title: Heritability of and mortality prediction with a longevity phenotype: the healthy aging index.
abstract: BACKGROUND
  Longevity-associated genes may modulate risk for age-related diseases and survival. The Healthy Aging Index (HAI) may be a subphenotype of longevity, which can be constructed in many studies for genetic analysis. We investigated the HAI's association with survival in the Cardiovascular Health Study and heritability in the Long Life Family Study.
  
  
  METHODS
  The HAI includes systolic blood pressure, pulmonary vital capacity, creatinine, fasting glucose, and Modified Mini-Mental Status Examination score, each scored 0, 1, or 2 using approximate tertiles and summed from 0 (healthy) to 10 (unhealthy). In Cardiovascular Health Study, the association with mortality and accuracy predicting death were determined with Cox proportional hazards analysis and c-statistics, respectively. In Long Life Family Study, heritability was determined with a variance component-based family analysis using a polygenic model.
  
  
  RESULTS
  Cardiovascular Health Study participants with unhealthier index scores (7-10) had 2.62-fold (95% confidence interval: 2.22, 3.10) greater mortality than participants with healthier scores (0-2). The HAI alone predicted death moderately well (c-statistic = 0.643, 95% confidence interval: 0.626, 0.661, p < .0001) and slightly worse than age alone (c-statistic = 0.700, 95% confidence interval: 0.684, 0.717, p < .0001; p < .0001 for comparison of c-statistics). Prediction increased significantly with adjustment for demographics, health behaviors, and clinical comorbidities (c-statistic = 0.780, 95% confidence interval: 0.765, 0.794, p < .0001). In Long Life Family Study, the heritability of the HAI was 0.295 (p < .0001) overall, 0.387 (p < .0001) in probands, and 0.238 (p = .0004) in offspring.
  
  
  CONCLUSIONS
  The HAI should be investigated further as a candidate phenotype for uncovering longevity-associated genes in humans.
authors.affiliation: Graduate School of Public Health, University of Pittsburgh, A527 Crabtree Hall, 130 DeSoto Street, Pittsburgh, PA 15261. newmana@edc.pitt.edu.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Sanders
authors.forename: Ryan L
authors.initials: RL
authors.lastname: Minster
authors.forename: M Michael
authors.initials: MM
authors.lastname: Barmada
authors.forename: Amy M
authors.initials: AM
authors.lastname: Matteini
authors.forename: Robert M
authors.initials: RM
authors.lastname: Boudreau
authors.forename: Kaare
authors.initials: K
authors.lastname: Christensen
authors.forename: Richard
authors.initials: R
authors.lastname: Mayeux
authors.forename: Ingrid B
authors.initials: IB
authors.lastname: Borecki
authors.forename: Qunyuan
authors.initials: Q
authors.lastname: Zhang
authors.forename: Thomas
authors.initials: T
authors.lastname: Perls
authors.forename: Anne B
authors.initials: AB
authors.lastname: Newman
mesh_terms: D000368:Aged; D000375:Aging / Q000235:genetics*; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D015438:Health Behavior; D006801:Humans; D008136:Longevity / Q000235:genetics*; D008297:Male; D010641:Phenotype; D012189:Retrospective Studies; D012307:Risk Factors; D015996:Survival Rate / Q000639:trends; D014481:United States / Q000453:epidemiology
keywords: Epidemiology; Genetics; Longevity; Successful aging.
references.citation: Diabetes Care. 1997 Jul;20(7):1183-97
references.pmid: 9203460
references.citation: J Gerontol A Biol Sci Med Sci. 2003 Mar;58(3):232-7
references.pmid: 12634289
references.citation: PLoS Genet. 2008 Aug 15;4(8):e1000161
references.pmid: 18704162
references.citation: JAMA. 2011 Jan 5;305(1):50-8
references.pmid: 21205966
references.citation: J Gerontol A Biol Sci Med Sci. 2010 Dec;65(12):1375-9
references.pmid: 20813793
references.citation: Arch Intern Med. 2000 Jun 26;160(12):1761-8
references.pmid: 10871968
references.citation: J Clin Psychiatry. 1987 Aug;48(8):314-8
references.pmid: 3611032
references.citation: Dan Med Bull. 2006 Nov;53(4):441-9
references.pmid: 17150149
references.citation: Biometrics. 1988 Sep;44(3):837-45
references.pmid: 3203132
references.citation: Nature. 2010 Mar 25;464(7288):504-12
references.pmid: 20336132
references.citation: Exp Gerontol. 2010 Jan;45(1):2-4
references.pmid: 19651201
references.citation: Stroke. 1996 Aug;27(8):1274-82
references.pmid: 8711786
references.citation: Circ Cardiovasc Genet. 2009 Feb;2(1):73-80
references.pmid: 20031568
references.citation: JAMA. 2005 Apr 13;293(14):1737-45
references.pmid: 15827312
references.citation: Ann Epidemiol. 1991 Feb;1(3):263-76
references.pmid: 1669507
references.citation: Am J Hum Genet. 1998 May;62(5):1198-211
references.pmid: 9545414
references.citation: J Clin Psychol. 1986 Jan;42(1):28-33
references.pmid: 3950011
references.citation: Circulation. 1995 Aug 15;92(4):720-6
references.pmid: 7641349
references.citation: J Gerontol A Biol Sci Med Sci. 2012 Dec;67(12):1439-46
references.pmid: 22546961
references.citation: J Am Geriatr Soc. 2001 Aug;49(8):1032-8
references.pmid: 11555063
references.citation: J Am Coll Cardiol. 2004 Jun 16;43(12):2236-41
references.pmid: 15193686
references.citation: Am J Epidemiol. 2009 Dec 15;170(12):1555-62
references.pmid: 19910380
references.citation: Exp Gerontol. 1988;23(4-5):223-39
references.pmid: 3058488
references.citation: J Gerontol A Biol Sci Med Sci. 2008 Jun;63(6):603-9
references.pmid: 18559635
references.citation: J Am Geriatr Soc. 2011 Sep;59(9):1581-8
references.pmid: 21883106
references.citation: Chest. 2003 Feb;123(2):387-98
references.pmid: 12576356
references.citation: Lancet. 1999 Aug 21;354(9179):652
references.pmid: 10466675
references.citation: Circulation. 1993 Sep;88(3):837-45
references.pmid: 8353913
references.citation: Arch Intern Med. 2008 Feb 11;168(3):277-83
references.pmid: 18268168
references.citation: JAMA. 1993 Jun 2;269(21):2741-8
references.pmid: 8492399
references.citation: J Gerontol A Biol Sci Med Sci. 2003 Aug;58(8):715-20
references.pmid: 12902529
references.citation: Am J Public Health. 2012 Apr;102(4):e3-10
references.pmid: 22397355
references.citation: Exp Gerontol. 2006 Dec;41(12):1243-6
references.pmid: 17071038
references.citation: J Gerontol A Biol Sci Med Sci. 2012 Apr;67(4):409-16
references.pmid: 21934123
references.citation: J Gerontol A Biol Sci Med Sci. 2012 Apr;67(4):395-405
references.pmid: 22219514
references.citation: PLoS One. 2012;7(1):e29848
references.pmid: 22279548
references.citation: Am J Med. 2004 Dec 1;117(11):851-60
references.pmid: 15589490