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.
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.


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.
LaGasse
James M
JM
Pacific Northwest Research Institute, Seattle, Washington 98122, USA.
Brantley
Michael S
MS
Leech
Nicola J
NJ
Rowe
Rachel E
RE
Monks
Stephanie
S
Palmer
Jerry P
JP
Nepom
Gerald T
GT
McCulloch
David K
DK
Hagopian
William A
WA
D000293:Adolescent; D001323:Autoantibodies / Q000097:blood*; D001324:Autoantigens; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000175:diagnosis / Q000453:epidemiology* / Q000276:immunology; D005260:Female; D005500:Follow-Up Studies; D005968:Glutamate Decarboxylase / Q000276:immunology*; D006630:Hispanic or Latino; D006801:Humans; D007328:Insulin / Q000097:blood*; D007515:Islets of Langerhans / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000097:blood; D011237:Predictive Value of Tests; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000097:blood; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D012680:Sensitivity and Specificity; D014861:Washington / Q000453:epidemiology; D044465:White People
D001323:Autoantibodies; D001324:Autoantigens; D007328:Insulin; D008565:Membrane Proteins; C024211:islet cell antibody; C516862:PTPRN protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D005968:Glutamate Decarboxylase