title: Incremental value of rare genetic variants for the prediction of multifactorial diseases.
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.
authors: Department of Epidemiology, Erasmus University Medical Center, Dr. Molewaterplein 50, Rotterdam, 3000 CA, The Netherlands.
authors: Raluca
authors: R
authors: Mihaescu
authors: 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.
authors: Michael J
authors: MJ
authors: Pencina
authors: Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, 1300 S. Second Street, Minneapolis, MN 55454-1015, USA.
authors: Alvaro
authors: A
authors: Alonso
authors: 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.
authors: Kathryn L
authors: KL
authors: Lunetta
authors: Department of Epidemiology, University of Washington, Seattle, 1959 NE Pacific Street, Seattle, WA 98195-7236, USA.
authors: Susan R
authors: SR
authors: Heckbert
authors: 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.
authors: Emelia J
authors: EJ
authors: Benjamin
authors: 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.
authors: A Cecile J W
authors: AC
authors: Janssens
references: Am J Epidemiol. 1989 Apr;129(4):687-702
references: 2646917
references: Stat Med. 2008 Jan 30;27(2):157-72; discussion 207-12
references: 17569110
references: Am J Hum Genet. 2010 May 14;86(5):730-42
references: 20434130
references: Nat Genet. 2008 Jun;40(6):695-701
references: 18509313
references: Clin Genet. 2011 Mar;79(3):199-206
references: 20831747
references: Arch Intern Med. 1998 Feb 9;158(3):229-34
references: 9472202
references: Mol Psychiatry. 2012 May;17(5):474-85
references: 21670730
references: J Electrocardiol. 2011 Nov-Dec;44(6):641-4
references: 21924735
references: PLoS Genet. 2011 Apr;7(4):e1002051
references: 21552331
references: Europace. 2011 Oct;13(10):1375-85
references: 21757483
references: Am J Hum Genet. 2010 Jun 11;86(6):832-8
references: 20471002
references: Science. 2010 Jul 2;329(5987):75-8
references: 20595611
references: Circulation. 2010 Jan 19;121(2):200-7
references: 20048208
references: Am J Epidemiol. 2008 Feb 1;167(3):362-8
references: 17982157
references: Nat Genet. 2008 May;40(5):592-599
references: 18391953
references: Ann Epidemiol. 1991 Feb;1(3):263-76
references: 1669507
references: J Hum Genet. 2010 Apr;55(4):219-26
references: 20203695
references: Hum Mol Genet. 2011 Oct 15;20(R2):R182-8
references: 21873261
references: Nat Genet. 2012 Apr 29;44(6):670-5
references: 22544366
references: Circulation. 2007 Feb 20;115(7):928-35
references: 17309939
references: Prev Med. 1975 Dec;4(4):518-25
references: 1208363
references: J Am Coll Cardiol. 2010 Nov 16;56(21):1712-9
references: 21070922
references: Nat Genet. 2009 Aug;41(8):879-81
references: 19597492
references: Nature. 2007 Jul 19;448(7151):353-7
references: 17603472
references: J Natl Cancer Inst. 2008 Jul 16;100(14):978-9
references: 18612128
references: N Engl J Med. 2011 Dec 1;365(22):2098-109
references: 22129254
references: Genet Med. 2006 Jul;8(7):395-400
references: 16845271
references: J Am Heart Assoc. 2013 Mar 18;2(2):e000102
references: 23537808
references: J Am Coll Cardiol. 2008 Jul 22;52(4):241-50
references: 18634977
references: BMC Proc. 2011 Nov 29;5 Suppl 9:S42
references: 22373267
references: PLoS One. 2009 Dec 02;4(12):e7969
references: 19956539
references: Am J Cardiol. 2011 Jan;107(1):85-91
references: 21146692
references: Lancet. 2009 Feb 28;373(9665):739-45
references: 19249635
references: BMC Proc. 2011 Nov 29;5 Suppl 9:S61
references: 22373337
references: Stat Med. 2011 Jan 15;30(1):11-21
references: 21204120
references: Science. 2009 Apr 17;324(5925):387-9
references: 19264985
references: Genetics. 2011 Nov;189(3):1061-8
references: 21840850
references: JAMA. 2004 Jun 16;291(23):2851-5
references: 15199036
references: Nat Genet. 2010 Mar;42(3):240-4
references: 20173747
references: Genet Epidemiol. 2011 May;35(4):236-46
references: 21308769