title: Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children.
abstract: OBJECTIVE
  Type 1 diabetes usually has a preclinical phase identified by circulating islet autoantibodies, but the rate of progression to diabetes after seroconversion to islet autoantibodies is uncertain.
  
  
  OBJECTIVE
  To determine the rate of progression to diabetes after islet autoantibody seroconversion.
  
  
  METHODS
  Data were pooled from prospective cohort studies performed in Colorado (recruitment, 1993-2006), Finland (recruitment, 1994-2009), and Germany (recruitment, 1989-2006) examining children genetically at risk for type 1 diabetes for the development of insulin autoantibodies, glutamic acid decarboxylase 65 (GAD65) autoantibodies, insulinoma antigen 2 (IA2) autoantibodies, and diabetes. Participants were all children recruited and followed up in the 3 studies (Colorado, 1962; Finland, 8597; Germany, 2818). Follow-up assessment in each study was concluded by July 2012.
  
  
  METHODS
  The primary analysis was the diagnosis of type 1 diabetes in children with 2 or more autoantibodies. The secondary analysis was the diagnosis of type 1 diabetes in children with 1 autoantibody or no autoantibodies.
  
  
  RESULTS
  Progression to type 1 diabetes at 10-year follow-up after islet autoantibody seroconversion in 585 children with multiple islet autoantibodies was 69.7% (95% CI, 65.1%-74.3%), and in 474 children with a single islet autoantibody was 14.5% (95% CI, 10.3%-18.7%). Risk of diabetes in children who had no islet autoantibodies was 0.4% (95% CI, 0.2%-0.6%) by the age of 15 years. Progression to type 1 diabetes in the children with multiple islet autoantibodies was faster for children who had islet autoantibody seroconversion younger than age 3 years (hazard ratio [HR], 1.65 [95% CI, 1.30-2.09; P < .001]; 10-year risk, 74.9% [95% CI, 69.7%-80.1%]) vs children 3 years or older (60.9% [95% CI, 51.5%-70.3%]); for children with the human leukocyte antigen (HLA) genotype DR3/DR4-DQ8 (HR, 1.35 [95% CI, 1.09-1.68; P = .007]; 10-year risk, 76.6% [95% CI, 69.2%-84%]) vs other HLA genotypes (66.2% [95% CI, 60.2%-72.2%]); and for girls (HR, 1.28 [95% CI, 1.04-1.58; P = .02];10-year risk, 74.8% [95% CI, 68.0%-81.6%]) vs boys (65.7% [95% CI, 59.3%-72.1%]).
  
  
  CONCLUSIONS
  The majority of children at risk of type 1 diabetes who had multiple islet autoantibody seroconversion progressed to diabetes over the next 15 years. Future prevention studies should focus on this high-risk population.
authors.affiliation: Institute of Diabetes Research, Helmholtz Zentrum München, and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Ingolstaedter Landstrase 1, Neuherberg, Germany 85764. anette-g.ziegler@helmholtz-muenchen.de
authors.forename: Anette G
authors.initials: AG
authors.lastname: Ziegler
authors.forename: Marian
authors.initials: M
authors.lastname: Rewers
authors.forename: Olli
authors.initials: O
authors.lastname: Simell
authors.forename: Tuula
authors.initials: T
authors.lastname: Simell
authors.forename: Johanna
authors.initials: J
authors.lastname: Lempainen
authors.forename: Andrea
authors.initials: A
authors.lastname: Steck
authors.forename: Christiane
authors.initials: C
authors.lastname: Winkler
authors.forename: Jorma
authors.initials: J
authors.lastname: Ilonen
authors.forename: Riitta
authors.initials: R
authors.lastname: Veijola
authors.forename: Mikael
authors.initials: M
authors.lastname: Knip
authors.forename: Ezio
authors.initials: E
authors.lastname: Bonifacio
authors.forename: George S
authors.initials: GS
authors.lastname: Eisenbarth
mesh_terms: D000293:Adolescent; D001323:Autoantibodies / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D003120:Colorado / Q000453:epidemiology; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000235:genetics / Q000276:immunology*; D018450:Disease Progression; D005260:Female; D005387:Finland / Q000453:epidemiology; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005858:Germany / Q000453:epidemiology; D005968:Glutamate Decarboxylase / Q000276:immunology; D006801:Humans; D007223:Infant; D007328:Insulin / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology*; D008297:Male; D011446:Prospective Studies; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8 / Q000276:immunology; D012306:Risk
chemical_list: D001323:Autoantibodies; D007328:Insulin; C516862:PTPRN protein, human; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2