MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Road, BS8 2PS, Bristol, UK.
Infection Science, North Bristol NHS Trust, Bristol, UK.
Eur J Epidemiol. 2024 May;39(5):451-465. doi: 10.1007/s10654-024-01113-9. Epub 2024 May 25.
Mendelian randomisation (MR) is an established technique in epidemiological investigation, using the principle of random allocation of genetic variants at conception to estimate the causal linear effect of an exposure on an outcome. Extensions to this technique include non-linear approaches that allow for differential effects of the exposure on the outcome depending on the level of the exposure. A widely used non-linear method is the residual approach, which estimates the causal effect within different strata of the non-genetically predicted exposure (i.e. the "residual" exposure). These "local" causal estimates are then used to make inferences about non-linear effects. Recent work has identified that this method can lead to estimates that are seriously biased, and a new method-the doubly-ranked method-has been introduced as a possibly more robust approach. In this paper, we perform negative control outcome analyses in the MR context. These are analyses with outcomes onto which the exposure should have no predicted causal effect. Using both methods we find clearly biased estimates in certain situations. We additionally examined a situation for which there are robust randomised controlled trial estimates of effects-that of low-density lipoprotein cholesterol (LDL-C) reduction onto myocardial infarction, where randomised trials have provided strong evidence of the shape of the relationship. The doubly-ranked method did not identify the same shape as the trial data, and for LDL-C and other lipids they generated some highly implausible findings. Therefore, we suggest there should be extensive simulation and empirical methodological examination of performance of both methods for NLMR under different conditions before further use of these methods. In the interim, use of NLMR methods needs justification, and a number of sanity checks (such as analysis of negative and positive control outcomes, sensitivity analyses excluding removal of strata at the extremes of the distribution, examination of biological plausibility and triangulation of results) should be performed.
孟德尔随机化(MR)是一种在流行病学研究中被广泛应用的技术,它利用遗传变异在受孕时的随机分配原理来估计暴露对结果的因果线性影响。该技术的扩展包括非线性方法,这些方法允许根据暴露水平的不同,对暴露对结果的影响进行差异化估计。一种广泛使用的非线性方法是残差方法,它可以在非遗传预测的暴露的不同层次内(即“残差”暴露)估计因果效应。然后,使用这些“局部”因果估计来对非线性效应进行推断。最近的研究表明,这种方法可能会导致严重的偏差估计,因此引入了一种新的方法——双重排名方法——作为一种更稳健的方法。在本文中,我们在 MR 背景下进行了负对照结局分析。这些分析是针对那些暴露不应具有因果效应的结局进行的。使用这两种方法,我们在某些情况下发现了明显有偏差的估计。我们还研究了一种具有稳健的随机对照试验效应估计的情况,即低密度脂蛋白胆固醇(LDL-C)降低对心肌梗死的影响,随机试验为这种关系的形状提供了强有力的证据。双重排名方法没有识别出与试验数据相同的形状,对于 LDL-C 和其他脂质,它们生成了一些非常不合理的结果。因此,我们建议在进一步使用这些方法之前,应该对两种方法在不同条件下对非线性 MR 的性能进行广泛的模拟和经验方法学检验。在此期间,NLMR 方法的使用需要有理由,并应进行一些合理性检查(例如分析负对照和正对照结局、对分布极端值的层次进行敏感性分析排除、检查生物学合理性和结果的三角测量)。