Generalizability and effect measure modification in sibling comparison studies

Sibling comparison studies have the attractive feature of being able to control for unmeasured confounding by factors that are shared within families. However, there is sometimes a concern that these studies may have poor generalizability (external validity) due to the implicit restriction to families that are covariate-discordant, i.e., those families where at least two siblings have different levels of at least one of the covariates (exposure or confounders) under investigation. Even if this selection mechanism has been noted by many authors, previous accounts of the problem tend to be brief. The purpose of this paper is to provide a formal discussion of the implicit restriction to covariate-discordant families in sibling comparison studies. We discuss when and how this restriction may impair the generalizability of the study, and we show that a similar generalizability problem may in fact arise even when all families are covariate-discordant, e.g. even if the exposure is continuous so that all siblings have different exposure levels. We show how this problem can be solved by using a so-called marginal between-within model for estimation of marginal exposure effects. Finally, we illustrate the theoretical conclusions with a simulation study.