title: A General and Robust Framework for Secondary Traits Analysis.
abstract: Case-control designs are commonly employed in genetic association studies. In addition to the case-control status, data on secondary traits are often collected. Directly regressing secondary traits on genetic variants from a case-control sample often leads to biased estimation. Several statistical methods have been proposed to address this issue. The inverse probability weighting (IPW) approach and the semiparametric maximum-likelihood (SPML) approach are the most commonly used. A new weighted estimating equation (WEE) approach is proposed to provide unbiased estimation of genetic associations with secondary traits, by combining observed and counterfactual outcomes. Compared to the existing approaches, WEE is more robust against biased sampling and disease model misspecification. We conducted simulations to evaluate the performance of the WEE under various models and sampling schemes. The WEE demonstrated robustness in all scenarios investigated, had appropriate type I error, and was as powerful or more powerful than the IPW and SPML approaches. We applied the WEE to an asthma case-control study to estimate the associations between the thymic stromal lymphopoietin gene and two secondary traits: overweight status and serum IgE level. The WEE identified two SNPs associated with overweight in logistic regression, three SNPs associated with serum IgE levels in linear regression, and an additional four SNPs that were missed in linear regression to be associated with the 75th quantile of IgE in quantile regression. The WEE approach provides a general and robust secondary analysis framework, which complements the existing approaches and should serve as a valuable tool for identifying new associations with secondary traits.
authors.affiliation: Heilbrunn Department of Population and Family Health, Columbia University, New York, New York 10032 xs2148@cumc.columbia.edu.
authors.forename: Xiaoyu
authors.identifier: http://orcid.org/0000-0003-1909-6244
authors.initials: X
authors.lastname: Song
authors.affiliation: Department of Biostatistics, Columbia University, New York, New York 10032.
authors.forename: Iuliana
authors.initials: I
authors.lastname: Ionita-Laza
authors.affiliation: Department of Population Health, New York University School of Medicine, New York, New York 10016.
authors.forename: Mengling
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Medicine, New York University School of Medicine, New York, New York 10016.
authors.forename: Joan
authors.initials: J
authors.lastname: Reibman
authors.affiliation: Department of Biostatistics, Columbia University, New York, New York 10032.
authors.forename: Ying
authors.initials: Y
authors.lastname: We
mesh_terms: D000465:Algorithms; D016022:Case-Control Studies; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood / Q000235:genetics / Q000276:immunology; D008957:Models, Genetic; D015233:Models, Statistical; D050177:Overweight / Q000235:genetics; D010641:Phenotype; D011336:Probability; D019655:Quantitative Trait, Heritable
chemical_list: D007073:Immunoglobulin E
keywords: case–control studies; estimating equations; secondary trait analysis