Abstract 3565: The Cox proportional hazards mixed model enables accurate estimation of the total effect somatic SNVs have on treatment outcomes
Authors: Taraszka Kodi , Gusev Alexander 
Published: March 2024

Heritability is the variation in disease susceptibility attributed to genetic variation and is a fundamental parameter for interpreting disease architecture and making predictions. In the context of germline genetics, variance component models are commonly used to estimate heritability for continuous or case-control phenotypes (under the liability threshold model, LTM). However, models for time-to-event (TTE) outcomes have been largely unstudied. This has limited the characterization of age-of-onset and treatment response phenotypes, the latter particularly relevant for clinical studies. Here, we propose and evaluate a Cox proportional hazard Mixed Model (COXMM) to enable accurate estimation for TTE phenotypes with censoring. We apply these methods to Real World data from the Profile cohort from Dana-Farber Cancer Institute, a large prospectively collected tumor sequencing cohort with detailed clinical annotation. We implemented an efficient COXMM with a random effect modeled by the genetic relatedness across individuals, and benchmarked its performance in extensive simulations. We simulated phenotypes according to generative models reflecting either LTM or TTE models. For TTE phenotypes, data followed various Weibull distributions with independent censoring. Across TTE simulations, COXMM produced unbiased estimates while the classic case-control heritability estimator showed significant downward bias. Likewise, restricting only to cases and estimating the heritability of age-of-onset as a normalized continuous phenotype produced biased estimates, due to the artificial exclusion of controls. For example, for an age-of-onset with heritability of 0.8 and 40% of individuals in the study being cases, COXMM correctly inferred the heritability to be 0.80 +/- 0.007, compared to 0.32 +/- 0.004 for a conventional case-control model, and 0.09 +/- 0.02 for a conventional case-only age-of-onset model. In the Profile cohort, we analyzed the impact of somatic SNVs on progression free survival (PFS) and overall survival (OS) in patients with non-small cell lung cancer (N=954 and N=1796, respectively). We restricted to somatic SNVs present in at least 5% of patients. For OS, we observed that the COXMM heritability estimate was significantly larger than those computed by case-control status and using a normalized case-only age/duration (COXMM: 0.19 +/- 0.003; Case-Control: 0.07 +/- 0.2; Duration: 0.04 +/- 0.01). We observed a similar phenomenon for PFS as well (COXMM: 0.11 +/- 0.01; Case-Control: 0.03 +/- 0.4; Duration: 0.03 +/- 0.02). These results demonstrate that somatic features are most strongly associated with TTE and can be accurately estimated with COXMM. COXMM enables the efficient quantification of TTE heritability for diverse clinical phenotypes and outperforms existing methods.

Citation Format: Kodi Taraszka, Alexander Gusev. The Cox proportional hazards mixed model enables accurate estimation of the total effect somatic SNVs have on treatment outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3565.