OBJECTIVE -Almost 90% of type 1 diabetes appears in individuals without a close family history. We sought to evaluate the best current predictive strategy, multiple defined autoantibodies, in a long-term prospective study in the general population. RESEARCH DESIGN AND METHODS -Autoantibodies to pancreatic islets (islet cellantibodies [ICAs]) and defined autoantibodies (d-aab) to human GAD, IA2/ICA512, and insulin were tested in 4,505 Washington schoolchildren. Eight years later, 3,000 (67%) subjects were recontacted, including 97% of subjects with any test Ͼ99th percentile.RESULTS -Six subjects developed diabetes (median interval 2.8 years), all from among the 12 individuals with multiple d-aab, representing 50% positive predictive value (95% CI 25-75%) and 100% sensitivity (58 -100%). Among the others, diabetes occurred in 0 of 6 with one d-aab plus ICA, 0 of 26 with ICA only, 0 of 7 with one d-aab equaling the 99th percentile and another d-aab equaling the 97.5th percentile, 0 of 86 with one d-aab, and 0 of 2,863 with no d-aab or ICA. Adjusted for verification bias, multiple d-aab were 99.9% specific (99.86 -99.93%). At this age, new d-aab seldom appeared. Once present, d-aab usually persisted regardless of disease progression, although less so for insulin autoantibodies. Insulin secretion by sequential glucose tolerance testing remained normal in four multiple d-aab subjects not developing diabetes. Of children developing diabetes, five of six (83%) would be included if HLA-DQ genotyping preceded antibody testing, but HLA-DQ did not explain outcomes among high-risk subjects, even when considered along with other genetic markers.CONCLUSIONS -Multiple d-aab were established by age 14 years and prospectively identified all schoolchildren who developed type 1 diabetes within 8 years. Diabetes Care 25:505-511, 2002T ype 1 diabetes is an organ-specific autoimmune disease with aberrant immune responses to specific ␤-cell autoantigens. Worldwide incidence appears to be increasing (1). Prevention is important because diabetes interrupts normal development in children and carries the threat of severe complications in the most active period of life (2).Both environmental and genetic factors play etiological roles. The most informative genetic locus, HLA class II, confers about half of the total genetic risk (3) but has low positive predictive value (PPV) when used alone in the general population (4,5). Autoantibodies provide a practical readout of ␤-cell autoimmunity, are easily sampled in venous blood, and have become a mainstay of type 1 diabetes prediction efforts. Initially described in terms of the islet cell antibody (ICA) immunofluorescence assay on pancreatic sections, autoantibodies are now often described in terms of defined ICA target antigens, such as insulin (6,7), GAD (8), and the tyrosine phosphatase homologue IA2/ICA512 (9 -11). Autoantibodies are useful to detect developing type 1 diabetes in close relatives of diabetic patients, whose risk is ϳ3%. However, most cases are sporadic rather than familial (...

The frequency of type 1 diabetes mellitus (T1DM)-associated HLA DQ alleles in the U.S. Pacific Northwest is as high as in Scandinavia, which has the highest T1DM incidence in the world. The high regional rate of islet autoimmunity observed among DPT-1 relatives supports this notion. Fortunately, Washington State archives dried blood spots after legislature-mandated newborn screening. The Diabetes Evaluation in Washington (DEW-IT) study aims to show that population-based prospective prediction of T1DM by HLA genotype screening followed by autoantibody surveillance can be performed within the public health infrastructure.