Get access

A comparison of strategies for analyzing dichotomous outcomes in genome-wide association studies with general pedigrees

Authors

  • Ming-Huei Chen,

    1. Department of Neurology, Boston University School of Medicine, Boston, Massachusetts
    2. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts
    3. The NHLBI's Framingham Heart Study, Framingham, Massachusetts
    Search for more papers by this author
  • Xuan Liu,

    1. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts
    Search for more papers by this author
  • Fengrong Wei,

    1. Department of Mathematics, University of West Georgia, Carrollton, Georgia
    Search for more papers by this author
  • Martin G. Larson,

    1. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts
    2. The NHLBI's Framingham Heart Study, Framingham, Massachusetts
    3. Department of Mathematics and Statistics, Boston University, Boston, Massachusetts
    Search for more papers by this author
  • Caroline S. Fox,

    1. The NHLBI's Framingham Heart Study, Framingham, Massachusetts
    2. Brigham and Women's Hospital, Division of Endocrinology, Hypertension, and Diabetes and Harvard Medical School, Boston, Massachusetts
    Search for more papers by this author
  • Ramachandran S. Vasan,

    1. The NHLBI's Framingham Heart Study, Framingham, Massachusetts
    2. Preventive Medicine and Epidemiology, Boston University School of Medicine, Boston, Massachusetts
    Search for more papers by this author
  • Qiong Yang

    Corresponding author
    1. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts
    2. The NHLBI's Framingham Heart Study, Framingham, Massachusetts
    • Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Avenue, Crosstown Center, CT325, Boston, MA 02118
    Search for more papers by this author

Abstract

Genome-wide association studies (GWAS) have been frequently conducted on general or isolated populations with related individuals. However, there is a lack of consensus on which strategy is most appropriate for analyzing dichotomous phenotypes in general pedigrees. Using simulation studies, we compared several strategies including generalized estimating equations (GEE) strategies with various working correlation structures, generalized linear mixed model (GLMM), and a variance component strategy (denoted LMEBIN) that treats dichotomous outcomes as continuous with special attentions to their performance with rare variants, rare diseases, and small sample sizes. In our simulations, when the sample size is not small, for type I error, only GEE and LMEBIN maintain nominal type I error in most cases with exceptions for GEE with very rare disease and genetic variants. GEE and LMEBIN have similar statistical power and slightly outperform GLMM when the prevalence is low. In terms of computational efficiency, GEE with sandwich variance estimator outperforms GLMM and LMEBIN. We apply the strategies to GWAS of gout in the Framingham Heart Study. Based on our results, we would recommend using GEE ind-san in the GWAS for common variants and GEE ind-fij or LMEBIN for rare variants for GWAS of dichotomous outcomes with general pedigrees. Genet. Epidemiol. 2011.  © 2011 Wiley Periodicals, Inc. 35:650-657, 2011

Ancillary