Sydney School of Public Health, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Centre for Kidney Research, Kids Research Institute, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
Sydney School of Public Health, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Centre for Kidney Research, Kids Research Institute, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
Kidney Int. 2023 Dec;104(6):1113-1123. doi: 10.1016/j.kint.2023.09.016. Epub 2023 Sep 30.
Confounding is a major limitation of observational studies. Mendelian randomization (MR) is a powerful study design that uses genetic variants as instrumental variables to enable examination of the causal effect of an exposure on an outcome in observational data. With the emergence of large-scale genome-wide association studies in nephrology over the past decade, MR has become a popular method to establish causal inferences. However, MR is a complex and challenging methodology that requires careful consideration to ensure robust results. This review article aims to summarize the basic concepts of MR, its application and relevance in nephrology, and the methodological challenges and limitations as well as discuss the current guidelines for design and reporting. With reference to a clinically relevant example of examining the causal relationship between the estimated glomerular filtration rate and cancer, this review outlines the key steps to conducting an MR study, including the key considerations and potential pitfalls at each step. These include defining the clinical question, selecting the data sources, identifying and refining appropriate genetic variants by considering linkage disequilibrium and associations with potential confounders, harmonization of variants across data sets, validation of the genetic instrument by assessing its strength, estimation of the causal effects, confirming the validity of the findings, and interpreting and reporting results.
混杂是观察性研究的主要局限性。孟德尔随机化（MR）是一种强大的研究设计，它使用遗传变异作为工具变量，以在观察性数据中检查暴露对结局的因果效应。在过去十年中，肾脏病学领域出现了大规模的全基因组关联研究，MR 已成为一种建立因果推断的流行方法。然而，MR 是一种复杂且具有挑战性的方法，需要仔细考虑以确保结果稳健。本文旨在总结 MR 的基本概念、在肾脏病学中的应用和相关性，以及方法学挑战和局限性，并讨论当前的设计和报告指南。本文通过一个与临床相关的例子，探讨了估算肾小球滤过率与癌症之间的因果关系，概述了进行 MR 研究的关键步骤，包括在每个步骤中需要考虑的关键因素和潜在陷阱。这些步骤包括定义临床问题、选择数据源、通过考虑连锁不平衡和与潜在混杂因素的关联来识别和精炼适当的遗传变异、在数据集之间协调变异、通过评估遗传工具的强度来验证其有效性、估计因果效应、确认发现的有效性，以及解释和报告结果。
