Islet autoantibody screening in at-risk adolescents to predict type 1 diabetes until young adulthood: a prospective cohort study

Abstract

Background: Screening for islet autoantibodies in children and adolescents identifies individuals who will later develop type 1 diabetes, allowing patient and family education to prevent diabetic ketoacidosis at onset and to enable consideration of preventive therapies. We aimed to assess whether islet autoantibody screening is effective for predicting type 1 diabetes in adolescents aged 10-18 years with an increased risk of developing type 1 diabetes.

Methods: Data were harmonised from prospective studies from Finland (the Diabetes Prediction and Prevention study), Germany (the BABYDIAB study), and the USA (Diabetes Autoimmunity Study in the Young and the Diabetes Evaluation in Washington study). Autoantibodies against insulin, glutamic acid decarboxylase, and insulinoma-associated protein 2 were measured at each follow-up visit. Children who were lost to follow-up or diagnosed with type 1 diabetes before 10 years of age were excluded. Inverse probability censoring weighting was used to include data from remaining participants. Sensitivity and the positive predictive value of these autoantibodies, tested at one or two ages, to predict type 1 diabetes by the age of 18 years were the main outcomes.

Findings: Of 20 303 children with an increased type 1 diabetes risk, 8682 were included for the analysis with inverse probability censoring weighting. 1890 were followed up to 18 years of age or developed type 1 diabetes between the ages of 10 years and 18 years, and their median follow-up was 18·3 years (IQR 14·5-20·3). 442 (23·4%) of 1890 adolescents were positive for at least one islet autoantibody, and 262 (13·9%) developed type 1 diabetes. Time from seroconversion to diabetes diagnosis increased by 0·64 years (95% CI 0·34-0·95) for each 1-year increment of diagnosis age (Pearson's correlation coefficient 0·88, 95% CI 0·50-0·97, p=0·0020). The median interval between the last prediagnostic sample and diagnosis was 0·3 years (IQR 0·1-1·3) in the 227 participants who were autoantibody positive and 6·8 years (1·6-9·9) for the 35 who were autoantibody negative. Single screening at the age of 10 years was 90% (95% CI 86-95) sensitive, with a positive predictive value of 66% (60-72) for clinical diabetes. Screening at two ages (10 years and 14 years) increased sensitivity to 93% (95% CI 89-97) but lowered the positive predictive value to 55% (49-60).

Interpretation: Screening of adolescents at risk for type 1 diabetes only once at 10 years of age for islet autoantibodies was highly effective to detect type 1 diabetes by the age of 18 years, which in turn could enable prevention of diabetic ketoacidosis and participation in secondary prevention trials.

Funding: JDRF International.

Figure 1:. Follow-up times for participants

Each horizontal line represents the timeline for each participant; the start of the line is the age at which follow-up started, and the end of the line is the age at which the participant was diagnosed with type 1 diabetes (red and grey lines) or lost to follow-up (blue and purple lines).

Figure 2:. Number of all participants, those who newly seroconverted, those who were islet autoantibody positive, and those diagnosed with type 1 diabetes

The number of participants at each age range (or age) includes those within a window from 6 months before to 6 months after the specified age (or age range). (A) Number of participants who had at least one follow-up visit between the age of 10 years and 18 years, followed up through each age range for each study site. (B) Number of participants who newly seroconverted at each age range (islet autoantibody incidence). (C) Number of participants with any islet autoantibody at each age range (islet autoantibody prevalence). (D) Number of participants diagnosed with type 1 diabetes at each age. DAISY=Diabetes Autoimmunity Study in the Young. DEW-IT=Diabetes Evaluation in Washington. DIPP=Diabetes Prediction and Prevention.

Figure 3:. Median time from seroconversion to diagnosis of type 1 diabetes

The median time from seroconversion to diagnosis of type 1 diabetes by age at diagnosis in the 227 participants followed up in the complete cohort. The horizontal line represents the median; the box extends from the 25th to 75th percentile; and the upper whisker extends to the last datum less than Q3 + 1·5 × IQR, and the lower whisker extends to the last datum greater than Q1 − 1·5 × IQR. Blue circles beyond the whiskers represent outliers.

Figure 4:. Comparative sensitivity and positive predictive value of screening for any islet autoantibody

Comparative sensitivity (A) and positive predictive value (B) from screening any islet autoantibody at single ages (diagonal numbers highlighted within black squares) and at all combinations of two ages between 10 years and 17 years for risk of type 1 diabetes in participants followed up beyond the age of 10 years. The positive predictive value at a single age or age pair indicates the likelihood that autoantibody-positive participants will develop type 1 diabetes during follow-up.