Abstract
CONTEXT: Single ZnT8 autoantibody (ZnT8A) positivity by standard radiobinding assay (RBA) is commonly seen in nondiabetes population-based screening and the risk of progression to type 1 diabetes (T1D) in subjects with single ZnT8A is unknown. OBJECTIVE: Identify the risk of progression to T1D in individuals positive only for ZnT8A. METHODS: We developed an electrochemiluminescence (ECL) assay to detect high-affinity ZnT8A and validated it in 3 populations: 302 patients newly diagnosed with T1D, 135 nondiabetic children positive for ZnT8A by RBA among 23 400 children screened by the Autoimmunity Screening for Kids (ASK) study, and 123 nondiabetic children multiple autoantibody positive or single ZnT8A positive by RBA participating in the Diabetes Autoimmunity Study in the Young (DAISY). RESULTS: In 302 patients with T1D at diagnosis, the positivity for ZnT8A was 62% both in RBA and ECL. Among ASK 135 participants positive for RBA-ZnT8A, 64 were detected ZnT8A as the only islet autoantibody. Of these 64, only 9 were confirmed by ECL-ZnT8A, found to be of high affinity with increased T1D risk. The overall positive predictive value of ECL-ZnT8A for T1D risk was 87.1%, significantly higher than that of RBA-ZnT8A (53.5%, P < .001). In DAISY, 11 of 2547 children who had no positivity previously detected for other islet autoantibodies were identified as single ZnT8A by RBA; of these, 3 were confirmed positive by ECL-ZnT8A and all 3 progressed to clinical T1D. CONCLUSION: A large proportion of ZnT8A by RBA are single ZnT8A with low T1D risk, whereas ZnT8A by ECL was of high affinity and high prediction for T1D development.