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      Capillary blood islet autoantibody screening for identifying pre-type 1 diabetes in the general population: design and initial results of the Fr1da study

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      type 1 diabetes, islet autoantibodies, screening, childhood

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          Abstract

          Introduction

          Type 1 diabetes can be diagnosed at an early presymptomatic stage by the detection of islet autoantibodies. The Fr1da study aims to assess whether early staging of type 1 diabetes (1) is feasible at a population-based level, (2) prevents severe metabolic decompensation observed at the clinical manifestation of type 1 diabetes and (3) reduces psychological distress through preventive teaching and care.

          Methods and analysis

          Children aged 2–5 years in Bavaria, Germany, will be tested for the presence of multiple islet autoantibodies. Between February 2015 and December 2016, 100 000 children will be screened by primary care paediatricians. Islet autoantibodies are measured in capillary blood samples using a multiplex three-screen ELISA. Samples with ELISA results >97.5th centile are retested using reference radiobinding assays. A venous blood sample is also obtained to confirm the autoantibody status of children with at least two autoantibodies. Children with confirmed multiple islet autoantibodies are diagnosed with pre-type 1 diabetes. These children and their parents are invited to participate in an education and counselling programme at a local diabetes centre. Depression and anxiety, and burden of early diagnosis are also assessed.

          Results

          Of the 1027 Bavarian paediatricians, 39.3% are participating in the study. Overall, 26 760 children have been screened between February 2015 and November 2015. Capillary blood collection was sufficient in volume for islet autoantibody detection in 99.46% of the children. The remaining 0.54% had insufficient blood volume collected. Of the 26 760 capillary samples tested, 0.39% were positive for at least two islet autoantibodies.

          Discussion

          Staging for early type 1 diabetes within a public health setting appears to be feasible. The study may set new standards for the early diagnosis of type 1 diabetes and education.

          Ethics dissemination

          The study was approved by the ethics committee of Technische Universität München (Nr. 70/14).

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          Most cited references 30

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          Harmonization of glutamic acid decarboxylase and islet antigen-2 autoantibody assays for national institute of diabetes and digestive and kidney diseases consortia.

          Autoantibodies to islet antigen-2 (IA-2A) and glutamic acid decarboxylase (GADA) are markers for diagnosis, screening, and measuring outcomes in National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) consortia studies. A harmonization program was established to increase comparability of results within and among these studies. Large volumes of six working calibrators were prepared from pooled sera with GADA 4.8-493 World Health Organization (WHO) units/ml and IA-2A 2-235 WHO units/ml. Harmonized assay protocols for IA-2A and GADA using (35)S-methionine-labelled in vitro transcribed and translated antigens were developed based on methods in use in three NIDDK laboratories. Antibody thresholds were defined using sera from patients with recent onset type 1 diabetes and healthy controls. To evaluate the impact of the harmonized assay protocol on concordance of IA-2A and GADA results, two laboratories retested stored TEDDY study sera using the harmonized assays. The harmonized assays gave comparable but not identical results in the three laboratories. For IA-2A, using a common threshold of 5 DK units/ml, 549 of 550 control and patient samples were concordantly scored as positive or negative, specificity was greater than 99% with sensitivity 64% in all laboratories. For GADA, using thresholds equivalent to the 97th percentile of 974 control samples in each laboratory, 1051 (97.9%) of 1074 samples were concordant. On the retested TEDDY samples, discordance decreased from 4 to 1.8% for IA-2A (n = 604 samples; P = 0.02) and from 15.4 to 2.7% for GADA (n = 515 samples; P < 0.0001). Harmonization of GADA and IA-2A is feasible using large volume working calibrators and common protocols and is an effective approach to ensure consistency in autoantibody measurements.
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            Diabetes Antibody Standardization Program: evaluation of assays for autoantibodies to glutamic acid decarboxylase and islet antigen-2.

            Islet autoantibodies are important in diabetes classification and risk assessment, and as endpoints in observational studies. The Diabetes Autoantibody Standardization Program (DASP) aims to improve and standardise measurement of autoantibodies associated with type 1 diabetes. We report results for glutamic acid decarboxylase autoantibodies (GADA) and islet antigen-2 autoantibodies (IA-2A) from three DASP workshops (2002--2005). Up to 60 laboratories in 18 countries participated in each workshop. Participants received coded serum aliquots from 50 patients with newly diagnosed type 1 diabetes (median age 18 years, range 9-35 years) and 100 blood donor controls. Results were analysed using receiver operator characteristic (ROC) curves with sensitivity adjusted to 95% specificity in workshop controls. GADA assays performed well in all three workshops (median area under the ROC curve [AUC] 0.94; interquartile range 0.91-0.95) and performance was similar to DASP 2000. Performance of IA-2A assays improved over the workshop programme. Median AUC was 0.81 (interquartile range 0.79-0.83) in DASP 2002, 0.82 (interquartile range 0.78-0.84) in 2003, and 0.85 (interquartile range 0.82-0.87) in 2005 (p < 0.0001). Performance of GADA ELISA improved between 2002 and 2005, and, in DASP 2005, achieved higher median AUC and adjusted sensitivity than RIA. IA-2A ELISA improved and, in DASP 2005, achieved AUCs equivalent to in-house RIA. Assays using IA-2ic or full length IA-2 clones were more sensitive than those using IA-2bdc, with higher AUC (p = 0.004). GADA and IA-2A assays perform well in discriminating health and disease. The workshop format highlights systematic differences related to assay method and allows full evaluation of novel methods. The programme of autoantibody workshops in type 1 diabetes provides a model for other autoimmune diseases.
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              Age-related islet autoantibody incidence in offspring of patients with type 1 diabetes.

              Seroconversion to islet autoantibodies precedes type 1 diabetes. This study aimed to identify periods of high seroconversion incidence, which could be targeted for mechanistic and therapeutic studies. Incidence of islet autoantibodies was calculated in 1,650 genetically at-risk children followed with measurements of islet autoantibodies and thyroid autoantibodies at age 9 months and 2, 5, 8, 11, 14 and 17 years. Peak incidence periods were confirmed in a second cohort of 150 children followed until age 6 years with three-monthly samples up to age 3 years. Islet autoantibody incidence (per 1,000 person-years) was 18.5 until age 9 months, 21 from 9 months to 2 years and <10 for intervals after age 2 years. The second cohort confirmed peak incidence around age 9 months and demonstrated an absence of seroconversion before this age. Seroconversion to insulin autoantibodies occurred earlier than other autoantibodies (p<0.01 against glutamic acid decarboxylase [GAD]-, insulinoma-associated protein 2 [IA-2]- and zinc transporter 8 [ZnT8]-autoantibodies). Early peak seroconversion incidence was most evident in children with high-risk HLA DR3/4-DQ8 or DR4/4-DQ8 genotypes. The age period 9 months to 2 years is associated with a high incidence of activation of type 1 diabetes associated autoimmunity in genetically at-risk children and should be targeted for effective primary prevention strategies.
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                Author and article information

                Journal
                BMJ Open
                BMJ Open
                bmjopen
                bmjopen
                BMJ Open
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                2044-6055
                2016
                16 May 2016
                : 6
                : 5
                Affiliations
                [1 ]Institute of Diabetes Research, Helmholtz Zentrum München, and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München , Neuherberg, Germany
                [2 ]Forschergruppe Diabetes e.V. , Neuherberg, Germany
                [3 ]Department of Pediatrics, Klinikum rechts der Isar, Technische Universität München , München, Germany
                [4 ]Department of Medical Psychology, Hannover Medical School , Hannover, Germany
                [5 ]Bavarian Health and Food Safety Authority , Oberschleißheim, Germany
                [6 ]Berufsverband der Kinder- und Jugendärzte e.V., Landesverband Bayern , Augsburg, Germany
                [7 ]PaedNetz Bayern e.V. , Rosenheim, Germany
                [8 ]Klinikum Augsburg, Klinik für Kinder und Jugendliche , Augsburg, Germany
                [9 ]Centre for Regenerative Therapies Dresden, Faculty of Medicine, Technische Universität , Dresden, Germany
                [10 ]Paul Langerhans Institute Dresden of Helmholtz Centre Munich at University Clinic Carl Gustav Carus of Technische Universität , Dresden, Germany
                Author notes
                [Correspondence to ] Professor Anette-G Ziegler; anette-g.ziegler@ 123456helmholtz-muenchen.de
                Article
                bmjopen-2016-011144
                10.1136/bmjopen-2016-011144
                4874167
                27194320
                Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

                This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

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                type 1 diabetes, islet autoantibodies, screening, childhood

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