In this paper, we simulate data sets that represent random samples drawn from a single population. However, in practice, MR investigations may be conducted with data from several studies, using either pooled data or a meta-analysis approach (17–19). Meta-analyses that derive their first-stage and reduced-form estimates from different studies are actually employing a form of 2-sample IV analysis, similar to that described here. Our results suggest that such approaches should focus on maximizing the number of participants in the meta-analysis with data on the IV and the outcome, even if data on the exposure are absent. A cautionary remark is that the magnitude of association of the IV with the exposure may be different in studies which derive their participants from different underlying populations, and heterogeneity in this association should be acknowledged where possible (17). Similarly, subsample IV approaches should utilize subsamples that are representative of the full sample. This issue may be especially problematic for MR studies of biomarkers if biospecimens are available for a subsample that is not representative of the full sample.
