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.

Figure 1

Cumulative risk of developing islet autoantibodies at each landmark age. Cumulative risks (line with shaded 95% CI) of developing any (A) or multiple islet autoantibodies (B) in children who were negative for the respective outcome at the ages of 7.5 months (red), 2.125 years (green), 4.25 years (blue), 6.25 years (dark green), and 8.25 years (purple). Exponential decay curves for the 5-year horizon risks for any islet autoantibodies (C) and multiple islet autoantibodies (D). The curve is represented by the equation: Risk = risk at baseline (0.625 years) × exp^{(λ × age−0.625)} − plateau risk. Exponential decay curves are shown for the 5-year horizon risks of developing multiple islet autoantibodies in children with a first-degree relative with type 1 diabetes (black, n = 955) and children in the general population (green, n = 7,601) (E); children with the HLA DR3/4-DQ8 (red, n = 3,339), DR4-DQ8/DR4-DQ8 (black, n = 1,674), DR4-DQ8/DR8 (blue, n = 1,474), and DR3/3 (green, n = 1,791) genotypes (F); and children in the general population with the HLA DR3/DR4-DQ8 or DR4-DQ8/DR4-DQ8 genotypes stratified by their genetic risk score into the upper score quartile (red, n = 1,104), 25th to 75th quartiles (black, n = 2,206), and lower quartile (blue, n = 1,103) (G). H: Also shown is the 5-year risk for multiple islet autoantibodies in children with genetic risk scores in the highest quartile relative to the children in the lowest quartile (blue) and to the children in the 25th to 75th quartiles (black).

Figure 2

Exponential risk decay curves for islet autoantibody phenotypes. Islet autoantibodies were categorized into the multiple (A and B) and single (C) islet autoantibody phenotypes. A: Exponential 5-year horizon risk decay curves for developing the multiple-first (blue), IAA-first-to-multiple (red), and GADA-first-to-multiple (black) phenotypes. B: The 5-year risk for developing the IAA-first-to-multiple or multiple-first phenotype (black line) or in the GADA-first-to-multiple phenotype (red line) in children categorized by their genetic risk scores for genes other than the HLA DR-DQ genotype. The curves show the relative risks for children with scores in the highest quartile (upper 25th percentile) relative to the children with scores in the lower three quartiles (lower 75th percentile). C: Exponential 5-year horizon risk decay curves for developing single IAA (red) and single GADA (black) phenotypes.

Figure 3

Sensitivity and PPV of multiple islet autoantibodies. Screening for multiple islet autoantibodies was simulated at a single time point (A) and at two time points (B). A: For a single time point, the sensitivity of multiple islet autoantibodies to identify all cases of type 1 diabetes that occurred in TEDDY children by the age of 12 years (blue symbols) and the PPV calculated as the 5-year risk of progressing to type 1 diabetes in children positive for multiple islet autoantibodies (black symbols) are shown for screening at the ages of 1–8 years. Error bars represent the 95% CI. B: For the strategy of screening at two time points, the sensitivity of multiple islet autoantibodies to identify all cases of type 1 diabetes that occurred in TEDDY children by the age of 12 years is given for each combination.