scroll to top

EBSCO Auth Banner

Let's find your institution. Click here.

Informed conditioning on clinical covariates increases power in case-control association studies.

  • Academic Journal
  • PLoS genetics [PLoS Genet] 2012; Vol. 8 (11), pp. e1003032. Date of Electronic Publication: 2012 Nov 08.
  • English
  • 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 χ(2) 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.
    Competing Interests: The authors have declared that no competing interests exist.
Additional Information
Publisher: Public Library of Science Country of Publication: United States NLM ID: 101239074 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1553-7404 (Electronic) Linking ISSN: 15537390 NLM ISO Abbreviation: PLoS Genet Subsets: MEDLINE
Original Publication: San Francisco, CA : Public Library of Science, c2005-
Science. 2010 Aug 13;329(5993):841-5. (PMID: 20647424)
Am J Hum Genet. 2006 Mar;78(3):498-504. (PMID: 16465623)
Nat Rev Cancer. 2005 Dec;5(12):977-85. (PMID: 16341085)
Arch Ophthalmol. 2007 Jan;125(1):55-62. (PMID: 17210852)
Nat Genet. 2012 Jul 22;44(8):848-51. (PMID: 22820511)
PLoS One. 2011 Feb 24;6(2):e17142. (PMID: 21390317)
PLoS Genet. 2010 Feb 26;6(2):e1000864. (PMID: 20195508)
Nat Genet. 2010 Jul;42(7):579-89. (PMID: 20581827)
Nat Genet. 2006 Aug;38(8):904-9. (PMID: 16862161)
Am J Hum Genet. 1996 Apr;58(4):836-43. (PMID: 8644748)
Annu Rev Public Health. 2002;23:151-69. (PMID: 11910059)
Carcinogenesis. 2009 Jun;30(6):987-90. (PMID: 19369581)
Carcinogenesis. 2008 Jun;29(6):1164-9. (PMID: 18258609)
Nat Genet. 2009 Mar;41(3):334-41. (PMID: 19198609)
Am J Hum Genet. 2011 Mar 11;88(3):294-305. (PMID: 21376301)
Science. 2007 May 11;316(5826):889-94. (PMID: 17434869)
Behav Genet. 2000 Mar;30(2):141-6. (PMID: 10979604)
Nat Genet. 2011 Mar 06;43(4):316-20. (PMID: 21378987)
Ethn Dis. 2009 Winter;19(1):49-55. (PMID: 19341163)
Nat Genet. 2011 Oct 23;43(12):1232-6. (PMID: 22019782)
J Natl Cancer Inst. 2011 Aug 17;103(16):1252-63. (PMID: 21791674)
Nat Genet. 2009 Dec;41(12):1335-40. (PMID: 19915574)
Clin Chem. 2008 Feb;54(2):249-55. (PMID: 18070814)
Genetics. 1989 Jan;121(1):185-99. (PMID: 2563713)
PLoS Genet. 2010 Aug 26;6(8):. (PMID: 20865176)
Nat Genet. 2007 Dec;39(12):1431-3. (PMID: 17982455)
PLoS Genet. 2012 May;8(5):e1002741. (PMID: 22693455)
Ann Hum Genet. 1967 Aug;31(1):1-20. (PMID: 6056557)
Nat Rev Genet. 2010 Jul;11(7):459-63. (PMID: 20548291)
Genet Epidemiol. 2009 Dec;33(8):717-28. (PMID: 19365863)
Nat Genet. 2011 Jul 10;43(8):785-91. (PMID: 21743467)
Br Med Bull. 1996 Jan;52(1):3-11. (PMID: 8746292)
Bioinformatics. 2012 Jul 1;28(13):1729-37. (PMID: 22556366)
Am J Epidemiol. 2012 May 15;175(10):1013-20. (PMID: 22306564)
Proc Natl Acad Sci U S A. 2009 Mar 10;106(10):3871-6. (PMID: 19202052)
Stat Med. 1994 Jan 30;13(2):153-62. (PMID: 8122051)
Nat Rev Genet. 2010 Apr;11(4):259-72. (PMID: 20212493)
Nature. 2008 Apr 3;452(7187):537-8. (PMID: 18385720)
Science. 1995 Jun 16;268(5217):1584-9. (PMID: 7777857)
Nat Genet. 2010 May;42(5):366-8. (PMID: 20428092)
PLoS Genet. 2008 Feb 29;4(2):e1000008. (PMID: 18454194)
Nat Genet. 2011 Oct 09;43(11):1127-30. (PMID: 21983786)
Proc Natl Acad Sci U S A. 2006 Sep 19;103(38):14068-73. (PMID: 16945910)
PLoS Genet. 2011 Aug;7(8):e1002237. (PMID: 21876681)
Circ Cardiovasc Genet. 2010 Jun;3(3):286-93. (PMID: 20400779)
Nat Genet. 2007 Jul;39(7):906-13. (PMID: 17572673)
Hum Hered. 2007;63(2):111-9. (PMID: 17283440)
Int J Biostat. 2008 Sep 29;4(1):Article 19. (PMID: 20231910)
Int J Oncol. 2005 Dec;27(6):1633-45. (PMID: 16273220)
Genet Epidemiol. 2010 Apr;34(3):246-53. (PMID: 20025064)
Genet Epidemiol. 2011 May;35(4):236-46. (PMID: 21308769)
PLoS Genet. 2010 Dec 02;6(12):e1001230. (PMID: 21151957)
Nat Genet. 2012 Jul 15;44(8):895-9. (PMID: 22797725)
Genet Epidemiol. 2012 May;36(4):409-18. (PMID: 22508388)
R01 CA092824 United States CA NCI NIH HHS; HL043851 United States HL NHLBI NIH HHS; U01-CA98233-07 United States CA NCI NIH HHS; R01 HG006399 United States HG NHGRI NIH HHS; 17552 United Kingdom ARC_ Arthritis Research UK; U01-CA98710-06 United States CA NCI NIH HHS; U01-CA98216-06 United States CA NCI NIH HHS; R01 CA047988 United States CA NCI NIH HHS; U19 HL069757 United States HL NHLBI NIH HHS; U01 CA098758 United States CA NCI NIH HHS; U01-CA98758-07 United States CA NCI NIH HHS; R21 ES020754 United States ES NIEHS NIH HHS; U01 HL069757 United States HL NHLBI NIH HHS; U01 CA098710 United States CA NCI NIH HHS; U19 CA148127 United States CA NCI NIH HHS; R01 ES020337 United States ES NIEHS NIH HHS; T32 ES007142 United States ES NIEHS NIH HHS; HL69757 United States HL NHLBI NIH HHS; R01 HL043851 United States HL NHLBI NIH HHS; 5T32ES007142-27 United States ES NIEHS NIH HHS; U01 CA098216 United States CA NCI NIH HHS; CA 047988 United States CA NCI NIH HHS; U01 CA098233 United States CA NCI NIH HHS; United States ImNIH Intramural NIH HHS
Date Created: 20121113 Date Completed: 20130513 Latest Revision: 20220129