Our previous data-driven analysis from five large-scale prospective studies discovered three trajectories (TR1, TR2, and TR3) composed of latent states for evolving patterns of islet autoantibodies (IAbs) : IAA, GADA and IA-2A. Here we examined the evolution of IAb levels within these trajectories for 2145 IAb positive participants, followed from early life, and compared those who progressed to T1D (n=643) to those who remained undiagnosed (n=1502) . Using threshold values determined by 5-year T1D risk, four levels were defined for each IAb (L0: negative; L1: lowest; L2: middle; L3: highest) and overlayed onto each visit (Figure) . In the diagnosed participants, high IAA levels were seen in TR1 and TR2 at ages <3 years, whereas IAA remained at lower levels in the undiagnosed. Proportions of dwell times at the four IAb levels significantly differed between the diagnosed and undiagnosed for GADA and IA-2A in all three trajectories (p<0.001) , but for IAA dwell times differed only within TR2 (p<0.05) . Overall, undiagnosed participants more frequently had low IAb levels and later appearance of IAb than those who were diagnosed (Figure) . Better characterization considering both timing and levels within distinct IAb trajectories towards T1D may lead to more personalized approaches to risk prediction and intervention.


B. Kwon: Employee; IBM. P. Achenbach: None. V. Anand: Employee; IBM, IBM. W. Hagopian: Research Support; Janssen Research & Development, LLC. J. Hu: Employee; IBM. E. Koski: Employee; IBM. Å. Lernmark: None. K. Ng: Employee; IBM. R. Veijola: None. B.I. Frohnert: Advisory Panel; Provention Bio, Inc.


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, 1-SRA-2016-342-M-R, 1-SRA-2019-732-M-B) , (DEW-IT: 1-SRA-2019-719-I-X, 1-RSC-2017-516-I-X) NIH (DAISY: DK032493, DK032083, DK104351; and DK116073; DiPiS: DK26190 CDC (DEW-IT: UR6/CCU017247) . European Union (DIPP: BMH4-CT98-3314) ; Novo Nordisk Foundation; Academy of Finland (Decision 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. German Federal Ministry of Education and Research to the German Center for Diabetes Research. 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) . Hussman Foundation and by the Washington State Life Science Discovery Fund.

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