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Res Synth Methods. 2019 Nov 23. doi: 10.1002/jrsm.1384. [Epub ahead of print]

Individual participant data meta-analysis of intervention studies with time-to-event outcomes: A review of the methodology and an applied example.

Author information

1
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
2
Cochrane Netherlands, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
3
Centre for Prognosis Research, Research Institute for Primary Care and Health Sciences, Keele University, Staffordshire, UK.
4
Department of Biostatistics, University of Liverpool, Liverpool, UK.
5
Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.

Abstract

Many randomized trials evaluate an intervention effect on time-to-event outcomes. Individual participant data (IPD) from such trials can be obtained and combined in a so-called IPD meta-analysis (IPD-MA), to summarize the overall intervention effect. We performed a narrative literature review to provide an overview of methods for conducting an IPD-MA of randomized intervention studies with a time-to-event outcome. We focused on identifying good methodological practice for modeling frailty of trial participants across trials, modeling heterogeneity of intervention effects, choosing appropriate association measures, dealing with (trial differences in) censoring and follow-up times, and addressing time-varying intervention effects and effect modification (interactions).We discuss how to achieve this using parametric and semi-parametric methods, and describe how to implement these in a one-stage or two-stage IPD-MA framework. We recommend exploring heterogeneity of the effect(s) through interaction and non-linear effects. Random effects should be applied to account for residual heterogeneity of the intervention effect. We provide further recommendations, many of which specific to IPD-MA of time-to-event data from randomized trials examining an intervention effect.We illustrate several key methods in a real IPD-MA, where IPD of 1225 participants from 5 randomized clinical trials were combined to compare the effects of Carbamazepine and Valproate on the incidence of epileptic seizures.

KEYWORDS:

heterogeneity; individual participant data; intervention; meta-analysis; time-to-event

PMID:
31759339
DOI:
10.1002/jrsm.1384

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