From September 2004 until February 2010, TEDDY enrolled 8676 children at birth, of whom 174 were excluded because of HLA ineligibility or indeterminate autoantibody status, leaving 8502 in the analysis. Children were followed quarterly for progression to diagnosis of diabetes. Follow-up of children with one or more islet autoantibodies continued on this schedule, whereas children who were autoantibody negative were followed semi-annually after 4 years of age. The median (IQR) age at last follow-up was 9.9 (8.1–11.5) years and the age range was 8–14 years.
As of 30 November 2018, 328 children (3.9%) had developed type 1 diabetes; 168 (2.0%) before 6 years of age and 160 (1.9%) at or after 6 years of age (Table 1). The incidence of type 1 diabetes remained fairly stable (Fig. 1), but the cumulative incidence differed by enrolment site (p = 0.0009, Fig. 2). However, the excess risk associated with enrolment from Germany may be the consequence of the high proportion of FDRs enrolled (36.1%) compared with all the other TEDDY sites (9.2%). By 10 years of age, children from Germany and Finland had a comparable cumulative diabetes risk, as did children from Sweden and the US, but the risk in Germany and Finland remained higher than in the other two countries. The difference in geographic distribution of new type 1 diabetes patients reflects a drop in the proportion from Finland and Germany and an increase in the US while the proportion remained unchanged in Sweden (p = 0.001).
The HLA distribution of diabetes patients was also different with an increase among those who were DR4/4 in the older age group and a corresponding decrease among those who were DR3/3 or had FDR-specific HLA genotypes (p = 0.005). Those who were diagnosed with diabetes at 6 years of age or older developed a persistent confirmed autoantibody at an older mean age than those who became autoantibody positive before the age of 6 (3.5 vs 1.5 years, p < 0.001). The mean duration of time between the first-appearing autoantibody and the diabetes diagnosis was also much longer (5.4 years vs 1.9 years, p < 0.001) in older than in younger children. Similar patterns were observed when considering the appearance of multiple persistent confirmed autoantibodies (3.9 years and 1.8 years) and time until progression to diabetes (4.9 years vs 1.6 years) (p < 0.001 for both).
The pattern of first-appearing autoantibody was also significantly different between those who were diagnosed with diabetes before 6 years of age and those who were diagnosed older (p = 0.001). As might be expected, the percentage of those with GADA as the first-appearing autoantibody was higher in the older group (26.9% vs 18.5%) and the percentage of those presenting with IAA first was much higher in the younger group (44.6% vs 28.1%). Interestingly, no children in the younger group presented with IA-2A as the first-appearing autoantibody, but 10 (6.3%) among the older children did. In six of these individuals, ZnT8A autoantibodies were also present when IA-2A autoantibodies were detected.
No autoantibodies were detected in 36 (11.0%) of the children diagnosed with diabetes. The median (IQR) interval between the last autoantibody testing and the diabetes diagnosis in the 22 children from the older age group was 8.6 years (7.0–8.9) suggesting that autoantibody positivity at diagnosis, or long before it, was unknown because of lack of testing and poor protocol compliance. Among the 14 who developed type 1 diabetes in the younger age group without detected autoantibodies, the median (IQR) interval was 2.3 years (0.85–2.86). There were six children under 6 years of age whose last autoantibody test was negative within 2 years preceding their diabetes diagnosis. Whole genome sequencing was available for three, one of whom had a variant in the HNF1A gene (rs762703502) associated with maturity-onset diabetes of the young, type 3.
Autoantibodies at the time of diabetes diagnosis showed that a higher per cent were IAA negative prior to diagnosis among the older group (28.8%) compared with the younger group (13.1%), p < 0.001. A lower per cent were ZnT8A negative in the older group (34.4%) compared with in the younger group (61.9%) (p < 0.001).
The incidence of diabetic ketoacidosis (DKA) at diagnosis was marginally lower (p = 0.046) in the older age group compared with in the younger group, but the proportion who were symptomatic or not at diagnosis was not different.
The HRs from a multivariate PH model of risk factors published by the TEDDY study also revealed some differences in their association with diabetes comparing the two age groups (Table 2). The risk of type 1 diabetes in families with a mother who had type 1 diabetes significantly increased compared with families without an affected relative, in the older age group (HR 2.64, 95% CI 1.36, 5.12, p = 0.004) whereas it was not a significant risk factor in the younger age group (HR 1.51, 95% CI 0.75, 3.05, p = 0.249). However, this difference in HRs was not statistically significant, reflecting the wide confidence intervals of the individual HRs. Also, the risk of diabetes associated with DR4/4 vs DR3/3 was significant in the older (HR 4.16, 95% CI 1.99, 8.69, p < 0.001), but not in the younger (HR 1.26, 95% CI 0.65, 2.44, p = 0.496) age group. This increase in HRs was statistically significant at p = 0.018, suggesting that the DR4/4 genotype has a larger role in development of type 1 diabetes in older than in younger individuals. Conversely, in the older age group, the type 1 diabetes risk associated with children from Finland and Germany significantly declined (HR 3.20, 95% CI 1.88, 5.45, p < 0.001 to HR 1.26, 95% CI 0.73, 2.18, p = 0.416 and HR 2.19, 95% CI 1.27, 3.78, p = 0.005 to HR 0.56, 95% CI 0.25, 1.27, p = 0.167, respectively) (p = 0.005 and p = 0.007, respectively) compared with children from the US. Other risk factors were, or were not, statistically significant in both age groups. However, the HRs comparing the two groups were not significantly different.
Once multiple autoantibodies were observed, the rate of progression to type 1 diabetes decreased as the age at initial seroconversion increased (p = 0.0003, Fig. 3a). Children under 2 years of age at initial seroconversion progressed much more rapidly to type 1 diabetes once multiple autoantibodies were detected (hazard rate of 0.19) through 6 years of follow-up. If diabetes did not develop during this interval of time, the rate of progression from multiple autoantibodies to type 1 diabetes (hazard rate 0.115) was approximately the same as the rate of progression to type 1 diabetes in the group who initially developed autoantibodies at an older age (hazard rate range from 0.072 to 0.116) irrespective of the age of seroconversion. Additionally, the rate of progression from multiple autoantibodies to type 1 diabetes was statistically associated with a family history of type 1 diabetes in the younger age group, but not in the older age group (p = 0.25, Fig. 3b).
Age at the onset of multiple autoantibodies, as a continuous variable, was also included in the analysis to explore whether the age groupings introduced artificial associations when comparing risk factors for early type 1 diabetes onset compared with later type 1 diabetes onset. Age at the onset of multiple autoantibodies was a highly significant factor in each age group (HR 0.56, 95% CI 0.45, 0.70, p < 0.001 and HR 0.83, 95% CI 0.75, 0.91, p < 0.001) showing decreasing risk with increasing age in both. After adjusting for the age at the development of multiple autoantibodies, the only remaining type 1 diabetes risk factors were family history of type 1 diabetes (father with type 1 diabetes vs those without family history of type 1 diabetes in the younger age group and mother or sibling with type 1 diabetes vs those without this type 1 diabetes family history in the older age group), and rs1004446_A (INS) (HR 0.55, p = 0.001), rs428595_A (PPIL2) (HR 1.88, p = 0.043) and rs10517086_A (HR 1.45, p = 0.033) in the younger age group and rs3825932_T (CTSH) (HR 0.57, p = 0.002), rs428595_A (PPIL2) (HR 1.97, p = 0.044) and rs73043122_C (RNASET2) (HR 2.70, p = 0.008) in the older age group.