Supplement_revision2.pdf (10.41 MB)
Download file

Islet Autoantibody Type-Specific Titer Thresholds Improve Stratification of Risk of Progression to Type 1 Diabetes in Children

Download (10.41 MB)
figure
posted on 10.11.2021, 19:16 by 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, the T1DI Study Group
OBJECTIVE: To utilize 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 US 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), glutamic acid decarboxylase (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=1076) or 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 50% or higher 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.

Funding

This work was supported by funding from JDRF (IBM: 1-RSC-2017-368-I-X, 1-IND-2019-717-I-X), (DAISY: 1-SRA-2019-722-I-X, 1-RSC-2017-517-I-X, 5-ECR-2017-388-A-N), (DiPiS: 1-SRA-2019-720-I-X, 1-RSC-2017-526-I-X), (DIPP: 1-RSC-2018-555-I-X), (DEW-IT: 1-SRA-2019-719-I-X, 1-RSC-2017-516-I-X) as well as NIH (DAISY: DK032493, DK032083, DK104351; and DK116073; DiPiS: DK26190 and the CDC (DEW-IT: UR6/CCU017247). The DIPP study was funded by JDRF (grants 1-SRA-2016-342-M-R, 1-SRA-2019-732-M-B); 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, SUS funds, Lion Club International, district 101-S, The royal Physiographic society, Skåne County Council Foundation for Research and Development as well as LUDC-IRC/EXODIAB funding from the Swedish foundation for strategic research (DNR IRC15-0067) and Swedish research council (DNR 2009-1039). Additional funding for DEW-IT was provided by the Hussman Foundation and by the Washington State Life Science Discovery Fund.

History