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|Title:||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|
Burke, Danielle L.
Crowther, Michael J.
Tudur Smith, Catrin
Riley, Richard D.
|Citation:||Statistics in Medicine, 2017, 36 (5), pp. 772-789|
|Abstract:||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.|
|Rights:||Copyright © the authors, 2016. This is an open-access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/ ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.|
|Appears in Collections:||Published Articles, Dept. of Health Sciences|
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