Weighted analysis of composite endpoints with simultaneous inference for flexible weight constraints

Stat Med. 2017 Feb 10;36(3):442-454. doi: 10.1002/sim.7147. Epub 2016 Oct 26.

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.

Keywords: chi-bar-square distribution; composite endpoint; conic constraints; multiplicity adjustment; simultaneous confidence intervals; weighted analyses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / therapeutic use
  • Cardiovascular Diseases / prevention & control
  • Chi-Square Distribution
  • Data Interpretation, Statistical*
  • Endpoint Determination / methods*
  • Humans
  • Models, Statistical
  • Randomized Controlled Trials as Topic / methods
  • Statistics as Topic
  • Time Factors
  • Treatment Failure
  • Treatment Outcome
  • Typhoid Fever / drug therapy

Substances

  • Anti-Bacterial Agents