Caution against examining the role of reverse causality in Mendelian Randomization
Recently, Mendelian Randomization (MR) has gained in popularity as a concept to assess the causal relationship between phenotypes in genetic association studies. An extension of standard MR methodology, the MR Steiger approach, has recently been developed to infer the causal direction between two ph...
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| Veröffentlicht in: | Genetic epidemiology Jg. 45; H. 5; S. 445 - 454 |
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01.07.2021
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| Abstract | Recently, Mendelian Randomization (MR) has gained in popularity as a concept to assess the causal relationship between phenotypes in genetic association studies. An extension of standard MR methodology, the MR Steiger approach, has recently been developed to infer the causal direction between two phenotypes in prospective studies. Through simulation studies, we examined and quantified the ability of the MR Steiger approach to determine the causal direction between two phenotypes (i.e., effect direction). Through simulation studies, our results show that the MR Steiger approach may fail to correctly identify the direction of causality. This is true, especially in the presence of pleiotropy. We also applied the MR Steiger method to the COPDGene study, a case‐control study of chronic obstructive pulmonary disease (COPD) in current and former smokers, to examine the role of smoking on lung function. We have created an R package on Github called reverseDirection which runs simulations for user‐specified scenarios to examine when the MR Steiger approach can correctly determine the causal direction between two phenotypes in any user specified scenario. In summary, our results emphasize the importance of caution when the MR Steiger approach is used in to infer the direction of causality. |
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| AbstractList | Recently, Mendelian Randomization (MR) has gained in popularity as a concept to assess the causal relationship between phenotypes in genetic association studies. An extension of standard MR methodology, the MR Steiger approach, has recently been developed to infer the causal direction between two phenotypes in prospective studies. Through simulation studies, we examined and quantified the ability of the MR Steiger approach to determine the causal direction between two phenotypes (i.e., effect direction). Through simulation studies, our results show that the MR Steiger approach may fail to correctly identify the direction of causality. This is true, especially in the presence of pleiotropy. We also applied the MR Steiger method to the COPDGene study, a case-control study of chronic obstructive pulmonary disease (COPD) in current and former smokers, to examine the role of smoking on lung function. We have created an R package on Github called reverseDirection which runs simulations for user-specified scenarios to examine when the MR Steiger approach can correctly determine the causal direction between two phenotypes in any user specified scenario. In summary, our results emphasize the importance of caution when the MR Steiger approach is used in to infer the direction of causality.Recently, Mendelian Randomization (MR) has gained in popularity as a concept to assess the causal relationship between phenotypes in genetic association studies. An extension of standard MR methodology, the MR Steiger approach, has recently been developed to infer the causal direction between two phenotypes in prospective studies. Through simulation studies, we examined and quantified the ability of the MR Steiger approach to determine the causal direction between two phenotypes (i.e., effect direction). Through simulation studies, our results show that the MR Steiger approach may fail to correctly identify the direction of causality. This is true, especially in the presence of pleiotropy. We also applied the MR Steiger method to the COPDGene study, a case-control study of chronic obstructive pulmonary disease (COPD) in current and former smokers, to examine the role of smoking on lung function. We have created an R package on Github called reverseDirection which runs simulations for user-specified scenarios to examine when the MR Steiger approach can correctly determine the causal direction between two phenotypes in any user specified scenario. In summary, our results emphasize the importance of caution when the MR Steiger approach is used in to infer the direction of causality. Recently, Mendelian Randomization (MR) has gained in popularity as a concept to assess the causal relationship between phenotypes in genetic association studies. An extension of standard MR methodology, the MR Steiger approach, has recently been developed to infer the causal direction between two phenotypes in prospective studies. Through simulation studies, we examine and quantified the ability of the MR Steiger approach to determine the causal direction between 2 phenotypes (i.e. effect direction). Through simulation studies, our results show that the MR Steiger approach may fail to correctly identify the direction of causality. This is true, especially in the presence of pleiotropy. We also applied the MR Steiger method to the COPDGene study, a case-control study of Chronic Obstructive Pulmonary Disease (COPD) in current and former smokers, to examine the role of smoking on lung function. We have created an R package on Github called reverseDirection which runs simulations for user-specified scenarios in order to examine when the MR Steiger approach can correctly determine the causal direction between two phenotypes in any user specified scenario. In summary, our results emphasize the importance of caution when the MR Steiger approach is used in to infer direction of causality. Recently, Mendelian Randomization (MR) has gained in popularity as a concept to assess the causal relationship between phenotypes in genetic association studies. An extension of standard MR methodology, the MR Steiger approach, has recently been developed to infer the causal direction between two phenotypes in prospective studies. Through simulation studies, we examined and quantified the ability of the MR Steiger approach to determine the causal direction between two phenotypes (i.e., effect direction). Through simulation studies, our results show that the MR Steiger approach may fail to correctly identify the direction of causality. This is true, especially in the presence of pleiotropy. We also applied the MR Steiger method to the COPDGene study, a case‐control study of chronic obstructive pulmonary disease (COPD) in current and former smokers, to examine the role of smoking on lung function. We have created an R package on Github called reverseDirection which runs simulations for user‐specified scenarios to examine when the MR Steiger approach can correctly determine the causal direction between two phenotypes in any user specified scenario. In summary, our results emphasize the importance of caution when the MR Steiger approach is used in to infer the direction of causality. Recently, Mendelian Randomization (MR) has gained in popularity as a concept to assess the causal relationship between phenotypes in genetic association studies. An extension of standard MR methodology, the MR Steiger approach, has recently been developed to infer the causal direction between two phenotypes in prospective studies. Through simulation studies, we examined and quantified the ability of the MR Steiger approach to determine the causal direction between two phenotypes (i.e., effect direction). Through simulation studies, our results show that the MR Steiger approach may fail to correctly identify the direction of causality. This is true, especially in the presence of pleiotropy. We also applied the MR Steiger method to the COPDGene study, a case‐control study of chronic obstructive pulmonary disease (COPD) in current and former smokers, to examine the role of smoking on lung function. We have created an R package on Github called reverseDirection which runs simulations for user‐specified scenarios to examine when the MR Steiger approach can correctly determine the causal direction between two phenotypes in any user specified scenario. In summary, our results emphasize the importance of caution when the MR Steiger approach is used in to infer the direction of causality. |
| Author | Lutz, Sharon M. Wu, Ann Chen Hokanson, John E. Vansteelandt, Stijn Lange, Christoph |
| AuthorAffiliation | 1. PRecisiOn Medicine Translational Research (PROMoTeR) Center, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA 5. Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK 3. Department of Epidemiology, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA 2. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA 4. Department of Applied Mathematics, Computer Science and Statistics, Ghent University, Ghent, BE |
| AuthorAffiliation_xml | – name: 2. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA – name: 5. Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK – name: 4. Department of Applied Mathematics, Computer Science and Statistics, Ghent University, Ghent, BE – name: 1. PRecisiOn Medicine Translational Research (PROMoTeR) Center, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA – name: 3. Department of Epidemiology, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA |
| Author_xml | – sequence: 1 givenname: Sharon M. orcidid: 0000-0002-1515-9431 surname: Lutz fullname: Lutz, Sharon M. email: smlutz@hsph.harvard.edu organization: Harvard T. H. Chan School of Public Health – sequence: 2 givenname: Ann Chen surname: Wu fullname: Wu, Ann Chen organization: Harvard Medical School and Harvard Pilgrim Health Care Institute – sequence: 3 givenname: John E. surname: Hokanson fullname: Hokanson, John E. organization: University of Colorado – sequence: 4 givenname: Stijn surname: Vansteelandt fullname: Vansteelandt, Stijn organization: London School of Hygiene and Tropical Medicine – sequence: 5 givenname: Christoph surname: Lange fullname: Lange, Christoph organization: Harvard T. H. Chan School of Public Health |
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| Cites_doi | 10.1038/d41586-019-03754-3 10.1093/hmg/ddw197 10.1093/ije/dyg070 10.1093/ntr/nty095 10.1002/sim.3034 10.1093/hmg/ddu328 10.1192/bjp.bp.109.065912 10.1002/gepi.21758 10.1002/sim.4138 10.1080/07853890802010709 10.1038/ijo.2010.137 10.1192/bjp.bp.109.074880 10.1371/journal.pgen.1007081 10.1093/biostatistics/kxx050 10.1093/ije/dyv080 10.1002/gepi.21965 10.1038/s41467-020-14452-4 10.7554/eLife.34408 10.1186/s12863-015-0299-4 10.3109/15412550903499522 10.1371/journal.pmed.1001618 10.1093/ije/dyh132 |
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| SubjectTerms | causal direction Causality Chronic obstructive pulmonary disease Lung diseases Mendelian Randomization Obstructive lung disease Phenotypes Pleiotropy Respiratory function reverse causality |
| Title | Caution against examining the role of reverse causality in Mendelian Randomization |
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