Mendelian randomization (MR) has become a popular approach to study causal effects by using genetic variants as instrumental variables. We propose a new MR method, GENIUS-MAWII, which simultaneously addresses the two salient phenomena that adversely affect MR analyses: many weak instruments and widespread horizontal pleiotropy. Similar to MR GENIUS \citep{Tchetgen2019_GENIUS}, we achieve identification of the treatment effect by leveraging heteroscedasticity of the exposure. We then derive the class of influence functions of the treatment effect, based on which, we construct a continuous updating estimator and establish its consistency and asymptotic normality under a many weak invalid instruments asymptotic regime by developing novel semiparametric theory. We also provide a measure of weak identification and graphical diagnostic tool. We demonstrate in simulations that GENIUS-MAWII has clear advantages in the presence of directional or correlated horizontal pleiotropy compared to other methods. We apply our method to study the effect of body mass index on systolic blood pressure using UK Biobank.
翻译:使用基因变异作为工具变量,我们提出了一种新的MR方法,即GENNIUS-MAWII,该方法同时解决了对MR分析产生不利影响的两个突出现象:许多薄弱仪器和广泛的横向胸膜。类似于MR GENISUS \ citep{Tchetgen2019_GENIUS},我们通过利用接触的超异性来查明治疗效果。然后我们得出治疗效果的影响功能类别,据此,我们建立一个不断更新的估测器,并通过开发新的半参数理论,在很多薄弱的无效仪器下建立一致性和无症状常态。我们还提供了一种微弱的识别和图形诊断工具。我们在模拟中表明,GENUS-MAWII与其他方法相比,在方向性或相关水平性胸膜上存在明显的优势。我们运用了我们的方法来研究人体指数对英国生物库的静态血压的影响。