Two-age islet-autoantibody screening for childhood type 1 diabetes: a prospective cohort study

Abstract

Background: Early prediction of childhood type 1 diabetes reduces ketoacidosis at diagnosis and provides opportunities for disease prevention. However, only highly efficient approaches are likely to succeed in public health settings. We sought to identify efficient strategies for initial islet autoantibody screening in children younger than 15 years.

Methods: We harmonised data from five prospective cohorts from Finland (DIPP), Germany (BABYDIAB), Sweden (DiPiS), and the USA (DAISY and DEW-IT) into the Type 1 Diabetes Intelligence (T1DI) cohort. 24 662 children at high risk of diabetes enrolled before age 2 years were included and followed up for islet autoantibodies and diabetes until age 15 years, or type 1 diabetes onset, whichever occurred first. Islet autoantibodies measured included those against glutamic acid decarboxylase, insulinoma antigen 2, and insulin. Main outcomes were sensitivity and positive predictive value (PPV) of detected islet autoantibodies, tested at one or two fixed ages, for diagnosis of clinical type 1 diabetes.

Findings: Of the 24 662 participants enrolled in the Type 1 Diabetes Intelligence cohort, 6722 total were followed up to age 15 years or until onset of type 1 diabetes. Type 1 diabetes developed by age 15 years in 672 children, but did not develop in 6050 children. Optimal screening ages for two measurements were 2 years and 6 years, yielding sensitivity of 82% (95% CI 79-86) and PPV of 79% (95% CI 75-80) for diabetes by age 15 years. Autoantibody positivity at the beginning of each test age was highly predictive of diagnosis in the subsequent 2-5·99 year or 6-15-year age intervals. Autoantibodies usually appeared before age 6 years even in children diagnosed with diabetes much later in childhood.

Interpretation: Our results show that initial screening for islet autoantibodies at two ages (2 years and 6 years) is sensitive and efficient for public health translation but might require adjustment by country on the basis of population-specific disease characteristics.

Funding: Juvenile Diabetes Research Foundation.

Figure 1:. Comparative sensitivity and PPV for any islet autoantibodies and multiple islet autoantibodies endpoints

Comparative sensitivity (A) and PPV (B) from screening multiple islet autoantibodies at two ages for type 1 diabetes risk by age 15 years in the entire T1DI cohort. Comparative sensitivity (C) and PPV (D) from screening of any islet autoantibodies for risk of type 1 diabetes by age 15 years in the entire T1DI cohort. The comparative analyses herein were used to identify optimum screening age or ages for later evaluation by direct observation. The diagonal numbers highlighted within black squares represent performance of screening at a single age. For example, in panel C, the comparative sensitivity of a result from screening of any islet autoantibodies at one age (4 years) was 46% (95% CI 43–49), whereas comparative sensitivity from screening at two ages (2 years and 6 years) was 66% (63–69). PPV=positive predictive value. T1DI=Type 1 Diabetes Intelligence.

Figure 2:. Bootstrap replication for optimal screening ages

(A) Analyses of optimal ages for screening of any islet autoantibodies for risk of type 1 diabetes by age 15 years in the T1DI cohort using bootstrap internal replication for each age pair. The four testing-age combinations with the greatest comparative sensitivities are shown. Testing at ages 2 years and 6 years performed best (smallest distance to the upper-left corner of the plot). (B) Using the testing age pair of 2 years and 6 years from panel A as a reference, we compared all other age combinations using internal bootstrapping replication. For each age combination, the dark area of the pie chart represents the proportion of screening tests resulting in a distance to the top-left corner in panel A at or below that of the age 2-year and 6-year test pair. No other combination was superior to testing at age 2 years and 6 years. T1DI=Type 1 Diabetes Intelligence.

Figure 3:. Comparison of performance metrics by HLA background and study cohort

(A) Comparative sensitivity (green) and PPV (purple) with 95% CIs of any islet antibodies at ages 2 years and 6 years for high-risk combined HLA groups A plus B versus lower-risk combined HLA groups C plus D. (B) Comparative sensitivity with 95% CIs of any islet autoantibodies with a two-age strategy using different age pairs and different study populations. Maximum sensitivity was at age pair 2 years and 6 years (blue) for DIPP (Finland), but age 2 years and 9 years (red) for DAISY (Colorado, USA). PPV=positive predictive value. DIPP=Diabetes Prediction and Prevention. DAISY=Diabetes Autoimmunity Study in the Young.

Figure 4:. Directly observed development of type 1 diabetes by islet autoantibody test results and by test ages and outcome horizons

(A) Observed mean proportion of children with the indicated number of islet autoantibodies who developed type 1 diabetes between the ages of 2 years and 5·99 years. (B) Observed mean proportion of children with the indicated number of islet autoantibodies who developed type 1 diabetes between the ages of 6 years and 15 years. This analysis considers only participants observed for the entire disease-onset range shown. (C) Observed sensitivity to detect cases of type 1 diabetes among the screened cohort, considering only participants tested at the indicated ages and observed to age 15 years. The observed PPV of any islet autoantibodies tested at ages 2 years and 6 years (bolded line) was 79% (95% CI 75–80). PPV=positive predictive value.