title: Predictive characteristics of diabetes-associated autoantibodies among children with HLA-conferred disease susceptibility in the general population.
abstract: OBJECTIVE
  As data on the predictive characteristics of diabetes-associated autoantibodies for type 1 diabetes in the general population are scarce, we assessed the predictive performance of islet cell autoantibodies (ICAs) in combination with autoantibodies against insulin (IAAs), autoantibodies against GAD, and/or islet antigen 2 for type 1 diabetes in children with HLA-defined disease predisposition recruited from the general population.
  
  
  METHODS
  We observed 7,410 children from birth (median 9.2 years) for beta-cell autoimmunity and diabetes. If a child developed ICA positivity or diabetes, the three other antibodies were measured in all samples available from that individual. Persistent autoantibody positivity was defined as continued positivity in at least two sequential samples including the last available sample.
  
  
  RESULTS
  Pre-diabetic ICA positivity was observed in 1,173 subjects (15.8%), 155 of whom developed type 1 diabetes. With ICA screening, 86% of 180 progressors (median age at diagnosis 5.0 years) were identified. Positivity for four antibodies was associated with the highest disease sensitivity (54.4%) and negative predictive values (98.3%) and the lowest negative likelihood ratio (0.5). The combination of persistent ICA and IAA positivity resulted in the highest positive predictive value (91.7%), positive likelihood ratio (441.8), cumulative disease risk (100%), and specificity (100%). Young age at seroconversion, high ICA level, multipositivity, and persistent positivity for IAA were significant risk markers for type 1 diabetes.
  
  
  CONCLUSIONS
  Within the general population, the combination of HLA and autoantibody screening resulted in disease risks that are likely to be as high as those reported among autoantibody-positive siblings of children with type 1 diabetes.
authors.affiliation: Hospital for Children and Adolescents and Folkhälsan Research Center, University of Helsinki, Helsinki, Finland.
authors.forename: Heli T A
authors.initials: HT
authors.lastname: Siljander
authors.forename: Satu
authors.initials: S
authors.lastname: Simell
authors.forename: Anne
authors.initials: A
authors.lastname: Hekkala
authors.forename: Jyrki
authors.initials: J
authors.lastname: Lähde
authors.forename: Tuula
authors.initials: T
authors.lastname: Simell
authors.forename: Paula
authors.initials: P
authors.lastname: Vähäsalo
authors.forename: Riitta
authors.initials: R
authors.lastname: Veijola
authors.forename: Jorma
authors.initials: J
authors.lastname: Ilonen
authors.forename: Olli
authors.initials: O
authors.lastname: Simell
authors.forename: Mikael
authors.initials: M
authors.lastname: Knip
mesh_terms: D000293:Adolescent; D001323:Autoantibodies / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D002648:Child; D015331:Cohort Studies; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000276:immunology*; D018450:Disease Progression; D004198:Disease Susceptibility; D005260:Female; D005387:Finland / Q000453:epidemiology; D005838:Genotype; D006683:HLA-DQ Antigens / Q000276:immunology*; D059866:HLA-DQ beta-Chains; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D011236:Prediabetic State / Q000276:immunology; D011237:Predictive Value of Tests; D012680:Sensitivity and Specificity
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D008562:Membrane Glycoproteins