title: Thirty-one novel biomarkers as predictors for clinically incident diabetes.
abstract: BACKGROUND
  The prevalence of diabetes is increasing in all industrialized countries and its prevention has become a public health priority. However, the predictors of diabetes risk are insufficiently understood. We evaluated, whether 31 novel biomarkers could help to predict the risk of incident diabetes.
  
  
  RESULTS
  The biomarkers were evaluated primarily in the FINRISK97 cohort (n = 7,827; 417 cases of clinically incident diabetes during the follow-up). The findings were replicated in the Health 2000 cohort (n = 4,977; 179 cases of clinically incident diabetes during the follow-up). We used Cox proportional hazards models to calculate the relative risk of diabetes, after adjusting for the classic risk factors, separately for each biomarker. Next, we assessed the discriminatory ability of single biomarkers using receiver operating characteristic curves and C-statistics, integrated discrimination improvement (IDI) and net reclassification improvement (NRI). Finally, we derived a biomarker score in the FINRISK97 cohort and validated it in the Health 2000 cohort. A score consisting of adiponectin, apolipoprotein B, C-reactive protein and ferritin almost doubled the relative risk of diabetes in the validation cohort (HR per one standard deviation increase 1.88, p = 2.8 e-5). It also improved discrimination of the model (IDI = 0.0149, p<0.0001) and reclassification of diabetes risk (NRI = 11.8%, p = 0.006). Gender-specific analyses suggested that the best score differed between men and women. Among men, the best results were obtained with the score of four biomarkers: adiponectin, apolipoprotein B, ferritin and interleukin-1 receptor antagonist, which gave an NRI of 25.4% (p<0.0001). Among women, the best score included adiponectin, apolipoprotein B, C-reactive protein and insulin. It gave an NRI of 13.6% (p = 0.041).
  
  
  CONCLUSIONS
  We identified novel biomarkers that were associated with the risk of clinically incident diabetes over and above the classic risk factors. This gives new insights into the pathogenesis of diabetes and may help with targeting prevention and treatment.
authors.affiliation: Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland. veikko.salomaa@thl.fi
authors.forename: Veikko
authors.initials: V
authors.lastname: Salomaa
authors.forename: Aki
authors.initials: A
authors.lastname: Havulinna
authors.forename: Olli
authors.initials: O
authors.lastname: Saarela
authors.forename: Tanja
authors.initials: T
authors.lastname: Zeller
authors.forename: Pekka
authors.initials: P
authors.lastname: Jousilahti
authors.forename: Antti
authors.initials: A
authors.lastname: Jula
authors.forename: Thomas
authors.initials: T
authors.lastname: Muenzel
authors.forename: Arpo
authors.initials: A
authors.lastname: Aromaa
authors.forename: Alun
authors.initials: A
authors.lastname: Evans
authors.forename: Kari
authors.initials: K
authors.lastname: Kuulasmaa
authors.forename: Stefan
authors.initials: S
authors.lastname: Blankenberg
mesh_terms: D052242:Adiponectin / Q000097:blood; D000328:Adult; D000368:Aged; D001055:Apolipoproteins B / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000032:analysis; D015331:Cohort Studies; D003920:Diabetes Mellitus / Q000175:diagnosis*; D005260:Female; D005293:Ferritins / Q000097:blood; D006801:Humans; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D012372:ROC Curve; D012306:Risk; D012737:Sex Factors
chemical_list: D052242:Adiponectin; D001055:Apolipoproteins B; D015415:Biomarkers; D002097:C-Reactive Protein; D005293:Ferritins
references.citation: Arch Intern Med. 2007 May 28;167(10):1068-74
references.pmid: 17533210
references.citation: Diabetes. 1995 Apr;44(4):369-74
references.pmid: 7698502
references.citation: Diabetes Care. 2005 Aug;28(8):2013-8
references.pmid: 16043747
references.citation: Diabetes. 2002 May;51(5):1596-600
references.pmid: 11978661
references.citation: Diabetes Care. 2009 Sep;32(9):1663-8
references.pmid: 19542207
references.citation: N Engl J Med. 2008 Nov 20;359(21):2220-32
references.pmid: 19020324
references.citation: JAMA. 2002 May 15;287(19):2570-81
references.pmid: 12020339
references.citation: Diabetes. 2004 Sep;53(9):2473-8
references.pmid: 15331562
references.citation: Curr Diab Rep. 2006 Dec;6(6):479-83
references.pmid: 17118233
references.citation: Eur Heart J. 2006 Feb;27(3):296-301
references.pmid: 16284204
references.citation: Am J Epidemiol. 2007 May 1;165(9):1047-54
references.pmid: 17284722
references.citation: Diabetes. 2005 Oct;54(10):2932-8
references.pmid: 16186395
references.citation: N Engl J Med. 2008 Nov 20;359(21):2208-19
references.pmid: 19020323
references.citation: Int J Epidemiol. 2010 Apr;39(2):504-18
references.pmid: 19959603
references.citation: Stat Med. 2008 Jan 30;27(2):157-72; discussion 207-12
references.pmid: 17569110
references.citation: Diabetes Care. 2009 Feb;32(2):287-94
references.pmid: 19017771
references.citation: BMJ. 2006 Jan 14;332(7533):73-8
references.pmid: 16371403
references.citation: Diabetologia. 2008 Jun;51(6):926-40
references.pmid: 18392804
references.citation: Curr Opin Nephrol Hypertens. 2003 May;12(3):273-82
references.pmid: 12698065
references.citation: Ann Intern Med. 2010 Feb 2;152(3):195-6; author reply 196-7
references.pmid: 20124243
references.citation: N Engl J Med. 2007 Apr 12;356(15):1517-26
references.pmid: 17429083
references.citation: Diabetes Care. 2007 May;30(5):1200-5
references.pmid: 17322479
references.citation: N Engl J Med. 2001 May 3;344(18):1343-50
references.pmid: 11333990
references.citation: Arch Intern Med. 2003 Jan 13;163(1):93-9
references.pmid: 12523922
references.citation: Nutr Metab Cardiovasc Dis. 2008 Nov;18(9):581-4
references.pmid: 18804989
references.citation: Diabetes Care. 2003 Mar;26(3):725-31
references.pmid: 12610029
references.citation: Diabetes Care. 2009 Mar;32(3):421-3
references.pmid: 19073760
references.citation: Diabetes Care. 2009 Jul;32(7):1207-12
references.pmid: 19564473
references.citation: JAMA. 2004 Feb 11;291(6):711-7
references.pmid: 14871914
references.citation: Diabetologia. 2007 May;50(5):949-56
references.pmid: 17333112
references.citation: N Engl J Med. 2002 Feb 7;346(6):393-403
references.pmid: 11832527
references.citation: Biometrics. 2000 Jun;56(2):337-44
references.pmid: 10877287
references.citation: Diabetes Care. 2008 Oct;31(10):2056-61
references.pmid: 18689695