Detecting pleiotropy in Mendelian randomisation studies with summary data and a continuous outcome
Detecting pleiotropy in Mendelian randomisation studies with summary data and a continuous outcome
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DOI：
10.1002/sim.6522
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发表时间：
2015-09-20
影响因子：
2
通讯作者：
Thompsonc, John R.
中科院分区：
文献类型：
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作者：
Del Greco, Fabiola M.;Minelli, Cosetta;Thompsonc, John R.
孟德尔随机化（MR）通过使用遗传变异作为工具变量来估计可改变的表型对结果的因果影响，但其有效性依赖于无多效性的假设，即基因仅通过给定的表型影响结果。排除多效性是困难的，但使用多种工具可以间接解决这个问题：如果所有基因都代表有效的工具，它们的MR估计值应该只是偶然变化。Sargan试验检测多效性时，个体表型，结果和基因型数据在相同的受试者进行测量。我们提出了一种替代方法，当只有汇总遗传数据或基因表型和基因结果的数据来自不同的主题。在MR Wald估计值的荟萃分析中，使用仪器间异质性Q检验（连同I-2指数）研究多效性的存在，这些估计值分别来自每种仪器。对于一个连续的结果，我们通过模拟评估的方法，并说明它使用已公布的数据。对于所有数据都来自相同受试者的情况，我们将其与Sargan检验进行比较。Q检验在小样本情况下趋于保守。它的功效随着多效性程度和样本量的增加而增加，I-2指数的精度也是如此，在这种情况下，结果与Sargan检验的结果相似。在基于汇总数据的大样本量MR研究中，仪器间Q检验是探索因多效性或其他原因导致的异质性的有用工具。版权所有（c）2015约翰威利父子有限公司
Mendelian randomisation (MR) estimates causal effects of modifiable phenotypes on an outcome by using genetic variants as instrumental variables, but its validity relies on the assumption of no pleiotropy, that is, genes influence the outcome only through the given phenotype. Excluding pleiotropy is difficult, but the use of multiple instruments can indirectly address the issue: if all genes represent valid instruments, their MR estimates should vary only by chance. The Sargan test detects pleiotropy when individual phenotype, outcome and genotype data are measured in the same subjects. We propose an alternative approach to be used when only summary genetic data are available or data on gene-phenotype and gene-outcome come from different subjects. The presence of pleiotropy is investigated using the between-instrument heterogeneity Q test (together with the I-2 index) in a meta-analysis of MR Wald estimates, derived separately from each instrument. For a continuous outcome, we evaluate the approach through simulations and illustrate it using published data. For the scenario where all data come from the same subjects, we compare it with the Sargan test. The Q test tends to be conservative in small samples. Its power increases with the degree of pleiotropy and the sample size, as does the precision of the I-2 index, in which case results are similar to those of the Sargan test. In MR studies with large sample sizes based on summary data, the between-instrument Q test represents a useful tool to explore the presence of heterogeneity due to pleiotropy or other causes. Copyright (c) 2015John Wiley & Sons, Ltd.