title: The benefits of using genetic information to design prevention trials.
abstract: Clinical trials for preventative therapies are complex and costly endeavors focused on individuals likely to develop disease in a short time frame, randomizing them to treatment groups, and following them over time. In such trials, statistical power is governed by the rate of disease events in each group and cost is determined by randomization, treatment, and follow-up. Strategies that increase the rate of disease events by enrolling individuals with high risk of disease can significantly reduce study size, duration, and cost. Comprehensive study of common, complex diseases has resulted in a growing list of robustly associated genetic markers. Here, we evaluate the utility--in terms of trial size, duration, and cost--of enriching prevention trial samples by combining clinical information with genetic risk scores to identify individuals at greater risk of disease. We also describe a framework for utilizing genetic risk scores in these trials and evaluating the associated cost and time savings. With type 1 diabetes (T1D), type 2 diabetes (T2D), myocardial infarction (MI), and advanced age-related macular degeneration (AMD) as examples, we illustrate the potential and limitations of using genetic data for prevention trial design. We illustrate settings where incorporating genetic information could reduce trial cost or duration considerably, as well as settings where potential savings are negligible. Results are strongly dependent on the genetic architecture of the disease, but we also show that these benefits should increase as the list of robustly associated markers for each disease grows and as large samples of genotyped individuals become available.
authors.affiliation: Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Youna
authors.initials: Y
authors.lastname: Hu
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Margaret G
authors.initials: MG
authors.lastname: Ehm
authors.forename: Nan
authors.initials: N
authors.lastname: Bing
authors.forename: Kijoung
authors.initials: K
authors.lastname: Song
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Nelson
authors.forename: Philippa J
authors.initials: PJ
authors.lastname: Talmud
authors.forename: Aroon D
authors.initials: AD
authors.lastname: Hingorani
authors.forename: Meena
authors.initials: M
authors.lastname: Kumari
authors.forename: Mika
authors.initials: M
authors.lastname: Kivimäki
authors.forename: Chun-Fang
authors.initials: CF
authors.lastname: Xu
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Waterworth
authors.forename: John C
authors.initials: JC
authors.lastname: Whittaker
authors.forename: Gonçalo R
authors.initials: GR
authors.lastname: Abecasis
authors.forename: Cathie
authors.initials: C
authors.lastname: Spino
authors.forename: Hyun Min
authors.initials: HM
authors.lastname: Kang
mesh_terms: D002986:Clinical Trials as Topic; D003362:Cost-Benefit Analysis; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000517:prevention & control*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000517:prevention & control*; D005820:Genetic Testing / Q000706:statistics & numerical data*; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics / Q000517:prevention & control*; D015233:Models, Statistical; D009203:Myocardial Infarction / Q000235:genetics / Q000517:prevention & control*; D010641:Phenotype; D012107:Research Design; D012307:Risk Factors
references.citation: PLoS Genet. 2011 Jul;7(7):e1002198
references.pmid: 21829380
references.citation: Clin Cancer Res. 2008 Oct 1;14(19):5984-93
references.pmid: 18829477
references.citation: Nat Genet. 2009 Jun;41(6):703-7
references.pmid: 19430480
references.citation: Cellscience. 2006 Apr 30;2(4):100-131
references.pmid: 16892160
references.citation: PLoS Genet. 2006 Sep 22;2(9):e157
references.pmid: 17002500
references.citation: N Engl J Med. 2008 Nov 20;359(21):2195-207
references.pmid: 18997196
references.citation: Biometrics. 2009 Mar;65(1):188-97
references.pmid: 18510654
references.citation: Nat Rev Drug Discov. 2004 May;3(5):417-29
references.pmid: 15136789
references.citation: N Engl J Med. 2008 Jun 26;358(26):2796-803
references.pmid: 18579814
references.citation: Eur J Hum Genet. 2011 Feb;19(2):180-5
references.pmid: 21081969
references.citation: Nat Genet. 2009 Mar;41(3):334-41
references.pmid: 19198609
references.citation: Arch Intern Med. 2007 May 28;167(10):1068-74
references.pmid: 17533210
references.citation: Diabetologia. 2009 Apr;52(4):600-8
references.pmid: 19139842
references.citation: Exp Clin Cardiol. 2009 Fall;14(3):33-7
references.pmid: 20098575
references.citation: Control Clin Trials. 1981 Jun;2(2):93-113
references.pmid: 7273794
references.citation: Pharmacol Ther. 2009 Mar;121(3):317-31
references.pmid: 19168093
references.citation: Invest Ophthalmol Vis Sci. 2009 May;50(5):2044-53
references.pmid: 19117936
references.citation: Lancet. 2009 Apr 4;373(9670):1175-82
references.pmid: 19329177
references.citation: BMJ. 2010 Jan 14;340:b4838
references.pmid: 20075150
references.citation: Lancet. 2006 Sep 23;368(9541):1096-105
references.pmid: 16997664
references.citation: Neurology. 2007 Oct 16;69(16):1622-34
references.pmid: 17938373
references.citation: N Engl J Med. 2006 Jul 20;355(3):241-50
references.pmid: 16855264
references.citation: Schizophr Bull. 2010 Jan;36(1):14-23
references.pmid: 19996148
references.citation: Arch Ophthalmol. 2011 Dec;129(12):1543-50
references.pmid: 21825180
references.citation: Radiology. 1982 Apr;143(1):29-36
references.pmid: 7063747
references.citation: Nat Genet. 2010 Jul;42(7):579-89
references.pmid: 20581827
references.citation: JAMA. 2007 Oct 10;298(14):1682-4
references.pmid: 17925520
references.citation: Diabetes. 2003 Apr;52(4):1052-5
references.pmid: 12663480
references.citation: Diabetes Care. 2004 Oct;27(10):2568-9; author reply 2569
references.pmid: 15451946
references.citation: Diabetes Care. 2009 Dec;32(12):2269-74
references.pmid: 19741189
references.citation: Am J Ophthalmol. 2012 Sep;154(3):568-578.e12
references.pmid: 22704140
references.citation: Circulation. 1980 Mar;61(3):503-8
references.pmid: 7353240
references.citation: Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7401-6
references.pmid: 20385819
references.citation: Nat Genet. 2010 Jul;42(7):565-9
references.pmid: 20562875
references.citation: Arch Ophthalmol. 2005 Mar;123(3):321-7
references.pmid: 15767473