Genetic association analysis under complex survey sampling: The hispanic community health study/study of latinos

Dan Yu Lin, Ran Tao, William D. Kalsbeek, Donglin Zeng, Franklyn Gonzalez, Lindsay Fernández-Rhodes, Mariaelisa Graff, Gary G. Koch, Kari E. North, Gerardo Heiss

Research output: Contribution to journalArticlepeer-review

54 Scopus citations


The cohort design allows investigators to explore the genetic basis of a variety of diseases and traits in a single study while avoiding major weaknesses of the case-control design. Most cohort studies employ multistage cluster sampling with unequal probabilities to conveniently select participants with desired characteristics, and participants from different clusters might be genetically related. Analysis that ignores the complex sampling design can yield biased estimation of the genetic association and inflation of the type I error. Herein, we develop weighted estimators that reflect unequal selection probabilities and differential nonresponse rates, and we derive variance estimators that properly account for the sampling design and the potential relatedness of participants in different sampling units. We compare, both analytically and numerically, the performance of the proposed weighted estimators with unweighted estimators that disregard the sampling design. We demonstrate the usefulness of the proposed methods through analysis of MetaboChip data in the Hispanic Community Health Study/Study of Latinos, which is the largest health study of the Hispanic/Latino population in the United States aimed at identifying risk factors for various diseases and determining the role of genes and environment in the occurrence of diseases. We provide guidelines on the use of weighted and unweighted estimators, as well as the relevant software.

Original languageEnglish (US)
Pages (from-to)675-688
Number of pages14
JournalAmerican Journal of Human Genetics
Issue number6
StatePublished - Dec 4 2014

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)


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