Sensitivity Analyses for Robust Causal Inference from Mendelian Randomization Analyses with Multiple Genetic Variants.
Sensitivity Analyses for Robust Causal Inference from Mendelian Randomization Analyses with Multiple Genetic Variants.
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DOI：
10.1097/ede.0000000000000559
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发表时间：
2017-01
期刊：
影响因子：
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通讯作者：
Thompson SG
中科院分区：
文献类型：
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作者：
Burgess S;Bowden J;Fall T;Ingelsson E;Thompson SG
补充数字内容可在正文中找到。孟德尔随机化研究正变得更加强大和简单，这是因为全基因组关联研究的规模和覆盖面越来越大，以及关于遗传与风险因素和疾病结果关联的汇总数据的可用性越来越高。然而，当在孟德尔随机化分析中使用来自不同基因区域的多个遗传变异时，所有的遗传变异都满足工具变量假设是非常不可信的。这意味着不应该仅仅依靠简单的工具变量分析来得出因果结论。在这篇文章中，我们讨论了一系列的敏感性分析，这些分析将支持或质疑带有多个遗传变量的孟德尔随机化分析的因果推断的有效性。我们专注于具有最大实际相关性的敏感性分析，以确保可靠的因果推断，以及那些可以使用汇总数据进行的分析。除了工具变量假设的合理性得到了强烈的生物学理解支持的情况外，孟德尔随机化分析中没有对违反工具变量假设的结果的稳健性进行评估的情况，应该被视为推测和不完整的。特别是，孟德尔随机调查的大量遗传变异没有这样的敏感性分析，应该持怀疑态度对待。
Supplemental Digital Content is available in the text. Mendelian randomization investigations are becoming more powerful and simpler to perform, due to the increasing size and coverage of genome-wide association studies and the increasing availability of summarized data on genetic associations with risk factors and disease outcomes. However, when using multiple genetic variants from different gene regions in a Mendelian randomization analysis, it is highly implausible that all the genetic variants satisfy the instrumental variable assumptions. This means that a simple instrumental variable analysis alone should not be relied on to give a causal conclusion. In this article, we discuss a range of sensitivity analyses that will either support or question the validity of causal inference from a Mendelian randomization analysis with multiple genetic variants. We focus on sensitivity analyses of greatest practical relevance for ensuring robust causal inferences, and those that can be undertaken using summarized data. Aside from cases in which the justification of the instrumental variable assumptions is supported by strong biological understanding, a Mendelian randomization analysis in which no assessment of the robustness of the findings to violations of the instrumental variable assumptions has been made should be viewed as speculative and incomplete. In particular, Mendelian randomization investigations with large numbers of genetic variants without such sensitivity analyses should be treated with skepticism.