title: Gene-Based Association Analysis for Censored Traits Via Fixed Effect Functional Regressions.
abstract: Genetic studies of survival outcomes have been proposed and conducted recently, but statistical methods for identifying genetic variants that affect disease progression are rarely developed. Motivated by our ongoing real studies, here we develop Cox proportional hazard models using functional regression (FR) to perform gene-based association analysis of survival traits while adjusting for covariates. The proposed Cox models are fixed effect models where the genetic effects of multiple genetic variants are assumed to be fixed. We introduce likelihood ratio test (LRT) statistics to test for associations between the survival traits and multiple genetic variants in a genetic region. Extensive simulation studies demonstrate that the proposed Cox RF LRT statistics have well-controlled type I error rates. To evaluate power, we compare the Cox FR LRT with the previously developed burden test (BT) in a Cox model and sequence kernel association test (SKAT), which is based on mixed effect Cox models. The Cox FR LRT statistics have higher power than or similar power as Cox SKAT LRT except when 50%/50% causal variants had negative/positive effects and all causal variants are rare. In addition, the Cox FR LRT statistics have higher power than Cox BT LRT. The models and related test statistics can be useful in the whole genome and whole exome association studies. An age-related macular degeneration dataset was analyzed as an example.
authors.affiliation: Division of Intramural Population Health Research, Biostatistics and Bioinformatics Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Ruzong
authors.initials: R
authors.lastname: Fan
authors.affiliation: Division of Intramural Population Health Research, Biostatistics and Bioinformatics Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Pulmonary Medicine, Allergy and Immunology, Children's Hospital of Pittsburgh at The University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Qi
authors.initials: Q
authors.lastname: Yan
authors.affiliation: Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.|Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Weeks
authors.affiliation: Division of Intramural Population Health Research, Biostatistics and Bioinformatics Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Regeneron Pharmaceuticals, Inc, Basking Ridge, New Jersey, United States of America.
authors.forename: Haobo
authors.initials: H
authors.lastname: Ren
authors.affiliation: Department of Statistics and Actuarial Science, Waterloo, ON, Canada.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Cook
authors.affiliation: Human Genetics Center, University of Texas, Houston, Texas, United States of America.
authors.forename: Momiao
authors.initials: M
authors.lastname: Xiong
authors.affiliation: Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, NIH, Bethesda, Maryland, United States of America.
authors.forename: Anand
authors.initials: A
authors.lastname: Swaroop
authors.affiliation: Division of Epidemiology and Clinical Applications, National Eye Institute, NIH, Bethesda, Maryland, United States of America.
authors.forename: Emily Y
authors.initials: EY
authors.lastname: Chew
authors.affiliation: Division of Pulmonary Medicine, Allergy and Immunology, Children's Hospital of Pittsburgh at The University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.|Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.|Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
mesh_terms: D003198:Computer Simulation; D018450:Disease Progression; D059472:Exome / Q000235:genetics; D056726:Genetic Association Studies / Q000379:methods*; D005820:Genetic Testing; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008957:Models, Genetic; D010641:Phenotype; D016016:Proportional Hazards Models; D012044:Regression Analysis
keywords: Cox models; association study; common variants; complex diseases; functional data analysis; rare variants