Prediction of Autoantibody Positivity and Progression to Type 1 Diabetes: Diabetes Autoimmunity Study in the Young (DAISY)

Abstract

Diabetes Autoimmunity Study in the Young (DAISY) has followed 1972 children for islet autoimmunity and diabetes: 837 first-degree relatives of persons with type 1 diabetes and 1135 general population newborns identified through human leukocyte antigen (HLA) screening. During follow-up of 4.06 yr (range, 0.17-9 yr), serial determination of autoantibodies to glutamic acid decarboxylase, protein tyrosine phosphatase IA2, and insulin has generated approximately 20,000 results. Among 162 children with at least one positive autoantibody, in 31% the test was false positive (autoantibodies were negative twice on blinded duplicate aliquots), in 31% it was transiently positive (confirmed on blinded duplicate aliquots but negative on follow-up), and in 36% it was persistently positive. Using proportional hazards modeling, the HLA-DR3/4 DQ8 genotype, another positive autoantibody at the first positive visit, and level of autoantibody were predictive of persistent positivity. Only HLA-DR3/4 DQ8 genotype was predictive of progression to diabetes in proportional hazards modeling. This prospective study reveals that cross-sectional determination of islet autoantibodies in a population with relatively low previous probability of autoimmunity identifies as "positive" a large number of individuals who are either false or transiently positive. Predictive value of autoantibodies increases with blinded duplicate and independent sample retesting and incorporation of the level of autoantibody in the predictive algorithm.

Autoantibodies in Diabetes

“…In contrast to findings in the BABY-DIAB study, early gluten exposure in the DAISY study was associated with transglutaminase IgG and IgA, but not GAD65Abs (33). In the most recent DAISY report, a total number of 112 islet autoantibody-positive children are followed, and of these, 24 have developed type 1 diabetes (34). Despite the fact that the IAA assay is not fully standardized to the same inter-laboratory precision as the assays for GAD65Abs and IA-2Abs (35), the DAISY authors suggest that insulin is the primary autoantigen and trigger of all subsequent islet autoimmunity (36).…”

Natural History of Type 1 Diabetes

“…Of the three islet autoantibodies discussed, IAAs are reported to be the least persistent (13,15,21), and not all children who develop IAAs retain IAAs or subsequently develop multiple islet autoantibodies. One reason why IAAs, and indeed GADAs or IA-2As, may not persist is because they may be transferred from the mother with type 1 diabetes during pregnancy (20,22).…”

Differential effects of DRB1*0301 and DQA1*0501-DQB1*0201 on the activation and progression of islet cell autoimmunity

“…[4][5][6] However, the length of the preclinical stage is highly variable, and fluctuations in autoantibody titers and expression are common. 7 Historically considered a disease of childhood, it is now clear that autoimmune diabetes may occur at any age, and, indeed, the majority of patients may develop the disease as adults. Nevertheless, most of what is known about the genetics of autoimmune diabetes is derived from studies of patients who developed the disease as children.…”

“…10,11 Far less is known about HLA effects on the emergence of autoantibodies, and it is controversial whether HLA influences the initial activation of islet autoimmunity, the severity and age of onset of clinical disease or both. 7,12,13 A direct involvement of class II molecules in disease pathogenesis has been implicated by their functional role in binding and presenting peptides to T lymphocytes, and studies showing differences in antigen selectivity and binding affinity for the products of high-and low-risk alleles. [14][15][16][17] However, there is limited genetic evidence to support this view because of the strong linkage disequilibrium across the MHC.…”