The prevalence of each autoantibody at the initial screening is shown in for both cohorts. Autoantibody prevalence was much higher in the Trials cohort, which is attributable to the selection for ICA positivity and for the additional trial entry criteria. Although some of those in the Trials cohort were ICA− at the initial screening, all eventually became ICA+ before randomization.
Prevalence of positive autoantibodies at initial screening
In the Questionnaire cohort, ICA512 positivity was most commonly associated with one or more autoantibodies (65%), whereas mIAA positivity was least commonly associated with other autoantibodies (22%). The percentages of GAD65 and ICA positivity with associated autoantibodies were 37 and 39%, respectively.
The occurrence of type 1 diabetes according to the number of biochemical autoantibodies is shown separately for the Questionnaire and Trials cohorts and in the aggregate in . In each cohort, there tended to be an increasing occurrence of type 1 diabetes as the number of autoantibodies increased (P < 0.001 for both).
Figure 1 Curves indicate the occurrence of type 1 diabetes (T1D) over follow-up according to the number of autoantibodies present at the initial screening in the Questionnaire cohort (A), in the Trials cohort (B), and in the cohorts combined (C). In all three (more ...)
The occurrence of type 1 diabetes among those with a single autoantibody is shown in for the Questionnaire cohort. None of the 407 individuals with the presence of only mIAA developed type 1 diabetes. The occurrence of type 1 diabetes was similar for those with GAD65 alone (4.4%), ICA512 alone (4.6%), and ICA alone (3.9%). In proportional hazards models, there were significant associations between the occurrence of type 1 diabetes and each of those autoantibodies occurring singly (P < 0.001 for all). When age was added as a covariate, the associations remained highly significant (P < 0.001).
Associations of type 1 diabetes occurrence with the presence of single autoantibodies in the Questionnaire cohort at initial screening
Supplemental Table A1 (available at http://care.diabetesjournals.org/cgi/content/full/dc09-0934/DC1
) shows the occurrence of type 1 diabetes among those who were single autoantibody–positive in the combined Questionnaire and Trials cohorts. The occurrence of type 1 diabetes for those with ICA alone was somewhat higher than the occurrence for the other autoantibodies alone.
The distribution of mIAA values was examined to determine whether the lack of occurrence of type 1 diabetes in those with mIAA alone could be the result of a preponderance of low titers. Because mIAAs were measured in two laboratories (positive results: n = 123 for Boston and n = 284 for Denver) and the threshold was higher for an abnormal value in Boston than in Denver (0.02 vs. 0.01), the distributions were examined for each laboratory. Among those with abnormal values, the median values for Boston and Denver were 0.108 and 0.024, respectively. The values for the 75th percentiles were 0.182 and 0.051, respectively. Thus, an appreciable proportion of the titers was clearly elevated.
shows the effect of adding each autoantibody as a second autoantibody to the presence of a single autoantibody (any of the other three). When ICA, ICA512, or GAD65 was each included as a second autoantibody, the occurrence of type 1 diabetes was significantly greater (P < 0.001 for each) than when there was single autoantibody positivity. However, with mIAA as a second autoantibody there was no significant difference from the presence of one autoantibody. (There was little difference in risk increment between GAD65 and ICA when either was the first autoantibody and the other was added [data not shown].) When each of the autoantibodies was present additionally as a third autoantibody (supplemental Fig. A1, available in an online appendix), the risk increased appreciably with ICA and ICA512 (both P < 0.001) but did not increase significantly with GAD65 and mIAA.
Figure 2 Curves indicate the occurrence of type 1 diabetes (T1D) in the Questionnaire cohort over follow-up for the presence of one autoantibody and for the additional presence of a second autoantibody at the initial screening. Thus, in each panel the groups that (more ...)
The Trials cohort was used to assess the influence of a second autoantibody besides ICA. There was an increase in the percentage of those developing type 1 diabetes when GAD65 and ICA512 each was present besides ICA (ICA alone: 13 of 65 [20%], ICA with GAD65: 30 of 87 [34%], and ICA with ICA512: 11 of 22 [50%]). However, when age was included as a covariate in proportional hazards models, neither the additional presence of GAD65 nor that of ICA512 was significant. The numbers for the additional presence of mIAA as a second autoantibody were too small for a meaningful analysis; however, 3 of 6 (50%) developed type 1 diabetes.
Associations of autoantibody titers were examined in the combined cohorts. Of those who did not develop type 1 diabetes (n = 28,652), ICA512 and GAD65 titers were much more strongly correlated (r = 0.31) than the titers of any other autoantibody pair (r ranged from 0.03 to 0.13). However, among those who developed type 1 diabetes (n = 383), although the ICA512-GAD65 correlation remained similar (r = 0.30), the correlations of other autoantibody pairs tended to increase, especially when the pair included an ICA titer (with ICA titer: r = 0.39 for GAD65 titer, r = 0.51 for ICA512 titer, and r = 0.34 for mIAA titer). In this large dataset, all correlations were significant (P < 0.001 for all).
The association between the development of type 1 diabetes and titer (log-transformed) was examined among those who were positive for single autoantibodies in the combined cohorts. Because of the lack of cases of type 1 diabetes for those with mIAA positivity alone, the analysis was not performed for that autoantibody. GAD65 titer (type 1 diabetes/total = 27 of 582) and ICA titer (29 of 472) were each predictive of type 1 diabetes (P < 0.01 for both, with and without age as a covariate). There was borderline significance (P = 0.04 and P = 0.07 with age added) for the ICA512 titer (6 of 113), but the number for that analysis was small.