Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression

International Journal of Epidemiology
Jack BowdenStephen Burgess

Abstract

The number of Mendelian randomization analyses including large numbers of genetic variants is rapidly increasing. This is due to the proliferation of genome-wide association studies, and the desire to obtain more precise estimates of causal effects. However, some genetic variants may not be valid instrumental variables, in particular due to them having more than one proximal phenotypic correlate (pleiotropy). We view Mendelian randomization with multiple instruments as a meta-analysis, and show that bias caused by pleiotropy can be regarded as analogous to small study bias. Causal estimates using each instrument can be displayed visually by a funnel plot to assess potential asymmetry. Egger regression, a tool to detect small study bias in meta-analysis, can be adapted to test for bias from pleiotropy, and the slope coefficient from Egger regression provides an estimate of the causal effect. Under the assumption that the association of each genetic variant with the exposure is independent of the pleiotropic effect of the variant (not via the exposure), Egger's test gives a valid test of the null causal hypothesis and a consistent causal effect estimate even when all the genetic variants are invalid instrumental variables. We ill...Continue Reading

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Jan 1, 2019·International Journal of Epidemiology·Xia JiangPRACTICAL, CRUK, BPC3, CAPS and PEGASUS consortia
Jun 25, 2019·European Psychiatry : the Journal of the Association of European Psychiatrists·Xue GaoTong Wang
Feb 10, 2019·European Journal of Epidemiology·Siddhartha KarPaul D P Pharoah
May 6, 2019·JAMA Network Open·Renato PolimantiPsychiatric Genomics Consortium Posttraumatic Stress Disorder Working Group
Aug 9, 2019·Osteoporosis International : a Journal Established As Result of Cooperation Between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA·A ZhouElina Hyppönen
Mar 30, 2019·International Journal of Rheumatic Diseases·Y H Lee
Feb 2, 2020·Cancer Causes & Control : CCC·Xia JiangPRACTICAL, CRUK, BPC3, CAPS and PEGASUS consortia
Aug 7, 2019·Journal of Hypertension·Shiu Lun Au YeungCatherine M Schooling
Apr 16, 2020·Frontiers in Genetics·Peng-Peng NiuYu-Ming Xu
Nov 21, 2019·Nature Communications·Laurence J HoweGibran Hemani
Jan 23, 2020·Brain : a Journal of Neurology·Marios K GeorgakisMartin Dichgans
May 7, 2020·International Journal of Epidemiology·Christina DardaniGemma C Sharp
Mar 11, 2020·Translational Psychiatry·Michael W LutzOrnit Chiba-Falek
Jun 28, 2020·Nature Communications·A Floriaan SchmidtAroon D Hingorani
Apr 21, 2020·European Journal of Epidemiology·Matilde Winter-JensenKristine H Allin
Feb 26, 2020·International Journal of Epidemiology·Jonas BovijnMichael V Holmes
Sep 25, 2020·Korean Circulation Journal·Jidong Sung
Aug 8, 2020·Frontiers in Genetics·Tao WangBao-Liang Sun
Apr 2, 2020·The American Journal of Clinical Nutrition·Saranya PalaniswamyMarjo-Riitta Järvelin
Sep 10, 2020·Frontiers in Genetics·Ming ShenHongyu Zhou
Sep 22, 2016·International Journal of Epidemiology·Jack BowdenGeorge Davey Smith
Mar 16, 2018·BMC Medicine·Linden Disney-HoggRichard S Houlston
Mar 20, 2018·International Journal of Obesity : Journal of the International Association for the Study of Obesity·Dipender GillCosetta Minelli
Sep 28, 2017·International Journal of Obesity : Journal of the International Association for the Study of Obesity·Theresia M SchnurrTorben Hansen
May 26, 2018·British Journal of Cancer·Sonja NeumeyerJenny Chang-Claude
Sep 12, 2018·Current Osteoporosis Reports·Katerina Trajanoska, Fernando Rivadeneira
Nov 22, 2018·International Journal of Epidemiology·Wes SpillerGeorge Davey Smith
Sep 23, 2018·Nutrients·Marilyn C Cornelis, Marcus R Munafo
Dec 13, 2018·Proceedings of the National Academy of Sciences of the United States of America·Amanda J LeaJenny Tung
Sep 14, 2018·Zeitschrift für Rheumatologie·S-C Bae, Y H Lee
Oct 26, 2018·Stroke; a Journal of Cerebral Circulation·Dipender GillAbbas Dehghan
Jun 27, 2019·Canadian Respiratory Journal : Journal of the Canadian Thoracic Society·Yu ShiXinchen Sun
Sep 14, 2019·Human Molecular Genetics·Abdel AbdellaouiDorret I Boomsma
Oct 3, 2018·BMC Proceedings·Sergi Sayols-BaixerasStella W Aslibekyan
Aug 24, 2019·The European Respiratory Journal·Diana A van der PlaatALEC project
Sep 11, 2019·European Heart Journal·Aroon D Hingorani