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On Efficient and Accurate Calculation of Significance P-Values for Sequence Kernel Association Testing of Variant Set.

TitleOn Efficient and Accurate Calculation of Significance P-Values for Sequence Kernel Association Testing of Variant Set.
Publication TypeJournal Article
Year of Publication2016
AuthorsWu B, Guan W
Secondary AuthorsPankow JS
JournalAnn Hum Genet
Volume80
Issue2
Pagination123-35
Date Published2016 Mar
ISSN1469-1809
KeywordsAlgorithms, Atherosclerosis, Blood Glucose, Computer Simulation, Exome, Genetic Association Studies, Genetic Variation, Glucose-6-Phosphatase, Humans, Models, Genetic, Software
Abstract

The objective of this paper is to discuss and develop alternative computational methods to accurately and efficiently calculate significance P-values for the commonly used sequence kernel association test (SKAT) and adaptive sum of SKAT and burden test (SKAT-O) for variant set association. We show that the existing software can lead to either conservative or inflated type I errors. We develop alternative and efficient computational algorithms that quickly compute the SKAT P-value and have well-controlled type I errors. In addition, we derive an alternative and simplified formula for calculating the significance P-value of SKAT-O, which sheds light on the development of efficient and accurate numerical algorithms. We implement the proposed methods in the publicly available R package that can be readily used or adapted to large-scale sequencing studies. Given that more and more large-scale exome and whole genome sequencing or re-sequencing studies are being conducted, the proposed methods are practically very important. We conduct extensive numerical studies to investigate the performance of the proposed methods. We further illustrate their usefulness with application to associations between rare exonic variants and fasting glucose levels in the Atherosclerosis Risk in Communities (ARIC) study.

DOI10.1111/ahg.12144
Alternate JournalAnn Hum Genet
PubMed ID26757198
PubMed Central IDPMC4761292
Grant ListHHSN268201100012C / HL / NHLBI NIH HHS / United States
HHSN268201000010C / HL / NHLBI NIH HHS / United States
RC2 HL102419 / HL / NHLBI NIH HHS / United States
HHSN268201100001I / HL / NHLBI NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
R01 CA134848 / CA / NCI NIH HHS / United States
HHSN268201100005G / HL / NHLBI NIH HHS / United States
HHSN268201100008I / HL / NHLBI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
HHSN268201100011I / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
HHSN268201000011C / HL / NHLBI NIH HHS / United States
GM083345 / GM / NIGMS NIH HHS / United States
CA134848 / CA / NCI NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
HHSN268201100005I / HL / NHLBI NIH HHS / United States
HHSN268201100002C / WH / WHI NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
R01 GM083345 / GM / NIGMS NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
HHSN268201100002I / HL / NHLBI NIH HHS / United States
HHSN268201000012C / HL / NHLBI NIH HHS / United States
HHSN268201100001C / WH / WHI NIH HHS / United States