Pham, TM;
White, IR;
Kahan, BC;
Morris, TP;
Stanworth, SJ;
Forbes, G;
(2021)
A comparison of methods for analyzing a binary composite endpoint with partially observed components in randomized controlled trials.
Statistics in Medicine
10.1002/sim.9203.
(In press).
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Abstract
Composite endpoints are commonly used to define primary outcomes in randomized controlled trials. A participant may be classified as meeting the endpoint if they experience an event in one or several components (eg, a favorable outcome based on a composite of being alive and attaining negative culture results in trials assessing tuberculosis treatments). Partially observed components that are not missing simultaneously complicate the analysis of the composite endpoint. An intuitive strategy frequently used in practice for handling missing values in the components is to derive the values of the composite endpoint from observed components when possible, and exclude from analysis participants whose composite endpoint cannot be derived. Alternatively, complete record analysis (CRA) (excluding participants with any missing components) or multiple imputation (MI) can be used. We compare a set of methods for analyzing a composite endpoint with partially observed components mathematically and by simulation, and apply these methods in a reanalysis of a published trial (TOPPS). We show that the derived composite endpoint can be missing not at random even when the components are missing completely at random. Consequently, the treatment effect estimated from the derived endpoint is biased while CRA results without the derived endpoint are valid. Missing at random mechanisms require MI of the components. We conclude that, although superficially attractive, deriving the composite endpoint from observed components should generally be avoided. Despite the potential risk of imputation model mis-specification, MI of missing components is the preferred approach in this study setting.
| Type: | Article |
|---|---|
| Title: | A comparison of methods for analyzing a binary composite endpoint with partially observed components in randomized controlled trials |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/sim.9203 |
| Publisher version: | https://doi.org/10.1002/sim.9203 |
| Language: | English |
| Additional information: | © 2021 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | RCTs, compatibility, composite endpoints, missing data, multiple imputation |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology > MRC Clinical Trials Unit at UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10135797 |
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