Staging of preclinical type 1 diabetes in siblings of affected children

Objectives. To assess whether it is clinically relevant to classify sibling s of children with recent-onset type 1 diabetes mellitus (T1DM) into variou s stages of preclinical diabetes, and to compare the risk of developing cli nical disease and the time to diagnosis between these stages. Study Design. From a total of 801 families taking part in the Childhood Dia betes in Finland Study, 758 initially unaffected siblings were graded into four stages of preclinical T1DM based on the number of disease-associated a utoantibodies detectable close to the time of diagnosis in the index case: no (no antibodies), early (one antibody specificity), advanced (two antibod ies), and late prediabetes (more than three antibodies). Another classifica tion system, used with 712 siblings, was based on a combination of the numb er of antibodies and the first-phase insulin response (FPIR) to intravenous glucose: no (no antibodies), early (one antibody specificity, normal FPIR) , advanced (two or more antibodies, normal FPIR), and late prediabetes (one or more antibodies, reduced FPIR). Results. Six out of 661 siblings who initially presented no signs of predia betes (0.9%; 95% confidence interval [CI], 0.3%-2.0%) progressed to clinica l T1DM. Based on the first set of criteria, 3 out of 49 individuals (6.1%; CI, 1.3%-16.9%; odds ratio [OR], 7.1; CI, 1.7-29.4) from the early prediabe tes category, 3 out of 13 with advanced prediabetes (23.1%; CI, 5.0%-53.8%; OR, 32.8; CI, 7.2-150), and 23 out of 35 with late prediabetes (65.7%; CI, 47.8%-80.9%; OR, 209; CI, 72.2-607) presented with clinical signs of T1DM. According to the second set of criteria 1 out of 15 siblings with early pr ediabetes (6.7%; CI, 0.2%-32.0%; OR, 7.8; CI, 0.9-69.1), 6 out of 23 with a dvanced prediabetes (26.1%; CI, 10.2%-48.4%; OR, 38.5; CI, 11.3-132), and 1 2 out of 13 with late prediabetes (92.3%; CI, 64.0%-99.8%; OR, 1310; CI, 14 6-11 737) presented with clinical signs of T1DM. The time to diagnosis was significantly shorter in those with late prediabetes initially than in thos e with no signs of prediabetes. Conclusions. Our observations indicate that it is possible to grade sibling s of children with newly diagnosed T1DM into categories with significant di fferences in the subsequent risk of clinical T1DM and time to diagnosis. Su ch a classification will become clinically relevant as soon as effective me asures are available for preventing or delaying the manifestation of overt T1DM.