SVSI: Fast and powerful set-valued system identification approach to identifying rare variants in sequencing studies for ordered categorical traits

Wenjian Bi, Guolian Kang, Yanlong Zhao, Yuehua Cui, Song Yan, Yun Li, Cheng Cheng, Stanley B. Pounds, Michael J. Borowitz, Mary V. Relling, Jun J. Yang, Zhifa Liu, Ching Hon Pui, Stephen P. Hunger, Christine M. Hartford, Wing Leung, Ji Feng Zhang

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)294-309
Number of pages16
JournalAnnals of Human Genetics
Volume79
Issue number4
DOIs
StatePublished - Jul 1 2015

Keywords

  • Genetic association study
  • Multiple thresholds
  • Ordered logistic model
  • Rare variants
  • Set-valued system identification

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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  • Cite this

    Bi, W., Kang, G., Zhao, Y., Cui, Y., Yan, S., Li, Y., Cheng, C., Pounds, S. B., Borowitz, M. J., Relling, M. V., Yang, J. J., Liu, Z., Pui, C. H., Hunger, S. P., Hartford, C. M., Leung, W., & Zhang, J. F. (2015). SVSI: Fast and powerful set-valued system identification approach to identifying rare variants in sequencing studies for ordered categorical traits. Annals of Human Genetics, 79(4), 294-309. https://doi.org/10.1111/ahg.12117