García-Closas M, Thompson W D, Robins J M
Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
Am J Epidemiol. 1998 Mar 1;147(5):426-33. doi: 10.1093/oxfordjournals.aje.a009467.
In case-control studies of interactions between genetic and environmental exposures, differential misclassification of the environmental exposure with respect to disease status can introduce spurious heterogeneity of the stratum-specific odds ratios. In this paper, the authors identify conditions under which differential misclassification does not introduce bias in the interaction parameter when no multiplicative interaction is present, and it biases the interaction parameter toward the null value when a multiplicative interaction is present. The conditions are that (i) conditional on potential confounders, the environmental exposure is independent of the genotype among the controls, and (ii) misclassification of the environmental exposure is nondifferential with respect to the genotype. These conditions can be tested from the misclassified data in the control group, since a test of the independence of the genotype and the misclassified environmental exposure among the controls is a test of the joint hypothesis that conditions (i) and (ii) are both true. Therefore, the authors propose a two-step test for interaction which first tests conditions (i) and (ii) and then goes on to test for interaction, provided the first step hypothesis is not rejected. A summary test procedure to test for gene-environment interactions in the presence of misclassification, based on both a conventional test for interaction and the two-step test, is recommended, and is illustrated with data from a case-control study of the role of diet as a modifier of the association between a metabolic polymorphism and lung cancer.
在基因与环境暴露相互作用的病例对照研究中，环境暴露在疾病状态方面的差异错误分类可能会导致层特异性比值比出现虚假的异质性。在本文中，作者确定了在不存在相乘交互作用时差异错误分类不会在交互参数中引入偏差，而在存在相乘交互作用时会使交互参数偏向无效值的条件。这些条件是：（i）以潜在混杂因素为条件，环境暴露在对照组中与基因型独立，以及（ii）环境暴露的错误分类在基因型方面是非差异的。这些条件可以从对照组的错误分类数据中进行检验，因为对对照组中基因型与错误分类的环境暴露的独立性检验是对条件（i）和（ii）均为真的联合假设的检验。因此，作者提出了一种用于交互作用的两步检验法，该方法首先检验条件（i）和（ii），然后在第一步假设未被拒绝的情况下继续检验交互作用。建议采用一种基于传统交互作用检验和两步检验法的汇总检验程序，用于在存在错误分类的情况下检验基因 - 环境相互作用，并通过一项关于饮食作为代谢多态性与肺癌关联修饰因素的病例对照研究的数据进行了说明。
