Impact of Selection Bias on Estimation of Subsequent Event Risk

• DOI: 10.1161/circgenetics.116.001616
• Publication Date: 2017-10-07T00:11:00Z
• Authors: Yi-Juan Hu; Amand F. Schmidt; Frank Dudbridge; Michael V. Holmes; James M. Brophy; Vinicius Tragante; Ziyi Li; Peizhou Liao; Arshed A. Quyyumi; Raymond O. McCubrey; Benjamin D. Horne; Aroon D. Hingorani; Folkert W. Asselb...; Riyaz S. Patel; Qi Long; Axel Åkerblom; Ale Algra; Hooman Allayee; Peter Almgren; Jeffrey L. Anderson; Maria G. Andreassi; Chiara V. Anselmi; Diego Ardissino; Benoit J. Arsenault; Christie M. Balla...; Ekaterina V. Bara...; Hassan Behloui; Thomas O. Bergmeijer; Connie R. Bezzina; Eythor Bjornsson; Simon C. Body; Bram Boeckx; Eric (H.) Boersma; Eric Boerwinkle; Peter Bogaty; Peter S. Braund; Lutz P. Breitling; Hermann Brenner; Carlo Briguori; Jasper J. Brugts; Ralph Burkhardt; Vicky A. Cameron; John F. Carlquist; Clara Carpeggiani; Kathryn F. Carrut...; Gavino Casu; Gianluigi Condorelli; Sharon Cresci; Nicolas Danchin; Ulf de Faire; John Deanfield; Graciela Delgado; Panos Deloukas; Kenan Direk; Robert N. Doughty; Heinz Drexel; Nubia E. Duarte; Marie-Pierre Dubé; Line Dufresne; James C. Engert; Niclas Eriksson; Natalie Fitzpatrick; Luisa Foco; Ian Ford; Keith A.A. Fox; Bruna Gigante; Crystel M. Gijsberts; Domenico Girelli; Yan Gong; Daniel F. Gudbjar...; Emil Hagström; Jaana Hartiala; Stanley L. Hazen; Claes Held; Anna Helgadottir; Harry Hemingway; Mahyar Heydarpour; Imo E. Hoefer; Kees Hovingh; Jaroslav A. Hubacek; Stefan James; Julie A. Johnson; J. Wouter Jukema; Marcin P. Kaczor; Karol A. Kaminski; Jiri Kettner; Marek Kiliszek; Marcus Kleber; Olaf H. Klungel; Daniel Kofink; Mika Kohonen; Salma Kotti; Pekka Kuukasjärvi; Bo Lagerqvist; Diether Lambrechts; Chim C. Lang; Jari O. Laurikka; Karin Leander; Vei-Vei Lee; Terho Lehtimäki; Andreas Leiherer; Petra A. Lenzini; Daniel Levin; Daniel Lindholm; Marja-Liisa Lokki; Paulo A. Lotufo; Leo-Pekka Lyytikä...; B. Khan Mahmoodi; Anke H. Maitland-...; Nicola Martinelli; Winfried März; Nicola Marziliano; Ruth McPherson; Olle Melander; Ute Mons; Jochen D. Muehlsc...; Joseph B. Muhlestein; Cristopher P. Nelson; Chris Newton Cheh; Oliviero Olivieri; Grzegorz Opolski; Colin N. Palmer; Guillaume Pare; Gerard Pasterkamp; Carl J. Pepine; Witold Pepinski; Alexandre C. Pereira; Anna P. Pilbrow; Louise Pilote; Jan Pitha; Rafal Ploski; A. Mark Richards; Christoph H. Saely; Nilesh J. Samani; Ayman Samman-Tahhan; Marek Sanak; Pratik B. Sandesara; Naveed Sattar; Markus Scholz; Agneta Siegbahn; Tabassome Simon; Juha Sinisalo; J. Gustav Smith; John A. Spertus; Kari Stefansson; Alexandre F.R. St...; David J. Stott; Wojciech Szczeklik; Anna Szpakowicz; Michael W.T. Tanck; Wilson H. Tang; Jean-Claude Tardif; Jur M. ten Berg; Andrej Teren; George Thanassoulis; Joachim Thiery; Gudmundur Thorgei...; Gudmar Thorleifsson; Unnur Thorsteinsd...; Adam Timmis; Stella Trompet; Frans van de Werf; Yolanda van der G...; Pim van der Haarst; Sander W. van der...; Ragnar O. Vilmund...; Salim S. Virani; Frank L.J. Visseren; Efthymia Vlachopo...; Lars Wallentin; Johannes Waltenbe...; Els Wauters; Arthur A.M. Wilde
• Keywords: Risk; Genetic association studies; COLLIDER BIAS; genetic association studies; Confidence intervals; Cardiology; HEART-DISEASE; OBESITY PARADOX; EXPLANATION; 519; 03 medical and health sciences; Humans; selection bias; False Positive Reactions; Alleles; confidence intervals; risk; Selection bias; Observer Variation; 0303 health sciences; Models, Genetic; Sample size; Genetic Diseases, Inborn; ASSOCIATION; sample size; 3. Good health; Cardiovascular Diseases; CARDIOVASCULAR-DISEASE; alleles; confidence intervals; genetic association studies; risk; sample size; selection bias; alleles; INDEX-EVENT; Medical Genetics

Background— Studies of recurrent or subsequent disease events may be susceptible to bias caused by selection of subjects who both experience and survive the primary indexing event. Currently, the magnitude of any selection bias, particularly for subsequent time-to-event analysis in genetic association studies, is unknown.

Methods and Results— We used empirically inspired simulation studies to explore the impact of selection bias on the marginal hazard ratio for risk of subsequent events among those with established coronary heart disease. The extent of selection bias was determined by the magnitudes of genetic and nongenetic effects on the indexing (first) coronary heart disease event. Unless the genetic hazard ratio was unrealistically large (>1.6 per allele) and assuming the sum of all nongenetic hazard ratios was <10, bias was usually <10% (downward toward the null). Despite the low bias, the probability that a confidence interval included the true effect decreased (undercoverage) with increasing sample size because of increasing precision. Importantly, false-positive rates were not affected by selection bias.

Conclusions— In most empirical settings, selection bias is expected to have a limited impact on genetic effect estimates of subsequent event risk. Nevertheless, because of undercoverage increasing with sample size, most confidence intervals will be over precise (not wide enough). When there is no effect modification by history of coronary heart disease, the false-positive rates of association tests will be close to nominal.