Predictive Characteristics of Diabetes-Associated Autoantibodies Among Children With HLA-Conferred Disease Susceptibility in the General Population

  1. Heli T.A. Siljander1,2,
  2. Satu Simell3,
  3. Anne Hekkala4,
  4. Jyrki Lähde2,
  5. Tuula Simell3,
  6. Paula Vähäsalo4,
  7. Riitta Veijola4,
  8. Jorma Ilonen5,6,
  9. Olli Simell3 and
  10. Mikael Knip1,2
  1. 1Hospital for Children and Adolescents and Folkhälsan Research Center, University of Helsinki, Helsinki, Finland;
  2. 2Department of Pediatrics, Tampere University Hospital, Tampere, Finland;
  3. 3Department of Pediatrics, University of Turku, Turku, Finland;
  4. 4Department of Pediatrics, University of Oulu, Oulu, Finland;
  5. 5Department of Clinical Microbiology, University of Kuopio, Kuopio, Finland;
  6. 6Immunogenetics Laboratory, University of Turku, Turku, Finland.
  1. Corresponding author: Mikael Knip, mikael.knip{at}


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.

RESEARCH DESIGN AND METHODS We observed 7,410 children from birth (median 9.2 years) for β-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.


  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received September 23, 2008.
    • Accepted August 7, 2009.
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  1. Diabetes vol. 58 no. 12 2835-2842
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