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.

兄弟姐妹比较研究具有一个吸引人的特点，即能够控制家庭内部共享的因素造成的无法测量的混杂因素。然而，有时人们担心这些研究可能具有较差的普遍性（外部有效性），因为隐含地限制了协变量不一致的家庭，即那些至少有两个兄弟姐妹的至少一个协变量水平不同的家庭（暴露或混杂因素）正在调查中。即使许多作者已经注意到这种选择机制，以前对该问题的描述往往很简短。本文的目的是对兄弟姐妹比较研究中协变量不一致家庭的隐含限制进行正式讨论。我们讨论了这种限制何时以及如何损害研究的普遍性，我们表明，即使所有家庭都是协变量不一致的，实际上也可能出现类似的普遍性问题，例如，即使暴露是连续的，因此所有兄弟姐妹都有不同的暴露水平。我们展示了如何通过使用所谓的边际组间模型来估计边际暴露效应来解决这个问题。最后，我们通过模拟研究来说明理论结论。