2391-P: Combination of Electrochemiluminescence-Based Autoantibodies and Genetic Risk Scores Enhances Type 1 Diabetes Prediction in Single-Antibody Positive Individuals

Introduction and Objective: In population screening for islet autoantibodies (IAbs) and type 1 diabetes (T1D) risk, most individuals tested ‘positive’ have only one detectable IAb. Single IAb by standard radio binding assay (RBA) has limited prediction for progression to stage 3 T1D. Combining electrochemiluminescence (ECL) antibody assays with T1D genetic risk score (GRS) may improve prediction. This study examined ECL IAbs, T1D GRS2, and their combined predictive value in TrialNet participants with a single IAb. Methods: We analyzed first available IAb-positive samples from 853 TrialNet screening study participants who tested positive by RBA for a single IAb confirmed across ≥2 consistent visits (575 with GADA, 236 with IAA, 42 with IA-2A). The samples were blindly tested with ECL IAb assays. All participants were previously genotyped using the TEDDY array (GWAS with exome and custom content) and had T1D GRS2 scores determined. Results: Of those with single IAb by RBA, 323/853 (37.9%) were confirmed with ECL assays, showing a significantly higher 5-year cumulative incidence of stage 3 T1D (14.7% vs. 2.2%, p 0.001) and higher T1D GRS2 scores (12.9 ± 2.4 vs. 11.8 ± 2.3, p 0.001) than those not confirmed by ECL assays. ECL-GADA was significantly correlated with T1D GRS2 for both positivity (r=0.26) and levels (r=0.18, both p 0.0001). Both ECL IAb positivity (HR 8.0, 95% CI 3.7-17.6) and T1D GRS2 (HR 1.3, 95% CI 1.1-1.6) independently predicted progression to stage 3 T1D after adjusting for age, sex and BMI. Using ROC AUC as a metric, combining ECL IAb and T1D GRS2 improved 5-year prediction of stage 3 T1D to AUC 0.816 compared to ECL IAb (AUC 0.806, n.s.) or GRS2 (AUC 0.743, p 0.01) alone. Conclusion: In summary, both ECL-detected IAbs and T1D GRS independently enhance the disease prediction among single IAb positive individuals. Their combination further improves prediction, supporting an integrated approach for improved risk stratification in early-stage T1D screening strategies. Disclosure X. Jia: None. C. Zhang: None. A. Steck: Consultant; Current; Sanofi. R.A. Oram: Other - Research support, The University of Exeter has a licensing and royalty agreement for a 10 SNP T1D GRS with Randox; Current; Randox. Other - Advisory Panel, Consulting, Invited talks; Current; Sanofi. Other - invited talk, internal teaching talk on genetics; Ended; Novo Nordisk. D. Cuthbertson: None. H. Parikh: None. S. Onengut-Gumuscu: None. S. Rich: Advisory Panel; Current; Sanofi. Research Support; Current; Sanofi, Leona M. and Harry B. Helmsley Charitable Trust. Other - Consulting Associate Editor, Diabetes Care; Current; American Diabetes Association. J. Krischer: None. P. Gottlieb: Consultant; Current; Eli Lilly and Company. Board Member; Current; IM Therapeutics. Other - CEO, CMO; Current; IM Therapeutics. Research Support; Current; Immune Tolerance Network, Nova Laboratories, National Institute of Diabetes and Digestive and Kidney Diseases. Advisory Panel; Current; Sanofi. Research Support; Current; Sanofi. Consultant; Current; SAB Biotherapeutics, Inc., Anaptys Bio, Cour, T1D Fund. Consultant; Ended; Imcyse, Viacyte, Abata. M. Redondo: Advisory Panel; Current; Sanofi. Other - Data Safety Monitoring committee; Current; Lilly. L. Yu: None. Funding Colorado Diabetes Research Center (DRC) Pilot and Feasibility (P&F) program