Mendelian randomisation is an accessible and valuable epidemiological approach to provide insight into the causal nature of relationships between risk factor exposures and disease outcomes.However,if performed without...Mendelian randomisation is an accessible and valuable epidemiological approach to provide insight into the causal nature of relationships between risk factor exposures and disease outcomes.However,if performed without critical thought,we may simply have replaced one set of implausible assumptions(no unmeasured confounding or reverse causation)with another set of implausible assumptions(no pleiotropy or other instrument invalidity).The most critical decision to avoid pleiotropy is which genetic variants to use as instrumental variables.Two broad strategies for instrument selection are a biologically motivated strategy and a genome-wide strategy;in general,a biologically motivated strategy is preferred.In this review,we discuss various ways of implementing a biologically motivated selection strategy:using variants in a coding gene region for the exposure or a gene region that encodes a regulator of exposure levels,using a positive control variable and using a biomarker as the exposure rather than its behavioural proxy.In some cases,a genome-wide analysis can provide important complementary evidence,even when its reliability is questionable.In other cases,a biologically-motivated analysis may not be possible.The choice of genetic variants must be informed by biological and functional considerations where possible,requiring collaboration to combine biological and clinical insights with appropriate statistical methodology.展开更多
目的确定内源性睾酮水平是否与血栓栓塞、心力衰竭和心肌梗死的发生有因果关系。设计对来自英国生物样本库和CARDIoGR A MplusC4D 1000基因组项目的参与者进行孟德尔随机化研究,以预测内源性睾酮的遗传变异作为工具变量,并将随机分配作...目的确定内源性睾酮水平是否与血栓栓塞、心力衰竭和心肌梗死的发生有因果关系。设计对来自英国生物样本库和CARDIoGR A MplusC4D 1000基因组项目的参与者进行孟德尔随机化研究,以预测内源性睾酮的遗传变异作为工具变量,并将随机分配作为额外的随机化证据来推断内源性睾酮水平与血栓栓塞、心力衰竭和心肌梗死发生的因果关系。展开更多
基金SB is supported by the Wellcome Trust(225790/Z/22/Z)the United Kingdom Research and Innovation Medical Research Council(MC_UU_00002/7)This research was supported by the National Institute for Health Research Cambridge Biomedical Research Centre(NIHR203312).
文摘Mendelian randomisation is an accessible and valuable epidemiological approach to provide insight into the causal nature of relationships between risk factor exposures and disease outcomes.However,if performed without critical thought,we may simply have replaced one set of implausible assumptions(no unmeasured confounding or reverse causation)with another set of implausible assumptions(no pleiotropy or other instrument invalidity).The most critical decision to avoid pleiotropy is which genetic variants to use as instrumental variables.Two broad strategies for instrument selection are a biologically motivated strategy and a genome-wide strategy;in general,a biologically motivated strategy is preferred.In this review,we discuss various ways of implementing a biologically motivated selection strategy:using variants in a coding gene region for the exposure or a gene region that encodes a regulator of exposure levels,using a positive control variable and using a biomarker as the exposure rather than its behavioural proxy.In some cases,a genome-wide analysis can provide important complementary evidence,even when its reliability is questionable.In other cases,a biologically-motivated analysis may not be possible.The choice of genetic variants must be informed by biological and functional considerations where possible,requiring collaboration to combine biological and clinical insights with appropriate statistical methodology.
文摘目的确定内源性睾酮水平是否与血栓栓塞、心力衰竭和心肌梗死的发生有因果关系。设计对来自英国生物样本库和CARDIoGR A MplusC4D 1000基因组项目的参与者进行孟德尔随机化研究,以预测内源性睾酮的遗传变异作为工具变量,并将随机分配作为额外的随机化证据来推断内源性睾酮水平与血栓栓塞、心力衰竭和心肌梗死发生的因果关系。
