One‐stage individual participant data meta‐analysis models: estimation of treatment‐covariate interactions must avoid ecological bias by separating out within‐trial and across‐trial information

• Published in: Statistics in medicine 2017-02, Vol.36 (5), p.772-789
• Main Authors: Hua, Hairui, Burke, Danielle L., Crowther, Michael J., Ensor, Joie, Tudur Smith, Catrin, Riley, Richard D.
• Format: Article
• Language: English
• Subjects: Age Factors; Anticonvulsants - therapeutic use; Bias; Clinical trials; Confounding Factors, Epidemiologic; ecological bias; effect modifier; Epilepsy; Epilepsy - drug therapy; Estimation bias; Female; Humans; Male; Medical statistics; Medical treatment; Meta-analysis; Meta-Analysis as Topic; Models, Statistical; Randomized Controlled Trials as Topic - methods; Randomized Controlled Trials as Topic - statistics & numerical data; Regression analysis; Sex Factors; stratified/precision medicine; Treatment Outcome; treatment‐covariate interaction
• ISSN: 0277-6715; 1097-0258
• DOI: 10.1002/sim.7171

Stratified medicine utilizes individual‐level covariates that are associated with a differential treatment effect, also known as treatment‐covariate interactions. When multiple trials are available, meta‐analysis is used to help detect true treatment‐covariate interactions by combining their data. Meta‐regression of trial‐level information is prone to low power and ecological bias, and therefore, individual participant data (IPD) meta‐analyses are preferable to examine interactions utilizing individual‐level information. However, one‐stage IPD models are often wrongly specified, such that interactions are based on amalgamating within‐ and across‐trial information. We compare, through simulations and an applied example, fixed‐effect and random‐effects models for a one‐stage IPD meta‐analysis of time‐to‐event data where the goal is to estimate a treatment‐covariate interaction. We show that it is crucial to centre patient‐level covariates by their mean value in each trial, in order to separate out within‐trial and across‐trial information. Otherwise, bias and coverage of interaction estimates may be adversely affected, leading to potentially erroneous conclusions driven by ecological bias. We revisit an IPD meta‐analysis of five epilepsy trials and examine age as a treatment effect modifier. The interaction is −0.011 (95% CI: −0.019 to −0.003; p = 0.004), and thus highly significant, when amalgamating within‐trial and across‐trial information. However, when separating within‐trial from across‐trial information, the interaction is −0.007 (95% CI: −0.019 to 0.005; p = 0.22), and thus its magnitude and statistical significance are greatly reduced. We recommend that meta‐analysts should only use within‐trial information to examine individual predictors of treatment effect and that one‐stage IPD models should separate within‐trial from across‐trial information to avoid ecological bias. © 2016 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.