Informed conditioning on clinical covariates increases power in case-control association studies
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–...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Public Library of Science
2012
|
| _version_ | 1797077694203035648 |
|---|---|
| author | Zaitlen, N Lindström, S Pasaniuc, B Cornelis, M Genovese, G Pollack, S Barton, A Bickeböller, H Bowden, D Eyre, S Freedman, B Friedman, D Field, J Groop, L Haugen, A Heinrich, J Henderson, B Hicks, P Hocking, L Kolonel, L Landi, M Langefeld, C Le Marchand, L Meister, M Morgan, A Raji, O Risch, A Rosenberger, A Scherf, D Steer, S Walshaw, M Waters, K Wilson, A Wordsworth, B Zienolddiny, S Tchetgen, E Haiman, C Hunter, D Plenge, R Worthington, J Christiani, D Schaumberg, D Chasman, D Altshuler, D Voight, B Kraft, P Patterson, N Price, A |
| author_facet | Zaitlen, N Lindström, S Pasaniuc, B Cornelis, M Genovese, G Pollack, S Barton, A Bickeböller, H Bowden, D Eyre, S Freedman, B Friedman, D Field, J Groop, L Haugen, A Heinrich, J Henderson, B Hicks, P Hocking, L Kolonel, L Landi, M Langefeld, C Le Marchand, L Meister, M Morgan, A Raji, O Risch, A Rosenberger, A Scherf, D Steer, S Walshaw, M Waters, K Wilson, A Wordsworth, B Zienolddiny, S Tchetgen, E Haiman, C Hunter, D Plenge, R Worthington, J Christiani, D Schaumberg, D Chasman, D Altshuler, D Voight, B Kraft, P Patterson, N Price, A |
| author_sort | Zaitlen, N |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T00:21:39Z |
| format | Journal article |
| id | oxford-uuid:7cc1e4fa-3a1f-4df1-860a-5df851e017b3 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T00:21:39Z |
| publishDate | 2012 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | oxford-uuid:7cc1e4fa-3a1f-4df1-860a-5df851e017b32022-03-26T20:59:14ZInformed conditioning on clinical covariates increases power in case-control association studiesJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:7cc1e4fa-3a1f-4df1-860a-5df851e017b3EnglishSymplectic Elements at OxfordPublic Library of Science2012Zaitlen, NLindström, SPasaniuc, BCornelis, MGenovese, GPollack, SBarton, ABickeböller, HBowden, DEyre, SFreedman, BFriedman, DField, JGroop, LHaugen, AHeinrich, JHenderson, BHicks, PHocking, LKolonel, LLandi, MLangefeld, CLe Marchand, LMeister, MMorgan, ARaji, ORisch, ARosenberger, AScherf, DSteer, SWalshaw, MWaters, KWilson, AWordsworth, BZienolddiny, STchetgen, EHaiman, CHunter, DPlenge, RWorthington, JChristiani, DSchaumberg, DChasman, DAltshuler, DVoight, BKraft, PPatterson, NPrice, AGenetic 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. |
| spellingShingle | Zaitlen, N Lindström, S Pasaniuc, B Cornelis, M Genovese, G Pollack, S Barton, A Bickeböller, H Bowden, D Eyre, S Freedman, B Friedman, D Field, J Groop, L Haugen, A Heinrich, J Henderson, B Hicks, P Hocking, L Kolonel, L Landi, M Langefeld, C Le Marchand, L Meister, M Morgan, A Raji, O Risch, A Rosenberger, A Scherf, D Steer, S Walshaw, M Waters, K Wilson, A Wordsworth, B Zienolddiny, S Tchetgen, E Haiman, C Hunter, D Plenge, R Worthington, J Christiani, D Schaumberg, D Chasman, D Altshuler, D Voight, B Kraft, P Patterson, N Price, A Informed conditioning on clinical covariates increases power in case-control association studies |
| title | Informed conditioning on clinical covariates increases power in case-control association studies |
| title_full | Informed conditioning on clinical covariates increases power in case-control association studies |
| title_fullStr | Informed conditioning on clinical covariates increases power in case-control association studies |
| title_full_unstemmed | Informed conditioning on clinical covariates increases power in case-control association studies |
| title_short | Informed conditioning on clinical covariates increases power in case-control association studies |
| title_sort | informed conditioning on clinical covariates increases power in case control association studies |
| work_keys_str_mv | AT zaitlenn informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT lindstroms informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT pasaniucb informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT cornelism informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT genoveseg informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT pollacks informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT bartona informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT bickebollerh informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT bowdend informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT eyres informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT freedmanb informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT friedmand informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT fieldj informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT groopl informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT haugena informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT heinrichj informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT hendersonb informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT hicksp informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT hockingl informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT kolonell informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT landim informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT langefeldc informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT lemarchandl informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT meisterm informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT morgana informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT rajio informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT rischa informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT rosenbergera informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT scherfd informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT steers informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT walshawm informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT watersk informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT wilsona informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT wordsworthb informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT zienolddinys informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT tchetgene informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT haimanc informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT hunterd informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT plenger informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT worthingtonj informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT christianid informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT schaumbergd informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT chasmand informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT altshulerd informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT voightb informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT kraftp informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT pattersonn informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies AT pricea informedconditioningonclinicalcovariatesincreasespowerincasecontrolassociationstudies |