malignant disease from 11 to 4 cases and reduced total thyroidectomies for benign lesions from to 15 to 9, an overall 50% reduction in suboptimal treatment.The overall performance of preoperative differential diagnosis for thyroid tumors with indeterminate FNA results can be substantially improved by the inclusion of molecular markers such as TERT.

View details for Web of Science ID 000223724700019

View details for PubMedID 15355904

The catalytic, asymmetric syntheses of quinine and quinidine were achieved in 16 steps. The recently developed salen(Al)-catalyzed enantioselective Michael addition of methyl cyanoacetate served to set the crucial C4 stereocenter in 92% ee, and a late-stage asymmetric dihydroxylation was used to differentiate the common intermediate and access the two desired diastereomeric products with high selectivity.

View details for DOI 10.1021/ja039550y

View details for Web of Science ID 000188318300006

View details for PubMedID 14733531

Alzheimer's disease, the most prevalent dementia, is a prominent source of chronic illness in the elderly. Laboratory evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) might prevent the onset of Alzheimer's disease. Since the early 1990s numerous observational epidemiological studies have also investigated this possibility. The purpose of this meta-analysis is to summarize and evaluate available evidence regarding exposure to nonaspirin NSAIDs and risk of Alzheimer's disease using meta-analyses of published studies.A systematic search was conducted using Medline, Biological Abstracts, and the Cochrane Library for publications 1960 onwards. All cross-sectional, retrospective, or prospective observational studies of Alzheimer's disease in relation to NSAID exposure were included in the analysis. At least 2 of 4 independent reviewers characterized each study by source of data and design, including method of classifying exposure and outcome, and evaluated the studies for eligibility. Discrepancies were resolved by consensus of all 4 reviewers.Of 38 publications, 11 met the qualitative criteria for inclusion in the meta-analysis. For the 3 case-control and 4 cross-sectional studies, the combined risk estimate for development of Alzheimer's disease was 0.51 (95% Cl=0.40-0.66) for NSAID exposure. In the prospective studies, the estimate was 0.74 (95% Cl=0.62-0.89) for 4 studies reporting lifetime NSAID exposure and it was 0.42 (95% Cl=0.26-0.66) for the 3 studies reporting a duration of use of 2 or more years.Based on analysis of prospective and nonprospective studies, NSAID exposure was associated with decreased risk of Alzheimer's disease. An issue that requires further exploration in future trials or observational studies is the temporal relationship between NSAID exposure and protection against Alzheimer's disease.

View details for DOI 10.1159/000078501

View details for Web of Science ID 000223490800001

View details for PubMedID 15279021

Hypermethylation of the 5' promoter region of the glutathione S-transferase pi gene (GSTP1) occurs at a very high frequency in prostate adenocarcinoma. We compared the results of blinded histologic review of sextant biopsy samples from 72 excised prostates with those obtained using a quantitative methylation-specific polymerase chain reaction assay (QMSP) for GSTP1. Formal surgical pathologic review of the resected prostates was used to determine the number of patients with (n = 61) and without (n = 11) prostate cancer. Histology alone detected prostate carcinoma with 64% sensitivity (95% confidence interval [CI] = 51% to 76%) and 100% specificity (95% CI = 72% to 100%), whereas the combination of histology and GSTP1 QMSP at an assay threshold greater than 10 detected prostate carcinoma with 75% sensitivity (95% CI = 63% to 86%) and 100% specificity (95% CI = 72% to 100%), an 11% improvement (95% CI = 5% to 22%) in sensitivity over histology alone. The combination of histology and GSTP1 QMSP at an assay threshold greater than 5 detected prostate adenocarcinoma with 79% sensitivity (95% CI = 68% to 89%), a 15% improvement (95% CI = 7% to 26%) over histology alone. Thus, GSTP1 QMSP improved the sensitivity of histologic review of random needle biopsies for prostate cancer diagnosis. Further studies should determine whether detection of GSTP1 hypermethylation in a biopsy sample with normal histology indicates the need for an early repeat biopsy at the same site.

View details for DOI 10.1093/jnci/djg082

View details for Web of Science ID 000186327800014

View details for PubMedID 14600096

View details for DOI 10.1093/ije/dyg294

View details for Web of Science ID 000186146300007

View details for PubMedID 14559733

It is a widely held belief that the current system of oversight of clinical research, particularly the means of assessing risks and minimizing harms to participants in clinical trials, could be improved. In particular, the system is inefficient with overemphasis on the monitoring ability of some groups such as research ethics review boards and investigators, underemphasis on others such as data monitoring committees (DMCs) and sponsors, confusion about responsibilities for safety and imperfect communication between these different groups. Research ethics review boards are not able to perform safety monitoring by review of individual adverse events and are often burdened by duplicative reviews of large multicenter studies. There are no standards for DMCs to ensure they can reliably identify safety issues. Sponsors may be overreliant on data audits and slow to disseminate safety data in a coherent summary. Investigators, their staffs and clinical sites may not fully appreciate all the nuances of good clinical practice or may be inattentive to the daily conduct of studies. Regulators, particularly those in the United States, have failed to completely harmonize their policies with each other or with international regulatory agencies. We recommend well-designed monitoring plans for all studies that are appropriate to their scope and risk, more centralized review of large multisite studies and closer local scrutiny of single-institution studies. In addition, sponsors should pay greater attention to monitoring adverse events and keeping up-to-date databases or investigator's brochures emphasizing safety issues. A minimal standard of education or expertise in good clinical practice should be established for investigators, their staffs and research ethics review board members. DMC composition and functions should be standardized and regulations should be harmonized nationally and internationally. Finally, there should be a concerted effort to study the efficacy of various components of the system.

View details for DOI 10.1016/S0197-2456(03)00005-9

View details for Web of Science ID 000183255400002

View details for PubMedID 12757992

Progressive heart failure is the most common mechanism of death among patients with advanced heart failure. Cardiac resynchronization, a pacemaker-based therapy for heart failure, enhances cardiac performance and quality of life, but its effect on mortality is uncertain.To determine whether cardiac resynchronization reduces mortality from progressive heart failure.MEDLINE (1966-2002), EMBASE (1980-2002), the Cochrane Controlled Trials Register (Second Quarter, 2002), The National Institutes of Health ClinicalTrials.gov database, the US Food and Drug Administration Web site, and reports presented at scientific meetings (1994-2002). Search terms included pacemaker, pacing, heart failure, dual-site, multisite, biventricular, resynchronization, and left ventricular preexcitation.Eligible studies were randomized controlled trials of cardiac resynchronization for the treatment of chronic symptomatic left ventricular dysfunction. Eligible studies reported death, hospitalization for heart failure, or ventricular arrhythmia as outcomes. Of the 6883 potentially relevant reports initially identified, 11 reports of 4 randomized trials with 1634 total patients were included in the meta-analysis.Trial reports were reviewed independently by 2 investigators in an unblinded standardized manner.Follow-up in the included trials ranged from 3 to 6 months. Pooled data from the 4 selected studies showed that cardiac resynchronization reduced death from progressive heart failure by 51% relative to controls (odds ratio [OR], 0.49; 95% confidence interval [CI], 0.25-0.93). Progressive heart failure mortality was 1.7% for cardiac resynchronization patients and 3.5% for controls. Cardiac resynchronization also reduced heart failure hospitalization by 29% (OR, 0.71; 95% CI, 0.53-0.96) and showed a trend toward reducing all-cause mortality (OR, 0.77; 95% CI, 0.51-1.18). Cardiac resynchronization was not associated with a statistically significant effect on non-heart failure mortality (OR, 1.15; 95% CI, 0.65-2.02). Among patients with implantable cardioverter defibrillators, cardiac resynchronization had no clear impact on ventricular tachycardia or ventricular fibrillation (OR, 0.92; 95% CI, 0.67-1.27).Cardiac resynchronization reduces mortality from progressive heart failure in patients with symptomatic left ventricular dysfunction. This finding suggests that cardiac resynchronization may have a substantial impact on the most common mechanism of death among patients with advanced heart failure. Cardiac resynchronization also reduces heart failure hospitalization and shows a trend toward reducing all-cause mortality.

View details for Web of Science ID 000180886000028

View details for PubMedID 12585952

Encouraged by direct-to-consumer marketing, smokers and their physicians are contemplating lung cancer screening with a promising but unproven imaging procedure, helical computed tomography (CT).To estimate the potential benefits, harms, and cost-effectiveness of lung cancer screening with helical CT in various efficacy scenarios.Using a computer-simulated model, we compared annual helical CT screening to no screening for hypothetical cohorts of 100 000 current, quitting, and former heavy smokers, aged 60 years, of whom 55% were men. We simulated efficacy by changing the clinical stage distribution of lung cancers so that the screened group would have fewer advanced-stage cancers and more localized-stage cancers than the nonscreened group (ie, a stage shift). Our model incorporated known biases in screening programs such as lead time, length, and overdiagnosis bias.We measured the benefits of screening by comparing the absolute and relative difference in lung cancer-specific deaths. We measured harms by the number of false-positive invasive tests or surgeries per 100 000 and incremental cost-effectiveness in US dollars per quality-adjusted life-year (QALY) gained.Over a 20-year period, assuming a 50% stage shift, the current heavy smoker cohort had 553 fewer lung cancer deaths (13% lung cancer-specific mortality reduction) and 1186 false-positive invasive procedures per 100 000 persons. The incremental cost-effectiveness for current smokers was $116 300 per QALY gained. For quitting and former smokers, the incremental cost-effectiveness was $558 600 and $2 322 700 per QALY gained, respectively. Other than the degree of stage shift, the most influential parameters were adherence to screening, degree of length or overdiagnosis bias in the first year of screening, quality of life of persons with screen-detected localized lung cancers, cost of helical CT, and anxiety about indeterminate nodule diagnoses. In 1-way sensitivity analyses, none of these parameters was sufficient to make screening highly cost-effective for any of the cohorts. In multiway sensitivity analyses, a program screening current smokers was $42 500 per QALY gained if extremely favorable estimates were used for all of the influential parameters simultaneously.Even if efficacy is eventually proven, screening must overcome multiple additional barriers to be highly cost-effective. Given the current uncertainty of benefits, the harms from invasive testing, and the high costs associated with screening, direct-to-consumer marketing of helical CT is not advisable.

View details for Web of Science ID 000180345100026

View details for PubMedID 12525232

Allelic imbalance (AI), the loss or gain of chromosomal regions, is found in many cancers. AI can be detected in genomic tumor DNA released into the blood after necrosis or apoptosis. We evaluated plasma DNA concentration, allelic status in plasma DNA, and serum CA 125 level as screening tests for ovarian and other cancers.Plasma samples were obtained from 330 women (44 normal healthy control individuals, 122 patients with various cancers, and 164 control patients with non-neoplastic diseases). Plasma DNA concentration was determined in all samples. Allelic status was determined by digital single nucleotide polymorphism (SNP) analysis with eight SNP markers in plasma DNA from 54 patients with ovarian cancer and 31 control patients. CA 125 was determined in 63 samples. Receiver-operating characteristic (ROC) curves were plotted, and the areas under the ROC curves--a measure of the overall ability of a diagnostic test with multiple cutoffs to distinguish between diseased and nondiseased individuals--were determined.The area under the ROC curve for plasma DNA concentration was 0.90 for patients with neoplastic disease versus healthy control individuals and 0.74 for patients with neoplastic diseases versus control patients with non-neoplastic diseases. For control subjects given a specificity of 100% (95% confidence interval [CI] = 92% to 100%), the highest sensitivity achieved was 57% (95% CI = 49% to 67%). AI in at least one SNP was found in 87% (95% CI = 60% to 98%) of patients with stage I/II ovarian cancer and 95% (95% CI = 83% to 99%) of patients with stage III/IV ovarian cancer, but AI was not found in 31 patients with non-neoplastic diseases (specificity = 100%, 95% CI = 89% to 100%). The area under the ROC curve assessing AI was 0.95. Combining the serum CA 125 level with the plasma DNA concentration increased the area under the ROC curve from 0.78 (CA 125 alone) to 0.84.Plasma DNA concentration may not be sensitive or specific enough for cancer screening or diagnosis, even when combined with CA 125. AI was detected with high specificity in plasma DNA from patients with ovarian cancer and should be studied further as a screening tool.

View details for Web of Science ID 000179265000010

View details for PubMedID 12441325

View details for Web of Science ID 000177865600009

View details for PubMedID 12204023

Acne is a very common problem with significant physical and psychological morbidity. The evidence basis for its treatment had not been systematically reviewed. Therefore, we performed an evidence review to provide researchers a basis for further studies, and to provide clinicians the background needed to interpret current and future clinical studies.We summarize the methodologic state of the acne literature in patients with acne who do not have complicating co-morbidities.This was an expert-advised literature synthesis. We used a structured literature search for English-language controlled trials in Cochrane CENTRAL, MEDLINE, OLDMEDLINE, HSTAT, CINAHL, and PsychInfo. Results underwent a structured data abstraction process, with review by at least 2 reviewers.Out of 1588 unique articles, 250 articles (274 controlled trials) over the past 50 years were reviewed: 57 (21%) trials had at least one major weakness and no strengths; 125 (47%) trials had at least one major strength and at least one major weakness; 48 (18%) trials had at least one major strength, and no major weaknesses. The remaining 16 (6%) were of intermediate quality or did not provide enough information to make a determination. One fourth of studies did not report patient age; one fourth did not report on patient gender. Only 8% mentioned patient race; only 2% mentioned skin type; 0.4% mentioned diet; none scored sexual maturity or insurance status. There were 1237 outcomes. There were more than 25 methods of assessing acne severity and more than 19 methods for counting lesions. There were only two trials that formally assessed psychological outcomes. More than 140 treatments were tested in 251 comparisons.Ranging over 50 years of research, the acne literature evidences great heterogeneity at all levels: patient characteristics, acne severity, outcome assessments, treatments, and comparisons. A list of methodologic recommendations is provided.

View details for DOI 10.1067/mjd.2002.120912

View details for Web of Science ID 000177206300007

View details for PubMedID 12140469

This study evaluated a novel high-resolution breast-specific gamma camera (HRBGC) for the detection of suggestive breast lesions.Fifty patients (with 58 breast lesions) for whom a scintimammogram was clinically indicated were prospectively evaluated with a general-purpose gamma camera and a novel HRBGC prototype. The results of conventional and high-resolution nuclear studies were prospectively classified as negative (normal or benign) or positive (suggestive or malignant) by 2 radiologists who were unaware of the mammographic and histologic results. All of the included lesions were confirmed by pathology.There were 30 benign and 28 malignant lesions. The sensitivity for detection of breast cancer was 64.3% (18/28) with the conventional camera and 78.6% (22/28) with the HRBGC. The specificity with both systems was 93.3% (28/30). For the 18 nonpalpable lesions, sensitivity was 55.5% (10/18) and 72.2% (13/18) with the general-purpose camera and the HRBGC, respectively. For lesions < or = 1 cm, 7 of 15 were detected with the general-purpose camera and 10 of 15 with the HRBGC. Four lesions (median size, 8.5 mm) were detected only with the HRBGC and were missed by the conventional camera.Evaluation of indeterminate breast lesions with an HRBGC results in improved sensitivity for the detection of cancer, with greater improvement shown for nonpalpable and < or =1-cm lesions.

View details for Web of Science ID 000176853400018

View details for PubMedID 12097461

Investigation of the nature and frequency of statistician involvement in medical research and its relation to the final editorial decision.Authors of original research articles who submitted to BMJ and Annals of Internal Medicine from May through August 2001 were sent a short questionnaire at the time of manuscript submission. Authors were asked if they received assistance from a person with statistical expertise, the nature of any such contribution, and reasons why, if no statistical input was received.The response rate was 75% (704/943); methodological input was reported for 514 (73%) of these papers. In 435 papers (85%), such input was provided by biostatisticians or epidemiologists and, if deemed significant, was typically associated with authorship. A total of 33 of 122 methodologists (27%) whose main contribution started at the analysis stage received neither acknowledgment nor authorship. Research without methodological assistance was more likely to be rejected without review (71% vs 57%; chi(2) = 10.6; P =.001) and possibly less likely to be accepted for publication (7% vs 11%; chi(2) = 2.37; P =.12).Statistical input to medical research is widely recommended but inconsistently obtained. Individuals providing such expertise are often not involved until the analysis of data and many go unrecognized by either authorship or acknowledgment.

View details for Web of Science ID 000176002200019

View details for PubMedID 12038922

Peptic ulcer surgery may carry an increased risk for pancreatic cancer development. Molecular analysis of K-ras codon 12, frequently mutated in conventional pancreatic cancers, might provide insight into the aetiological mechanisms.The relative risk of pancreatic cancer was computed by multivariate and person-year analysis in a cohort of 2633 patients who had undergone gastrectomy. Lung cancer risk was analysed as an indirect means of assessing smoking behaviour. K-ras codon 12 mutational analysis was performed on 15 postgastrectomy pancreatic cancers.There was an overall increased risk of pancreatic carcinoma of 1.8 (95% confidence interval, 1.3 to 2.6) five to 59 years postoperatively, which gradually increased to 3.6 at 35 years or more after surgery (chi(2) test for trend, p < 0.05). Multivariate analysis indicated that parameters other than postoperative interval did not influence the risk. Lung cancer risk was significantly increased after surgery, but no time trend was observed. The spectrum and prevalence of K-ras codon 12 mutations were comparable to conventional pancreatic cancer.Remote partial gastrectomy is associated with an increased risk of pancreatic cancer. Postgastrectomy and non-postgastrectomy pancreatic cancers may share similar aetiological factors, such as smoking. However, the neoplastic process in patients who have undergone gastrectomy appears to be accelerated by factors related to the surgery itself.

View details for Web of Science ID 000175538200004

View details for PubMedID 11986336

Chromosome imbalances occur in many cancers and represent important biological properties of tumours. However, measurements of such imbalances are difficult. We used a new, quantitative approach to investigate the prognostic value of chromosome imbalances in early-stage colorectal cancers.We studied 180 patients with no evidence of lymph-node or distant metastases at the time of surgery. DNA from paraffin-embedded tumours was tested for imbalances of chromosome 8p and 18q by digital SNP (single-nucleotide polymorphism)-a technique in which each allele in a sample is directly counted. Surviving patients had median follow-up of 68 months, and disease recurrence was used as the clinical endpoint.Tumours were divided into three groups: "L" tumours (n=93) had allelic imbalances of chromosomes 8p and 18q, "L/R" tumours (n=60) had allelic imbalances of either chromosome 8p or 18q but not both, and "R" tumours (n=27) retained allelic balance for both chromosomes. 5-year disease-free survival was 100% (95% CI 80-100) for patients with R tumours, 74% (61-87) for patients with L/R tumours, and 58% (47-69) for those with L tumours. These differences were significant (p<0.0001) and were independent of other variables--eg, Duke's stage A tumours of class L were much more likely to recur than Duke's stage B tumours of class R (p=0.002).In patients without metastasis, allelic imbalance is a better predictor of prognosis than histopathological stage.

View details for Web of Science ID 000173350800014

View details for PubMedID 11812558

The gene encoding the DNA repair enzyme O(6)-methylguanine DNA methyltransferase (MGMT) is transcriptionally silenced by promoter hypermethylation in several human cancers, including diffuse large B-cell lymphoma (B-DLCL). MGMT promoter hypermethylation is a favorable prognostic marker in patients with brain tumors treated with alkylating agents.In a retrospective cohort study, we used methylation-specific polymerase chain reaction to analyze the MGMT promoter methylation status in tumor DNA of B-DLCL patients receiving cyclophosphamide as part of multidrug regimens. Molecular data were compared with patient response with the use of Student's t test. Disease-free survival and overall survival were estimated by the Kaplan-Meier method and compared with the use of the log-rank test. Multivariable survival analyses were performed with the Cox proportional hazards model. All statistical tests were two-sided.Thirty (36%) of 84 B-DLCL patients showed MGMT promoter hypermethylation in their lymphomas. The presence of MGMT methylation was associated with a statistically significant increase in overall survival (hazard ratio for time to death for nonmethylation versus methylation = 2.8; 95% confidence interval (CI) = 1.2 to 7.5; P =.01) and progression-free survival (hazard ratio for time to progression for nonmethylation versus methylation = 2.6; 95% CI = 1.3 to 5.8; P =.02). MGMT promoter hypermethylation was both independent of and stronger than established prognostic factors, such as age, disease stage, serum lactic dehydrogenase level, and performance status.MGMT promoter hypermethylation appears to be a useful marker for predicting survival in patients with B-DLCL treated with multidrug regimens including cyclophosphamide.

View details for Web of Science ID 000173058600011

View details for PubMedID 11773279

The purpose of this study was to determine which clinical and laboratory features correlate with serious hemorrhage in thrombocytopenic oncology patients. A retrospective review was conducted of all thrombocytopenic adult patients admitted to the Johns Hopkins Oncology Center, Baltimore, MD, over the last 10 years. We performed multiple logistic regression analysis on 2942 patients looking at the frequency of serious bleeding as a function of platelet count and numerous features that may correlate with hemorrhage. Multivariate analyses showed no relationship between either the first morning platelet count or the lowest platelet count of the day and the risk of hemorrhage. Of the other features we examined, several correlated independently with bleeding, including uremia (odds ratio [OR] 1.64; 95% confidence interval [CI], 1.40 to 1.92), hypoalbuminemia (OR 1.54; 95% CI, 1.33 to 1.79), recent bone marrow transplantation (OR 1.32; 95% CI, 1.22 to 1.43), and recent hemorrhage (OR 6.72; 95% CI, 5.53 to 8.18). Leukopenia was associated with a decreased risk of bleeding (OR 0.70; 95% CI, 0.60 to 0.82). Although this large study identified a number of clinical and laboratory features that correlated significantly with bleeding, the ORs of these factors were not large and all were much less than previous bleeding. These findings suggest that the major goal of transfusion support should be the aggressive therapeutic use of blood products rather than prophylactic use based on such weak clinical correlates and on the platelet count, which was not a correlate at all in multivariate analysis.

View details for PubMedID 11788928

Sickle cell anemia (SCA) is an inherited disorder of beta-globin, resulting in red blood cell rigidity, anemia, painful crises, organ infarctions, and reduced life expectancy. Allogeneic blood or marrow transplantation (BMT) can cure SCA but is associated with an 8% to 10% mortality rate, primarily from complications of marrow-ablative conditioning. Transplantation of allogeneic marrow after less intensive conditioning reduces toxicity but may result in stable mixed hematopoietic chimerism. The few SCA patients who inadvertently developed mixed chimerism after BMT remain symptom free, suggesting that mixed chimerism can reduce disease-related morbidity. However, because the effects of various levels of mixed chimerism on organ pathology have not been characterized, this study examined the histologic effects of an increasing percentage of normal donor hematopoiesis in a mouse model of BMT for SCA. In lethally irradiated normal mice that were reconstituted with varying ratios of T-cell-depleted marrow from normal and transgenic "sickle cell" mice, normal myeloid chimerism in excess of 25% was associated with more than 90% normal hemoglobin (Hb). However, 70% normal myeloid chimerism was required to reverse the anemia. Organ pathology, including liver infarction, was present in mice with sickle Hb (HbS) levels as low as 16.8% (19.6% normal myeloid chimerism). Histologic abnormalities increased in severity up to 80% HbS, but were less severe in mice with more than 80% HbS than in those with 40% to 80% HbS. Therefore, stable mixed chimerism resulting from nonmyeloablative BMT may reduce the morbidity from SCA, but prevention of all disease complications may require minimizing the fraction of circulating sickle red cells. (Blood. 2001;97:3960-3965)

View details for Web of Science ID 000169164300043

View details for PubMedID 11389040

View details for Web of Science ID 000169364100010

View details for PubMedID 11403761

Colorectal cancer cells are shed into the stool, providing a potential means for the early detection of the disease using noninvasive approaches. Our goal was to develop reliable, specific molecular genetic tests for the detection of colorectal cancer in stool samples.Stool DNA was isolated from paired stools and primary tumor samples from 51 colorectal cancer patients. Three genetic targets-TP53, BAT26, and K-RAS-were used to detect tumor-associated mutations in the stool prior to or without regard to the molecular analyses of the paired tumors. TP53 gene mutations were detected with a mismatch-ligation assay that detects nine common p53 gene mutations. Deletions within the BAT26 locus were detected by a modified solid-phase minisequencing method. Mutations in codons 12 and 13 of K-RAS were detected with a digital polymerase chain reaction-based method.TP53 gene mutations were detected in the tumor DNA of 30 patients, all of whom had the identical TP53 mutation in their stools. Tumors from three patients contained a noninherited deletion at the BAT26 locus, and the same alterations were identified in these patients' stool specimens. Nineteen of 50 tumors tested had a K-RAS mutation; identical mutations were detected in the paired stool DNA samples from eight patients. In no case was a mutation found in stool that was not also present in the primary tumor. Thus, the three genetic markers together detected 36 (71%) of 51 patients (95% confidence interval [CI] = 56% to 83%) with colorectal cancer and 36 (92%) of 39 patients (95% CI = 79% to 98%) whose tumors had an alteration.We were able to detect the majority of colorectal cancers by analyzing stool DNA for just three genetic markers. Additional work is needed to determine the specificity of these genetic tests for detecting colorectal neoplasia in asymptomatic patients and to more precisely estimate the prevalence of the mutations and sensitivity of the assay.

View details for Web of Science ID 000169105100012

View details for PubMedID 11390535

To compare the accuracy of diagnosis of invasive breast cancer with 11- and 8-gauge stereotactic vacuum-assisted biopsy (SVAB) devices and to correlate lesion diameter and accuracy of breast cancer diagnosis at SVAB.During a 22-month period, 489 SVAB procedures were performed with an 11-gauge probe and 305 with an 8-gauge probe. SVAB and surgical pathologic results of 104 breast carcinomas were reviewed and correlated with lesion size, number of specimens obtained, and type of SVAB probe used.Four of 38 ductal carcinoma in situ (DCIS) lesions diagnosed with 11-gauge SVAB demonstrated invasion at surgery, whereas one of 23 DCIS lesions diagnosed with 8-gauge SVAB demonstrated invasion at surgery (P =.6). A mean of 12 specimens per lesion were obtained in each group. In lesions 30 mm or larger, the underestimation rate for DCIS was 43% (three of seven) with 11-gauge SVAB and 17% (one of six) with 8-gauge SVAB (P =.6). Overall, the rate of underestimation for DCIS was significantly higher in lesions 30 mm or larger (four of 13) than in smaller lesions (one of 48, P =.006).This study demonstrated no difference in breast cancer diagnosis with the 8- and 11-gauge SVAB systems, but the accuracy of breast cancer diagnosis was greater in lesions smaller than 30 mm than in larger lesions.

View details for Web of Science ID 000168864800029

View details for PubMedID 11376271

Proliferative epithelial lesions in the smaller caliber pancreatic ducts and ductules have been the subject of numerous morphologic, clinical, and genetic studies; however, a standard nomenclature and diagnostic criteria for classifying these lesion have not been established. To evaluate the uniformity of existing systems for grading duct lesions in the pancreas, 35 microscopic slides with 35 representative duct lesions were sent to eight expert pathologists from the United States, Canada, and Europe. Kappa values for interobserver agreement could not be calculated initially because more than 70 different diagnostic terms were used by the eight pathologists. In several cases, the diagnoses rendered for a single duct lesion ranged from "hyperplasia," to "metaplasia," to "dysplasia," to "carcinoma in situ." This review therefore demonstrated the need for a standard nomenclature and classification system. Subsequently, during a working group meeting, the pathologists agreed to adopt a single standard system. The terminology pancreatic intraepithelial neoplasia (or PanIN) was selected, and diagnostic criteria for each grade of PanIN were established (http://pathology.jhu.edu/pancreas_panin). This new system was then evaluated by having the eight pathologists rereview the original 35 cases. Only seven different diagnoses were rendered, and kappa values of 0.43, 0.14, and 0.42 were obtained for PanINs 1, 2, and 3 respectively. Cases assigned other diagnoses (e.g., squamous metaplasia) collectively had a kappa value of 0.41. These results show both the potential of the classification system, and also the difficulty of classifying these lesions even with a consistent nomenclature. However, even when there is lack of consensus, having a restricted set of descriptions and terms allows a better understanding of the reasons for disagreement. It is suggested that we adopt and apply this system uniformly, with continued study of its reliability and use, and possibly further refinement. The acceptance of a standard classification system will facilitate the study of pancreatic duct lesions, and will lead ultimately to a better understanding of their biologic importance.

View details for Web of Science ID 000168418500003

View details for PubMedID 11342768

Chromosomal instability is believed to be a common feature of most human tumors, but the stage at which such instability originates has not been defined. At the molecular level, chromosomal instability is characterized by allelic imbalance (AI), representing losses or gains of defined chromosomal regions. We have assessed AI in early colorectal tumors using newly developed methods for assessing AI in complex cell populations. A total of 32 adenomas of average size (2 mm; range, 1-3 mm) were studied. AI of chromosome 5q markers occurred in 55% of tumors analyzed, consistent with a gatekeeping role of the adenomatous polyposis coli tumor suppressor gene located at chromosomal position 5q21. AI was also detected in each of the other four chromosomes tested. The fractions of adenomas with AI of chromosomes 1p, 8p, 15q, and 18q were 10,19, 28, and 28%, respectively. Over 90% of the tumors exhibited AI of at least one chromosome, and 67% had allelic imbalance of a chromosome other than 5q. These findings demonstrate that AI is a common event, even in very small tumors, and suggest that chromosomal instability occurs very early during colorectal neoplasia.

View details for Web of Science ID 000167020100005

View details for PubMedID 11221861

Hepatitis C is the leading cause of chronic liver disease in the United States. Several trials have found that interferon and ribavirin combination therapy is more efficacious than interferon monotherapy for previously untreated patients and those who relapsed after prior interferon monotherapy, but its effectiveness for nonresponders to prior interferon monotherapy is unclear.To assess the efficacy and safety of interferon and ribavirin vs interferon alone for treatment of patients with chronic hepatitis C who previously did not respond to interferon monotherapy.A systematic search was performed using MEDLINE and the Science Citation Index for publications from 1966 to December 1999. A manual reference search and a manual review of relevant specialty journals also were performed, and input from clinical hepatology experts was sought.Included studies were randomized, controlled clinical trials comparing interferon and ribavirin with interferon alone and reporting virological and biochemical outcomes after a follow-up period. Of 50 identified studies, 12 trials (941 patients) were included in the analysis.Two investigators reviewed trials independently for methods, inclusion and exclusion criteria, and outcomes. Disagreements were resolved by discussion. Abstracted data included study and patient characteristics and virological, biochemical, and histological outcomes. A quality evaluation questionnaire was used to score studies.The pooled virological response rate for combination therapy was 14% (95% confidence interval [CI], 11%-17%), with a risk difference favoring combination therapy of 7% (95% CI, 2%-13%). Use of interferon alfa-2a/2b and ribavirin, 1000 to 1200 mg/d, was associated with a pooled virological response rate of 18% and a risk difference of 16% (95% CI, 11%-21%). When interferon alfa-n/n3 and a lower dosage of ribavirin (600-800 mg/d) were used, the risk difference was 0% (95% CI, -7% to 7%). Combination therapy was associated with more adverse effects and an increased rate of discontinuation of treatment compared with interferon monotherapy.For chronic hepatitis C that is nonresponsive to prior interferon monotherapy, combination therapy is more effective than re-treatment with interferon alone. Response rates remain less than 20% even in the most responsive subgroups, demonstrating a need for better therapeutic options.

View details for Web of Science ID 000166227000028

View details for PubMedID 11176813

The analysis of loss of heterozygosity (LOH) is perhaps the most widely used technique in cancer genetics. In primary tumors, however, the analysis of LOH is fraught with technical problems that have limited its reproducibility and interpretation. In particular, tumors are mixtures of neoplastic and nonneoplastic cells, and the DNA from the nonneoplastic cells can mask LOH. We here describe a new experimental approach, involving two components, to overcome these problems. First, a form of digital PCR was employed to directly count, one by one, the number of each of the two alleles in tumor samples. Second, Bayesian-type likelihood methods were used to measure the strength of the evidence for the allele distribution being different from normal. This approach imparts a rigorous statistical basis to LOH analyses, and should be able to provide more reliable information than heretofore possible in LOH studies of diverse tumor types.

View details for Web of Science ID 000166261400025

View details for PubMedID 11135558

The Peutz-Jeghers syndrome (PJS) is an autosomal dominant polyposis disorder with increased risk of multiple cancers, but literature estimates of risk vary.We performed an individual patient meta-analysis to determine the relative risk (RR) of cancer in patients with PJS compared with the general population based on 210 individuals described in 6 publications.For patients with PJS, the RR for all cancers was 15.2 (95% confidence limits [CL], 2, 19). A statistically significant increase of RR was noted for esophagus (57; CL, 2.5, 557), stomach (213; CL, 96, 368), small intestine (520; CL, 220, 1306), colon (84; CL, 47, 137), pancreas (132; CL, 44, 261), lung (17.0; CL, 5.4, 39), breast (15.2; CL, 7.6, 27), uterus (16.0; CL, 1.9, 56), ovary (27; CL, 7.3, 68), but not testicular or cervical malignancies. Cumulative risk for all cancer was 93% from age 15 to 64 years old.Patients with PJS are at very high relative and absolute risk for gastrointestinal and nongastrointestinal cancers.

View details for DOI 10.1053/gast.2000.20228

View details for Web of Science ID 000165833800007

View details for PubMedID 11113065

The DNA-repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) inhibits the killing of tumor cells by alkylating agents. MGMT activity is controlled by a promoter; methylation of the promoter silences the gene in cancer, and the cells no longer produce MGMT. We examined gliomas to determine whether methylation of the MGMT promoter is related to the responsiveness of the tumor to alkylating agents.We analyzed the MGMT promoter in tumor DNA by a methylation-specific polymerase-chain-reaction assay. The gliomas were obtained from patients who had been treated with carmustine (1,3-bis(2-chloroethyl)-1-nitrosourea, or BCNU). The molecular data were correlated with the clinical outcome.The MGMT promoter was methylated in gliomas from 19 of 47 patients (40 percent). This finding was associated with regression of the tumor and prolonged overall and disease-free survival. It was an independent and stronger prognostic factor than age, stage, tumor grade, or performance status.Methylation of the MGMT promoter in gliomas is a useful predictor of the responsiveness of the tumors to alkylating agents.

View details for Web of Science ID 000165152800001

View details for PubMedID 11070098

Physicians have little evidentiary guidance for pharmacologic agent selection for atrial fibrillation (AF).To assess antiarrhythmic agent efficacy for AF conversion and subsequent maintenance of sinus rhythm (MSR).We searched the clinical trial database of the Cochrane Collaboration and MEDLINE encompassing literature from 1948 to May 1998.We selected 36 (28%) articles eligible as randomized trials of nonpostoperative AF conversion or MSR in adults.Study quality; rates of conversion, MSR, and adverse events were extracted.Compared with control treatment (placebo, verapamil, diltiazem, or digoxin), the odds ratio (OR) for conversion was greatest for ibutilide/dofetilide (OR=29.1; 95% confidence interval [CI], 9.8-86.1) and flecainide (OR=24.7; 95% CI, 9.0-68.3). Less strong but conclusive evidence existed for propafenone (OR=4.6; 95% CI, 2.6-8.2). Quinidine (OR=2.9; 95% CI, 1.2-7.0) had moderate evidence of efficacy for conversion. Disopyramide (OR=7.0; 95% CI, 0.3-153.0) and amiodarone (OR=5.7; 95% CI, 1.0-33.4) had suggestive evidence of efficacy. Sotalol (OR=0.4; 95% CI, 0.0-3.0) had suggestive evidence of negative efficacy. For MSR, strong evidence of efficacy existed for quinidine (OR=4.1; 95% CI, 2.5-6.7), disopyramide (OR=3.4; CI, 1.6-7.1), flecainide (OR=3.1; 95% CI, 1.5-6.2), propafenone (OR=3.7; 95% CI, 2.4-5.7), and sotalol (OR=7.1; 95% CI, 3.8-13.4). The only amiodarone data, from comparison with disopyramide, provided moderate evidence of efficacy for MSR. No trial evaluated procainamide. Direct agent comparisons and adverse event data were limited.Although multiple antiarrhythmic agents had strong evidence of efficacy compared with control treatment for MSR, ibutilide/dofetilide and flecainide had particularly strong evidence of efficacy compared with control treatment for AF conversion. There is sparse and inconclusive evidence on direct agent comparisons and adverse event rates. Obtaining information regarding these relative efficacies should be a research priority.

View details for Web of Science ID 000165251700009

View details for PubMedID 11093570

Standard therapy for lymphoma consists of a cyclophosphamide (C), doxorubicin, vincristine (V), and prednisone (P) (CHOP) combination regimen. Liposomal daunorubicin (DaunoXome) is an alternative to doxorubicin for patients with lymphoma because of its more favorable safety profile and potentially more selective uptake in lymphoma. The objectives of this study were to determine the maximum tolerated dose (MTD) of liposomal daunorubucin with CVP (COP-X) and the tolerability of the regimen in patients with indolent lymphoma.Patients with low-grade and intermediate-grade lymphoma having adequate cardiac, hepatic, and renal function were enrolled. Patients received C 750 mg/m2, V 1.4 mg/m2 (maximum 2.0 mg), and liposomal daunorubicin 50-100 mg/m2 i.v. on day 1 and P 100 mg p.o. on days 1-5. MTD was the liposomal daunorubicin dose associated with 20% dose-limiting toxicity (ANC 5 days or febrile neutropenia).Twenty patients, median age 59 years, were treated. The liposomal daunorubicin MTD combined with CVP was 70-80 mg/m2, depending on patient population. No significant non-hematologic toxicity occurred. Response rate was 44% (2 complete and 5 partial responses).A liposomal daunorubicin dose of 80 mg/m2 in the COP-X regimen was well tolerated with little nonhematologic toxicity.

View details for Web of Science ID 000088219600014

View details for PubMedID 10942057

View details for PubMedID 11471248

To develop a model for Bayesian communication to enable readers to make reported data more relevant by including their prior knowledge and values.To change their practice, clinicians need good evidence, yet they also need to make new technology applicable to their local knowledge and circumstances. Availability of the Web has the potential for greatly affecting the scientific communication process between research and clinician. Going beyond format changes and hyperlinking, Bayesian communication enables readers to make reported data more relevant by including their prior knowledge and values. This paper addresses the needs and implications for Bayesian communication. FORMULATION: Literature review and development of specifications from readers', authors', publishers', and computers' perspectives consistent with formal requirements for Bayesian reasoning.Seventeen specifications were developed, which included eight for readers (express prior knowledge, view effect size and variability, express threshold, make inferences, view explanation, evaluate study and statistical quality, synthesize multiple studies, and view prior beliefs of the community), three for authors (protect the author's investment, publish enough information, make authoring easy), three for publishers (limit liability, scale up, and establish a business model), and two for computers (incorporate into reading process, use familiar interface metaphors). A sample client-only prototype is available at http://omie.med.jhmi.edu/bayes.Bayesian communication has formal justification consistent with the needs of readers and can best be implemented in an online environment. Much research must be done to establish whether the formalism and the reality of readers' needs can meet.

View details for Web of Science ID 000087055700006

View details for PubMedID 10833162

Ataxia telangiectasia (A-T) is a rare disorder with many distinctive neurologic features. Although there is substantial individual variation in the rate of progression of these features, their relationship to one another or to age has not been characterized.We formulated and tested multiple elements that assess different neurologic functions known to be affected by A-T. The overall index was applied to 52 patients with A-T, 2 to 29 years of age.Seven elements items proved to be informative, and three elements were added based on face validity. In a linear regression model of individuals under 19 years of age, controlled for correlation within sibships, age accounted for 87% of the variation in the A-T Index.Despite substantial individual variability of the phenotypic elements of A-T, scores on this multidimensional index have a very high correlation with age, indicating that there is a characteristic rate of progression of the disease, although functional domains in the brain are differentially affected. The pattern of scores suggests that a severe and a mild form of A-T may be distinguished by this quantitative measure. With further development this index may become useful as an outcome measure for treatment studies and prognosis.

View details for Web of Science ID 000086460900022

View details for PubMedID 10751267

Our goal was to determine what drugs are most efficacious for controlling the ventricular rate in patients with atrial fibrillation.We conducted a systematic review of the literature published before May 1998, beginning with searches of The Cochrane Collaboration's CENTRAL database and MEDLINE.We included English-language articles describing randomized controlled trials of drugs used for heart rate control in adults with atrial fibrillation. DATA COLLECTION/ANALYSIS: Abstracts of trials were reviewed independently by 2 members of the study team. We reviewed English-language abstracts of non-English-language publications to assess qualitative consistency with our results.Forty-five articles evaluating 17 drugs met our criteria for review. In the 5 trials of verapamil and 5 of diltiazem, heart rate was reduced significantly (P <.05), both at rest and with exercise, compared with placebo, with equivalent or improved exercise tolerance in 6 of 7 comparisons. In 7 of 12 comparisons of a beta-blocker with placebo, the beta-blocker was efficacious for control of resting heart rate, with evidence that the effect is drug specific, as nadolol and atenolol proved to be most efficacious. All 9 comparisons demonstrated good heart rate control with beta-blockers during exercise, although exercise tolerance was compromised in 3 of 9 comparisons. In 7 of 8 trials, digoxin administered alone slowed the resting heart rate more than placebo, but it did not significantly slow the rate during exercise in 4 studies. The trials evaluating other drugs yielded insufficient evidence to support their use, but those drugs may yet be promising.The calcium-channel blockers verapamil or diltiazem, or select beta-blockers are efficacious for heart rate control at rest and during exercise for patients with atrial fibrillation without a clinically important decrease in exercise tolerance. Digoxin is useful when rate control during exercise is less a concern.

View details for Web of Science ID 000087077800008

View details for PubMedID 10678340

Appropriate use of drugs to prevent thromboembolism in patients with atrial fibrillation (AF) involves comparing the patient's risk of stroke and risk of hemorrhage. This review summarizes the evidence regarding the efficacy of these medications.We conducted a meta-analysis of randomized controlled trials of drugs used to prevent thromboembolism in adults with nonpostoperative AF. Articles were identified through the Cochrane Collaboration's CENTRAL database and MEDLINE until May 1998.Eleven articles met criteria for inclusion in this review. Warfarin was more efficacious than placebo for primary stroke prevention (aggregate odds ratio [OR] of stroke = 0.30, 95% confidence interval [CI] 0.19, 0.48), with moderate evidence of more major bleeding (OR 1.90; 95% CI 0.89, 4.04). Aspirin was inconclusively more efficacious than placebo for stroke prevention (OR 0.56, 95% CI 0.19, 1.65), with inconclusive evidence regarding more major bleeds (OR 0.81, 95% CI 0.37, 1.77). For primary prevention, assuming a baseline risk of 45 strokes per 1,000 patient-years, warfarin could prevent 30 strokes at the expense of only 6 additional major bleeds. Aspirin could prevent 17 strokes, without increasing major hemorrhage. In direct comparison, there was evidence suggesting fewer strokes among patients on warfarin than among patients on aspirin (aggregate OR 0.64, 95% CI 0.43, 0.96), with only suggestive evidence for more major hemorrhage (OR 1.60, 95% CI 0.77,3.35). However, in younger patients, with a mean age of 65 years, the absolute reduction in stroke rate with warfarin compared with aspirin was low (5.5 per 1,000 person-years) compared with an older group (15 per 1,000 person-years).In general, the evidence strongly supports warfarin for patients with AF at average or greater risk of stroke. Aspirin may prove to be useful in subgroups with a low risk of stroke, although this is not definitively supported by the evidence.

View details for Web of Science ID 000084835900009

View details for PubMedID 10632835

Despite increasing evidence of benefit from adjuvant chemotherapy, older women with breast cancer are commonly given less aggressive treatment than younger patients. Conflicting prior data regarding age-related toxicity prompted this prospective study. Forty-four women (aged 35-79 years) with early-stage breast cancer were treated with four cycles of adjuvant therapy with doxorubicin 60 mg/m2 i.v. and cyclophosphamide 600 mg/m2 i.v. every 21 days. They were monitored for myelosuppression, cardiotoxicity, and decrease in quality of life. Pharmacokinetics were analyzed using cycle 1 plasma samples. Bone marrow granulocyte and macrophage colony-forming units (CFU-GM) were assayed in vitro for dose response to 4-hydroperoxycyclophosphamide and doxorubicin before cycle 1. There was moderate evidence of age-related decrease in nadir absolute neutrophil count (ANC) when age was viewed as a continuous variable. On average there was a 10/microliter drop in cycle 1 nadir ANC for every year increase in age (p = 0.02). However, when age was viewed as a categorical variable (age or = 65 years), a similar proportion of women in each group reached an ANC 0.12). Pharmacokinetic analyses did not demonstrate age-related differences in the clearance of either doxorubicin or cyclophosphamide (p > 0.8). Pharmacodynamic analysis of individual patient bone marrow progenitor cell sensitivity did not reveal any correlation with age (p > 0.48). In women undergoing adjuvant therapy for breast cancer, no clinically significant age-related trends in toxicity were observed. These data suggest that older age alone should not exclude patients from receiving adjuvant therapy with doxorubicin and cyclophosphamide.

View details for Web of Science ID 000088285900004

View details for PubMedID 10923100

We conducted the first phase 2 and pharmacologic study to evaluate the combination of novobiocin (a coumeromycin antibiotic that has been shown to augment alkylating agent cytotoxicity in experimental models) and high-dose cyclophosphamide and thiotepa followed by autologous marrow support in women with chemosensitive advanced breast cancer. Its aims were (1) to determine progression-free survival (PFS) and overall survival (OS), (2) to evaluate the pharmacokinetics of cyclophosphamide and thiotepa, and (3) to measure the ability of novobiocin to reverse alkylator drug resistance in vitro. Forty-one women with chemotherapy-responsive advanced breast cancer received cyclophosphamide (4 g/m2) for peripheral blood stem cell mobilization (treatment 1) followed by high-dose cyclophosphamide (1.5 g/m2 per day for 4 days), thiotepa (200 mg/m2 per day for 4 days), and novobiocin (4 g/day orally for 7 days) (treatment 2) and autologous marrow support. The median PFS was 10 months (range, 0.2-70.6 months) and OS, 21.5 months (range, 0.2-70.6 months). There was no statistically significant relationship between PFS or OS and area-under-the-curve values of cyclophosphamide, thiotepa, or 4-hydroxycyclophosphamide. Patient plasma samples (n = 12) obtained during novobiocin therapy were able to reverse alkylator drug resistance in an in vitro colony-forming assay. Correlative laboratory studies in an in vitro model system demonstrated that patient plasma after novobiocin treatment resulted in the magnitude of resistance reversal that had been predicted by prior preclinical experiments. Clinically, however, this activity of novobiocin did not translate into a substantial increase in PFS or OS compared with historical controls treated with high-dose alkylator therapy alone.

View details for Web of Science ID 000090022500006

View details for PubMedID 10905771

Sulindac regresses colorectal adenomas in patients with familial adenomatous polyposis (FAP), although the mechanism of polyp regression is unclear.To determine whether differences occur in alteration of rectal epithelial apoptotic index and expression of apoptosis related proteins in FAP patients treated with sulindac compared with placebo.Twenty one FAP patients; 12 had not undergone colectomy.Patients with FAP were treated with sulindac 150 mg orally twice a day for three months (n=10) or placebo (n=11). Colorectal polyp number was determined and biopsies of the normal rectal mucosa were performed before and after three months of treatment. Response to treatment and alteration of the apoptotic ratio (index in base of crypt divided by index in surface epithelium) were evaluated. Bcl-2, bax, p21/WAF-1, and p53 proteins were assessed semiquantitatively by immunohistochemistry.Significant decreases in polyp number and in the apoptotic ratio were seen in patients treated with sulindac compared with controls. The mean percentage change in polyp number from baseline was -46% in the sulindac group and +13% in the placebo group (p=0.005). Mean percentage change in the apoptotic ratio was -8% and +25% in the sulindac and placebo treated patients, respectively (p=0.004). No differences in expression or compartmentalisation of apoptosis related proteins were noted between treatment groups.Sulindac regression of colorectal adenomas is accompanied by alteration of the rectal epithelial apoptotic ratio with relative increase in apoptosis in surface cells compared with the deeper crypt. The utility of the apoptotic ratio as an intermediate biomarker for colorectal tumorigenesis deserves further study.

View details for Web of Science ID 000083947700010

View details for PubMedID 10562579

PGP9.5 is a neurospecific peptide that functions to remove ubiquitin from ubiquitinated proteins and prevents them from targeted degradation by proteasomes. Using the serial analysis of gene expression method (SAGE), we observed that the PGP9.5 transcript was highly expressed in primary lung cancers and lung cancer cell lines but was not detectable in the normal lung. Here we examined the expression of PGP9.5 protein in normal lung epithelium, lung tumor cell lines, and 98 resected primary non-small-cell lung carcinomas (NSCLCs). We found PGP9.5 reactivity in normal lung in a pattern compatible with K-cells of the diffuse neuroendocrine system. However, the PGP9.5 was present in both small-cell lung cancer (SCLC) and NSCLC cell lines (22/24) independent of neuronal differentiation. In primary NSCLCs, 54% (53/98) of the cases had positive PGP9.5 staining, and the expression of protein was strongly associated with pathological stage of the cancer. It was present in 44% (29/66) of stage I NSCLCs and in 75% (24/32) of stage II and IIIA NSCLCs (p = 0.0032). These results suggest that the increased expression of PGP9.5 is specifically associated with lung cancer development and may serve as a potential marker for the detection of lung cancer.

View details for Web of Science ID 000082537800007

View details for PubMedID 10487828

The genetic epidemiology of colorectal adenomas has not been studied prospectively in colonoscopy patients without cancer.To study genetic alterations in colorectal adenomas and correlate these with patient demographics and adenoma characteristics.Mutations and allelic deletions in 201 adenomas from 60 patients were compared with demographic features, adenoma characteristics, and family history.The most common alteration was K-ras proto-oncogene mutation, present in 35% of adenomas and 65% of patients. Patients 65 years of age and older had a decreased probability of K-ras mutations (26% versus 45%). Overexpression of p53 gene product was present in only 6% of adenomas but was more frequent in villous or tubulovillous adenomas (19% versus 3%). Allelic loss of chromosome 18q was present in only 2% of adenomas and was significantly less frequent than p53 overexpression. DNA replication errors (RER) were present in 7% of adenomas and 15% of patients, including multiple adenomas in four patients (two with hereditary non-polyposis colorectal cancer syndrome). Only 36% of RER positive adenomas had alteration of BAT-26 alleles, none had alteration of BAT-25, and only one (8%) had mutation in the transforming growth factor beta type II receptor gene. RER positive adenomas were more likely to have a K-ras mutation. In patients with multiple adenomas, there was concordance of p53 overexpression and RER but not of K-ras mutations.Genetic progression in colorectal adenomas is heterogeneous, involving factors related to patient age and the presence of RER for the occurrence of ras mutations, but different intraindividual characteristics for the occurrence of p53 alterations and RER.

View details for Web of Science ID 000080513100017

View details for PubMedID 10323885

View details for Web of Science ID 000079533300010

View details for PubMedID 10189332

To describe the current policies regarding statistical review of clinical research in biomedical journals.Cross-sectional survey.Editors of biomedical journals that publish original clinical research.General policies on statistical review, types of persons used for statistical reviewing, compensation of statistical reviewers, percentage of articles subject to such review, percentage of time statistical review makes an important difference, journal circulation, and selectivity.Of 171 journals, 114 (67%) responded to the survey. About one third of journals had policies that guaranteed statistical review for all accepted manuscripts. In approximately half of the journals, articles were sent for statistical review at the discretion of the editor. There was some evidence that statistical review policies differed between journals of different circulation size. In journals in the top quartile of circulation (> 25,000) the probability of definitely having a statistical review before an acceptance decision was 52%, but it was only 27% in journals in the lower three quartiles (p = .09). The probability of a statistical consultant on staff ranged from 31% in the bottom quarter, to 58% in the middle two, to 82% in the highest quarter (p < .001). Editors judged that statistical review resulted in an important change in a manuscript about half of the time.Except in the largest circulation medical journals, the probability of formal methodologic review of original clinical research is fairly low. As readers and researchers depend on the journals to assess the validity of the statistical methods and logic used in published reports, this is potentially a serious problem. This situation may exist because the cost of such statistical review can be considerable, and because finding appropriate reviewers can be difficult. It may also exist partly because editors or publishers may not regard such review as important. The professions of medical publishing, statistics, epidemiology, and other quantitative disciplines should work together to address this problem.

View details for Web of Science ID 000076927000005

View details for PubMedID 9824521

Many journals provide peer reviewers with written instructions regarding review criteria, such as the originality of results, but little research has been done to investigate ways to improve or facilitate the peer review task.To assess the value that peer reviewers place on receipt of supplemental materials (eg, abstracts of related papers and preprints of related unpublished manuscripts).Questionnaire survey sent to all 733 peer reviewers recruited by the Journal of the National Cancer Institute to review 356 manuscripts consecutively sent out for review from February 24, 1997, through January 16, 1998. The inclusion of supplemental materials with manuscript review packages was optional.The peer reviewers' assessment of the actual or potential usefulness of supplemental materials on the performance of peer review.A total of 481 (66%) of 733 questionnaires were returned. Of the 471 respondents' questionnaires that could be used, 217 (46%) indicated that they received abstracts, and 44 (10%) of 458 respondents indicated that they received preprints. Higher proportions of peer reviewers who received supplemental materials than those who had not received them felt that they were (or would be) useful to them when reviewing the manuscript (63% [95% confidence interval (CI), 57%-69%] vs 45% [95% CI, 38%-52%]; P<.001) and to the peer review process in general (80% [95% CI, 75%-85%] vs 64% [95% CI, 58%-70%]; P<.001).The majority of respondents indicated that supplemental materials helped (or would have helped) them evaluate manuscripts and valued them more highly when they actually received them.

View details for Web of Science ID 000074706000024

View details for PubMedID 9676679

View details for PubMedID 11657084

View details for Web of Science ID 000073422300002

View details for PubMedID 9583709

T cell depletion (TCD) performed by elutriation has decreased the incidence of acute and chronic graft-versus-host disease (GvHD) following bone marrow transplantation (BMT). However, as with all forms of TCD, patients may experience graft failure (10%), delayed engraftment, and mixed chimerism. Because 66%-75% of the CD34+ cells coseparate with the small lymphocytes, which are removed by elutriation, we designed a phase I trial in HLA-identical siblings to determine if the readdition of these previously lost small CD34+ cells would improve elutriation's engraftment kinetics. CD34+ cells were isolated from the small cell fraction of 10 consecutive donor grafts and infused into the recipients along with the TCD graft. The positively selected product had a mean T cell content of 1.2 x 10(5)/kg and was 80% CD34+, doubling the CD34+ content of the graft. All patients engrafted promptly with a median time to 500 neutrophils/mm3, untransfused 50,000 platelets/mm3, and discharge from the hospital of 19 (range 10-25), 24 (14-52), and 24 (18-29) days, respectively. Acute GvHD occurred in 2 patients, and no patient had chronic GvHD. Augmenting stem cell dose may be an efficient and safe alternative for overcoming TCD-associated delayed engraftment and graft failure, rather than increasing immunosuppression.

View details for Web of Science ID 000073441200007

View details for PubMedID 9597572

CD44, a cell hyaluronate receptor, is implicated in the metastatic behavior of some cancer cells. This study analyzed CD44 expression in topographic tissue sites of colorectal cancers to determine its association with patient survival and clinicopathological characteristics. Immunohistochemical localization of the core CD44 and the v6 splice variant domains was examined by use of paraffin-fixed sections from 133 stage II or III colorectal cancers that previously had been evaluated for other diagnostic markers. Expression in malignant epithelium, stromal matrix, and stromal cells was compared to patient survival by univariate, multivariate, and bootstrap (reproducibility) analysis. Core CD44 staining was present in the malignant epithelium of 85% of tumors, the stromal matrix of 90%, and the stromal cells of 98%. The v6 splice variant domain was present in the epithelium of 77% of tumors but was less frequent in the stromal matrix (12%; P < 0.001) and stromal cells (17%; P < 0.001). Absence of core CD44 immunoreactivity in the stromal matrix was associated with increased death rate (hazard ratio, 2.4; 95% confidence interval, 1.2-4.8; P = 0.02), making this one of the most significant adverse prognostic variables, along with an age of 60 years or older, poor differentiation of the cancer, extramural venous invasion, chromosome 18q allelic loss, and nonwhite race. This study shows that core CD44 and v6 splice variant antigens are differentially expressed in the epithelium and stroma of colorectal cancers. A model that includes core CD44 immunoreactivity in stromal matrix along with other prognostic factors may improve identification of high-risk and low-risk patients.

View details for Web of Science ID 000071623200004

View details for PubMedID 9516948

During tumorigenesis, positive selection is exerted upon those tumor cells that alter rate-limiting regulatory pathways. A corollary of this principle is that mutation of one gene abrogates the need for alteration of another gene in the same pathway and also that the coexistence in a single tumor of mutations in different genes implies their involvement in distinct tumor-suppressive pathways. We studied 42 pancreatic adenocarcinomas for genetic alterations in the K-ras oncogene and the p16, p53, and DPC4 tumor suppressor genes. All of them had the K-ras gene mutated. Thirty-eight % of the tumors had four altered genes, another 38% had three altered genes, 15% had two altered genes, and 8% of the tumors had one altered gene. Interestingly, we noted a high concordance of DPC4 and p16 inactivations (P = 0.007), suggesting that the genetic inactivation of p16 increases the selective advantage of subsequent mutation in DPC4. No statistically significant association was identified between the alteration of these cancer genes and pathological or clinical parameters. This type of multigenic analysis in human tumors may serve to substantiate experimental tumor models and thus increase our understanding of the truly physiologically relevant tumor-suppressive pathways that are abrogated during human tumorigenesis.

View details for Web of Science ID A1997WW56900022

View details for PubMedID 9135016

The p53 gene (also known as TP53) may be the most common genetic target involved in the malignant transformation of human cells. Direct sequence analysis has demonstrated that alteration of this gene occurs in approximately 45% of head and neck squamous cell carcinomas. The consequences of p53 mutations in these cancers with respect to tumor behavior and patient survival have not been rigorously determined.We evaluated the implications of p53 mutations in relation to the control of locoregional disease and overall survival following radiation therapy.Data from 110 consecutive patients with invasive disease who were treated with primary radiation therapy (given with curative intent) or with adjuvant radiation therapy (following complete surgical extirpation of gross disease) were included in the analysis. A 1.8-kilobase fragment of the p53 gene encompassing exons 5-9 was amplified from the DNA of stored (frozen) tumor specimens; the amplified DNA was cloned and sequenced by use of standard techniques. Overall survival and locoregional disease-free survival after the completion of radiation therapy were estimated by the Kaplan-Meier method; survival comparisons were made by use of the logrank test or proportional hazards regression models. Reported P values are two-sided.Fortyeight (44%) of the 110 tumors had cells bearing p53 mutations. The risk of locoregional recurrence following either primary or adjuvant radiation therapy was significantly greater (i.e., the time to recurrence was shorter) for patients whose tumors contained mutant p53 genes (univariate model hazard ratio [HR] for p53 mutation versus wild-type = 2.2; 95% confidence interval [CI] = 1.2-4.1; P = .02). The presence of regional lymph node metastases (presence versus absence, HR = 2.0; 95% CI = 1.0-4.2; P = .05) and treatment type (primary radiation therapy versus surgery plus adjuvant radiation therapy, HR = 2.3; 95% CI = 1.2-4.3; P = .01) were also associated with greater risks of locoregional failure. The presence of p53 mutations and lymph node metastases and treatment with primary, as opposed to adjuvant, radiation therapy remained significant risk factors in multivariate regression analysis. No relationship was demonstrated between p53 status and overall survival (mutant versus wild-type, HR = 1.1; 95% CI = 0.6-2.1; P = .66); however, a relationship was shown for tumor stage and overall survival (stages III and IV [more advanced] versus stages I and II [less advanced], HR = 3.3; 95% CI = 1.0-10.8; P = .05). Mutation of the p53 gene was not associated with patient age, sex, tumor stage, primary tumor site, regional lymph node status, degree of tumor cell differentiation, or treatment method.Mutation of the p53 gene is associated with an increased risk of locoregional failure in patients with invasive head and neck squamous cell carcinoma who are treated with radiation therapy.

View details for Web of Science ID A1996VQ46500015

View details for PubMedID 8901856

The cell surface glycoprotein CD44 is expressed primarily in the region of cell replication in the lower crypt epithelium of colorectal mucosa, and its expression is markedly increased in colorectal neoplasms, suggesting that expression is linked to proliferation. The association between CD44 expression and replication in individual cells was therefore analyzed by double-label immunohistochemistry for CD44 and the cell-cycle-dependent protein proliferating cell nuclear antigen (PCNA). Enhanced expression of CD44 in colorectal neoplasms occurred not only in epithelial cells but also in stromal cells, including lymphocytes and macrophages. On a topographical basis, the cellular localization of CD44 and PCNA were commonly different. Quantitatively, in all cell types studied (epithelial cells and stroma of colorectal mucosa, adenomas, and carcinomas) PCNA was present most frequently in cells lacking CD44. Statistical analysis by logistic regression models indicated that cells negative for CD44 had a higher probability of being positive for PCNA than did cells positive for CD44 (P < 0.001). These data suggest that the enhanced level of CD44 in colorectal neoplasms is asynchronous with cell replication and reflects mechanisms that act on nonproliferative stromal lymphocytes and other mononuclear cells as well as the epithelial cells.

View details for Web of Science ID A1996VM31400009

View details for PubMedID 8863664

To compare the efficacy and safety of inpatient oral antibiotic treatment (oral) versus standard parenteral antibiotic treatment (intravenous) for right-sided staphylococcal endocarditis in injection drug users.In a prospective, randomized, non-blinded trial, febrile injection drug users were assigned to begin oral or intravenous (IV) treatment on admission, before blood culture results were available. Oral therapy consisted of ciprofloxacin and rifampin. Parenteral therapy was oxacillin or vancomycin, plus gentamicin for the first 5 days. Antibiotic dosing was adjusted for renal dysfunction. Administration of other antibacterial drugs was not permitted during the treatment or follow-up periods. Bacteremic subjects having right-sided staphylococcal endocarditis received 28 days of inpatient therapy with the assigned antibiotics. Test-of-cure blood cultures were obtained during inpatient observation 6 and 7 days after the completion of antibiotic therapy, and again at outpatient follow-up 1 month later. Criteria for treatment failure and for drug toxicity were prospectively defined.Of 573 injection drug users who were hospitalized because of a febrile illness and suspected right-sided staphylococcal endocarditis, 93 subjects (16.2%) had two or more sets of blood cultures positive for staphylococci; 85 of these bacteremic subjects (14.8%) satisfied diagnostic criteria for at least possible right-sided staphylococcal endocarditis (no other source of bacteremia was apparent) and entered the trial. Forty-four (oral, 19; IV, 25) of these 85 subjects completed inpatient treatment and evaluation including test-of-cure blood cultures. There were four treatment failures (oral, 1 [5.2%]; IV, 3 [12.0%]; not significant, Fisher's exact test). Drug toxicity was significantly more common in the parenterally treated group (oral, 3%; IV, 62%; P < 0.0001), consisting largely of oxacillin-associated increases in liver enzymes.For selected patients with right-sided staphylococcal endocarditis, oral ciprofloxacin plus rifampin is effective and is associated with less drug toxicity than is intravenous therapy.

View details for Web of Science ID A1996UY64700011

View details for PubMedID 8686718

: Patients with ulcerative colitis are at increased risk for colorectal adenocarcinoma compared with the general population. Although surveillance for colorectal malignancy and dysplasia (a premalignant lesion) has been recommended, a benefit in reducing mortality from colorectal cancer via surveillance or prophylactic colectomy is still being debated. We reviewed the outcome of 40 consecutive patients with ulcerative colitis with colorectal adenocarcinoma diagnosed between 1956 and 1991 at The Johns Hopkins Hospital. The diagnosis of ulcerative colitis and the tumor, node, metastasis (TNM) stage of colorectal cancer were obtained from clinicopathologic records. Follow-up information was complete for all patients. Patients were divided into two groups: 18 asymptomatic patients who had colorectal cancer detected by colonoscopy, biopsies for dysplasia, or barium enema, or had undergone "prophylactic" colectomy as part of a colorectal cancer-prevention strategy (asymptomatic group), whereas 22 patients did not undergo cancer-prevention testing or prophylactic surgery and had symptoms of colorectal cancer (symptomatic group). Colorectal cancer was diagnosed at a statistically significantly earlier cancer stage in the asymptomatic group [12 (67%) of 18 at stage I or II] compared with those in the symptomatic group [two (9%) of 22 at stage I or II] (Wilcoxon test, p < 0.01). Colorectal cancer 5-year survival in the asymptomatic group was 89% [confidence limit (CL), 6197%] and in the symptomatic group, 19% (CL, 6-39%). Patients with ulcerative colitis and asymptomatic colorectal cancer detected as part of a prevention strategy had malignancies that were less invasive and showed greatly increased survival compared with patients with symptomatic colorectal cancer.

View details for Web of Science ID A1996UL03300002

View details for PubMedID 23282450

Although several morphological and molecular genetic studies have implicated various grades of pancreatic duct hyperplasia as precursor lesions to infiltrating pancreatic adenocarcinoma, the identity of preinvasive pancreatic neoplasms remains controversial. In the present study, the authors examined the expression of the epidermal growth factor receptor homologue, HER-2/neu (c-erbB-2), in pancreatic duct lesions adjacent to infiltrating pancreas cancers in a series of 19 cases of pancreatic duct adenocarcinoma. HER-2/neu expression was examined because it has been identified in a proportion of infiltrating pancreas cancers and because it may provide early neoplasms with a growth advantage over adjacent nonneoplastic epithelium. In normal pancreatic ducts and ductules, HER-2/neu expression was absent in all but one case. By contrast, HER-2/neu was expressed in 82% (P = .008 vs normal ) of ducts with flat mucinous hyperplasia, 86% (P = .03 vs normal) of ducts with papillary mucinous hyperplasia without atypia, 92% (P = .001 vs normal) of ducts with atypical papillary mucinous hyperplasia, and all specimens with carcinoma in situ. HER-2/neu expression was observed in 69% (P = .002 vs normal) of the moderately differentiated infiltrating carcinomas and none of the poorly differentiated infiltrating carcinomas. These data establish HER-2/neu as a potential mediator of growth factor-related signal transduction in pancreatic duct lesions, and provide additional support for the hypothesis that lesions formerly regarded as various grades of hyperplasia instead may represent intraepithelial neoplasms with the potential for subsequent invasion and metastasis.

View details for Web of Science ID A1996TU85500004

View details for PubMedID 8617452

To determine if caretakers of young children with IDDM could consistently reproduce small incremental measurements of insulin (U100).Fifteen caretakers of children with IDDM were asked to deliver repeated small doses of insulin, including doses separated by only 0.25 U of insulin. A sensitive gravimetric technique was used to determine the error in measurement of these low doses of insulin. Statistical analysis was used to evaluate accuracy and internal consistency of each caretaker at each dose.The means +/- SD at each dose level were as follows: 2.75 +/- 0.13 U at 2.5 U, 3.19 +/- 0.13 U at 3.0 U, 3.55 +/- 0.13 U at 3.25 U, and 3.70 +/- 0.11 U at 3.5 U. All doses were biased toward overadministration. There was as statistically significant difference in the dose delivered when the target doses were varied by only 0.25 U. The average differences and standard errors between 2.5 U and 3.0 U, 3.0 U and 3.25 U, and 3.25 U and 3.5 U were 0.44 +/- 0.20 U, 0.36 +/- 0.018 U, and 0.15 +/- 0.017 U, respectively.Participants were not accurate in measuring small insulin doses, consistently overdrawing insulin by an average of 0.22 U. Caretakers are reasonably internally consistent with a given dose, since participants were able to measure statistically significant differences in 0.25 U dose changes. The error in insulin measurement does not vary with the intended dose level. Caretakers in the same family deliver insulin doses as variable from each other as they are from the population as a whole; however, when two or more individuals are responsible for one insulin dose in a child with IDDM, they have a combined variability that is approximately 40% greater than a single individual's variability.

View details for Web of Science ID A1996TW85800012

View details for PubMedID 8720535

Mutation of the p53 gene is reported to be of prognostic importance in colorectal carcinomas. Immunohistochemical staining of the accumulated p53 gene product may be a simple alternative for p53 mutation analysis. Previous studies addressing the prognostic importance of p53 expression, however, yielded contradictory results. Therefore, we evaluated the importance of p53 expression as a marker for long-term prognosis in a well-characterised study population of 109 colorectal carcinomas. After antigen retrieval with target unmasking fluid (TUF), immunostaining of p53 was performed with both monoclonal antibody DO7 and polyclonal antibody CM1. Objective quantification of the p53 signal was assessed by a computerised image analyser. p53 expression was higher in non-mucinous tumours than in mucinous tumours (p53 labelling index = 30% and 17% respectively, P = 0.05), and in metastatic tumours compared with non-metastatic tumours (p53 labelling index = 37% and 22% respectively, P = 0.05). Other histopathological features were not related to p53 expression. In multivariate analysis, Dukes' stage (P = 0.02) and histological grade (P = 0.05) stood out as independent markers for prognosis. p53 expression was not an independent marker for prognosis. At present, p53 expression is not a useful marker for long-term prognosis. Further insight into the relationship between p53 mutations and p53 expression is needed to elucidate more precisely the clinical relevance of p53 alterations.

View details for Web of Science ID A1995RB64600025

View details for PubMedID 7779721

This single-institution study examined the outcome after pancreaticoduodenectomy in patients with adenocarcinoma of the head of the pancreas.In recent years, pancreaticoduodenectomy for adenocarcinoma of the head of the pancreas has been associated with decreased morbidity and mortality and, in some centers, 5-year survival rates in excess of 20%.Two hundred one patients with pathologically verified adenocarcinoma of the head of the pancreas undergoing pancreaticoduodenectomy at The Johns Hopkins Hospital between 1970 and 1994 were analyzed (the last 100 resections were performed between March 1991 and April 1994). This is the largest single-institution experience reported to date.The overall postoperative in-hospital mortality rate was 5%, but has been 0.7% for the last 149 patients. The actuarial 5-year survival for all 201 patients was 21%, with a median survival of 15.5 months. There were 11 5-year survivors. Patients resected with negative margins (curative resections: n = 143) had an actuarial 5-year survival rate of 26%, with a median survival of 18 months, whereas those with positive margins (palliative resections; n = 58) fared significantly worse, with an actuarial 5-year survival rate of 8% and a median survival of 10 months (p < 0.0001). Survival has improved significantly from decade to decade (p < 0.002), with the 3-year actuarial survival of 14% in the 1970s, 21% in the 1980s, and 36% in the 1990s. Factors significantly favoring long-term survival by univariate analyses included tumor diameter < 3 cm, negative nodal status, diploid tumor DNA content, tumor S phase fraction < 18%, pylorus-preserving resection, < 800 mL intraoperative blood loss, < 2 units of blood transfused, negative resection margins, and use of postoperative adjuvant chemotherapy and radiation therapy. Multivariate analyses indicated the strongest predictors of long-term survival were diploid tumor DNA content, tumor diameter < 3 cm, negative nodal status, negative resection margins, and decade of resection.The survival of patients with pancreatic adenocarcinoma treated by pancreaticoduodenectomy is improving. Aspects of tumor biology, such as DNA content, tumor diameter, nodal status and margin status, are the strongest predictors of outcome.

View details for Web of Science ID A1995RF53600011

View details for PubMedID 7794076

Surgical oncologists rely heavily on the histopathological assessment of surgical margins to ensure total excision of the tumor in patients with head and neck cancer. However, current techniques may not detect small numbers of cancer cells at the margins of resection or in cervical lymph nodes.We used molecular techniques to determine whether clonal populations of infiltrating tumor cells harboring mutations of the p53 gene could be detected in histopathologically negative surgical margins and cervical lymph nodes of patients with squamous-cell carcinoma of the head and neck.We identified 25 patients with primary squamous-cell carcinoma of the head and neck containing a p53 mutation who appeared to have had complete tumor resection on the basis of a negative histopathological assessment. In 13 of these 25 patients, molecular analysis was positive for a p53 mutation in at least one tumor margin. In 5 of 13 patients with positive margins by this method (38 percent), the carcinoma has recurred locally, as compared with none of 12 patients with negative margins (P = 0.02 by the log-rank test). Furthermore, molecular analysis identified neoplastic cells in 6 of 28 lymph nodes (21 percent) that were initially negative by histopathological assessment.Among specimens initially believed to be negative by light microscopy, a substantial percentage of the surgical margins and lymph nodes from patients with squamous-cell carcinoma of the head and neck contained p53 mutations specific for the primary tumor. Patients with these positive margins appear to have a substantially increased risk of local recurrence. Molecular analysis of surgical margins and lymph nodes can augment standard histopathological assessment and may improve the prediction of local tumor recurrence.

View details for Web of Science ID A1995QF77000004

View details for PubMedID 7619114

To identify prognostic indicators in breast cancer patients with malignant pleural effusions, we analyzed the cytopathologic features of 57 fluids representing the first pathologic diagnosis of a distant metastasis in these women. The specimens were analyzed prior to reviewing the clinical records. The median survival of 55 patients who died of the disease was five months following the effusion diagnosis (range, 1-114). Univariate analysis identified three cytopathologic features that correlated with relatively prolonged survival: arrangement of tumor cells in spheroids, slight nuclear atypia and low mitotic rate. Women whose tumor cells formed spheroids survived a median of 24.5 months as compared to 4 months for women with all other architectural patterns (P = .004). Multivariate analysis revealed that slight nuclear atypia and low mitotic rate strongly correlated with spheroid formation. Since breast cancers that form spheroids in effusions portend a relatively favorable prognosis, we recommend that cytopathologists comment on this pattern when reporting on metastatic breast carcinoma in pleural fluids.

View details for Web of Science ID A1994PX23800012

View details for PubMedID 7992584

To study readers' judgments of manuscript quality and the degree to which readers agreed with peer reviewers.Cross-sectional study.Annals of Internal Medicine.One hundred thirteen consecutive manuscripts reporting original research and selected for publication. Each of two manuscript versions (one before and one after revision) was judged by two readers, randomly sampled from those who said (based on the title) that they would read the article; one peer reviewer (peer), chosen in the usual way for Annals; and one expert in clinical research methods (expert). Each judge completed an instrument that included a 10-point subjective summary grade of manuscript quality.Agreement on the 10-point summary grade of manuscript quality between reader-expert, reader-peer, and reader-reader.Readers and peers gave high grades (77% and 73% gave a grade of 5 or better, respectively), while experts were more critical (52% gave a grade of 5 or better; P 69%) but agreement beyond chance was poor (kappa < 0.04). One third of readers (33%) thought that the manuscript had little relevance to their work.Readers, like most peer reviewers, are generally satisfied with the quality of manuscripts but would like research articles to be more relevant to their clinical practice.

View details for Web of Science ID A1994NV42400009

View details for PubMedID 8015119

To investigate the speed of the transfer of new statistical methods into the medical literature and, on the basis of current data, to predict what methods medical journal editors should expect to see in the next decade.Influential statistical articles were identified and the time pattern of citations in the medical literature was ascertained. In addition, longitudinal studies of the statistical content of articles in medical journals were reviewed.Cumulative number of citations in medical journals of each article in the years after publication.Annual citations show some evidence of decreasing lag times between the introduction of new statistical methods and their appearance in medical journals. Newer technical innovations still typically take 4 to 6 years before they achieve 25 citations in the medical literature. Few methodological advances of the 1980s seem yet to have been widely cited in medical journals. Longitudinal studies indicate a large increase in the use of more complex statistical methods.Time trends suggest that technology diffusion has speeded up during the last 30 years, although there is still a lag of several years before medical citations begin to accrue. Journals should expect to see more articles using increasingly sophisticated methods. Medical journals may need to modify reviewing procedures to deal with articles using these complex new methods.

View details for Web of Science ID A1994NV42400013

View details for PubMedID 8015123

To evaluate the effects of peer review and editing on manuscript quality.Editorial offices of Annals of Internal Medicine.Masked before-after study. MANUSCRIPTS: 111 consecutive original research manuscripts accepted for publication at Annals between March 1992 and March 1993.We used a manuscript quality assessment tool of 34 items to evaluate the quality of the research report, not the quality of the research itself. Each item was scored on a 1 to 5 scale. Forty-four expert assessors unaware of the design or aims of the study evaluated the manuscripts, with different persons evaluating the two versions of each manuscript (before and after the editorial process).33 of the 34 items changed in the direction of improvement, with the largest improvements seen in the discussion of study limitations, generalizations, use of confidence intervals, and the tone of conclusions. Overall, the percentage of items scored three or more increased by an absolute 7.3% (95% CI, 3.3% to 11.3%) from a baseline of 75%. The average item score improved by 0.23 points (CI, 0.07 to 0.39) from a baseline mean of 3.5. Manuscripts rated in the bottom 50% showed two- to threefold larger improvements than those in the top 50%, after correction for regression to the mean.Peer review and editing improve the quality of medical research reporting, particularly in those areas that readers rely on most heavily to decide on the importance and generalizability of the findings.

View details for Web of Science ID A1994PN27100003

View details for PubMedID 8198342

View details for PubMedID 11659840

Mutations in the p53 tumor suppressor gene are frequently identified in human neoplasms. These mutations may be associated with stabilization and, therefore, with overexpression of the p53 protein product as determined by immunohistochemical staining. Using a new antigen retrieval method and a polyclonal antibody to p53 (CM-1), the authors examined 48 formalin-fixed paraffin-embedded adenocarcinomas of the pancreas for overexpression of the p53 gene product. These 48 carcinomas were obtained from a series of patients with well-documented clinical histories and extensive follow-up. The carcinomas had been analyzed previously for K-ras gene mutations, tumor ploidy, and tumor proliferating index. Specific diffuse nuclear staining for the p53 protein was identified in 19 of the 48 (40%) infiltrating carcinomas examined. Focal or negative staining was seen in the remaining 29 cases (60%). In addition, 17 of the neoplasms contained synchronous in situ carcinomas; two (12%) of these displayed diffuse nuclear staining for the p53 protein. Overexpression of p53 was associated with aneuploidy (P = .05), which had been a poor prognosticator in this series of adenocarcinomas of the pancreas. Although overexpression of p53 appeared to be associated with poor prognosis (hazard ratio, 1.8; P = .07), this was not statistically significant. Overexpression of p53 was not significantly associated with K-ras oncogene mutations or tumor proliferating index. The authors conclude that overexpression of the p53 protein occurs frequently in invasive adenocarcinomas of the pancreas and in some in situ carcinomas, as well.

View details for Web of Science ID A1994NQ30200003

View details for PubMedID 8209852

Accelerated arteriosclerosis is now the major long-term complication of heart transplantation. Defining the risk factors associated with the development of accelerated arteriosclerosis will provide not only a means of identifying patients at risk for this complication but also clues to the etiology of accelerated arteriosclerosis. The purpose of this study was to examine the relationship between peritransplant myocardial ischemic injury and the development of accelerated arteriosclerosis. In a case-control study we examined the first three endomyocardial biopsies from 50 heart transplant recipients and graded the degree of ischemic injury present in these biopsies. The histologic changes graded in the biopsies included contraction band necrosis, coagulative necrosis, and macrophagic removal of ischemically injured myocytes. Of the 50 recipients included in the study, 25 had angiographic evidence of accelerated arteriosclerosis and 25 did not. In multivariate analysis, which included the number of class I major histocompatibility (MHC) antigen mismatches between the donor and the recipient, the recipient's post-transplant cytomegalovirus status, the donor's age, and the number of rejection episodes, the histologic degree of ischemic injury present in the biopsies emerged as the strongest predictor of the development of accelerated arteriosclerosis (RR 2.6, 95% CI 1.2-5.8, p = 0.02). These results suggest that ischemic injury to the heart during the peritransplant period significantly contributes to the development of accelerated arteriosclerosis in heart transplant recipients and that histologic changes in early posttransplant biopsies can be used to identify recipients at risk of developing accelerated arteriosclerosis.

View details for Web of Science ID A1994ND58100002

View details for PubMedID 8141428

View details for PubMedID 8173657

View details for Web of Science ID A1994MZ61300025

View details for PubMedID 8173006

To assess the efficacy of immune globulin in preventing CMV infection, interstitial pneumonia, GVHD and death after BMT, we reviewed and synthesized data from 12 published studies (with 1282 patients) in which immune globulin was used prophylactically in BMT patients, controls were included and clinical outcomes were assessed. Data synthesis indicates that immune globulin significantly reduces fatal CMV infection (odds ratio (OR) 0.47, 95% confidence interval (CI) 0.23-0.99), CMV pneumonia (OR 0.61, CI 0.42-0.89), non-CMV interstitial pneumonia (OR 0.57, CI 0.35-0.95) and total mortality (OR 0.74, CI 0.55-0.99). The reduction in acute GVHD was not quite significant (OR CI 0.45-1.02). Complications decrease with both hyperimmune and conventional immune globulin. For CMV-negative transplant recipients, immune globulin decreases symptomatic CMV infection (OR 0.55, CI 0.31-0.94) and interstitial pneumonia (OR 0.34, CI 0.15-0.77). For CMV-positive recipients, immune globulin prevents interstitial pneumonia (OR 0.45, CI 0.26-0.80) but not symptomatic CMV infection (CI 0.41-2.80). We conclude that immune globulin is efficacious in preventing major complications of BMT in both CMV-negative and CMV-positive recipients.

View details for Web of Science ID A1993LX82500016

View details for PubMedID 8241987

We examined 82 surgically resected or biopsied, formalin-fixed, paraffin-embedded primary adenocarcinomas of the pancreas for the presence of activating point mutations in codon 12 of the K-ras oncogene. Mutations were detected using primer-mediated, mutant-enriched, polymerase chain reaction-restriction fragment length polymorphism analysis and characterized further by allele-specific oligonucleotide hybridization. This combination of mutant-enriched polymerase chain reaction-restriction fragment length polymorphism analysis and allele-specific oligonucleotide hybridization results in a rapid and sensitive characterization of the mutations in codon 12 of K-ras. Sixty-eight (83%) of the 82 carcinomas examined harbored a point mutation. Of the 68 mutations, 33 (49%) were guanine to adenine transitions, 27 (39%) were guanine to thymine transversions, and eight (12%) were guanine to cytosine transversions. Mutations were found in carcinomas of the head (61 of 75, 81%) as well as in carcinomas of the body or tail (seven of seven, 100%) of the pancreas. The overall prevalence of K-ras point mutations in adenocarcinomas of the pancreas obtained from patients who smoked cigarettes at some point during their lives (88%; 86% in current smokers and 89% in ex-smokers) was greater than that seen in pancreatic adenocarcinomas from patients who never smoked cigarettes (68%, P = 0.046). The presence of K-ras point mutations did not correlate with tumor ploidy, tumor proliferating index, or patient survival. These results demonstrate that primer-mediated, mutant-enriched polymerase chain reaction-restriction fragment length polymorphism analysis combined with allele-specific oligonucleotide hybridization can be used to detect and characterize mutations in codon 12 of the K-ras oncogene in formalin-fixed, paraffin-embedded tissues, and the results confirm that activating point mutations in codon 12 of the K-ras oncogene occur frequently in adenocarcinomas of the pancreas.

View details for Web of Science ID A1993LQ67500025

View details for PubMedID 8342602

Point mutations in codon 12 of the K-ras protooncogene occur more frequently in lung adenocarcinomas from smokers (30%) than they do in lung adenocarcinomas from nonsmokers (7%), suggesting that smoking is an important factor in the induction of these mutations. The lack of well defined "early" premalignant or in situ glandular neoplasms of the lung, however, has not permitted direct evaluation of the chronology of ras activation in the development of lung adenocarcinomas. To circumvent the need to evaluate precursor lesions, we examined lung adenocarcinomas from former smokers for point mutations in K-ras.Mutations in codon 12 of K-ras were detected using polymerase chain reaction amplification and mutation-specific oligonucleotide probes. The types and frequencies of mutations found in adenocarcinomas obtained from 57 former smokers were compared to those found in 27 adenocarcinomas from patients who never smoked and to those found in 27 adenocarcinomas from patients who were current smokers.The overall prevalence of K-ras point mutations in lung adenocarcinomas obtained from former smokers (32%) was not different from that seen in adenocarcinomas from patients who were current smokers (30%, P = 0.83), and was greater than that seen in adenocarcinomas from patients who never smoked (7%, P = 0.015). This pattern was independent of the duration of abstinence from smoking. Furthermore, the predominant type of mutation found in tumors from former smokers was a guanine-to-thymine transversion, the specific type of mutation induced by benzo(a)pyrene, one of the chemical carcinogens found in tobacco smoke.These findings support previous findings that suggest that codon 12 of the K-ras oncogene may be a specific target of the mutagenic activity of tobacco smoke, and suggest that DNA alterations at this site can occur early and irreversibly during the development of adenocarcinomas of the lung.

View details for Web of Science ID A1993LL90500018

View details for PubMedID 8319174

Mutations in the p53 tumor suppressor gene are frequently observed in primary lung adenocarcinomas, suggesting that these mutations are critical events in the malignant transformation of airway cells. These mutations are often associated with stabilization of the p53 gene product, resulting in the accumulation of p53 protein. In this study, 70 formalin-fixed, paraffin-embedded primary lung adenocarcinomas resected for potential cure were examined for p53 overexpression. These 70 lung adenocarcinomas were obtained from a series of patients with well-documented clinical histories, and all 70 carcinomas had been previously evaluated for point mutations in codon 12 of the K-ras oncogene. Overexpression of the p53 protein was detected using an antigen retrieval system (Target Unmasking Fluid) and the anti-p53 antibody CM-1. CM-1 is a polyclonal antibody directed against the wild-type p53 protein. Overexpression of the p53 protein was found in 23 (33%) of the 70 lung adenocarcinomas. In all 23 cases, overexpression was confined to neoplastic cells. Overexpression of the p53 protein correlated with cigarette smoking: 10 (56%) of the 18 adenocarcinomas from patients who were current smokers overexpressed p53 compared with 13 (33%) of the 40 adenocarcinomas from patients who had quit smoking and 0 (0%) of the 12 adenocarcinomas from patients who had never smoked (p = 0.002, trend test). Overexpression of the p53 protein was also related to the degree of histologic differentiation: 48% of the p53 negative carcinomas were well differentiated, whereas only 13% (p = 0.003) of the carcinomas in which p53 was overexpressed were well differentiated. Overexpression of the p53 protein did not correlate with point mutations in codon 12 of the K-ras oncogene, nor did it correlate with tumor stage or patient survival. These findings indicate that p53 protein is frequently overexpressed in primary lung adenocarcinomas. Furthermore, the association of tobacco smoking with this overexpression suggests that the p53 gene is a target of specific mutagens in tobacco smoke.

View details for Web of Science ID A1993KN93700001

View details for PubMedID 8434702

Neuroblastoma is one of the most common malignant neoplasms in children under age 5 years. Little progress has been made in the prognosis of advanced stage disease in the past three decades. Since the development in the 1960s of a simple urine test to detect neuroblastoma metabolites, there has been hope that mortality from this disease could be reduced by early detection via mass screening of young infants. Encouraging reports from Japan on mass screening programs instituted in the 1970s have been appearing in the medical literature since 1982, resulting in widespread interest in screening. This article applies standard epidemiologic criteria for screening evaluations to the Japanese reports. We find that the data needed to definitively assess the value of screening were not a part of those reports and that the benefits claimed from the reported data could be due to overdiagnosis. In addition, the most recent Japanese data, combined with recent advances in biologic understanding of neuroblastoma, show that screening at age 6 months may not detect tumors with poor prognoses. Even if it could, it is uncertain whether those outcomes could be substantially altered by earlier diagnosis. Although a final verdict on the value of neuroblastoma screening is not yet possible, these neuroblastoma studies are an excellent example of how screening results must be viewed with extreme caution in the absence of age-specific, population-based incidence and mortality rates.

View details for Web of Science ID A1991GZ35000019

View details for PubMedID 1669671

Although gastric cancer incidence is decreasing in the western world, it remains an important cause of death, and there has been debate about screening persons who have undergone gastrectomy for benign ulcers. The authors analyzed risk factors for stomach cancer mortality in an Amsterdam cohort of 2,633 postgastrectomy patients, followed from their initial surgery between 1931 and 1960 until 1975, with 99.7% complete follow-up. Increased stomach cancer mortality was observed in the study population (compared with the general Dutch population) among males 25 years or more after surgery (observed/expected, 5.0; 95% confidence interval (Cl) 2.8-8.3), and among females 15-24 years postoperatively (observed/expected, 3.5; 95% Cl 1.0-9.0). A multivariate Poisson regression analysis showed that after control for age at time of surgery and calendar year of operation, the most important risk factors were time since surgery (0-4 years, relative risk (RR) = 1.0; 5-14 years, RR = 4.1, 95% Cl 0.93-18.5; 15-24 years, RR = 9.4, 95% Cl 2.1-42.3; and 25-46 years, RR = 55.6, 95% Cl 11.7-265.4) and ulcer location (gastric versus duodenal ulcer, RR = 2.6, 95% Cl 1.4-4.8). Surveillance for postgastrectomy cancer could be considered 15-25 years after a patient undergoes surgery for gastric ulcer disease.

View details for Web of Science ID A1991FX66900002

View details for PubMedID 1853856

To determine whether dilated cardiomyopathy, myocarditis or cardiac transplantation affect the relation between plasma immunoreactive atrial natriuretic factor (ANF) and cardiac filling pressures, right atrial plasma ANF concentration, pulmonary arterial wedge pressure and right atrial pressure were measured in patients with dilated cardiomyopathy (n = 48), dilated cardiomyopathy secondary to myocarditis (n = 20) and prior cardiac transplantation (n = 34). ANF level significantly correlated with both pulmonary arterial wedge and right atrial pressures in patients with dilated cardiomyopathy; however, the presence or absence of myocarditis did not significantly alter these relations (p = 0.88 and p = 0.33 for interaction terms, respectively). For the combined group the ANF-pulmonary arterial wedge pressure relation had a slope of 8.1 pg/ml/mm Hg (95% confidence interval (CI), 5.4 to 10.8; p = 0.0001) and the ANF-right atrial pressure relation a slope of 13.6 pg/ml/mm Hg (CI, 8.5 to 18.7; p = 0.0001). Receiver operator curve analysis identified an optimal dividing point of ANF 150 pg/ml with 100% (CI, 72 to 100%) of patients with right atrial pressure greater than or equal to 8 mm Hg having ANF greater than or equal to 150 pg/ml, but only 56% (CI, 42 to 69%) with pressure less than 8 mm Hg having ANF less than 150 pg/ml. Unlike the patients with cardiomyopathy (with or without myocarditis), cardiac transplant recipients displayed no correlation between ANF level and either pulmonary arterial wedge pressure (p = 0.50) or right atrial pressure (p = 0.29) despite similarly elevated ANF concentrations (mean +/- standard deviation 168 (83) pg/ml in transplant patients versus 185 (114) pg/ml in cardiomyopathy patients). It is concluded that left and right intracardiac pressures are important determinants of circulating ANF level unaffected by inflammation in patients with cardiomyopathy.(ABSTRACT TRUNCATED AT 250 WORDS)

View details for Web of Science ID A1991EX48700011

View details for PubMedID 1825259

View details for Web of Science ID A1991EV33900014

View details for PubMedID 1984750

We have developed a flow cytometric assay for the determination of cellular expression of terminal deoxynucleotidyl transferase (TdT) and applied this to the detection of minimal residual T cell acute lymphoblastic leukemia (T-ALL). The flow cytometric assay for TdT demonstrated requisite specificity: TdT was localized to the nucleus, and was detected in MOLT3 T lymphoblasts, clinical T-ALL samples, and normal bone marrow B lymphoid precursors, but in neither the KG1a myeloid leukemia cell line nor normal myeloid cells. Co-expression of TdT and the pan T cell marker CD5 was used to quantify T lymphoblasts. 0.25 +/- 0.13% of normal adult bone marrow CD5+ cells were TdT+; these may represent early T lymphoid precursors. When admixed with normal bone marrow, CD5+TdT+ leukemic cells could be detected above background levels at an added concentration of 0.035% (95% confidence interval 0.028-0.43%). Long term follow-up of a large number of patients will be required to determine the clinical significance of a minimal burden of leukemic cells.

View details for Web of Science ID A1990DZ70000015

View details for PubMedID 1698878

BMDS-PHD - Biomedical Data Science (PhD)

Program overview.

The Biomedical Data Science Program is interdisciplinary and offers instruction and research opportunities leading to MS and PhD degrees in Biomedical Data Science. The program emphasizes research to develop novel computational methods that can advance biomedicine. Students receive training in investigating new approaches to conceptual modeling and developing new algorithms that address challenging problems in the biological sciences and clinical medicine.

Admissions Information

The program can provide flexibility and complement Stanford’s other applied medical research opportunities. Special arrangements may be made for those with unusual needs or those simultaneously enrolled in other degree programs within the university. Similarly, students with prior relevant training may have the curriculum adjusted to eliminate requirements met as part of prior training.

The GRE is not required for admission.

Individuals wishing to prepare themselves for careers as independent researchers in biomedical data science, with applications experience in bioinformatics, clinical informatics, or imaging informatics, should apply for admission to the doctoral program. Graduate Degrees summarizes the university’s basic requirements (residence, dissertation, examination, and so on) for a doctorate.

more coming soon

Gateways to the Laboratory: How an MD-PhD Program Increased the Number of Minority Physician-Scientists

Traditional underrepresented minority (URM) groups (African Americans, Hispanic Americans, Native Americans) remain underrepresented among physician-scientists. To address the dearth of URM physician-scientists, in 1993 the Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program developed a pipeline program, Gateways to the Laboratory (Gateways), which focuses on increasing the breadth and depth of the URM physician-scientist pipeline by offering an all-encompassing summer research training program which mirrors the life of a physician-scientist. This includes hypothesis-driven research and clinical shadowing opportunities, coupled with weekly career development workshops and extensive multitiered mentoring. Among the 245 alumni who had "graduated" from Gateways as of 2013, 88% have pursued or completed advanced degrees. Among these, 74% completed or are pursuing MD, PhD, or MD-PhD degrees; and 17% completed or are pursuing combined MD-PhD degrees, over one-third of whom are enrolled in the Tri-Institutional MD-PhD Program. Gateways outcomes are compared to other programs with similar missions, which shows that Gateways has been successful at preparing URMs for MD-PhD Programs. The program serves as a model for how to increase the national pool of competitive URM MD-PhD applicants.

More Publications

A novel patient recruitment strategy: patient selection directly from the community through linkage to clinical data, spirituality in hospice care : how staff and volunteers can support the dying and their families, progress and possibility.

• Courtney Wusthoff, MD

Professor of Neurology (Pediatric Neurology) and, by courtesy, of Pediatrics (Neonatology)

• Print Profile
• Email Profile
• https://med.stanford.edu/wusthoff-lab.html

Academic Appointments

• Professor - University Medical Line, Neurology
• Professor - University Medical Line (By courtesy), Pediatrics - Neonatal and Developmental Medicine
• Member, Bio-X
• Member, Maternal & Child Health Research Institute (MCHRI)
• Member, Wu Tsai Neurosciences Institute

Administrative Appointments

• Director of Neurocritical Care, Lucile Packard Children's Hospital Stanford (2019 - Present)
• Neurology Director, LPCH Neuro NICU, Lucile Packard Children's Hospital (2013 - Present)

Professional Education

• Board Certification: American Board of Psychiatry and Neurology, Neurology with Special Qualifications in Child Neurology (2009)
• Internship: Children's Hospital of Oakland (2006) CA
• Medical Education: University of California at San Francisco School of Medicine (2004) CA
• Fellowship: Children's Hospital of Philadelphia Child Neurology (2010) PA
• Board Certification: American Board of Psychiatry and Neurology, Epilepsy (2014)
• Board Certification: American Board of Pediatrics, Pediatrics (2009)
• Residency: Children's Hospital of Oakland (2009) CA
• Clinical (Primary) This is the primary clinic for this clinical provider. For additional clinical locations and information, please visit the link(s) listed below in the 'Additional Clinical Info' section. Child Neurology 730 Welch Rd Ste 206 Palo Alto CA 94304 Tel: (650) 723-0993 Fax: (650) 721-6350
• Stanford Medicine Children's Health
• Get a Second Opinion

Current Research and Scholarly Interests

My projects focus on clinical research in newborns with, or at risk, for brain injury. I use EEG in at-risk neonates to better understand the underlying pathophysiology of risk factors that may lead to worse outcomes. I am particularly interested in neonatal seizures and how they may exacerbate perinatal brain injury with a goal to identify treatments that might protect the vulnerable brain. I am also interested in EEG in other pediatric populations, as well as medical ethics and global health.

Clinical Trials

Neonatal Seizure Registry - Developmental Functional EValuation Recruiting

The NSR-DEV study is a longitudinal cohort study of around 280 Neonatal Seizure Registry participants that aims to evaluate childhood outcomes after acute symptomatic neonatal seizures, as well as examine risk factors for developmental disabilities and whether these are modified by parent well-being.

Lead Sponsor

Stanford investigators.

  View full details

High-dose Erythropoietin for Asphyxia and Encephalopathy Not Recruiting

Hypoxic-ischemic encephalopathy (HIE) occurs when a baby gets reduced blood flow and oxygen to the brain near the time of birth. This results in death or neurologic disabilities including cerebral palsy and cognitive impairment in up to half of affected infants. This clinical trial will determine if the drug erythropoietin (Epo) added to hypothermia (usual therapy) will improve outcomes for infants suffering from HIE.

Stanford is currently not accepting patients for this trial. For more information, please contact SPECTRUM, .

• Susan R. Hintz, M.D., M.S. Epi.

2023-24 Courses

• Directed Reading in Neurology and Neurological Science NENS 299 (Win, Spr)
• Directed Reading in Pediatrics PEDS 299 (Win, Spr)
• Early Clinical Experience PEDS 280 (Win, Spr)
• Early Clinical Experience in Neurology and Neurological Sciences NENS 280 (Win, Spr)
• Graduate Research NENS 399 (Win, Spr)
• Graduate Research PEDS 399 (Win, Spr)
• Medical Scholars Research NENS 370 (Aut, Win, Spr, Sum)
• Medical Scholars Research PEDS 370 (Win, Spr)
• Undergraduate Directed Reading/Research PEDS 199 (Win, Spr)
• Undergraduate Research NENS 199 (Win, Spr)

All Publications

Publications (117).

• All Publications (117)
• Featured Publications (1)
• Journal Articles (113)
• Conference Proceedings (4)

Profiles With Related Publications

Kanwaljeet S. Anand

Professor of pediatrics (pediatric critical care) and of anesthesiology, perioperative and pain medicine.

Justin Nathaniel Baker

Deborah e. addicott - john a. kriewall and elizabeth a. haehl family professor of pediatrics.

Patrick Barnes

Professor of radiology (pediatric radiology) at the stanford university medical center, emeritus.

Sonia Bonifacio

Clinical professor, pediatrics - neonatal and developmental medicine.

Valerie Chock

Professor of pediatrics (neonatology) and, by courtesy, of obstetrics and gynecology (maternal fetal medicine).

Atman Desai, MD

Clinical professor, neurosurgery.

Heidi M. Feldman

Ballinger-swindells endowed professor of developmental and behavioral pediatrics.

Robert Fisher, MD, PhD

The maslah saul, md, professor and professor, by courtesy, of neurosurgery.

Professor of Statistics and of Computer Science

Gary Glover

Professor of radiology (radiological sciences lab) and, by courtesy, of psychology and of electrical engineering.

Jin S. Hahn, MD

Professor of neurology at the stanford university medical center, emeritus.

Corey Keller, MD, PhD

Assistant professor of psychiatry and behavioral sciences (public mental health and population sciences), publication topics for this person.

• Anticonvulsants
• Brain Diseases
• Brain Mapping
• Cerebral Cortex
• Child, Preschool
• Electroencephalography
• Follow-Up Studies
• Genetic Testing
• Hypothermia, Induced
• Hypoxia-Ischemia, Brain
• Infant, Newborn
• Infant, Premature
• Intelligence Tests
• Magnetic Resonance Imaging
• Monitoring, Physiologic
• Neurophysiology
• Predictive Value of Tests
• Prospective Studies
• Retrospective Studies
• Risk Factors
• Spasms, Infantile
• Status Epilepticus
• Time Factors
• Treatment Outcome

• Student Housing Operations
• Stanford Conferences
• Stanford Dining, Hospitality & Auxiliaries
• Maintenance Operations & Capital Projects
• Finance & Administration
• Human Resources
• Information Technology
• Strategic Communications & Marketing
• R&DE Calendar
• Capital Projects
• Diversity, Equity, Inclusion & Belonging
• Sustainability Accomplishments and News
• Sustainability Awards
• Sustainability by R&DE Division
• Sustainable Food in R&DE
• Sustainability Interns
• Sustainable Living
• Living in Housing Overview
• Residence Agreement
• Housing Service Centers
• Preparing to Move In
• Now You're Home
• Dining Options
• Mail & Deliveries
• Sublicensing in Graduate Housing
• Stanford Guest House

Hello, we see you are using Firefox to view this website. In order to view background videos on several pages, please enable "Autoplay" for this site.

To do so, click the Autoplay icon right next to the field for entering website addresses, and select "Allow Audio and Video" (see screenshot above).

This will allow this site to play all background videos, but will not affect any other websites. You will need to refresh your browser for the setting to take effect.

Once you dismiss this message, it will not be shown again.

General Housing Statistics

Approximately 4,825 graduate students live in on-campus housing and about 1,138 are assigned to subsidized off-campus apartments this year.

Assignment Round Statistics

Statistics will be added throughout the year as the assignment rounds are completed.

  View historical graduate housing assignment statistics.

2023-24 First Round Summer Quarter Assignment Results

Overall first-round summer quarter statistics.

In the 2023-24 first round of the Graduate Housing summer assignments, there were a total of 502 students who applied for Graduate Housing. After the first round, there were a total of 18 unassigned students (1 single graduate student, 12 couples without children, and 5 students with children). For more details, see below.

2023-24 Spring Rolling Assignment Results

2023-24 first round spring quarter assignment results, overall first-round spring quarter statistics.

In the 2023-24 first round of the Graduate Housing spring assignments, there were a total of 103 students who applied for Graduate Housing. After the first round, there were a total of 15 unassigned students (1 new students with high priority, 4 continuing doctoral students with medium priority, 1 second year master's student with low priority, and 9 non-matriculated students). For more details, see below.

All Graduate Students

By housing category, 2023-24 winter rolling assignment results, 2023-24 first round winter quarter assignment results, overall first-round winter quarter statistics.

In the 2023-24 first round of the Graduate Housing winter assignments, there were a total of 228 students who applied for Graduate Housing. After the first round, there were a total of 44 unassigned students (3 new students with high priority, 5 continuing doctoral students with medium priority, 2 second year master's student with low priority, 1 continuing students without priority and 33 non-matriculated students). For more details, see below.

2023-24 Autumn Rolling Assignment Results

2023-24 second round autumn quarter assignment results, overall second-round lottery statistics.

In the second-round 2023-24 Lottery, there were a total of 364 students who applied for Graduate Housing and 585 who applied for reassignment. After the second round, there were a total of 164 unassigned students (23 new students, 36 continuing doctoral students with medium priority, 58 continuing students with low priority and 47 continuing students without priority years). For more details, see below.

All Graduate Students Seeking Assignment

Student seeking assignment by housing category, student seeking reassignment by housing category.

*Non-matriculated students were not eligible to apply for graduate housing in the Second Round Lottery for Single Graduate and Couples Without Children housing.

2023-24 First Round Autumn Quarter Lottery Assignment Results

Overall First-Round Lottery Statistics

In the 2023-24 Lottery, there were a total of 7,142 students who applied for Graduate Housing. After the first round, there were a total of 294 unassigned students (24 new students, 64 continuing doctoral students with medium priority, 108 continuing students with low priority and 98 continuing students without priority years). For more details, see below.

*Non-matriculated students were not eligible to apply for graduate housing in the First Round Lottery for Single Graduate and Couples Without Children housing.

Historical Graduate Housing Assignment Statistics

2022-23 Graduate Housing Statistics

2021-22 Graduate Housing Statistics

2020-21 Graduate Housing Statistics

2019-20 Graduate Housing Statistics

2018-19 Graduate Housing Statistics

2017-18 Graduate Housing Statistics

2016-17 Graduate Housing Statistics

2015-16 Graduate Housing Statistics

2014-15 Graduate Housing Statistics

2013-14 Graduate Housing Statistics

2012-13 Graduate Housing Statistics

2011-12 Graduate Housing Statistics

Along with Stanford news and stories, show me:

• Student information
• Faculty/Staff information

We want to provide announcements, events, leadership messages and resources that are relevant to you. Your selection is stored in a browser cookie which you can remove at any time using “Clear all personalization” below.

• A seminar series convened humanities scholars across disciplines to discuss the pervasive nature of data and explore its place in the humanities.
• The next seminar takes place on May 30 and will address what digitization means for the study of antiquity.
• The series will conclude with a symposium on Friday, May 31, from 9 a.m. to 5 p.m. at Wallenberg Hall.

In today’s digital age, data is everywhere. From our smartphones to our voting behaviors, the sheer amount of data generated and collected today is unprecedented.

This data holds the power to reveal profound insights about our world, yet it also raises many questions: What biases influence particular data sets? How do we assign authentic and accurate meaning to data? What are its social and political implications? Where should it be stored, and who should own it? 

These and many other questions are the focus of a year-long seminar series titled “The Data that Divides Us: Recalibrating Data Methods for New Knowledge Frameworks Across the Humanities.” Supported by the Andrew W. Mellon Foundation Sawyer Seminar award and hosted by the Center for Spatial and Textual Analysis (CESTA), the series convenes humanities scholars across disciplines to discuss the pervasive nature of data and to explore its place in the humanities.

“This series is a venue that allows humanists to bring the conversation around data more cogently together across different humanities fields and in relation to data science,” said Giovanna Ceserani, associate professor of classics in the School of Humanities and Sciences , CESTA faculty director, and one of the faculty leads of the series. 

The next seminar will take place on May 30, followed by a symposium on May 31. 

Humanists and data

While data is often associated with the work of engineers, mathematicians, and data scientists, humanities scholars argue that much can be lost when a subject – such as historical events, demographics, or human behaviors – is analyzed strictly by the numbers it produces.

If we start to understand the world only in terms of data, we may lose the more complex interpretations that come with a traditional humanistic inquiry.” Giovanna Ceserani Associate Professor of Classics

“If we start to understand the world only in terms of data, we may lose the more complex interpretations that come with a traditional humanistic inquiry,” Ceserani said.

Humanities scholarship can analyze subjects and their data through unique lenses, producing novel insights. In the first seminar, “The Place of Data,” scholars Alan Liu and Roopika Risam explored how data can reflect or cause modern social divisions. Their research analyzes data related to geography, race, and gender, examining how this information intersects with social divisions and how data can address these issues.

In another seminar titled “Catastrophe, Data, and Transformation,” historian Jessica Otis discussed her NSF-funded project Death by Numbers . This project involved transcribing, publishing, and analyzing London’s mortality statistics to understand how the lived experiences of plague outbreaks intersected with the mentality of early modern England, while Dagomar Degroot discussed modern climate data.

The fifth part of the series featured Marlene Daut, a professor of French and African American studies at Yale University, in a seminar called “Recuperating Forgotten Narratives,” which explored what happens to text when it is digitized and turned into data.

Daut discussed her work to collect and digitize early 19th-century Haitian print media, such as old newspaper articles and other rare or inaccessible materials, documenting Haiti around the time of the country’s revolution. By making such documents accessible online, she found they often contradicted conventional portrayals of Haiti or corrected false narratives about, for example, France’s involvement in slavery there. She also found that Haitians visiting the site were using it to identify relatives for genealogical research.

“The papers [and] the almanacs contained all these names, and so people are using this digital archive the way that they use municipal archives and physical archives, which is to help complete their family trees,” Daut said.

Discussion of the significance of data for family tree research continued in the following seminar, “The Data of Enslavement,” presented by historians Greg O’Malley and Alex Borucki. They shared their project of the Intra-American Slave Trade Database , an online research tool that documents more than 35,000 slave trading voyages from one port in the Americas to another. In related seminars, scholar Lauren Klein discussed different ethical approaches to the data of the slave trade illustrating how visual choices can humanize the stories data tells, and scholar Ayesha Hardison discussed her work collecting and preserving thousands of novels and other texts by Black authors. 

Approaches to data

Data scientists often acquire a large data set from a particular source, then organize and analyze it. Humanities research tends to be more selective, explained Chloé Brault, a Stanford PhD candidate in comparative literature.

“We’re often in the practice of creating our own data,” she said. “For example, that might look like a literary scholar selecting 100 novels to analyze.”

Brault, who is a Mellon Sawyer dissertation fellow, is working on a dissertation investigating the literary production of 1970s Montreal. Using computational tools and carefully selected texts, she measures how literary language changed, or remained the same, between the 1970s and 2020s. 

Ceserani said that asking “ What is the place of data in our work? ” forces humanists to look at the objects they study differently and more critically.

“It forces us to ask questions of data scientists, of their received sources, and their evidence, and to clarify what rises to the status of evidence in their inquiries,” she said. "It also forces us to enter into productive conversations with data scientists, and ask questions of their received data sources." 

Upcoming events

The final seminar is titled “ Ancient Data and Its Divisions ” and presented by Chiara Palladino, assistant professor of classics at Furman University, Eric Harvey, a researcher collaborating with CESTA, and Chris Johanson, associate professor of classics and digital humanities at the University of California, Los Angeles. It will take place Thursday, May 30, from 5:30 to 7 p.m. at Wallenberg Hall. 

The Mellon Sawyer Seminar Series will conclude with a symposium on Friday, May 31, from 9 a.m. to 5 p.m. at Wallenberg Hall. In addition to Ceserani, the faculty PIs for the series are Mark Algee-Hewitt , associate professor of English and digital humanities, Grant Parker , associate professor of classics and African and African American studies, and Laura Stokes , associate professor of history. The series also supports Mellon Sawyer graduate dissertation fellow Matthew Warner, a PhD candidate in English, and postdoctoral scholar Dr. Nichole Nomura, who studies 20th-century American literature and digital humanities. 

In addition to CESTA, the series and symposium are supported by the Stanford Humanities Center (SHC) and the Dean’s Office of the School of Humanities and Sciences.

For more information

Alan Liu is a professor of English at the University of California, Santa Barbara; Roopika Risam is a professor of film and media studies and of comparative literature at Dartmouth College; Jessica Otis is an assistant professor of history at George Mason University; Dagomar Degroot, an associate professor of environmental history at Georgetown University; Greg O’Malley is a professor of history at the University of California, Santa Cruz; Alex Borucki is a professor of history at the University of California, Irvine; Lauren Klein, a professor of quantitative theory and methods and of English at Emory University; and Ayesha Hardison is an associate professor of English and of women, gender, and sexuality studies at the University of Kansas.

• See us on twitter
• See us on facebook
• See us on youtube
• See us on linkedin

Dr. Korah Joins Stem Cell Biology PhD Program

May 30, 2023.

Dr. Maria Korah

General Surgery Resident Dr. Maria Korah has been admitted to Stanford’s Stem Cell Biology PhD Program.

“I have been fascinated by translational basic science research and how impactful it can be in advancing patient care,” said Korah. Graduate education will allow me the rigorous training I will need for conducting hypothesis-driven independent research.”

Korah says she became interested in regenerative medicine and stem cell biology through her research in Dr. Kevan Herold’s lab while she was a medical student at Yale.

“I had the opportunity to study autoimmune diabetes, a condition where pancreatic beta cells are destroyed through an autoimmune process,” said Korah. “I was really awestruck by this concept and the broad implications it has in a wide array of disciplines, and I feel really grateful to be able to immerse myself in this field further.”

Korah will be conducting research under the mentorship of Dr. Michael Longaker and Dr. Dan Delitto, and working on projects aimed at advancing patient care through translational basic research in the field of wound healing and fibrosis.

Korah will take a break from her clinical duties to participate in the PhD program.

“[Completing a] PhD can take several years to complete and the timing is very dependent on your personal progression,” said Korah. “It really is structured around your own mastery of the field you are studying, which is both thrilling and terrifying!”

Media Contact

About Stanford Surgery

The Stanford University Department of Surgery is dedicated to inventing the future of surgical care through:

• pioneering cutting-edge research,  • developing the next generation of leaders, and  • healing through incomparable surgical skills and compassion. 

To learn more, please visit surgery.stanford.edu

2024 Class of Presidential Leadership Scholars Announced

Ninth annual class comprised of 60 accomplished leaders including servicemembers, educators, public servants, corporate professionals and physicians -- including our own Dr. Stephanie Chao.

The SUS is Pleased to Honor the 2023 SUS Trailblazer Award Winner: Carla Pugh, MD, PhD - Society of University Surgeons (SUS)

The Society of University Surgeons (SUS) has awarded Carla Pugh, MD, PhD, Thomas Krummel Professor of Surgery at Stanford Medicine and Director of the Technology Enabled Clinical Improvement (T.E.C.I.) Center, the 2023 SUS Trailblazer Award. Dr. Pugh will be presented with the Trailblazer Award by SUS President Dr. Timothy Donahue on Tuesday, February 6, 2024, […]

Dr. Sorondo wins VESS Resident Research Award

Vascular Surgery Resident Dr. Sabina Sorondo received the 2024 VESS Resident Research Award from the Vascular and Endovascular Surgery Society for her project entitled “Assessing Soluble Guanylate Cyclase Stimulators in PAD.”

Inside ASRM2024: Stanford Plastic Surgery Recap

The American Society for Reconstructive Microsurgery held its 2024 meeting in Nassau, Bahamas

Global Engagement supports first-of-its-kind workshop in Ethiopia

The Division of Plastic and Reconstructive Surgery at Stanford, jointly with ReSurge International, lead a groundbreaking workshop from November 29 to December 1, 2023, at ALERT Hospital in Addis Ababa, Ethiopia. The project, entitled "Validating a Scalable Approach to Microsurgery Education in Resource-Limited Countries,” was supported by Stanford Surgery’s Global Engagement Program.

Spotlight: Dung Nguyen

Dr. Dung Nguyen is the Director of Breast Reconstruction and the Associate Director of Microsurgery in the Division of Plastic Surgery at Stanford Medicine. She has participated in numerous international teaching and medical mission trips.

Coronavirus (COVID-19): Latest Updates | Visitation Policies Visitation Policies Visitation Policies Visitation Policies Visitation Policies | COVID-19 Testing | Vaccine Information Vaccine Information Vaccine Information

2023/2024 PhD Recipients Thesis Titles

2022-2023 PhD Thesis Titles    2021-2022 PhD Thesis Titles    2020-2021 PhD Thesis Titles   

2018-2019 PhD Thesis Titles    2017-2018 PhD Thesis Titles    2019-2020 PhD Thesis Titles   

2018-2019 PhD Thesis Titles    2017-2018 PhD Thesis Titles    2016-2017 PhD Thesis Titles  

2015-2016 PhD Thesis Titles    2013-2014 PhD Thesis Titles    2012-2013 PhD Thesis Titles   

2011-2012 PhD Thesis Titles  

Candidates for the Degree Doctor of Philosophy

Solomon abiola, b.s. princeton university, m.s. carnegie mellon university; translational biomedical science.

Thesis: The Rise of Temperature and Fall of Fever: A 21st-Century Translational Science Approach to Infectious Disease Forecast using Machine Learning Transformers, mHealth Application Node and Wearable Device Edge

Advisor: Dr. Benjamin Miller  

Sara Ali, B.S. Rochester Institute Of Technology, M.S. University of Rochester; Biophysics

Thesis: A Bioinformatics Pipeline for Identifying Structurally Conserved ncRNAs: From Prediction to Validation

Advisor: Dr. David Mathews  

Naemah Alkhars, B.S. Kuwait University, M.S. University of Rochester; Translational Biomedical Science

Thesis: Three-dimensional Maternal influence on Children at High Risk of Severe Early Childhood

Advisor: Dr. Jin Xiao  

Katherine Andersh, B.S. University Of Arizona, M.S. University of Rochester; Neuroscience

Thesis: The role of proinflammatory cytokines in glaucomatous neurodegeneration

Advisor: Dr. Richard Libby  

Uday Baliga, B.S. Colorado State University, M.S. University of Rochester; Pathology

Thesis: Gene Delivery:  Multigenic approaches

Advisor: Dr. David Dean  

Sara Blick-Nitko, B.S. Rochester Institute of Technology, M.S. University of Rochester; Pathology

Thesis: Platelet Ido1 in Plasmodium yoelii Uncomplicated Malaria Infection

Advisor: Dr. Craig Morrell  

Zachary Brehm, B.M. SUNY College Potsdam, M.S. SUNY College Potsdam; Statistics

Thesis: Statistical Methods for the Analysis of Complex Tissue Bulk RNA-seq Data

Advisor: Dr. Matthew McCall  

Tina Bui-Bullock, B.S. The University Of Texas At Austin, M.S. University of Rochester; Microbiology and Immunology

Thesis: Elucidating Host Factors That Modulate Staphylococcus aureus Osteomyelitis Severity in Obesity-Related Type 2 Diabetes

Advisor: Dr. Steven Gill  

Kimberly Burgos Villar, B.A. Daemen College, M.S. University of Rochester; Pathology

Thesis: Expression and Function of SPRR1A, a Novel Marker of the Ischemic Cardiac Border Zone

Advisor: Dr. Eric Small  

Wesley Chiang, B.S. University Of California-Irvine, M.S. University of Rochester; Biophysics

Thesis: Nano for Neuro: Developing Hybrid Quantum Dot Nano-Bio Assemblies to Probe Neuroinflammatory Activation

Advisor: Dr. Todd Krauss  

Jessica Ciesla, B.S. SUNY College of Environmental Science and Forestry, M.S. University of Rochester; Biochemistry

Thesis: Mechanisms Through Which Metabolism and the Human Cytomegalovirus UL26 Protein Contribute to Anti-Viral Signaling

Advisor: Dr. Joshua Munger  

Martin Cole, B.E. The Open University, M.S. University of Rochester; Statistics

Thesis: Scratching the Surface: Surface-Based Cortical Registration and Analysis of Connectivity Functions

Advisor: Dr. Xing Qiu  

Luke Duttweiler, B.A. Houghton College, M.A. SUNY Brockport, M.A. University of Rochester; Statistics

Thesis: Spectral Bayesian Network Theory: Graph Theoretic Solutions to Problems in Bayesian Networks

Advisor: Dr. Sally Thurston and Dr. Anthony Almudevar  

Esraa Furati, M.B.B.S. University of Dammam, M.S. University of Rochester; Pharmacology

Thesis: Insights into the Roles of Aging and Chemokine Signaling During Neuromuscular Regeneration

Advisor: Dr. Joe Chakkalakal

Erin Gibbons, B.S. University Of Connecticut, M.S. University of Rochester; Microbiology and Immunology

Thesis: Investigation of mTORC1-mediated genes Neutrophil Elastase and Glycoprotein-NMB  Demonstrates Tumor Promotion and GPNMB as a Serum Biomarker for  Lymphangioleiomyomatosis (LAM)

Advisor: Dr. Stephen Hammes  

Christie Gilbert Klaczko, B.S. SUNY College of Environmental Science and Forestry; Translational Biomedical Science

Thesis: Oral Cross-kingdom Bacterial-fungal Interactions in a Cross-sectional Pregnant Population Living in Low Socioeconomic Status in Rochester, New York

Jimin Han, B.S. Duquesne University, M.S. University of Rochester; Pathology

Thesis: Investigating the role of CLN3 in retinal pigment epithelium dysfunction in CLN3-Batten

Advisor: Dr. Ruchira Singh  

Jarreau Harrison, B.S. CUNY Medgar Evers College, M.S. University of Rochester; Pharmacology

Thesis: HSPB8 Attenuates Pathological Tau Accumulation

Advisor: Dr. Gail Johnson  

Alicia Healey, B.S. Simmons College, M.S. University of Rochester; Microbiology and Immunology

Thesis:Aryl hydrocarbon receptor activation modulates monocytic cell responses during respiratory viral infection

Advisor: Dr. B. Paige Lawrence  

Omar Hedaya, B.S. Kuwait University, M.S. University of Rochester; Biochemistry

Thesis: uORF-mediated Translational Regulation of GATA4 in the Heart

Advisor: Dr. Peng Yao  

Emma House, B.S. Wayne State University, M.S. University of Rochester; Pathology

Thesis: Investigating the Role of CD4+ T Cells in Flavorings-Related Lung Disease

Advisor: Dr. Matthew D. McGraw  

Yechu Hua, B.A. Shanghai Jiao Tong University; Health Services Research and Policy

Thesis: Did Greater Price Transparency of Hospital Care Lower Health Care Costs?

Advisor: Dr. Yue Li  

Feng Jiang, B.S. Wuhan University, M.S. University of Rochester; Biochemistry

Thesis: The Molecular Mechanism and Biological Impact of Cis-acting Elements and Trans-acting Factors in mRNA Translation Regulation

Amber Kautz, B.S. Cornell University, M.S. Boston University; Epidemiology

Thesis: Maternal Non-Adherence to the Dietary Fat Recommendations During Pregnancy and Neonatal Adiposity and Infant Weight Gain: The Role of Inflammation

Advisor: Dr. Diana Fernandez  

Gabrielle Kosoy, B.S. SUNY College At Geneseo, M.S. University of Rochester; Biophysics

Thesis: Understanding vaccine antibody response: high throughput measurements of equilibrium affinity constants for influenza, cross-reactivity of SARS antibodies, and asthmatic response

Thomas Lamb Jr., B.S. St Josephs College, M.S. University of Rochester; Toxicology

Thesis: Chemical Characterization and Lung Toxicity of Humectants and Flavored E-cigarettes

Advisor: Dr. Irfan Rahman  

Linh Le, B.S. Truman State University, M.S. Truman State University, M.S. University of Rochester; Neuroscience

Thesis: The effects of microglial adrenergic signaling and microglial renewal on Alzheimer’s disease pathology

Advisor: Dr. Ania Majewska  

Jiatong Liu, B.S. Huazhong University of Science and Technology, M.S. University of Rochester; Pathology

Thesis: The Role of Senescent Cells in Aging Fracture Healing

Advisor: Dr. Lianping Xing  

Daniel Lopez, B.A. University Of California-Los Angeles, M.A. Stanford University. MPH Cuny Hunter College; Epidemiology

Thesis: The Neurobiological Correlates of Problematic Gaming Behaviors in Adolescents

Advisor: Dr. Edwin van Wijngaarden  

Ferralita Madere, B.S. Xavier University Of Louisiana, M.S. University of Rochester; Microbiology

Thesis: Elucidating Complex Transkingdom Interactions in the Female Reproductive Tract Microbiome in Health and Disease

Advisor: Dr. Cynthia Monaco  

Courtney Markman, B.S. Rochester Institute Of Technology, M.S. University of Rochester; Pathology

Thesis: The role(s) of JAG1 during Embryonic Cochlear Development

Advisor: Dr. Amy Kiernan  

Andrew Martin, B.S. North Adams State College, M.S. University of Rochester; Microbiology

Thesis: Mechanism and Consequence of IFN--mediated Loss of Tissue Resident Macrophages on Host Immunity to Toxoplasma gondii

Advisor: Dr. Felix Yarovinsky  

Alyssa Merrill, B.S. Nazareth College Of Rochester, M.S. University of Rochester; Toxicology

Thesis: Pregnancy-dependent Cardiometabolic Effects of Anti-estrogenic Endocrine Disrupting Chemicals

Advisor: Dr.Marissa Sobolewski and Dr. Deborah Cory-Slechta  

Briaunna Minor, B.S. Xavier University Of Louisiana, M.S. University of Rochester; Microbiology

Thesis: Implications for Targeting Tumor Associated Neutrophils to Attenuate Estrogen Mediated Lymphangioleiomyomatosis Progression

Mostafa Mohamed, M.S. Alexandria University, M.D. Alexandria University; Epidemiology

Thesis: Association Between Chemotherapy Dosing, Treatment Tolerability, and Survival Among Older Adults with Advanced Cancer

Advisor: Dr. David Rich  

Adrián Moisés Molina Vargas, B.S. University of Alcala, M.S. University of Rochester; Genetics

Thesis: Developing Design Strategies for Efficient and Specific CRISPR Cas13 RNA-Targeting Applications

Advisor: Dr. Mitchell O'Connell  

Teraisa Mullaney, B.S. Rochester Institute Of Technology, M.S Rochester Institute Of Technology, M.S. University of Rochester; Health Services Research and Policy

Thesis: Understanding the Role of Navigation Capital in Health Services and Social Determinants of Health: A Health Capability Explanation

Advisor: Dr. Peter Veazie  

Daxiang Na, B.S. Peking University, M.S. Peking University, M.S. Brandeis University, M.S. University of Rochester; Genetics

Thesis: An Investigation of the Relationship between Auditory Dysfunctions and Alzheimer’s Disease Using Amyloidosis Mouse Models

Advisor: Dr. Patricia White  

Thomas O'Connor, B.S. SUNY University at Buffalo, M.S. University of Rochester; Genetics

Thesis: Adaptive and Protective Responses of Skeletal Muscle to Endurance Exercise in the Context of Aging, Juvenile Radiotherapy, and Tubular Aggregate Myopathy

Advisor: Dr. Robert Dirksen and Dr. James Palis  

Raven Osborn, B.A. University Of Missouri-Columbia; Translational Biomedical Science

Thesis: Single-cell gene regulatory network analysis reveals cell population-specific responses to SARS-CoV-2 infection in lung epithelial cells

Advisor: Dr. Juilee Thakar and Dr. Stephen Dewhurst  

Emily Przysinda, B.A. Skidmore College, M.S. University of Rochester; Neurobiology and Anatomy

Thesis: Social processing and underlying language deficits in schizophrenia during naturalistic video viewing

Advisor: Dr. Edmund Lalor  

Emily Quarato, B.S. University Of Alabama At Birmingham, M.S. University of Rochester; Program

Thesis: High levels of mesenchymal stromal cell efferocytosis induces senescence and causes bone loss

Advisor: Dr. Laura Calvi  

Zahíra Quiñones Tavárez, B.S. Pontificial Catholic University Mother and Teacher, M.P.H. University of Rochester; Translational Biomedical Science

Thesis: Linking Exposure to Flavors in Electronic Cigarettes and Coughing

Advisor: Dr. Deborah Ossip  

Matthew Raymonda, B.S. University Of North Carolina At Wilmington, M.S. University of Rochester; Biochemistry

Thesis: Identifying Metabolic Vulnerabilities Associated with Viral Infections

Savanah Russ, B.A. SUNY Geneseo, M.P.H Yale University; Epidemiology

Thesis: Association Between Community-Level Socioeconomic Status and Spatiotemporal Variation in COVID-19 Vaccine Uptake

Advisor: Dr. Yu Liu  

Cooper Sailer, B.S. University at Buffalo, M.A. University at Buffalo, M.S. University of Rochester; Pathology

Thesis: Characterization of CAR-T cell phenotypes to augment response against solid tumors

Advisor: Dr. Minsoo Kim  

Jishyra Serrano, B.S. Universidad Adventista De Las Antillas; Translational Biomedical Science

Thesis: Prenatal Maternal Stress and Inflammation: Association to Childhood Temperament

Advisor: Dr. Thomas O'Connor  

Yuhang Shi, B.A. Henan Agricultural University, M.S. University of Rochester; Microbiology

Thesis: Interactions Between Viruses and the Innate Antiviral Factors SERINC5, BST2 and BCA2

Advisor: Dr. Ruth Serra-Moreno  

Anjali Sinha, B.E. PES Institute of Technology, M.S. University at Buffalo, M.S. University of Rochester; Neuroscience

Thesis: Role of mAChR signaling and M-current in EVS mediated responses of mammalian vestibular afferents

Advisor: Dr. J. Chris Holt  

Celia Soto, B.S. SUNY Geneseo, M.S. University of Rochester; Pathology

Thesis: Elevated Lactate in Acute Myeloid Leukemia (AML) Bone Marrow Microenvironment Dysfunction

Advisor: Dr. Benjamin Frisch  

Michael Sportiello, B.S. University Of Wisconsin-Milwaukee, M.S. University of Rochester; Microbiology

Thesis: Investigating CD8 T cell tissue resident memory phenotype, function, metabolic activity, and differentiation

Advisor: Dr. David Topham  

Kumari Yoshita Srivastava, B.S. National Institute of Science Education And Research, M.S. National Institute of Science Education And Research, M.S. University of Rochester; Biophysics

Thesis: Structure and Function Analysis of Bacterial Riboswitches that Control Translation

Advisor: Dr. Joseph Wedekind  

Kathryn Toffolo, B.S. SUNY College at Buffalo, M.S. University of Rochester; Neuroscience

Thesis: Semantic Language Processing: Insight into Underlying Circuitry and Development using Neurophysiological and Neuroimaging Methods

Advisor: Dr. John J. Foxe  

Megan Ulbrich, B.S. University Of Pittsburgh, M.S. University of Rochester; Microbiology and Immunology

Thesis: The Activity of Vibrio cholerae Effector VopX Targets Host Cell Pathways that Reorganize the Actin Cytoskeleton

Advisor: Dr. Michelle Dziejman  

Erik Vonkaenel, B.S. Slippery Rock University Of Pennsylvania, M.A. University of Rochester; Statistics

Thesis: Methods for Microglia Image Analysis

Amanda Wahl, B.S. Saint John Fisher College, M.S. University of Rochester; Pharmacology

Thesis: Redefining the function of salivary duct cell populations utilizing a structural, functional, and computational approach

Advisor: Dr. David Yule  

Yunna Xie, B.S. Sichuan University, M.S. Universität Heidelberg; Health Services Research & Policy

Thesis: Is Physician Expertise Working as a Barrier to the Implementation of New Clinical Interventions? A Neural Network Approach

Shen Zhou, B.S. Shanghai University, M.S. Brandeis University, M.S. University of Rochester; Genetics

Thesis: The Study of c-Cbl in Clear Cell Sarcoma

Advisor: Dr. Mark Noble

Back to the top