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Informed Conditioning on Clinical Covariates Increases Power in Case-Control Association Studies
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نویسنده
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zaitlen n. ,lindström s. ,pasaniuc b. ,cornelis m. ,genovese g. ,pollack s. ,barton a. ,bickeböller h. ,bowden d.w. ,eyre s. ,freedman b.i. ,friedman d.j. ,field j.k. ,groop l. ,haugen a. ,heinrich j. ,henderson b.e. ,hicks p.j. ,hocking l.j. ,kolonel l.n. ,landi m.t. ,langefeld c.d. ,le marchand l. ,meister m. ,morgan a.w. ,raji o.y. ,risch a. ,rosenberger a. ,scherf d. ,steer s. ,walshaw m. ,waters k.m. ,wilson a.g. ,wordsworth p. ,zienolddiny s. ,tchetgen e.t. ,haiman c. ,hunter d.j. ,plenge r.m. ,worthington j. ,christiani d.c. ,schaumberg d.a. ,chasman d.i. ,altshuler d. ,voight b. ,kraft p. ,patterson n. ,price a.l.
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منبع
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plos genetics - 2012 - دوره : 8 - شماره : 11
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چکیده
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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. © 2012 zaitlen et al.
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آدرس
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department of epidemiology,harvard school of public health,boston,ma,united states,department of biostatistics,harvard school of public health,boston,ma,united states,broad institute of harvard and massachusetts institute of technology,cambridge,ma,united states,program in molecular and genetic epidemiology,harvard school of public health,boston,ma, United States, department of epidemiology,harvard school of public health,boston,ma,united states,program in molecular and genetic epidemiology,harvard school of public health,boston,ma, United States, department of epidemiology,harvard school of public health,boston,ma,united states,department of biostatistics,harvard school of public health,boston,ma,united states,broad institute of harvard and massachusetts institute of technology,cambridge,ma,united states,program in molecular and genetic epidemiology,harvard school of public health,boston,ma, United States, channing laboratory,department of medicine,brigham and women's hospital and harvard medical school,boston,ma, United States, division of nephrology,department of medicine,beth israel deaconess medical center and harvard medical school,boston,ma, United States, department of epidemiology,harvard school of public health,boston,ma,united states,department of biostatistics,harvard school of public health,boston,ma,united states,broad institute of harvard and massachusetts institute of technology,cambridge,ma,united states,program in molecular and genetic epidemiology,harvard school of public health,boston,ma, United States, arthritis research uk epidemiology unit,manchester academic health science centre,the university of manchester,manchester, United Kingdom, department of genetic epidemiology,university medical centre,university of göttingen,göttingen, Germany, center for human genomics,wake forest school of medicine,winston-salem,nc, United States, arthritis research uk epidemiology unit,manchester academic health science centre,the university of manchester,manchester, United Kingdom, department of internal medicine/section on nephrology,wake forest school of medicine,winston-salem,nc, United States, division of nephrology,department of medicine,beth israel deaconess medical center and harvard medical school,boston,ma, United States, roy castle lung cancer research programme,university of liverpool,liverpool, United Kingdom, department of clinical sciences,diabetes and endocrinology research unit,scania university hospital,lund university,malmö, Sweden, section for toxicology,national institute of occupational health,oslo, Norway, institute of epidemiology,german research centre for environmental health,neuherberg, Germany, department of preventive medicine,university of southern california keck school of medicine,los angeles,ca, United States, department of biochemistry,wake forest university school of medicine,winston-salem,nc, United States, musculoskeletal research programme,division of applied medicine,university of aberdeen,aberdeen, United Kingdom, epidemiology program,cancer research center,university of hawaii,honolulu,hi, United States, division of cancer epidemiology and genetics,national cancer institute,national institutes of health,bethesda,md, United States, division of public health sciences,wake forest university school of medicine,winston-salem,nc, United States, epidemiology program,cancer research center,university of hawaii,honolulu,hi, United States, thoraxklinik am universitätsklinikum,heidelberg,germany,translational lung research centre heidelberg (tlrc-h),german center for lung research,heidelberg, Germany, nihr-leeds musculoskeletal biomedical research unit,leeds, United Kingdom, roy castle lung cancer research programme,university of liverpool,liverpool, United Kingdom, translational lung research centre heidelberg (tlrc-h),german center for lung research,heidelberg,germany,dkfz-german cancer research center,heidelberg, Germany, department of genetic epidemiology,university medical centre,university of göttingen,göttingen, Germany, dkfz-german cancer research center,heidelberg, Germany, king's college hospital national health service foundation trust,london, United Kingdom, liverpool heart and chest hospital,liverpool, United Kingdom, department of preventive medicine,university of southern california keck school of medicine,los angeles,ca, United States, deptartment of infection and immunity,university of sheffield,sheffield, United Kingdom, nihr oxford musculoskeletal biomedical research unit,nuffield orthopaedic centre,oxford, United Kingdom, section for toxicology,national institute of occupational health,oslo, Norway, department of epidemiology,harvard school of public health,boston,ma,united states,department of biostatistics,harvard school of public health,boston,ma, United States, department of preventive medicine,university of southern california keck school of medicine,los angeles,ca, United States, department of epidemiology,harvard school of public health,boston,ma,united states,broad institute of harvard and massachusetts institute of technology,cambridge,ma,united states,program in molecular and genetic epidemiology,harvard school of public health,boston,ma,united states,channing laboratory,department of medicine,brigham and women's hospital and harvard medical school,boston,ma, United States, broad institute of harvard and massachusetts institute of technology,cambridge,ma,united states,division of rheumatology,immunology,and allergy,division of genetics,brigham and women's hospital,boston,ma, United States, arthritis research uk epidemiology unit,manchester academic health science centre,the university of manchester,manchester, United Kingdom, department of epidemiology,harvard school of public health,boston,ma,united states,department of environmental health,harvard school of public health,boston,ma, United States, department of epidemiology,harvard school of public health,boston,ma,united states,division of preventive medicine,department of medicine,brigham and women's hospital,boston,harvard medical school,massachusetts,united kingdom,schepens eye research institute,department of ophthalmology,harvard medical school,boston,ma, United States, schepens eye research institute,department of ophthalmology,harvard medical school,boston,ma, United States, broad institute of harvard and massachusetts institute of technology,cambridge,ma,united states,center for human genetic research,department of molecular biology and diabetes unit,massachusetts general hospital,boston,ma,united states,departments of genetics and medicine,harvard medical school,boston,ma, United States, broad institute of harvard and massachusetts institute of technology,cambridge,ma,united states,center for human genetic research,department of molecular biology and diabetes unit,massachusetts general hospital,boston,ma,united states,departments of genetics and medicine,harvard medical school,boston,ma, United States, department of epidemiology,harvard school of public health,boston,ma,united states,department of biostatistics,harvard school of public health,boston,ma,united states,broad institute of harvard and massachusetts institute of technology,cambridge,ma,united states,program in molecular and genetic epidemiology,harvard school of public health,boston,ma, United States, broad institute of harvard and massachusetts institute of technology,cambridge,ma, United States, department of epidemiology,harvard school of public health,boston,ma,united states,department of biostatistics,harvard school of public health,boston,ma,united states,broad institute of harvard and massachusetts institute of technology,cambridge,ma,united states,program in molecular and genetic epidemiology,harvard school of public health,boston,ma, United States
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Authors
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