University of Oulu

Kenney Ng, Harry Stavropoulos, Vibha Anand, Riitta Veijola, Jorma Toppari, Marlena Maziarz, Markus Lundgren, Kathy Waugh, Brigitte I. Frohnert, Frank Martin, William Hagopian, Peter Achenbach; for the T1DI Study Group, Islet Autoantibody Type-Specific Titer Thresholds Improve Stratification of Risk of Progression to Type 1 Diabetes in Children. Diabetes Care 5 January 2022; 45 (1): 160–168.

Islet autoantibody type-specific titer thresholds improve stratification of risk of progression to type 1 diabetes in children

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Author: Ng, Kenney1; Stavropoulos, Harry1; Anand, Vibha1;
Organizations: 1IBM Research, Cambridge MA and Yorktown Heights, NY
2Department of Pediatrics, PEDEGO Research Unit, University of Oulu and Oulu University Hospital, Oulu, Finland
3Institute of Biomedicine and Centre for Population Health Research, University of Turku, Turku, Finland
4Department of Pediatrics, Turku University Hospital, Turku, Finland
5Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden
6Clinical Research Center, Skåne University Hospital, Malmö, Sweden
7Barbara Davis Center for Diabetes, University of Colorado, Denver, CO
8JDRF, New York, NY
9Pacific Northwest Research Institute, Seattle, WA
10Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
Format: article
Version: accepted version
Access: open
Online Access: PDF Full Text (PDF, 12.7 MB)
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Language: English
Published: American Diabetes Association, 2022
Publish Date: 2023-03-14


Objective: To use islet autoantibody titers to improve the estimation of future type 1 diabetes risk in children.

Research design and methods: Prospective cohort studies in Finland, Germany, Sweden, and the U.S. followed 24,662 children at increased genetic or familial risk to develop islet autoimmunity and diabetes. For 1,604 children with confirmed positivity, titers of autoantibodies against insulin (IAA), GAD antibodies (GADA), and insulinoma-associated antigen 2 (IA-2A) were harmonized for diabetes risk analyses.

Results: Survival analysis from time of confirmed positivity revealed markedly different 5-year diabetes risks associated with IAA (n = 909), GADA (n = 1,076), and IA-2A (n = 714), when stratified by quartiles of titer, ranging from 19% (GADA 1st quartile) to 60% (IA-2A 4th quartile). The minimum titer associated with a maximum difference in 5-year risk differed for each autoantibody, corresponding to the 58.6th, 52.4th, and 10.2nd percentile of children specifically positive for each of IAA, GADA, and IA-2A, respectively. Using these autoantibody type-specific titer thresholds in the 1,481 children with all autoantibodies tested, the 5-year risk conferred by single (n = 954) and multiple (n = 527) autoantibodies could be stratified from 6 to 75% (P < 0.0001). The thresholds effectively identified children with a ≥50% 5-year risk when considering age-specific autoantibody screening (57–65% positive predictive value and 56–74% sensitivity for ages 1–5 years). Multivariable analysis confirmed the significance of associations between the three autoantibody titers and diabetes risk, informing a childhood risk surveillance strategy.

Conclusions: This study defined islet autoantibody type-specific titer thresholds that significantly improved type 1 diabetes risk stratification in children.

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Series: Diabetes care
ISSN: 0149-5992
ISSN-E: 1935-5548
ISSN-L: 0149-5992
Volume: 45
Issue: 1
Pages: 160 - 168
DOI: 10.2337/dc21-0878
Type of Publication: A1 Journal article – refereed
Field of Science: 3121 General medicine, internal medicine and other clinical medicine
3123 Gynaecology and paediatrics
Funding: This work was supported by funding from JDRF (IBM: 1-RSC-2017-368-I-X, 1-IND2019-717-I-X; DAISY: 1-SRA-2019-722-I-X, 1-RSC2017-517-I-X, 5-ECR-2017-388-A-N; DiPiS: 1-SRA2019-720-I-X, 1-RSC-2017-526-I-X; DIPP: 1-RSC2018-555-I-X, 1-SRA-2016-342-M-R, 1-SRA-2019-732-M-B; and DEW-IT: 1-SRA-2019-719-I-X, 1-RSC-2017-516-I-X) as well as National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (DAISY: DK032493, DK032083, DK104351, and DK116073; DiPiS: DK26190) and the Centers for Disease Control and Prevention (DEW-IT: UR6/CCU017247). The DIPP study was also funded by European Union (grant BMH4-CT98-3314), Novo Nordisk Foundation, Academy of Finland (Decision No. 292538 and Centre of Excellence in Molecular Systems Immunology and Physiology Research 2012-2017, Decision No. 250114), Special Research Funds for University Hospitals in Finland, Diabetes Research Foundation, Finland, and Sigrid Juselius Foundation, Finland. The BABYDIAB study was funded by the German Federal Ministry of Education and Research to the German Center for Diabetes Research. The DiPiS study was funded by Swedish Research Council (grant no. 14064), Swedish Childhood Diabetes Foundation, Swedish Diabetes Association, Nordisk Insulin Fund, Skåne University Hospital Fund, Lions Club International, district 101-S, The Royal Physiographic Society, Skåne County Council Foundation for Research and Development, as well as Lund University Diabetes Centre Industrial Research Centre/EXODIAB funding from the Swedish Foundation for Strategic Research (DNR IRC15-0067) and the Stiftelsen for Strategisk Forskning (DNR 2009-1039). Additional funding for DEW-IT was provided by the Hussman Foundation and by the Washington State Life Science Discovery Fund.
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