Saunders Gretchen R B, McGue Matt, Malone Stephen M
Department of Psychology, University of Minnesota, Minneapolis, MN, USA.
Twin Res Hum Genet. 2019 Oct;22(5):290-296. doi: 10.1017/thg.2019.67. Epub 2019 Sep 27.
Genetically informative research designs are becoming increasingly popular as a way to strengthen causal inference with their ability to control for genetic and shared environmental confounding. Co-twin control (CTC) models, a special case of these designs using twin samples, decompose the overall effect of exposure on outcome into a within- and between-twin-pair term. Ideally, the within-twin-pair term would serve as an estimate of the exposure effect controlling for genetic and shared environmental factors, but it is often confounded by factors not shared within a twin-pair. Previous simulation work has shown that if twins are less similar on an unmeasured confounder than they are on an exposure, the within-twin-pair estimate will be a biased estimate of the exposure effect, even more biased than the individual, unpaired estimate. The current study uses simulation and analytical derivations to show that while incorporating a covariate related to the nonshared confounder in CTC models always reduces bias in the within-pair estimate, it will be less biased than the individual estimate only in a narrow set of circumstances. The best case for bias reduction in the within-pair estimate occurs when the within-twin-pair correlation in exposure is less than the correlation in the confounder and the twin-pair correlation in the covariate is high. Additionally, the form of covariate inclusion is compared between adjustment for only one's own covariate value and adjustment for the deviation of one's own value from the covariate twin-pair mean. Results show that adjusting for the deviation from the twin-pair mean results in equal or reduced bias.
基因信息研究设计正变得越来越流行，因为它们能够控制基因和共同环境混杂因素，从而加强因果推断。共双胞胎对照（CTC）模型是这些设计中的一种特殊情况，使用双胞胎样本，将暴露对结局的总体效应分解为双胞胎对内和双胞胎对间的项。理想情况下，双胞胎对内的项将作为控制基因和共同环境因素后的暴露效应估计值，但它常常受到双胞胎对内部未共享因素的混杂影响。先前的模拟研究表明，如果双胞胎在未测量的混杂因素上的相似性低于在暴露因素上的相似性，那么双胞胎对内的估计值将是暴露效应的有偏估计，甚至比个体的、未配对的估计值偏差更大。当前的研究使用模拟和分析推导表明，虽然在CTC模型中纳入与非共享混杂因素相关的协变量总是会降低对内估计值的偏差，但只有在一组狭窄的情况下，它的偏差才会小于个体估计值。当双胞胎对内暴露的相关性小于混杂因素的相关性且协变量在双胞胎对间的相关性较高时，对内估计值偏差减少的最佳情况就会出现。此外，还比较了仅调整自身协变量值与调整自身值与协变量双胞胎对均值的偏差这两种协变量纳入形式。结果表明，调整与双胞胎对均值的偏差会导致偏差相等或减小。
