Informed Conditioning on Clinical Covariates Increases Power in Case-Control Association Studies

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Author
Lindström, Sara
Pasaniuc, Bogdan
Barton, Anne
Bickeböller, Heike
Bowden, Donald W.
Eyre, Steve
Freedman, Barry I.
Field, John K.
Groop, Leif
Haugen, Aage
Heinrich, Joachim
Henderson, Brian E.
Hicks, Pamela J.
Hocking, Lynne J.
Kolonel, Laurence N.
Landi, Maria Teresa
Langefeld, Carl D.
Le Marchand, Loic
Meister, Michael
Morgan, Ann W.
Raji, Olaide Y.
Risch, Angela
Rosenberger, Albert
Scherf, David
Steer, Sophia
Walshaw, Martin
Waters, Kevin M.
Wilson, Anthony G.
Wordsworth, Paul
Zienolddiny, Shanbeh
Tchetgen, Eric Tchetgen
Haiman, Christopher
Worthington, Jane
Voight, Benjamin
Patterson, Nick
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1371/journal.pgen.1003032Metadata
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Zaitlen, Noah, Sara Lindström, Bogdan Pasaniuc, Marilyn Cornelis, Giulio Genovese, Samuela Pollack, Anne Barton, et al. 2012. Informed conditioning on clinical covariates increases power in case-control association studies. PLoS Genetics 8(11): e1003032.Abstract
Genetic case-control association studies often include data on clinical covariates, such as body mass index (BMI), smoking status, or age, that may modify the underlying genetic risk of case or control samples. For example, in type 2 diabetes, odds ratios for established variants estimated from low–BMI cases are larger than those estimated from high–BMI cases. An unanswered question is how to use this information to maximize statistical power in case-control studies that ascertain individuals on the basis of phenotype (case-control ascertainment) or phenotype and clinical covariates (case-control-covariate ascertainment). While current approaches improve power in studies with random ascertainment, they often lose power under case-control ascertainment and fail to capture available power increases under case-control-covariate ascertainment. We show that an informed conditioning approach, based on the liability threshold model with parameters informed by external epidemiological information, fully accounts for disease prevalence and non-random ascertainment of phenotype as well as covariates and provides a substantial increase in power while maintaining a properly controlled false-positive rate. Our method outperforms standard case-control association tests with or without covariates, tests of gene x covariate interaction, and previously proposed tests for dealing with covariates in ascertained data, with especially large improvements in the case of case-control-covariate ascertainment. We investigate empirical case-control studies of type 2 diabetes, prostate cancer, lung cancer, breast cancer, rheumatoid arthritis, age-related macular degeneration, and end-stage kidney disease over a total of 89,726 samples. In these datasets, informed conditioning outperforms logistic regression for 115 of the 157 known associated variants investigated (P-value = 1×\(10^{−9}\)). The improvement varied across diseases with a 16% median increase in χ2 test statistics and a commensurate increase in power. This suggests that applying our method to existing and future association studies of these diseases may identify novel disease loci.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3493452/pdf/Terms of Use
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