title: What Cure Models Can Teach us About Genome-Wide Survival Analysis.
abstract: The aim of logistic regression is to estimate genetic effects on disease risk, while survival analysis aims to determine effects on age of onset. In practice, genetic variants may affect both types of outcomes. A cure survival model analyzes logistic and survival effects simultaneously. The aim of this simulation study is to assess the performance of logistic regression and traditional survival analysis under a cure model and to investigate the benefits of cure survival analysis. We simulated data under a cure model and varied the percentage of subjects at risk for disease (cure fraction), the logistic and survival effect sizes, and the contribution of genetic background risk factors. We then computed the error rates and estimation bias of logistic, Cox proportional hazards (PH), and cure PH analysis, respectively. The power of logistic and Cox PH analysis is sensitive to the cure fraction and background heritability. Our results show that traditional Cox PH analysis may erroneously detect age of onset effects if no such effects are present in the data. In the presence of genetic background risk even the cure model results in biased estimates of both the odds ratio and the hazard ratio. Cure survival analysis takes cure fractions into account and can be used to simultaneously estimate the effect of genetic variants on disease risk and age of onset. Since genome-wide cure survival analysis is not computationally feasible, we recommend this analysis for genetic variants that are significant in a traditional survival analysis.
authors.affiliation: Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research (CNCR), Neuroscience Campus Amsterdam (NCA), VU Amsterdam, Amsterdam, The Netherlands. s.stringer@vu.nl.
authors.forename: Sven
authors.identifier: http://orcid.org/0000-0003-3115-8532
authors.initials: S
authors.lastname: Stringer
authors.affiliation: Department of Psychiatry, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Damiaan
authors.initials: D
authors.lastname: Denys
authors.affiliation: Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center, Utrecht, The Netherlands.
authors.forename: René S
authors.initials: RS
authors.lastname: Kahn
authors.affiliation: Department of Psychiatry, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Eske M
authors.initials: EM
authors.lastname: Derks
mesh_terms: D003198:Computer Simulation; D055106:Genome-Wide Association Study; D006801:Humans; D016015:Logistic Models; D008957:Models, Genetic; D016016:Proportional Hazards Models; D016019:Survival Analysis
keywords: Accelerated failure time model; Cox regression; Logistic regression; Proportional hazards model; Simulation study