Adjustment for index event bias in genome-wide association studies of subsequent events

• Published in: Nature communications Vol. 10; no. 1; p. 1561
• Main Authors: Dudbridge, Frank, Allen, Richard J., Sheehan, Nuala A., Schmidt, A. Floriaan, Lee, James C., Jenkins, R. Gisli, Wain, Louise V., Hingorani, Aroon D., Patel, Riyaz S.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.04.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 45/43; 631/114/2415; 631/208/205/2138; 692/308/174; 692/308/2056; Bias; Computer Simulation; Crohn Disease - epidemiology; Crohn Disease - genetics; Fibrosis; Genetic effects; Genetic Predisposition to Disease; Genome-wide association studies; Genome-Wide Association Study; Genomes; Humanities and Social Sciences; Humans; Idiopathic Pulmonary Fibrosis - epidemiology; Idiopathic Pulmonary Fibrosis - genetics; Incidence; Lung diseases; Medical prognosis; Models, Genetic; Mucin-5B - genetics; multidisciplinary; Odds Ratio; Polymorphism, Single Nucleotide; Prognosis; Regression Analysis; Science; Science (multidisciplinary); Survival
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-09381-w

Following numerous genome-wide association studies of disease susceptibility, there is increasing interest in genetic associations with prognosis, survival or other subsequent events. Such associations are vulnerable to index event bias, by which selection of subjects according to disease status creates biased associations if common causes of incidence and prognosis are not accounted for. We propose an adjustment for index event bias using the residuals from the regression of genetic effects on prognosis on genetic effects on incidence. Our approach eliminates this bias when direct genetic effects on incidence and prognosis are independent, and otherwise reduces bias in realistic situations. In a study of idiopathic pulmonary fibrosis, we reverse a paradoxical association of the strong susceptibility gene MUC5B with increased survival, suggesting instead a significant association with decreased survival. In re-analysis of a study of Crohn’s disease prognosis, four regions remain associated at genome-wide significance but with increased standard errors. Different from GWAS for susceptibility to disease, GWAS for prognosis or survival may be vulnerable to selection bias. Here, Dudbridge et al present an approach to reduce index event bias in simulated and realistic situations, and apply it to GWAS of survival with idiopathic pulmonary fibrosis and Crohn’s disease prognosis.