Progression likelihood score identifies substages of presymptomatic type 1 diabetes in childhood public health screening

Abstract

Aims/hypothesis The aim of this study was to develop strategies that identify children from the general population who have late-stage presymptomatic type 1 diabetes and may, therefore, benefit from immune intervention. Methods We tested children from Bavaria, Germany, aged 1.75–10 years, enrolled in the Fr1da public health screening programme for islet autoantibodies (n=154,462). OGTT and HbA1c were assessed in children with multiple islet autoantibodies for diagnosis of presymptomatic stage 1 (normoglycaemia) or stage 2 (dysglycaemia) type 1 diabetes. Cox proportional hazards and penalised logistic regression of autoantibody, genetic, metabolic and demographic information were used to develop a progression likelihood score to identify children with stage 1 type 1 diabetes who progressed to stage 3 (clinical) type 1 diabetes within 2 years. Results Of 447 children with multiple islet autoantibodies, 364 (81.4%) were staged. Undiagnosed stage 3 type 1 diabetes, presymptomatic stage 2, and stage 1 type 1 diabetes were detected in 41 (0.027% of screened children), 30 (0.019%) and 293 (0.19%) children, respectively. The 2 year risk for progression to stage 3 type 1 diabetes was 48% (95% CI 34, 58) in children with stage 2 type 1 diabetes (annualised risk, 28%). HbA1c, islet antigen-2 autoantibody positivity and titre, and the 90 min OGTT value were predictors of progression in children with stage 1 type 1 diabetes. The derived progression likelihood score identified substages corresponding to ≤90th centile (stage 1a, n=258) and >90th centile (stage 1b, n=29; 0.019%) of stage 1 children with a 4.1% (95% CI 1.4, 6.7) and 46% (95% CI 21, 63) 2 year risk of progressing to stage 3 type 1 diabetes, respectively. Conclusions/interpretation Public health screening for islet autoantibodies found 0.027% of children to have undiagnosed clinical type 1 diabetes and 0.038% to have undiagnosed presymptomatic type 1 diabetes. Of the latter group, our novel likelihood ratio score predicted approximately 50% risk of developing clinical diabetes within 2 years. Graphical abstract

Pediatric diabetes update

“…This is evidenced by a population study in Bavaria, Germany where 154 462 children aged 2-10 years were enrolled in the Fr1da public health screening program for T1DM. 4 Out of this cohort, only 541 participants (0.35%) screened positive of whom only 0.08% (119) were positive for T1DM. Therefore, the population prevalence numbers show that the path forward requires we develop effective treatment approaches post diagnosis.…”

“…However, the overall prevalence of autoimmunity for T1DM is quite low. This is evidenced by a population study in Bavaria, Germany where 154 462 children aged 2–10 years were enrolled in the Fr1da public health screening program for T1DM 4 . Out of this cohort, only 541 participants (0.35%) screened positive of whom only 0.08% (119) were positive for T1DM.…”

Clinical Significance of Diabetes-Mellitus-Associated Antibodies in Rheumatoid Arthritis

“…It is estimated that about 90% of patients with T1D have autoantibodies, which are often present years before diagnosis and act as predictive biomarkers for the disease. The number of antibodies, along with the type, titers, affinity, and age of seroconversion are all associated with the development of clinically distinguishable DM [ 27 , 28 ]. Recently, a variant called latent autoimmune diabetes in adults (LADA) was defined.…”

Novel approaches to the treatment of type 1 diabetes

“…Such approaches, however, require the identification of very small numbers of predisposed persons in the overall population, a daunting exercise. A German study carried out in more than 150 000 children found only 0.35% to be positive for islet antibodies, of whom only 0.08% progressed to develop diabetes 2 . The identification of a number of experimental treatment options for T1D after clinical onset offer intriguing alternative possibilities.…”

“…A German study carried out in more than 150 000 children found only 0.35% to be positive for islet antibodies, of whom only 0.08% progressed to develop diabetes. 2 The identification of a number of experimental treatment options for T1D after clinical onset offer intriguing alternative possibilities.…”