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Analysis of Sequence Data Under Multivariate Trait-Dependent Sampling.

TitleAnalysis of Sequence Data Under Multivariate Trait-Dependent Sampling.
Publication TypeJournal Article
Year of Publication2015
AuthorsTao R, Zeng D, Franceschini N, North KE, Boerwinkle E
Secondary AuthorsLin D-Y
JournalJ Am Stat Assoc
Volume110
Issue510
Pagination560-572
Date Published2015 Jun 01
ISSN0162-1459
Abstract

High-throughput DNA sequencing allows for the genotyping of common and rare variants for genetic association studies. At the present time and for the foreseeable future, it is not economically feasible to sequence all individuals in a large cohort. A cost-effective strategy is to sequence those individuals with extreme values of a quantitative trait. We consider the design under which the sampling depends on multiple quantitative traits. Under such trait-dependent sampling, standard linear regression analysis can result in bias of parameter estimation, inflation of type I error, and loss of power. We construct a likelihood function that properly reflects the sampling mechanism and utilizes all available data. We implement a computationally efficient EM algorithm and establish the theoretical properties of the resulting maximum likelihood estimators. Our methods can be used to perform separate inference on each trait or simultaneous inference on multiple traits. We pay special attention to gene-level association tests for rare variants. We demonstrate the superiority of the proposed methods over standard linear regression through extensive simulation studies. We provide applications to the Cohorts for Heart and Aging Research in Genomic Epidemiology Targeted Sequencing Study and the National Heart, Lung, and Blood Institute Exome Sequencing Project.

DOI10.1080/01621459.2015.1008099
Alternate JournalJ Am Stat Assoc
PubMed ID26366025
PubMed Central IDPMC4565625
Grant ListP01 CA142538 / CA / NCI NIH HHS / United States
R01 CA082659 / CA / NCI NIH HHS / United States
R01 GM047845 / GM / NIGMS NIH HHS / United States
R37 GM047845 / GM / NIGMS NIH HHS / United States