title: Successful prospective prediction of type 1 diabetes in schoolchildren through multiple defined autoantibodies: an 8-year follow-up of the Washington State Diabetes Prediction Study.
abstract: OBJECTIVE
  Almost 90% of type 1 diabetes appears in individuals without a close family history. We sought to evaluate the best current predictive strategy, multiple defined autoantibodies, in a long-term prospective study in the general population.
  
  
  METHODS
  Autoantibodies to pancreatic islets (islet cell antibodies [ICAs]) and defined autoantibodies (d-aab) to human GAD, IA2/ICA512, and insulin were tested in 4,505 Washington schoolchildren. Eight years later, 3,000 (67%) subjects were recontacted, including 97% of subjects with any test >99th percentile.
  
  
  RESULTS
  Six subjects developed diabetes (median interval 2.8 years), all from among the 12 individuals with multiple d-aab, representing 50% positive predictive value (95% CI 25-75%) and 100% sensitivity (58-100%). Among the others, diabetes occurred in 0 of 6 with one d-aab plus ICA, 0 of 26 with ICA only, 0 of 7 with one d-aab equaling the 99th percentile and another d-aab equaling the 97.5th percentile, 0 of 86 with one d-aab, and 0 of 2,863 with no d-aab or ICA. Adjusted for verification bias, multiple d-aab were 99.9% specific (99.86-99.93%). At this age, new d-aab seldom appeared. Once present, d-aab usually persisted regardless of disease progression, although less so for insulin autoantibodies. Insulin secretion by sequential glucose tolerance testing remained normal in four multiple d-aab subjects not developing diabetes. Of children developing diabetes, five of six (83%) would be included if HLA-DQ genotyping preceded antibody testing, but HLA-DQ did not explain outcomes among high-risk subjects, even when considered along with other genetic markers.
  
  
  CONCLUSIONS
  Multiple d-aab were established by age 14 years and prospectively identified all schoolchildren who developed type 1 diabetes within 8 years.
authors.affiliation: Pacific Northwest Research Institute, Seattle, Washington 98122, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: LaGasse
authors.forename: Michael S
authors.initials: MS
authors.lastname: Brantley
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Leech
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Rowe
authors.forename: Stephanie
authors.initials: S
authors.lastname: Monks
authors.forename: Jerry P
authors.initials: JP
authors.lastname: Palmer
authors.forename: Gerald T
authors.initials: GT
authors.lastname: Nepom
authors.forename: David K
authors.initials: DK
authors.lastname: McCulloch
authors.forename: William A
authors.initials: WA
authors.lastname: Hagopian
mesh_terms: D000293:Adolescent; D001323:Autoantibodies / Q000097:blood*; D001324:Autoantigens; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000175:diagnosis / Q000453:epidemiology* / Q000276:immunology; D005260:Female; D005500:Follow-Up Studies; D005968:Glutamate Decarboxylase / Q000276:immunology*; D006630:Hispanic or Latino; D006801:Humans; D007328:Insulin / Q000097:blood*; D007515:Islets of Langerhans / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000097:blood; D011237:Predictive Value of Tests; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000097:blood; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D012680:Sensitivity and Specificity; D014861:Washington / Q000453:epidemiology; D044465:White People
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D007328:Insulin; D008565:Membrane Proteins; C024211:islet cell antibody; C516862:PTPRN protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D005968:Glutamate Decarboxylase