Display options
Cite
Mihaescu R, Pencina MJ, Alonso A, et al. Incremental value of rare genetic variants for the prediction of multifactorial diseases. Genome Med. 2013;5(8):76doi: 10.1186/gm480.
Mihaescu, R., Pencina, M. J., Alonso, A., Lunetta, K. L., Heckbert, S. R., Benjamin, E. J., & Janssens, A. C. (2013). Incremental value of rare genetic variants for the prediction of multifactorial diseases. Genome medicine, 5(8), 76. https://doi.org/10.1186/gm480
Mihaescu, Raluca, et al. "Incremental value of rare genetic variants for the prediction of multifactorial diseases." Genome medicine vol. 5,8 (2013): 76. doi: https://doi.org/10.1186/gm480
Mihaescu R, Pencina MJ, Alonso A, Lunetta KL, Heckbert SR, Benjamin EJ, Janssens AC. Incremental value of rare genetic variants for the prediction of multifactorial diseases. Genome Med. 2013 Aug 20;5(8):76. doi: 10.1186/gm480. eCollection 2013. PMID: 23961719; PMCID: PMC3971349.
Copy Download .nbib Format: NLM
Share it on

Genome Med. 2013 Aug 20;5(8):76. doi: 10.1186/gm480. eCollection 2013.

Incremental value of rare genetic variants for the prediction of multifactorial diseases.

Genome medicine

Raluca Mihaescu, Michael J Pencina, Alvaro Alonso, Kathryn L Lunetta, Susan R Heckbert, Emelia J Benjamin, A Cecile J W Janssens

Affiliations

  1. Department of Epidemiology, Erasmus University Medical Center, Dr. Molewaterplein 50, Rotterdam, 3000 CA, The Netherlands.
  2. Department of Biostatistics, Boston University, 801 Massachusetts Avenue, Boston, MA 02118, USA ; Harvard Clinical Research Institute, 930-W Commonwealth Avenue, Boston, MA 02215-1212, USA.
  3. Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, 1300 S. Second Street, Minneapolis, MN 55454-1015, USA.
  4. Department of Biostatistics, Boston University, 801 Massachusetts Avenue, Boston, MA 02118, USA ; The National Heart, Lung, and Blood Institute's Framingham Heart Study, 73 Mt. Wayte Avenue, Framingham, MA 01702-5827, USA.
  5. Department of Epidemiology, University of Washington, Seattle, 1959 NE Pacific Street, Seattle, WA 98195-7236, USA.
  6. The National Heart, Lung, and Blood Institute's Framingham Heart Study, 73 Mt. Wayte Avenue, Framingham, MA 01702-5827, USA ; Cardiology and Preventive Medicine Section, Boston University School of Medicine, Boston, 715 Albany Street, MA 02118, USA ; Department of Epidemiology, Boston University School of Public Health, Boston, 715 Albany Street, MA 02118, USA.
  7. Department of Epidemiology, Erasmus University Medical Center, Dr. Molewaterplein 50, Rotterdam, 3000 CA, The Netherlands ; Emory University, Rollins School of Public Health, 1518 Clifton Road, Atlanta, GA 30322 USA.

PMID: 23961719 PMCID: PMC3971349 DOI: 10.1186/gm480

Abstract

BACKGROUND: It is often assumed that rare genetic variants will improve available risk prediction scores. We aimed to estimate the added predictive ability of rare variants for risk prediction of common diseases in hypothetical scenarios.

METHODS: In simulated data, we constructed risk models with an area under the ROC curve (AUC) ranging between 0.50 and 0.95, to which we added a single variant representing the cumulative frequency and effect (odds ratio, OR) of multiple rare variants. The frequency of the rare variant ranged between 0.0001 and 0.01 and the OR between 2 and 10. We assessed the resulting AUC, increment in AUC, integrated discrimination improvement (IDI), net reclassification improvement (NRI(>0.01)) and categorical NRI. The analyses were illustrated by a simulation of atrial fibrillation risk prediction based on a published clinical risk model.

RESULTS: We observed minimal improvement in AUC with the addition of rare variants. All measures increased with the frequency and OR of the variant, but maximum increment in AUC remained below 0.05. Increment in AUC and NRI(>0.01) decreased with higher AUC of the baseline model, whereas IDI remained constant. In the atrial fibrillation example, the maximum increment in AUC was 0.02 for a variant with frequency = 0.01 and OR = 10. IDI and NRI showed at most minimal increase for variants with frequency greater than or equal to 0.005 and OR greater than or equal to 5.

CONCLUSIONS: Since rare variants are present in only a minority of affected individuals, their predictive ability is generally low at the population level. To improve the predictive ability of clinical risk models for complex diseases, genetic variants must be common and have substantial effect on disease risk.

References

  1. Am J Epidemiol. 1989 Apr;129(4):687-702 - PubMed
  2. Stat Med. 2008 Jan 30;27(2):157-72; discussion 207-12 - PubMed
  3. Am J Hum Genet. 2010 May 14;86(5):730-42 - PubMed
  4. Nat Genet. 2008 Jun;40(6):695-701 - PubMed
  5. Clin Genet. 2011 Mar;79(3):199-206 - PubMed
  6. Arch Intern Med. 1998 Feb 9;158(3):229-34 - PubMed
  7. Mol Psychiatry. 2012 May;17(5):474-85 - PubMed
  8. J Electrocardiol. 2011 Nov-Dec;44(6):641-4 - PubMed
  9. PLoS Genet. 2011 Apr;7(4):e1002051 - PubMed
  10. Europace. 2011 Oct;13(10):1375-85 - PubMed
  11. Am J Hum Genet. 2010 Jun 11;86(6):832-8 - PubMed
  12. Science. 2010 Jul 2;329(5987):75-8 - PubMed
  13. Circulation. 2010 Jan 19;121(2):200-7 - PubMed
  14. Am J Epidemiol. 2008 Feb 1;167(3):362-8 - PubMed
  15. Nat Genet. 2008 May;40(5):592-599 - PubMed
  16. Ann Epidemiol. 1991 Feb;1(3):263-76 - PubMed
  17. J Hum Genet. 2010 Apr;55(4):219-26 - PubMed
  18. Hum Mol Genet. 2011 Oct 15;20(R2):R182-8 - PubMed
  19. Nat Genet. 2012 Apr 29;44(6):670-5 - PubMed
  20. Circulation. 2007 Feb 20;115(7):928-35 - PubMed
  21. Prev Med. 1975 Dec;4(4):518-25 - PubMed
  22. J Am Coll Cardiol. 2010 Nov 16;56(21):1712-9 - PubMed
  23. Nat Genet. 2009 Aug;41(8):879-81 - PubMed
  24. Nature. 2007 Jul 19;448(7151):353-7 - PubMed
  25. J Natl Cancer Inst. 2008 Jul 16;100(14):978-9 - PubMed
  26. N Engl J Med. 2011 Dec 1;365(22):2098-109 - PubMed
  27. Genet Med. 2006 Jul;8(7):395-400 - PubMed
  28. J Am Heart Assoc. 2013 Mar 18;2(2):e000102 - PubMed
  29. J Am Coll Cardiol. 2008 Jul 22;52(4):241-50 - PubMed
  30. BMC Proc. 2011 Nov 29;5 Suppl 9:S42 - PubMed
  31. PLoS One. 2009 Dec 02;4(12):e7969 - PubMed
  32. Am J Cardiol. 2011 Jan;107(1):85-91 - PubMed
  33. Lancet. 2009 Feb 28;373(9665):739-45 - PubMed
  34. BMC Proc. 2011 Nov 29;5 Suppl 9:S61 - PubMed
  35. Stat Med. 2011 Jan 15;30(1):11-21 - PubMed
  36. Science. 2009 Apr 17;324(5925):387-9 - PubMed
  37. Genetics. 2011 Nov;189(3):1061-8 - PubMed
  38. JAMA. 2004 Jun 16;291(23):2851-5 - PubMed
  39. Nat Genet. 2010 Mar;42(3):240-4 - PubMed
  40. Genet Epidemiol. 2011 May;35(4):236-46 - PubMed

Publication Types