Addressing Systematic Missing Data in the Context of Causally Interpretable Meta-analysis

Evidence synthesis involves drawing conclusions from trial samples that may differ from the target population of interest, and there is often heterogeneity among trials in sample characteristics, treatment implementation, study design, and assessment of covariates. Stitching together this patchwork of evidence requires subject-matter knowledge, a clearly defined target population, and guidance on how to weigh evidence from different trials. Transportability analysis has provided formal identifiability conditions required to make unbiased causal inference in the target population. In this manuscript, we review these conditions along with an additional assumption required to address systematic missing data. The identifiability conditions highlight the importance of accounting for differences in treatment effect modifiers between the populations underlying the trials and the target population. We perform simulations to evaluate the bias of conventional random effect models and multiply imputed estimates using the pooled trials sample and describe causal estimators that explicitly address trial-to-target differences in key covariates in the context of systematic missing data. Results indicate that the causal transportability estimators are unbiased when treatment effect modifiers are accounted for in the analyses. Results also highlight the importance of carefully evaluating identifiability conditions for each trial to reduce bias due to differences in participant characteristics between trials and the target population. Bias can be limited by adjusting for covariates that are strongly correlated with missing treatment effect modifiers, including data from trials that do not differ from the target on treatment modifiers, and removing trials that do differ from the target and did not assess a modifier.