Use of multiple covariates in assessing treatment-effect modifiers: A methodological review of individual participant data meta-analyses

Abstract

Individual participant data (IPD) meta-analyses of randomised trials are considered a reliable way to assess participant-level treatment effect modifiers but may not make the best use of the available data. Traditionally, effect modifiers are explored one covariate at a time, which gives rise to the possibility that evidence of treatment-covariate interaction may be due to confounding from a different, related covariate. We aimed to evaluate current practice when estimating treatment-covariate interactions in IPD meta-analysis, specifically focusing on involvement of additional covariates in the models. We reviewed 100 IPD meta-analyses of randomised trials, published between 2015 and 2020, that assessed at least one treatment-covariate interaction. We identified four approaches to handling additional covariates: (1) Single interaction model (unadjusted): No additional covariates included (57/100 IPD meta-analyses); (2) Single interaction model (adjusted): Adjustment for the main effect of at least one additional covariate (35/100); (3) Multiple interactions model: Adjustment for at least one two-way interaction between treatment and an additional covariate (3/100); and (4) Three-way interaction model: Three-way interaction formed between treatment, the additional covariate and the potential effect modifier (5/100). IPD is not being utilised to its fullest extent. In an exemplar dataset, we demonstrate how these approaches lead to different conclusions. Researchers should adjust for additional covariates when estimating interactions in IPD meta-analysis providing they adjust their main effects, which is already widely recommended. Further, they should consider whether more complex approaches could provide better information on who might benefit most from treatments, improving patient choice and treatment policy and practice.

Keywords: confounding; effect modification; individual participant data; meta-analysis; participant-level covariate; treatment-covariate interaction.

Figure 1

Study selection flow diagram. *Full-text articles were not assessed for eligibility once 100 eligible IPD meta-analyses had been identified IPD refers to individual participant data, RCT refers to randomised controlled trial. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 2

Fixed-effect meta-analysis of five trials for a continuous outcome using exemplar dataset. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 3

Differences in mean differences and interaction p-values for the investigation of effect modifiers Covariate 1 and Covariate 2 in the exemplar dataset, dependent on model choice. [Colour figure can be viewed at wileyonlinelibrary.com]