A Robust and Powerful Set-Valued Approach to Rare Variant Association Analyses of Secondary Traits in Case-Control Sequencing Studies

doi:10.1534/genetics.116.192377

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	A Robust and Powerful Set-Valued Approach to Rare Variant Association Analyses of Secondary Traits in Case-Control Sequencing Studies
	Kang, Guolian 1; Bi, Wenjian 1; Zhang, Hang 2,3; Pounds, Stanley 1; Cheng, Cheng 1; Shete, Sanjay 4; Zou, Fei 5; Zhao, Yanlong2 ; Zhang, Ji-Feng2,3 ; Yue, Weihua 6,7
	2017-03-01
Source Publication	GENETICS
ISSN	0016-6731
Volume	205 Issue:3 Pages:1049-1062
Abstract	In many case-control designs of genome-wide association (GWAS) or next generation sequencing (NGS) studies, extensive data on secondary traits that may correlate and share the common genetic variants with the primary disease are available. Investigating these secondary traits can provide critical insights into the disease etiology or pathology, and enhance the GWAS or NGS results. Methods based on logistic regression (LG) were developed for this purpose. However, for the identification of rare variants (RVs), certain inadequacies in the LG models and algorithmic instability can cause severely inflated type I error, and significant loss of power, when the two traits are correlated and the RV is associated with the disease, especially at stringent significance levels. To address this issue, we propose a novel set-valued (SV) method that models a binary trait by dichotomization of an underlying continuous variable, and incorporate this into the genetic association model as a critical component. Extensive simulations and an analysis of seven secondary traits in a GWAS of benign ethnic neutropenia show that the SV method consistently controls type I error well at stringent significance levels, has larger power than the LG-based methods, and is robust in performance to effect pattern of the genetic variant (risk or protective), rare or common variants, rare or common diseases, and trait distributions. Because of the SV method's striking and profound advantage, we strongly recommend the SV method be employed instead of the LG-based methods for secondary traits analyses in case-control sequencing studies.
Keyword	secondary traits rare variants association analyses case-control sequencing study set-valued model
DOI	10.1534/genetics.116.192377
Language	英语
Funding Project	intramural research program of NHLBI ; NIDDK at the National Institutes of Health (NIH) ; CIDR[HHSN268200782096C] ; CIDR[HHSN268201100011I] ; American Lebanese and Syrian Associated Charities ; National Natural Science Foundation of China[11171333] ; National Natural Science Foundation of China[61134013] ; National Natural Science Foundation of China[81571313] ; National Natural Science Foundation of China[81221002]
WOS Research Area	Genetics & Heredity
WOS Subject	Genetics & Heredity
WOS ID	WOS:000395807200004
Publisher	GENETICS SOCIETY AMERICA
Citation statistics
Document Type	期刊论文
Identifier	http://ir.amss.ac.cn/handle/2S8OKBNM/25019
Collection	系统科学研究所
Corresponding Author	Kang, Guolian; Yue, Weihua
Affiliation	1.St Jude Childrens Res Hosp, Dept Biostat, Memphis, TN 38105 USA 2.Chinese Acad Sci, Acad Math & Syst Sci, Key Lab Syst & Control, Beijing 100190, Peoples R China 3.Univ Chinese Acad Sci, Sch Math Sci, Beijing 100049, Peoples R China 4.Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA 5.Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA 6.Peking Univ, Minist Hlth, Key Lab Mental Hlth, Inst Mental Hlth, Beijing 100191, Peoples R China 7.Peking Univ, Hosp 6, Natl Clin Res Ctr Mental Disorders, Beijing 100191, Peoples R China
Recommended Citation GB/T 7714	Kang, Guolian,Bi, Wenjian,Zhang, Hang,et al. A Robust and Powerful Set-Valued Approach to Rare Variant Association Analyses of Secondary Traits in Case-Control Sequencing Studies[J]. GENETICS,2017,205(3):1049-1062.
APA	Kang, Guolian.,Bi, Wenjian.,Zhang, Hang.,Pounds, Stanley.,Cheng, Cheng.,...&Yue, Weihua.(2017).A Robust and Powerful Set-Valued Approach to Rare Variant Association Analyses of Secondary Traits in Case-Control Sequencing Studies.GENETICS,205(3),1049-1062.
MLA	Kang, Guolian,et al."A Robust and Powerful Set-Valued Approach to Rare Variant Association Analyses of Secondary Traits in Case-Control Sequencing Studies".GENETICS 205.3(2017):1049-1062.

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