Landmark models to define the age-adjusted risk of developing stage 1 type 1 diabetes across childhood and adolescence

Abstract

Background: Autoimmune diseases are often preceded by an asymptomatic autoantibody-positive phase. In type 1 diabetes, the detection of autoantibodies to pancreatic islet antigens in genetically at-risk children is prognostic for future clinical diabetes. Testing for islet autoantibodies is, therefore, performed in a range of clinical studies. Accurate risk estimates that consider the a priori genetic risk and other risk modifiers are an important component of screening. The age of an individual is an under-appreciated risk modifier. The aim of this study was to provide age-adjusted risk estimates for the development of autoantibodies across childhood in genetically at-risk children.

Methods: The prospective BABYDIAB and BABYDIET studies included 2441 children from birth who had a first-degree relative with type 1 diabetes. Children were born between 1989 and 2006 and were regularly followed from birth for the development of islet autoantibodies and diabetes. A landmark analysis was performed to estimate the risk of islet autoantibodies at birth and at the age 3.5, 6.5 and 12.5 years. Exponential decay curves were fitted for the risk by the age of 20 years.

Results: The risk of islet autoantibodies by the age of 20 years was 8%, 4.6%, 2.6% and 0.9%, at the landmark ages of birth, 3.5, 6.5 and 12.5 years, respectively. The short-term risks (within 6 years of follow-up) at these landmark ages were 5.3%, 2.9%, 1.8% and 1%, respectively. The decline in autoantibody risk with age was modelled using a one-phase exponential decay curve (r = 0.99) with a risk half-life of 3.7 years. This risk decay model was remarkably consistent when the outcome was defined as islet autoantibody-positive or multiple islet autoantibody-positive and when the study cohort was stratified by HLA risk genotype. A similar decay model was observed for coeliac disease-associated transglutaminase antibodies in the same cohort. Unlike the risk of developing islet autoantibodies, the rate of developing clinical diabetes in children who were islet autoantibody-positive did not decline with age.

Conclusion: The risk of developing autoantibodies drops exponentially with age in children with a first-degree relative with type 1 diabetes.

Keywords: Autoimmunity; Islet autoantibodies; Landmark risk; Type 1 diabetes.

Fig. 1

Cumulative risks of developing islet autoantibodies. a, c Cumulative risks of developing any (a) or multiple islet autoantibodies (c) in the total cohort from birth (red), 3.5 years (green), 6.5 years (blue) and 12.5 years (grey) of age. b, d Dynamic predictions for the risks of developing any (b) or multiple (d) islet autoantibodies during the next 6 years of life

Fig. 2

Cumulative risks of developing islet autoantibodies in children with DR3/4-DQ8 or DR4-DQ8/DR4-DQ8 genotypes. a, c Cumulative risks of developing any (a) or multiple islet autoantibodies (c) in children with DR3/4-DQ8 or DR4-DQ8/DR4-DQ8 genotypes from birth (red), 3.5 years (green), 6.5 years (blue) and 12.5 years (grey) of age. b, d Dynamic predictions for the risks of developing any (b) or multiple (d) islet autoantibodies during the next 6 years of life

Fig. 3

One-phase exponential decay function for risk of developing islet autoantibodies by 20 years of age. a All children. b Children with the high-risk HLA DR3-DR4-DQ8 or DR4-DQ8/DR4-DQ8 genotypes

Fig. 4

Cumulative risks of developing type 1 diabetes in islet autoantibody positive children. The cumulative risks were calculated from 1.5 years (red), 3.5 years (green), 6.5 years (blue), and 12.5 years (grey) in children who were islet autoantibody positive (multiple or single) at the respective landmark