Characteristics of the study population by DAA development are presented in . Of the 42,447 subjects aged 3–18 years screened for DAAs in the DPT-1 Study, 3,235 subjects (7.6%) were autoantibody positive at the time of initial screening. Of these, (, first column) 1,454 subjects (3.4%) were ICA positive, 1,758 (4.1%) were GAD65 positive, 899 (2.1%) were ICA512 positive, and 1,094 (2.6%) were mIAA positive. At the initial screen, 39,212 subjects were autoantibody negative. There was no significant difference in age (P = 0.2964) or race/ethnicity (P = 0.0798) between the two groups (DAA+ vs. DAA−). There were small proportional differences between sexes (P = 0.008) (), and there was a significantly higher proportion of siblings of patients with type 1 diabetes (P < 0.0001) in children positive for an autoantibody.
Characteristics of the screened population aged 3–18 years
Number of subjects autoantibody positive and screened/rescreened by specific autoantibody
For those DAA negative at the initial screen and who returned for at least one rescreening (n = 11,813), 469 (4.0%) seroconverted to DAA(s) positive, 258 (2.2%) to ICA positive, 234 (2.0%) to GAD65 positive, and 99 (0.8%) to ICA512 positive (). These children were significantly younger (P < 0.0001) in median age (years [quartile 1–quartile 3]) at the initial screen (7.1 years [5.1–10.0] vs. 8.2 years [5.5–11.6]) compared with the remaining children who did not seroconvert (n = 11,344). Median (Q1–Q3) time of follow-up for those who returned for a rescreening in the study was 27.1 months (20.1–49.1). There were no differences in race (P = 0.39), relation to proband (P = 0.11), or sex (P = 0.42) among those who seroconverted and those that remained autoantibody negative throughout follow-up. Fifty-four percent (n = 251) of the children who seroconverted did so by 11 years of age, with 75% seroconversion by 13 years of age. There was no significant difference in the number of rescreens for those who seroconverted ≤10 versus >10 years of age (P = 0.76).
DAAs had varying patterns of presentation in those children who seroconverted. Median ages at seroconversion (years [Q1–Q3]) were similar with the exception that children seroconverted to GAD65 at a significantly younger age than to ICA (P = 0.02) (GAD65, 9.5 years [7.1–12.6]; ICA, 10.2 years [8.2–13.7]; and ICA512, 9.9 years [7.3–13.5]). For those individuals who developed multiple autoantibodies, GAD65 seroconversion generally occurred earlier than ICA or ICA512, with ICA seroconversion usually occurring after ICA512. If a child tested positive for two DAAs at the same testing, it was likely a combination of GAD65 and ICA512, as the timing of each of these DAAs generally preceded the occurrence of ICA, giving rise to two positive autoantibodies.
The 2-year risk for seroconversion by age showed significant decreases (P < 0.001) with increasing age for all DAAs (). GAD65 2-year risk had a significantly different slope of decline compared with ICA512 (P < 0.0001) and ICA (P < 0.0001) across all ages, with GAD65 risk having a steeper slope for those aged 6 years and under. ICA risk was significantly higher than ICA512 risk for all ages (P = 0.003). The 2-year risk for any DAA was significantly (P < 0.0001) higher across all ages than for any two DAAs.
Figure 1 Two-year risk of autoantibody seroconversion by autoantibody and development of any autoantibody(s) by age (years). GAD65, gray dashed line; ICA, solid black line; ICA512, black dashed line; any autoantibody, black dotted line; and any two autoantibodies, (more ...)
Using Cox proportional hazards models, the age at initial screening was identified as a significant predictor for risk of autoantibody seroconversion for all autoantibodies (ICA, P = 0.01; ICA512, P = 0.004; GAD65, P < 0.0001). In univariate models, siblings had a 46% (HR 1.46, 95% CI 1.06–2.03) greater risk of GAD65 seroconversion (P = 0.02), and females had 21% (0.79, 0.64–0.98) lower risk of ICA seroconversion (P = 0.03). Race/ethnicity was not a significant predicator for autoantibody seroconversion in this cohort. In multivariable models adjusted for race, sex, relation to index proband, and rescreen interval, age at initial screening was the primary predicator of autoantibody seroconversion for any DAA (P < 0.0001). The risk of DAA seroconversion greatly increased if the subject was already positive for another autoantibody. DAA seroconversion risk significantly decreased with increasing age for GAD65 (HR 0.90, 95% CI 0.87–0.93, P < 0.0001), ICA (0.96, 0.93–0.99, P = 0.01), and ICA512 (0.92, 0.87–0.98, P = 0.004). For each 1-year increase in age in this cohort, the risk of any autoantibody seroconversion (0.95, 0.92–0.97, P < 0.0001) decreased by 5% and for two autoantibodies risk decreased by 13% (0.87, 0.82–0.93, P < 0.0001).
Lastly, 69 (15%) of the 469 that seroconverted during rescreening developed multiple autoantibodies. Of the 69, 45 (65%) seroconverted to multiple autoantibodies at the same screening and 24 (35%) developed multiple autoantibodies over time. Twenty-four of the 469 subjects (5%) who DAA seroconverted developed type 1 diabetes. At the time of diagnosis, 8% were ICA positive only, 4% were GAD65 positive only, 4% were GAD65 and ICA512 positive, 17% were ICA and GAD65 positive, 21% were ICA512 and ICA positive, and 45% were positive for all three autoantibodies. There were 19 subjects that developed type 1 diabetes who had no autoantibodies at the last screening before diagnosis (median was 15 months prior to diagnosis). The median age (Q1–Q3) at type 1 diabetes diagnosis was 12.4 years (9.7–14.7).