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Family-based association tests for rare variants with censored traits.

Publication ,  Journal Article
Qi, W; Allen, AS; Li, Y-J
Published in: PLoS One
2019

We propose a set of family-based burden and kernel tests for censored traits (FamBAC and FamKAC). Here, censored traits refer to time-to-event outcomes, for instance, age-at-onset of a disease. To model censored traits in family-based designs, we used the frailty model, which incorporated not only fixed genetic effects of rare variants in a region of interest but also random polygenic effects shared within families. We first partitioned genotype scores of rare variants into orthogonal between- and within-family components, and then derived their corresponding efficient score statistics from the frailty model. Finally, FamBAC and FamKAC were constructed by aggregating the weighted efficient scores of the within-family components across rare variants and subjects. FamBAC collapsed rare variants within subject first to form a burden test that followed a chi-squared distribution; whereas FamKAC was a variant component test following a mixture of chi-squared distributions. For FamKAC, p-values can be computed by permutation tests or for computational efficiency by approximation methods. Through simulation studies, we showed that type I error was correctly controlled by FamBAC for various variant weighting schemes (0.0371 to 0.0527). However, FamKAC type I error rates based on approximation methods were deflated (max 0.0376) but improved by permutation tests. Our simulations also demonstrated that burden test FamBAC had higher power than kernel test FamKAC when high proportion (e.g. ≥ 80%) of causal variants had effects in the same direction. In contrast, when the effects of causal variants on the censored trait were in mixed directions, FamKAC outperformed FamBAC and had comparable or higher power than an existing method, RVFam. Our proposed framework has the flexibility to accommodate general nuclear families, and can be used to analyze sequence data for censored traits such as age-at-onset of a complex disease of interest.

Duke Scholars

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2019

Volume

14

Issue

1

Start / End Page

e0210870

Location

United States

Related Subject Headings

  • Proportional Hazards Models
  • Models, Genetic
  • Male
  • Humans
  • Genotype
  • Genetic Variation
  • Genetic Association Studies
  • General Science & Technology
  • Gene Frequency
  • Female
 

Citation

APA
Chicago
ICMJE
MLA
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Qi, W., Allen, A. S., & Li, Y.-J. (2019). Family-based association tests for rare variants with censored traits. PLoS One, 14(1), e0210870. https://doi.org/10.1371/journal.pone.0210870
Qi, Wenjing, Andrew S. Allen, and Yi-Ju Li. “Family-based association tests for rare variants with censored traits.PLoS One 14, no. 1 (2019): e0210870. https://doi.org/10.1371/journal.pone.0210870.
Qi W, Allen AS, Li Y-J. Family-based association tests for rare variants with censored traits. PLoS One. 2019;14(1):e0210870.
Qi, Wenjing, et al. “Family-based association tests for rare variants with censored traits.PLoS One, vol. 14, no. 1, 2019, p. e0210870. Pubmed, doi:10.1371/journal.pone.0210870.
Qi W, Allen AS, Li Y-J. Family-based association tests for rare variants with censored traits. PLoS One. 2019;14(1):e0210870.

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2019

Volume

14

Issue

1

Start / End Page

e0210870

Location

United States

Related Subject Headings

  • Proportional Hazards Models
  • Models, Genetic
  • Male
  • Humans
  • Genotype
  • Genetic Variation
  • Genetic Association Studies
  • General Science & Technology
  • Gene Frequency
  • Female