title: SVSI: fast and powerful set-valued system identification approach to identifying rare variants in sequencing studies for ordered categorical traits.
abstract: In genetic association studies of an ordered categorical phenotype, it is usual to either regroup multiple categories of the phenotype into two categories and then apply the logistic regression (LG), or apply ordered logistic (oLG), or ordered probit (oPRB) regression, which accounts for the ordinal nature of the phenotype. However, they may lose statistical power or may not control type I error due to their model assumption and/or instable parameter estimation algorithm when the genetic variant is rare or sample size is limited. To solve this problem, we propose a set-valued (SV) system model to identify genetic variants associated with an ordinal categorical phenotype. We couple this model with a SV system identification algorithm to identify all the key system parameters. Simulations and two real data analyses show that SV and LG accurately controlled the Type I error rate even at a significance level of 10(-6) but not oLG and oPRB in some cases. LG had significantly less power than the other three methods due to disregarding of the ordinal nature of the phenotype, and SV had similar or greater power than oLG and oPRB. We argue that SV should be employed in genetic association studies for ordered categorical phenotype.
authors.affiliation: Key Laboratory of Systems and Control, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing 100190, P.R.C.
authors.forename: Wenjian
authors.initials: W
authors.lastname: Bi
authors.affiliation: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, U.S.A.
authors.forename: Guolian
authors.initials: G
authors.lastname: Kang
authors.affiliation: Key Laboratory of Systems and Control, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing 100190, P.R.C.
authors.forename: Yanlong
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Statistics and Probability, Michigan State University, East Lansing, Michigan 48824, U.S.A.
authors.forename: Yuehua
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Department of Genetics, Department of Biostatistics, University of North Carolina, Chapel Hill, NC 27599, U.S.A.
authors.forename: Song
authors.initials: S
authors.lastname: Yan
authors.affiliation: Department of Genetics, Department of Biostatistics, University of North Carolina, Chapel Hill, NC 27599, U.S.A.|Department of Computer Science, University of North Carolina, Chapel Hill, NC 27599, U.S.A.
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, U.S.A.
authors.forename: Cheng
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, U.S.A.
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Pounds
authors.affiliation: Johns Hopkins Medical Institute, Baltimore, MD 21231, U.S.A.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Borowitz
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, U.S.A.
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, U.S.A.
authors.forename: Jun J
authors.initials: JJ
authors.lastname: Yang
authors.affiliation: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, U.S.A.
authors.forename: Zhifa
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, U.S.A.|Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, 38163, U.S.A.
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.affiliation: University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado 80045, U.S.A.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunger
authors.affiliation: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, U.S.A.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Hartford
authors.affiliation: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, U.S.A.|Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, 38163, U.S.A.
authors.forename: Wing
authors.initials: W
authors.lastname: Leung
authors.affiliation: Key Laboratory of Systems and Control, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing 100190, P.R.C.
authors.forename: Ji-Feng
authors.initials: JF
authors.lastname: Zhang
mesh_terms: D000465:Algorithms; D003198:Computer Simulation; D056726:Genetic Association Studies; D006801:Humans; D016015:Logistic Models; D008957:Models, Genetic; D018365:Neoplasm, Residual / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics
keywords: Ordered logistic model; genetic association study; multiple thresholds; rare variants; set-valued system identification