Retrospective Association Analysis of Binary Traits: Overcoming Some Limitations of the Additive Polygenic Model

Abstract

Case-control genetic association analysis is an extremely common tool in human complex trait mapping. From a statistical point of view, the analysis of binary traits poses somewhat different challenges from the analysis of quantitative traits. Desirable features of a binary trait mapping approach would include (1) phenotype modeled as binary, with appropriate dependence between the mean and variance; (2) appropriate correction for relevant covariates; (3) appropriate correction for sample structure of various types, including related individuals, admixture and other types of population structure; (4) both fast and accurate computations; (5) robustness to ascertainment and other types of phenotype model misspecification, and (6) ability to leverage partially missing data to increase power. We review these challenges and argue, both theoretically and in simulations, for the value of retrospective association analysis as a way to overcome some of the limitations of the phenotype model, including model misspecification due to ascertainment. We give an overview of two recent retrospective methods, CARAT and CERAMIC, that are designed to meet criteria 1-6.

Comparison of mixed model based approaches for correcting for population substructure with application to extreme phenotype sampling.

“…However, for binary traits in the presence of covariates, this assumption does not hold. Therefore, fitting a binary response with linear mixed models may fail to correct the type 1 error rate [23] or result in a loss of power [24]. Mixed model approaches that do not treat disease status as a continuous random variable have recently been developed.…”

Retrospective Association Analysis of Longitudinal Binary Traits Identifies Important Loci and Pathways in Cocaine Use

“…Prospective analysis in which a population-based model is used ignores ascertainment bias and can result in compromised statistical inference. Furthermore, in the ascertained sample, the prospective approach conditional on the genotype and covariates may lose information when the joint distribution of the genotype and covariates carries additional information on whether the phenotype is associated with the genotype (Jiang et al 2015). In this regard, several retrospective association methods have been proposed for analyzing ascertained population-based case-control studies (Hayeck et al 2015;Jiang et al 2016), family-based studies of continuous traits (Jakobsdottir and McPeek 2013), family-based case-control studies (Zhong et al 2016;Hayeck et al 2017), and family-based longitudinal quantitative traits (Wu and McPeek 2018).…”

“…In this regard, several retrospective association methods have been proposed for analyzing ascertained population-based case-control studies (Hayeck et al 2015;Jiang et al 2016), family-based studies of continuous traits (Jakobsdottir and McPeek 2013), family-based case-control studies (Zhong et al 2016;Hayeck et al 2017), and family-based longitudinal quantitative traits (Wu and McPeek 2018). Compared to prospective tests, retrospective tests conditional on the phenotype and covariates are more robust to misspecification of the trait model (Jiang et al 2015).…”

Retrospective Association Analysis of Longitudinal Binary Traits Identifies Important Loci and Pathways in Cocaine Use

“…Prospective analysis, in which a population-based model is used, ignores ascertainment bias and can result in compromised statistical inference. Furthermore, in the ascertained sample, the prospective approach conditional on the genotype and covariates may lose information when the joint distribution of the genotype and covariates carries additional information on whether the phenotype is associated with the genotype (Jiang et al 2015). In this regard, several retrospective association methods have been proposed for analyzing ascertained population-based case-control studies (Hayeck et al 2015;Jiang et al 2016), family-based studies of continuous traits (Jakobsdottir and McPeek 2013), family-based case-control studies (Zhong et al 2016;Hayeck et al 2017), and family-based longitudinal quantitative traits (Wu and McPeek 2018).…”