Successful Prospective Prediction of Type 1 Diabetes in Schoolchildren Through Multiple Defined Autoantibodies

Abstract

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 (...

HLA-DQB1 genotypes, islet antibodies and beta cell function in the classification of recent-onset diabetes among young adults in the nationwide Diabetes Incidence Study in Sweden

“…However, patients with islet antibodies and samples taken 6 month after diagnosis had low F-P-C-peptide concentrations, irrespective of risk HLA-DQB1 genotypes, again underlining that in the presence of islet antibodies, genetic risk assessment based on HLA is not important in the classification. It was also observed previously, that in the presence of islet antibodies genetic risk or protection does not matter in the prediction of diabetes development [19][20][21]. Our observation that low F-P-C-peptide was associated with risk HLA-genotypes in Ab-indicates, that risk HLA-DQB1 genotypes per se may be associated with impaired beta-cell function.…”

Prediction of type 1 diabetes among siblings of affected children and in the general population

“…Positivity for multiple autoantibodies is a rare phenomenon in the general population, and since only seven individuals in the population cohort developed double positivity, the statistical power to confirm the similar progression rates in the two cohorts remained relatively weak. However, from previous studies we know that an overwhelming majority of the progressors develop multiple-autoantibody positivity months to years before the diagnosis, and that combined GADA and IA-2A screening identified all single positive and 96% of the multiple-positive progressors among the DiMe siblings and all European and American schoolchildren testing positive for multiple antibodies [4][5][6]. Our data confirmed the previously published observation that a single-point negative autoantibody test is associated with an extremely low risk of developing type 1 diabetes, in the general population in particular [11].…”

“…Although information on the predictive characteristics of diabetes-associated autoantibodies in the general population is limited, there are indications that the predictive value of positivity for multiple autoantibodies, i.e. two or more, is close to that observed among first-degree relatives [4,5]. We present here direct comparisons of the predictive characteristics of GADA, IA-2A and their combination between first-degree relatives and a representative general population cohort over an observation period of 15 years.…”

Environmental Triggers and Determinants of Type 1 Diabetes

“…In family studies, positivity for three to four autoantibodies is associated with a risk of developing clinical type 1 diabetes in the range of 60 -100% over the next 5-10 years. Preliminary studies in the general population indicate that the predictive value of multiple autoantibody positivity is approaching that observed among first-degree relatives (7,8).…”