During a median follow-up of 7.0 years, 169 children developed persistent islet autoantibodies (one or more autoantibody on at least two consecutive visits), and 55 of those progressed to diabetes. A total of 89% of children who progressed to diabetes, so far, expressed two or more autoantibodies.
In a life-table analysis (), children expressing two or more autoantibodies showed a nearly linear progression to diabetes. The cumulative incidence of diabetes by 10 years of follow-up differed significantly by the number of autoantibodies: 74, 70, and 15% in patients with three, two, and one autoantibodies, respectively (P < 0.0001). There was no significant difference in the progression to diabetes between relatives and general population subjects. The high-risk DR3/4-DQB1*0302 genotype was an additional predictor of a 10-year progression to diabetes in children expressing one autoantibody (30 vs. 13%; P = 0.035) or two autoantibodies (100 vs. 54%; P = 0.029), but not among patients expressing three autoantibodies (73.6 vs. 75.1%; P = 0.91). Children with persistently positive IAA levels had a higher progression rate to diabetes (100% by 5.6 years) than children with fluctuating IAA levels (63% by the 10-year follow-up) (P < 0.0001) ().
Figure 1 A: Progression to diabetes in children positive for anti-islet autoantibodies (n = 169). There was no significant difference in the progression rate between subjects with two or three positive antibodies. B: Progression to diabetes in children with persistently (more ...)
The age of appearance of autoantibody was a major determinant of the age at diabetes diagnosis, accounting for 47% of the variance (r = 0.69, P < 0.0001). The mean age of appearance of first autoantibody varied by group: 6.1, 5.5, and 3.8 years for one, two, or three antibodies, respectively (P = 0.0007).
We performed multiple regression analyses, including age at the first positive antibody, initial number of positive antibodies, family history, high-risk HLA-DR3/4, ethnicity, and IAA, GAD, and IA-2 levels (both initial and mean levels). In multiple regression analyses, including initial IAA, GAD, and IA-2 levels, the age at diabetes diagnosis was best predicted by initial IAA level, initial number of positive antibodies, and age at the first positive antibody (r = 0.83 and P < 0.0001) (). When analyzing mean IAA, GAD, and IA-2 levels, only mean IAA levels and age of the first positive antibody were significant predictors of age of diabetes diagnosis (r = 0.79, P < 0.0001) ().