Linear mixed models for investigating effect modification in subgroup meta-analysis

Subgroup meta-analysis can be used for comparing treatment effects between subgroups using information from multiple trials. If the effect of treatment is differential depending on subgroup, the results could enable personalization of the treatment. We propose using linear mixed models for estimating treatment effect modification in aggregate data meta-analysis. The linear mixed models capture existing subgroup meta-analysis methods while allowing for additional features such as flexibility in modeling heterogeneity, handling studies with missing subgroups and more. Reviews and simulation studies of the best suited models for estimating possible differential effect of treatment depending on subgroups have been studied mostly within individual participant data meta-analysis. While individual participant data meta-analysis in general is recommended over aggregate data meta-analysis, conducting an aggregate data subgroup meta-analysis could be valuable for exploring treatment effect modifiers before committing to an individual participant data subgroup meta-analysis. Additionally, using solely individual participant data for subgroup meta-analysis requires collecting sufficient individual participant data which may not always be possible. In this article, we compared existing methods with linear mixed models for aggregate data subgroup meta-analysis under a broad selection of scenarios using simulation and two case studies. Both the case studies and simulation studies presented here demonstrate the advantages of the linear mixed model approach in aggregate data subgroup meta-analysis.