Successful Prospective Prediction of Type 1 Diabetes in Schoolchildren Through Multiple Defined Autoantibodies
An 8-year follow-up of the Washington State Diabetes Prediction Study
- James M. LaGasse, MS1,
- Michael S. Brantley1,
- Nicola J. Leech, MD2,
- Rachel E. Rowe, MD2,
- Stephanie Monks, PHD3,
- Jerry P. Palmer, MD3,
- Gerald T. Nepom, MD, PHD2,
- David K. McCulloch, MD34 and
- William A. Hagopian, MD, PHD13
- 1Pacific Northwest Research Institute, Seattle, Washington
- 2Virginia Mason Research Center, Seattle, Washington
- 3Departments of Medicine and Biostatistics, University of Washington, Seattle, Washington
- 4McCoy Institute and Group Health Cooperative of Puget Sound, Seattle, Washington
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 cell antibodies [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 >99th 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.
- AIRg, acute insulin response to glucose
- d-aab, defined autoantibody
- ICA, islet cell antibody
- JDFU, Juvenile Diabetes Foundation units
- PPV, positive predictive value
Address correspondence and reprint requests to William Hagopian, MD, PhD, Pacific Northwest Research Institute, 720 Broadway, Seattle, WA 98122. E-mail:.
Received for publication 19 June 2001 and accepted in revised form 6 December 2001.
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
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