title: Weighted analysis of composite endpoints with simultaneous inference for flexible weight constraints.
abstract: Composite endpoints are widely used as primary endpoints of randomized controlled trials across clinical disciplines. A common critique of the conventional analysis of composite endpoints is that all disease events are weighted equally, whereas their clinical relevance may differ substantially. We address this by introducing a framework for the weighted analysis of composite endpoints and interpretable test statistics, which are applicable to both binary and time-to-event data. To cope with the difficulty of selecting an exact set of weights, we propose a method for constructing simultaneous confidence intervals and tests that asymptotically preserve the family-wise type I error in the strong sense across families of weights satisfying flexible inequality or order constraints based on the theory of χ¯2-distributions. We show that the method achieves the nominal simultaneous coverage rate with substantial efficiency gains over Scheffé's procedure in a simulation study and apply it to trials in cardiovascular disease and enteric fever. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.
authors: Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Vietnam.
authors: Anh Nguyen
authors: AN
authors: Duc
authors: Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Vietnam.|Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.
authors: Marcel
authors: M
authors: Wolbers
mesh_terms: D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000517:prevention & control; D016009:Chi-Square Distribution; D003627:Data Interpretation, Statistical; D023381:Endpoint Determination / Q000379:methods*; D006801:Humans; D015233:Models, Statistical; D016032:Randomized Controlled Trials as Topic / Q000379:methods; D013223:Statistics as Topic; D013997:Time Factors; D017211:Treatment Failure; D016896:Treatment Outcome; D014435:Typhoid Fever / Q000188:drug therapy
chemical_list: D000900:Anti-Bacterial Agents
keywords: chi-bar-square distribution; composite endpoint; conic constraints; multiplicity adjustment; simultaneous confidence intervals; weighted analyses