An Age-Related Exponential Decline in the Risk of Multiple Islet Autoantibody Seroconversion During Childhood

Abstract

OBJECTIVE Islet autoimmunity develops before clinical type 1 diabetes and includes multiple and single autoantibody phenotypes. The objective was to determine age-related risks of islet autoantibodies that reflect etiology and improve screening for presymptomatic type 1 diabetes. RESEARCH DESIGN AND METHODS The Environmental Determinants of Diabetes in the Young study prospectively monitored 8,556 genetically at-risk children at 3- to 6-month intervals from birth for the development of islet autoantibodies and type 1 diabetes. The age-related change in the risk of developing islet autoantibodies was determined using landmark and regression models. RESULTS The 5-year risk of developing multiple islet autoantibodies was 4.3% (95% CI 3.8–4.7) at 7.5 months of age and declined to 1.1% (95% CI 0.8–1.3) at a landmark age of 6.25 years (P < 0.0001). Risk decline was slight or absent in single insulin and GAD autoantibody phenotypes. The influence of sex, HLA, and other susceptibility genes on risk subsided with increasing age and was abrogated by age 6 years. Highest sensitivity and positive predictive value of multiple islet autoantibody phenotypes for type 1 diabetes was achieved by autoantibody screening at 2 years and again at 5–7 years of age. CONCLUSIONS The risk of developing islet autoimmunity declines exponentially with age, and the influence of major genetic factors on this risk is limited to the first few years of life.