The Prediction of Type 1 Diabetes by Multiple Autoantibody Levels and Their Incorporation Into an Autoantibody Risk Score in Relatives of Type 1 Diabetic Patients

Abstract

OBJECTIVEWe assessed whether a risk score that incorporates levels of multiple islet autoantibodies could enhance the prediction of type 1 diabetes (T1D).RESEARCH DESIGN AND METHODSTrialNet Natural History Study participants (n = 784) were tested for three autoantibodies (GADA, IA-2A, and mIAA) at their initial screening. Samples from those positive for at least one autoantibody were subsequently tested for ICA and ZnT8A. An autoantibody risk score (ABRS) was developed from a proportional hazards model that combined autoantibody levels from each autoantibody along with their designations of positivity and negativity.RESULTSThe ABRS was strongly predictive of T1D (hazard ratio [with 95% CI] 2.72 [2.23–3.31], P < 0.001). Receiver operating characteristic curve areas (with 95% CI) for the ABRS revealed good predictability (0.84 [0.78–0.90] at 2 years, 0.81 [0.74–0.89] at 3 years, P < 0.001 for both). The composite of levels from the five autoantibodies was predictive of T1D before and after an adjustment for the positivity or negativity of autoantibodies (P < 0.001). The findings were almost identical when ICA was excluded from the risk score model. The combination of the ABRS and the previously validated Diabetes Prevention Trial–Type 1 Risk Score (DPTRS) predicted T1D more accurately (0.93 [0.88–0.98] at 2 years, 0.91 [0.83–0.99] at 3 years) than either the DPTRS or the ABRS alone (P ≤ 0.01 for all comparisons).CONCLUSIONSThese findings show the importance of considering autoantibody levels in assessing the risk of T1D. Moreover, levels of multiple autoantibodies can be incorporated into an ABRS that accurately predicts T1D.

Baseline heterogeneity in glucose metabolism marks the risk for type 1 diabetes and complicates secondary prevention

“…Once the child had developed dysglycemia, high-level IA-2A did not act as a strong additional risk factor for progression to type 1 diabetes. Hence, high-level IA-2A levels may not be an independent risk factor for progression to type 1 diabetes as previously reported [26,24] but rather be related to and precede dysglycemia observed prior to the clinical onset of type 1 diabetes.…”

“…High titres [24] as well as increasing titres [25] of IA-2 have previously been found to predict clinical onset of type 1 diabetes. We could confirm this finding in our young population of GAD65A positive children.…”

2. Classification and Diagnosis of Diabetes

“…A recent study reported the risk of progression to type 1 diabetes from the time of seroconversion to autoantibody positivity in three pediatric cohorts from Finland, Germany, and the U.S. Of the 585 children who developed more than two autoantibodies, nearly 70% developed type 1 diabetes within 10 years and 84% within 15 years (19,20). These findings are highly significant because, while the German group was recruited from offspring of parents with type 1 diabetes, the Finnish and American groups were recruited from the general population.…”

2. Classification and Diagnosis of Diabetes

“…A recent study reported the risk of progression to type 1 diabetes from the time of seroconversion to autoantibody positivity in three pediatric cohorts from Finland, Germany, and the U.S. Of the 585 children who developed more than two autoantibodies, nearly 70% developed type 1 diabetes within 10 years and 84% within 15 years (16,18). These findings are highly significant because, while the German group was recruited from offspring of parents with type 1 diabetes, the Finnish and American groups were recruited from the general population.…”