PREDICTION OF IDDM IN THE GENERAL-POPULATION - STRATEGIES BASED ON COMBINATIONS OF AUTOANTIBODY MARKERS

Strategies for assessing risk of progression to IDDM, based on single and combined autoantibody measurement, were evaluated in 2,855 schoolc hildren (median age 11.4 years) and 256 children with newly diagnosed IDDM (median age 10.2 years), recruited to a population-based study in the Oxford region. In 256 children with IDDM, levels of antibodies gr eater than or equal to 97.5th centile of the schoolchild population we re found in 225 (88%) for islet cell antibodies (ICAs), in 190 (74%) f or antibodies to GAD, in 193 (75%) for antibodies to protein tyrosine phosphatase IA-2 (IA-2), and in 177 (69%) for autoantibodies to insuli n (IAAs). Estimates of risk of progression to IDDM within 10 years, de rived by comparing the distribution of antibody markers in the two pop ulations (schoolchildren and children with IDDM), were 6.7% (ICAs), 6. 6% (GAD antibodies), 5.6% (IA-2 antibodies), and 4.8% (IAAs) for schoo lchildren with levels above the 97.5th centile, increasing to 20, 23, 24, and 11%, respectively, for antibody levels >99.5th centile. Most c hildren with IDDM had multiple antibody markers, and 89% of those diag nosed over age 10 years had greater than or equal to 2 antibodies abov e the 97.5th centile, as compared against 0.7% of schoolchildren, in w hom this combination gave a 27% 10-year estimated risk of IDDM. Risk i ncreased but sensitivity fell as combined antibody thresholds were rai sed, or the number of antibodies above the threshold was increased. St rategies based on detection of greater than or equal to 2 antibodies w ith primary testing for GAD and IA-2 antibodies and second line testin g for ICAs and/or IAAs were evaluated. Detection of at least two marke rs selected from GAD antibodies greater than or equal to 97.5th centil e and/or IA-2 antibodies greater than or equal to 99.5th centile and/o r ICAs greater than or equal to 97.5th centile identified 0.25% of sch oolchildren and 83% of children with newly diagnosed IDDM, with an est imated risk of 71% (95% CI 57-91). Although confirmation from prospect ive studies is still needed, this analysis suggests that antibody comb inations can predict diabetes in the general population.