论文标题

几乎确切的孟德尔随机化

Almost exact Mendelian randomization

论文作者

Tudball, Matthew J, Smith, George Davey, Zhao, Qingyuan

论文摘要

Mendelian随机化(MR)是一种自然的实验设计,基于从父母到后代的基因随机传播。但是,这种推论基础通常仅是隐式或用作非正式理由。随着父源数据的数据越来越广泛,我们提倡一种基于这种自然随机化的MR的不同方法,从而正式化了MR和随机对照试验之间的类比。我们首先为MR开发因果图形模型,该模型代表了几种生物学过程和现象,包括种群结构,配子形成,受精,遗传联系和多效性。然后,该因果图用于检测基于人群的MR研究中的偏见,并确定足够的混杂调整集以纠正这些偏见。然后,我们使用减数分裂和施肥中的外源随机性在家庭内MR设计中进行了随机测试,该随机性在遗传学中进行了广泛研究。除了它的透明度和概念上的吸引力外,我们的方法还提供了一些实际的优势,包括对刻痕的表型模型的鲁棒性,对弱工具的鲁棒性以及消除人口结构,分类交配,王朝效应和横向pleotigropropy产生的偏见。我们以对父母和孩子的雅芳纵向研究中对一对阴性和阳性对照的分析进行了分析。随附的R软件包可以在https://github.com/matt-tudball/almostexactmr上找到。

Mendelian randomization (MR) is a natural experimental design based on the random transmission of genes from parents to offspring. However, this inferential basis is typically only implicit or used as an informal justification. As parent-offspring data becomes more widely available, we advocate a different approach to MR that is exactly based on this natural randomization, thereby formalizing the analogy between MR and randomized controlled trials. We begin by developing a causal graphical model for MR which represents several biological processes and phenomena, including population structure, gamete formation, fertilization, genetic linkage, and pleiotropy. This causal graph is then used to detect biases in population-based MR studies and identify sufficient confounder adjustment sets to correct these biases. We then propose a randomization test in the within-family MR design using the exogenous randomness in meiosis and fertilization, which is extensively studied in genetics. Besides its transparency and conceptual appeals, our approach also offers some practical advantages, including robustness to misspecified phenotype models, robustness to weak instruments, and elimination of bias arising from population structure, assortative mating, dynastic effects, and horizontal pleiotropy. We conclude with an analysis of a pair of negative and positive controls in the Avon Longitudinal Study of Parents and Children. The accompanying R package can be found at https://github.com/matt-tudball/almostexactmr.

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