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

Predictive Characteristics of Diabetes-Associated Autoantibodies Among Children With HLA-Conferred Disease Susceptibility in the General Population Heli T.A. Siljander 1 , 2 , Satu Simell 3 , Anne Hekkala 4 , Jyrki Lähde 2 , Tuula Simell 3 , Paula Vähäsalo 4 , Riitta Veijola 4 , Jorma Ilonen 5 , 6 , Olli Simell 3 and Mikael Knip 1 , 2 1 Hospital for Children and Adolescents and Folkhälsan Research Center, University of Helsinki, Helsinki, Finland; 2 Department of Pediatrics, Tampere University Hospital, Tampere, Finland; 3 Department of Pediatrics, University of Turku, Turku, Finland; 4 Department of Pediatrics, University of Oulu, Oulu, Finland; 5 Department of Clinical Microbiology, University of Kuopio, Kuopio, Finland; 6 Immunogenetics Laboratory, University of Turku, Turku, Finland. Corresponding author: Mikael Knip, mikael.knip{at}hus.fi . 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. 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