Benjamini and Hochberg suggest that the false discovery rate may be the appropriate error rate to control in many applied multiple testing problems. A simple procedure was given there as an FDR controlling procedure for independent test statistics and was shown to be much more powerful than comparable procedures which control the traditional familywise error rate. We prove that this same procedure also controls the false discovery rate when the test statistics have positive regression dependency on each of the test statistics corresponding to the true null hypotheses. This condition for positive dependency is general enough to cover many problems of practical interest, including the comparisons of many treatments with a single control, multivariate normal test statistics with positive correlation matrix and multivariate $t$. Furthermore, the test statistics may be discrete, and the tested hypotheses composite without posing special difficulties. For all other forms of dependency, a simple conservative modification of the procedure controls the false discovery rate. Thus the range of problems for which a procedure with proven FDR control can be offered is greatly increased.

/pdf/the-control-of-the-false-discovery-rate-in-multiple-testing-426hrdkyhb.pdf

The control of the false discovery rate in multiple testing under dependency

Jeffrey L. Anderson, MD, FACC, FAHA, Chair 

Jonathan L. Halperin, MD, FACC, FAHA, Chair-Elect 

Nancy M. Albert, PhD, RN, FAHA

Biykem Bozkurt, MD, PhD, FACC, FAHA

Ralph G. Brindis, MD, MPH, MACC

Mark A. Creager, MD, FACC, FAHA[#][1]

Lesley H. Curtis, PhD, FAHA

David DeMets, PhD[#][1]

Robert A

/pdf/2014-aha-acc-hrs-guideline-for-the-management-of-patients-1v8ficsqox.pdf

2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society

Guidelines summarize and evaluate all currently available evidence on a particular issue with the aim of assisting physicians in selecting the best management strategy for an individual patient suffering from a given condition, taking into account the impact on outcome, as well as the risk–benefit ratio of particular diagnostic or therapeutic means. Guidelines are no substitutes for textbooks. The legal implications of medical guidelines have been discussed previously.

A large number of Guidelines have been issued in recent years by the European Society of Cardiology (ESC) as well as by other societies and organizations. Because of the impact on clinical practice, quality criteria for development of guidelines have been established in order to make all decisions transparent to the user. The recommendations for formulating and issuing ESC Guidelines can be found on the ESC Web Site (http://www.escardio.org/guidelines-surveys/esc-guidelines/about/Pages/rules-writing.aspx).

In brief, experts in the field are selected and undertake a comprehensive review of the published evidence for management and/or prevention of a given condition. A critical evaluation of diagnostic and therapeutic procedures is performed, including assessment of the risk–benefit ratio. Estimates of expected health outcomes for larger societies are included, where data exist. The level of evidence and the strength of recommendation of particular treatment options are weighed and graded according to pre-defined scales, as outlined in Tables 1 and 2 .

View this table:

Table 1 
Classes of recommendations



View this table:

Table 2 
Levels of evidence



The experts of the writing panels have provided disclosure statements of all relationships they may have that might be perceived as real or potential sources of conflicts of interest. These disclosure forms are kept on file at the European Heart House, headquarters of the ESC. Any changes in conflict of interest that arise during the writing period must be notified to the ESC. The Task Force report received its entire financial support from …

/pdf/guidelines-for-the-management-of-atrial-fibrillation-the-1cikaj4630.pdf

Guidelines for the management of atrial fibrillation The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC)

Guidelines summarize and evaluate all currently available evidence on a particular issue with the aim of assisting physicians in selecting the best management strategy for an individual patient suffering from a given condition, taking into account the impact on outcome, as well as the risk–benefit ratio of particular diagnostic or therapeutic means. Guidelines are no substitutes for textbooks. The legal implications of medical guidelines have been discussed previously.

A large number of Guidelines have been issued in recent years by the European Society of Cardiology (ESC) as well as by other societies and organizations. Because of the impact on clinical practice, quality criteria for development of guidelines have been established in order to make all decisions transparent to the user. The recommendations for formulating and issuing ESC Guidelines can be found on the ESC Web Site (http://www.escardio.org/knowledge/guidelines/rules).

In brief, experts in the field are selected and undertake a comprehensive review of the published evidence for management and/or prevention of a given condition. A critical evaluation of diagnostic and therapeutic procedures is performed, including assessment of the risk–benefit ratio. Estimates of expected health outcomes for larger societies are included, where data exist. The level of evidence and the strength of recommendation of particular treatment options are weighed and graded according to pre-defined scales, as outlined in Tables 1 and 2 .

View this table:

Table 1 
Classes of recommendations



View this table:

Table 2 
Levels of evidence



The experts of the writing panels have provided disclosure statements of all relationships they may have that might be perceived as real or potential sources of conflicts of interest. These disclosure forms are kept on file at the European Heart House, headquarters of the ESC. Any changes in conflict of interest that arise during the writing period must be notified to the ESC. The Task Force report received its entire financial support from …

Guidelines for the management of atrial fibrillation

Economic Control of Quality of Manufactured Product.

A method for group sequential trials that is based on the inverse normal method for combining the results of the separate stages is proposed. Without exaggerating the Type I error rate, this method enables data-driven sample size reassessments during the course of the study. It uses the stopping boundaries of the classical group sequential tests. Furthermore, exact test procedures may be derived for a wide range of applications. The procedure is compared with the classical designs in terms of power and expected sample size.

Adaptive sample size calculations in group sequential trials.

We would like to thank Dr Takagi et al. 1 for their comments that underscore the findings of our meta-analysis with regard to the favourable effect of statin treatment on the endpoint early all-cause mortality after cardiac surgery. In their systematic review,2 which exclusively included evidence from full-text …

/pdf/impact-of-preoperative-statin-therapy-on-adverse-d5jyyd05dk.pdf

Impact of preoperative statin therapy on adverse postoperative outcomes in patients undergoing cardiac surgery: a meta-analysis of over 30 000 patients

The U.S. FDA has published a draft guidance on "Adaptive Design Clinical Trials for Drugs and Biologics", which gives regulatory guidance on methodological issues in exploratory and confirmatory clinical trials planned with an adaptive design. This comment summarizes the discussion within the joint working group "Adaptive Designs and Multiple Testing Procedures" of the Austro-Swiss and German regions of the International Biometric Society held at the 90-day public comment period in spring 2010.

Comments on the draft guidance on “Adaptive design clinical trials for drugs and biologics” of the U.S. Food and Drug Administration

Clinical trials are often concerned with the comparison of two treatment groups with multiple endpoints. As alternatives to the commonly used methods, the T2 test and the Bonferroni method, O'Brien (1984, Biometrics 40, 1079-1087) proposes tests based on statistics that are simple or weighted sums of the single endpoints. This approach turns out to be powerful if all treatment differences are in the same direction [compare Pocock, Geller, and Tsiatis (1987, Biometrics 43, 487-498)]. The disadvantage of these multivariate methods is that they are suitable only for demonstrating a global difference, whereas the clinician is further interested in which specific endpoints or sets of endpoints actually caused this difference. It is shown here that all tests are suitable for the construction of a closed multiple test procedure where, after the rejection of the global hypothesis, all lower-dimensional marginal hypotheses and finally the single hypotheses are tested step by step. This procedure controls the experimentwise error rate. It is just as powerful as the multivariate test and, in addition, it is possible to detect significant differences between the endpoints or sets of endpoints.

Procedures for two-sample comparisons with multiple endpoints controlling the experimentwise error rate.

‘Multistage testing with adaptive designs’ was the title of an article by Peter Bauer that appeared 1989 in the German journal Biometrie und Informatik in Medizin und Biologie. The journal does not exist anymore but the methodology found widespread interest in the scientific community over the past 25 years. The use of such multistage adaptive designs raised many controversial discussions from the beginning on, especially after the publication by Bauer and Kohne 1994 in Biometrics: Broad enthusiasm about potential applications of such designs faced critical positions regarding their statistical efficiency. Despite, or possibly because of, this controversy, the methodology and its areas of applications grew steadily over the years, with significant contributions from statisticians working in academia, industry and agencies around the world. In the meantime, such type of adaptive designs have become the subject of two major regulatory guidance documents in the US and Europe and the field is still evolving. Developments are particularly noteworthy in the most important applications of adaptive designs, including sample size reassessment, treatment selection procedures, and population enrichment designs. In this article, we summarize the developments over the past 25 years from different perspectives. We provide a historical overview of the early days, review the key methodological concepts and summarize regulatory and industry perspectives on such designs. Then, we illustrate the application of adaptive designs with three case studies, including unblinded sample size reassessment, adaptive treatment selection, and adaptive endpoint selection. We also discuss the availability of software for evaluating and performing such designs. We conclude with a critical review of how expectations from the beginning were fulfilled, and – if not – discuss potential reasons why this did not happen. © 2015 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

/pdf/twenty-five-years-of-confirmatory-adaptive-designs-3255o18f2p.pdf

Gernot Wassmer

Papers

Adaptive sample size calculations in group sequential trials.

Impact of preoperative statin therapy on adverse postoperative outcomes in patients undergoing cardiac surgery: a meta-analysis of over 30 000 patients

Comments on the draft guidance on “Adaptive design clinical trials for drugs and biologics” of the U.S. Food and Drug Administration

Procedures for two-sample comparisons with multiple endpoints controlling the experimentwise error rate.

Twenty-five years of confirmatory adaptive designs: opportunities and pitfalls