Karolinska Institutet, Nobels väg 12 A, 171 77, Stockholm, Sweden.
Karolinska Institutet, Maria Aspmans Gata 30A, 17164, Solna, Sweden.
Eur J Epidemiol. 2022 May;37(5):461-476. doi: 10.1007/s10654-022-00844-x. Epub 2022 Mar 21.
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.
同胞比较研究具有一个吸引人的特点，即能够通过控制家庭内部共享的未测量混杂因素来进行。然而，人们有时担心这些研究可能由于对协变量不一致的家庭（即至少有两个兄弟姐妹具有至少一个正在研究的协变量（暴露或混杂因素）的不同水平）的隐含限制而具有较差的可推广性（外部有效性）。即使许多作者已经注意到了这种选择机制，但以前对这个问题的描述往往很简短。本文的目的是对同胞比较研究中对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会损害研究的可推广性，并表明即使所有家庭都是协变量不一致的，例如即使暴露是连续的，以至于所有兄弟姐妹都具有不同的暴露水平，实际上也可能会出现类似的可推广性问题。我们展示了如何通过使用所谓的边际在-内模型来解决这个问题，以估计边际暴露效应。最后，我们通过模拟研究说明了理论结论。
