Andreas Weiss1,2, Jose Zapardiel-Gonzalo1,2, Franziska Voss1, Manja Jolink1, Joanna Stock1, Florian Haupt1,2,3, Kerstin Kick4, Tiziana Welzhofer4, Anja Heublein1, Christiane Winkler1,2,3, Peter Achenbach1,2,3,4, Anette-Gabriele Ziegler5,6,7,8, Ezio Bonifacio2,9,10. 1. Institute of Diabetes Research, Helmholtz Munich, German Research Center for Environmental Health, Munich, Germany. 2. German Center for Diabetes Research (DZD), Munich, Germany. 3. Forschergruppe Diabetes e.V. at Helmholtz Zentrum München, Munich, Germany. 4. Technical University Munich, School of Medicine, Forschergruppe Diabetes at Klinikum rechts der Isar, Munich, Germany. 5. Institute of Diabetes Research, Helmholtz Munich, German Research Center for Environmental Health, Munich, Germany. anette-g.ziegler@helmholtz-muenchen.de. 6. German Center for Diabetes Research (DZD), Munich, Germany. anette-g.ziegler@helmholtz-muenchen.de. 7. Forschergruppe Diabetes e.V. at Helmholtz Zentrum München, Munich, Germany. anette-g.ziegler@helmholtz-muenchen.de. 8. Technical University Munich, School of Medicine, Forschergruppe Diabetes at Klinikum rechts der Isar, Munich, Germany. anette-g.ziegler@helmholtz-muenchen.de. 9. Center for Regenerative Therapies Dresden, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany. 10. Paul Langerhans Institute Dresden of Helmholtz Centre Munich at University Clinic Carl Gustav Carus of TU Dresden, Faculty of Medicine, Dresden, Germany.
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 stage 2 or stage 1b type 1 diabetes, with 50% risk to develop clinical type 1 diabetes within 2 years.
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 stage 2 or stage 1b type 1 diabetes, with 50% risk to develop clinical type 1 diabetes within 2 years.
Keywords:
Clinical trial modelling; Glucose tolerance; Immunotherapy; Islet autoantibodies; Population screening; Progression score; Public health screening; Type 1 diabetes
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