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非线性孟德尔随机化:通过模拟和实证示例评估残差法和双排序法中的效应修饰作用。

Non-linear Mendelian randomization: evaluation of effect modification in the residual and doubly-ranked methods with simulated and empirical examples.

作者信息

Hamilton Fergus W, Hughes David A, Lu Tianyuan, Kutalik Zoltán, Gkatzionis Apostolos, Tilling Kate, Hartwig Fernando P, Davey Smith George

机构信息

MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

Infection Science, North Bristol NHS Trust, Bristol, UK.

出版信息

Eur J Epidemiol. 2025 Jun 2. doi: 10.1007/s10654-025-01208-x.

Abstract

Non-linear Mendelian randomisation (NLMR) is a relatively recently developed approach to estimate the causal effect of an exposure on an outcome where this is expected to be non-linear. Two commonly used techniques-based on stratifying the exposure and performing Mendelian randomisation (MR) within each strata-are the residual and doubly-ranked methods. The residual method is known to be biased in the presence of genetic effect heterogeneity-where the effect of the genotype on the exposure varies between individuals. The doubly-ranked method is considered to be less sensitive to genetic effect heterogeneity. In this paper, we simulate genetic effect heterogeneity and confounding of the exposure and outcome and identify that both methods are susceptible to likely unpredictable bias in this setting. Using UK Biobank, we identify empirical evidence of genetic effect heterogeneity and show via simulated outcomes that this leads to biased MR estimates within strata, whilst conventional MR across the full sample remains unbiased. We suggest that these biases are highly likely to be present in other empirical NLMR analyses using these methods and urge caution in current usage. Simulated outcome analyses may represent a useful test to identify if genetic effect heterogeneity is likely to bias NLMR estimates in future analyses.

摘要

非线性孟德尔随机化(NLMR)是一种相对较新开发的方法,用于估计暴露对预期为非线性的结局的因果效应。两种常用技术——基于对暴露进行分层并在每个分层内进行孟德尔随机化(MR)——是残差法和双重排序法。已知在存在基因效应异质性的情况下,残差法存在偏差,即基因型对暴露的效应在个体之间有所不同。双重排序法被认为对基因效应异质性不太敏感。在本文中,我们模拟了基因效应异质性以及暴露和结局的混杂情况,并确定在这种情况下两种方法都容易出现可能无法预测的偏差。利用英国生物银行,我们确定了基因效应异质性的经验证据,并通过模拟结局表明,这会导致分层内的MR估计有偏差,而全样本的传统MR仍然无偏差。我们认为,在使用这些方法的其他实证NLMR分析中极有可能存在这些偏差,并敦促在当前使用中谨慎行事。模拟结局分析可能是一种有用的检验方法,用于确定基因效应异质性在未来分析中是否可能使NLMR估计产生偏差。

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