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Original article
Screening for coeliac disease in 1624 mainly asymptomatic children with type 1 diabetes: is genotyping for coeliac-specific human leucocyte antigen the right approach?
  1. Elisabeth Binder1,
  2. Tilmann Rohrer2,
  3. Christian Denzer3,
  4. Wolfgang Marg4,
  5. Ute Ohlenschläger5,
  6. Heike Schenk-Huber6,
  7. Ulrike Schierloh7,
  8. Heino Skopnik8,
  9. Elke Elisabeth Fröhlich-Reiterer9,
  10. Reinhard W Holl10,11,
  11. Nicole Prinz10,11
  1. 1 Department of Pediatrics, Medical University Innsbruck, Innsbruck, Austria
  2. 2 Department of Pediatrics and Neonatology, Saarland University Hospital, Saarland, Germany
  3. 3 Department of Pediatrics and Adolescent Medicine, University Medical Centre Ulm, Ulm, Germany
  4. 4 Center for Pediatrics and Adolescent Medicine, Prof.-Hess-Kinderklinik, Bremen Mitte Hospital, Bremen, Germany
  5. 5 Department of Pediatrics, University Hospital Frankfurt, Frankfurt, Germany
  6. 6 Westpfalz Klinikum GmbH, Kaiserslautern, Germany
  7. 7 Clinque Pédiatrique, Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg
  8. 8 Department of Pediatrics, Children’s Hospital Worms, Worms, Germany
  9. 9 Department of Paediatrics, Medical University of Graz, Graz, Austria
  10. 10 Institute of Epidemiology and Medical Biometry, Zentralinstitut für Biomedizinische Technik, University of Ulm, Ulm, Germany
  11. 11 German Center for Diabetes Research (DZD), Munich-Neuherberg, Germany
  1. Correspondence to Dr Elisabeth Binder, Department of Pediatrics, Medical University Innsbruck, Innsbruck 6020, Austria; elisabeth.binder{at}i-med.ac.at

Abstract

Objectives To investigate the frequency of coeliac disease (CD)-specific human leucocyte antigen (HLA) genotypes in paediatric patients with type 1 diabetes (T1D), who are known to have a higher prevalence of CD than the general population, and to evaluate whether HLA genotyping is a suitable first-line screening method for CD.

Study design The study was a multicentre observational analysis of patients with T1D aged <20 years of whom a subgroup had undergone HLA genotyping. Patient data were retrieved from the Diabetes Prospective Follow-up database, a large diabetes follow-up registry. The present analysis included data from 439 centres throughout Germany, Austria, Switzerland and Luxembourg.

Results In March 2017, the database contained 75 202 patients with T1D (53% male, mean age (SD) 14.6 (4.1) years, mean age at diagnosis 8.8 (4.3) years and mean diabetes duration 5.8 (4.3) years). 1624 patients had undergone coeliac-specific HLA genotyping, of whom 1344 (82.8%) were positive for HLA-DQ2, HLA-DQ8 or both, while 17.2% had no coeliac-specific HLA-markers. 26.6% of at-risk patients had a clinical suspected diagnosis of CD, and 3.6% had biopsy-proven CD.

Conclusions Genotyping for HLA-DQ2, HLA-DQ8 or both is positive in the vast majority (>80%) of patients with T1D. Therefore, screening for coeliac-specific HLA genotypes as a first-line test is not a suitable method to exclude CD in T1D. Regular screening for coeliac-specific antibodies in T1D is still recommended.

  • diabetes
  • gastroenterology
  • immunology
  • screening
  • paediatric practice

https://doi.org/10.1136/archdischild-2018-315549

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    What is already known on this topic?

    • Patients with type 1 diabetes (T1D) are known to be at high risk for the development of coeliac disease due to the shared human leucocyte antigen (HLA) genetics.

    • The ESPGHAN (European Society for Paediatric Gastroenterology Hepatology and Nutrition) recommends coeliac-specific HLA genotyping as a screening method in patients at risk.

    What this study adds?

    • The vast majority (82.8%) of patients with T1D is positive for HLA-DQ2, HLA-DQ8 or both.

    • Even in patients with T1D negative for coeliac-specific HLA antigens, a biopsy-proven coeliac disease could be diagnosed.

    • HLA genotyping in patients with T1D is not useful as a screening method for the development of coeliac disease.

    Introduction

    Type 1 diabetes mellitus (T1D) is frequently associated with other autoimmune disorders such as coeliac disease (CD),1 an immune-mediated systemic disorder elicited by the protein gluten in genetically susceptible patients. The overall prevalence of CD in Western populations of all ages is 0.3%–1%,2 whereas CD prevalence in paediatric and adolescent patients with T1D is 6.2%–10%,3 4 and even up to 15%5, depending on country and diagnostic work-up.6 T1D and CD are known to have overlapping genetic risk factors.7 Shared susceptibility alleles in the HLA region contribute to the coexistence of T1D and CD.8 CD has a multifactorial inheritance; nevertheless, the HLA region is the major CD-predisposing genetic factor and accounts for approximately 40% of disease heritability.9–11 As the classic intestinal and extraintestinal symptoms of CD are absent up to 70% in patients with T1D12 13 and untreated CD in patients with T1D might be associated with unstable levels of blood glucose, a higher risk of hypoglycaemia and an increased risk of developing retinopathy,14 15 the importance of screening for CD is widely acknowledged. In view of the effects of undiagnosed CD, such as villous atrophy16 leading to intestinal malabsorption with the consequence of iron deficiency, anaemia and growth retardation, early diagnosis is important to implement lifelong gluten-free diet in order to prevent further illness.16 According to the guidelines established by the International Society for Paediatric and Adolescent Diabetes (ISPAD),17 patients with T1D should be screened annually or biennially for coeliac-specific antibodies, such as anti-tissue transglutaminase (tTG) antibodies or anti-endomysial antibodies. The current guidelines of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN)18 recommend HLA genotyping as a first-line test in asymptomatic patients belonging to a high-risk group, as do patients with T1D. If test results are positive, screening with anti-tTG IgA is advised18 which then would not be required in patients without HLA-DQ2 or HLA-DQ8 genotypes.19 Negativity for all antibodies on an unrestricted diet or absence of both HLA-DQ2 and HLA-DQ8 strongly contradicts the diagnosis of CD. Being aware of the high linkage disequilibrium, one could estimate that only a small number of patients will benefit from the HLA screening guidelines.17 Therefore, the aim of this study was to investigate the HLA genotypes of patients with T1D to assess whether using this screening method as a first-line test could in any way benefit patients with T1D.

    Methods

    Study design

    This multicentre observational study analysed data from the Diabetes Prospective Follow-up (DPV) initiative, a large standardised diabetes registry including data from four Central European countries, that is, Germany, Austria, Switzerland and Luxembourg. DPV prospectively collects demographic and clinical data from routine care in electronic form, covering an estimated proportion of >80% of all paediatric patients with diabetes in the Central European region it serves. Twice a year, the data are anonymised and transferred to Ulm University, Germany, for central quality assurance and analysis. Collection of the DPV data has been started in 1995. Informed consent for participation in the DPV initiative was obtained from patients or their parents by verbal or written procedure, as approved by the responsible administrators for data protection of each centre. Analysis of anonymised data for the purposes of the present study has been approved by the Ethics Committee of Ulm University, Germany.20

    Study population

    The present survey included patients from 439 centres located in the four participating countries. At the time of analysis in March 2017, the DPV registry comprised 4 65 977 registered patients, of whom 1 15 400 had T1D. Patients were eligible for the study if they had a clinical diagnosis of T1D, were aged less than 20 years and older than 6 months at diagnosis of T1D. 75 202 fulfilled these criteria. Patients with T2D or other forms of diabetes (eg, genetic forms) were excluded. A subgroup of 1624 (2.2%) patients from 140 centres had undergone HLA genotyping (figure 1).

    Figure 1
    Figure 1

    Flow chart of Diabetes Prospective Follow-up (DPV)-registered patients included in the study, and subsets of human leucocyte antigen (HLA)-genotyped patients. T1D, type 1 diabetes.

    HLA genotyping

    The main class I and II HLA haplotypes associated with CD (DQA1*05,02,03 DQB1*02,0301,0302 and DRB1*03,11,12,07,04) were genotyped. Genotyping assays were performed at specialised laboratories using standardised methods.

    Anti-tTG, anti-endomysium and anti-gliadin antibodies

    Serum levels of anti-tTG IgA antibodies were measured. In case of IgA deficiency, IgG-based antibodies were additionally determined. Unclear results of anti-TG antibodies lead to supplementary measurement of anti-endomysium. As the DPV data collection spans a long period of time, anti-gliadin antibodies were also evaluated in cases with older datasets where no other antibody assay has been available.

    Diagnosis of CD

    In the DPV registry, a clinical suspected diagnosis of CD implies the presence of symptoms and/or elevated antibodies in accordance with current guidelines,21 22 whereas histologically proven CD is classified as biopsy confirmed.

    Statistical analysis

    All statistical analysis was carried out using SAS V.9.4. Descriptive results are given as mean and SD, or proportion. Group comparisons were performed using the Kruskal-Wallis test for continuous parameters and the χ² test for binary data. As multiple tests were performed, p-values were adjusted using the false discovery rate algorithm. A two-tailed p<0.05 was considered significant.

    Results

    Study population characteristics

    Table 1 summarises the demographic and clinical characteristics of the eligible study population and the subgroups of HLA-genotyped, HLA-positive and HLA-negative patients. 53% of the 75 202 patients included were male. Mean age (SD) was 14.6 (4.1) years, mean age at diabetes onset was 8.8 (4.3) years and mean diabetes duration was 5.8 (4.3) years. 49 246 patients (65.5%) had been screened for coeliac-specific antibodies, that is, anti-tTG IgA, anti-endomysium and/or anti-gliadin antibodies. 13.4% of antibody-tested patients were positive for at least one of the three antibodies.

    View this table:
    Table 1

    Demographic and clinical characteristics of the study population, HLA-genotyped patients and coeliac-specific HLA-positive and HLA-negative patients

    HLA-genotyped patients

    Of the HLA-genotyped patients, 1344 (82.8%) had positive tests for HLA-DQ2, HLA-DQ8 or both. Two hundred and eighty (17.2%) patients were not positive for HLA-DQ2 or HLA-DQ8. Figure 2 shows the distribution of the HLA markers in this subgroup.

    Figure 2
    Figure 2

    Distribution of coeliac-specific human leucocyte antigen (HLA) genotypes in 1624 patients with type 1 diabetes.

    Of the HLA-DQ2 and/or HLA-DQ8-positive patients, 89.7% had undergone coeliac-specific antibody screening, with 369 (30.6%) testing positive for either anti-tTG IgA, anti-endomysial and/or anti-gliadin antibodies (table 1). A clinical suspected diagnosis of CD (symptoms and/or elevated antibodies) was recorded in 26.6% of HLA-positive patients, whereas a biopsy-proven CD diagnosis was documented in 3.6% of cases.

    Of the patients without any CD-specific HLA alleles, 83.6% had undergone serological testing—49 (20.9%) tested positive for at least one of the above-mentioned antibodies (table 1). Even in HLA-negative patients, a biopsy-proven CD was present in seven cases.

    Discussion

    This study used data from the large, well-established DPV registry to investigate the presence of coeliac-specific HLA genotypes in patients with T1D and to evaluate the benefit of HLA screening as a first-line test in this high-risk group. In concordance with national reports,22–24 our multinational analysis confirms strong HLA-DQ2/8 positivity in patients with T1D.23–25 Over 80% of patients had positive tests for coeliac-specific HLA markers. This is not surprising in view of the expected high linkage disequilibrium between diabetes-specific and coeliac-specific HLA genotypes.11 26 The frequency of positive coeliac-specific HLA markers in our cohort is slightly lower than revealed in similar published data from other European countries.23–25 Previous studies reported 92% positivity for Austria22 and 94% positivity for Scotland,25 while a cohort of 110 patients with T1D from the Netherlands24 showed 86% positive results for HLA-DQ8, HLA-DQ2 or both.

    Compared with the high number of patients (n=1344) at an increased risk for being diagnosed with CD based on positive tests for CD-specific HLA genotypes, a clinical suspected diagnosis of CD was recorded in 26.6% and a biopsy-proven CD in 3.6%. This result is concordant with previously published data from Sweden and Australia.3 27

    The ESPGHAN guidelines assume that CD could be excluded in 99% of HLA-negative individuals and no further test would be required.18 In clear contrast, our study indicates that in T1D less than 20% of patients would benefit from these new guidelines. The vast majority would still need further antibody screening tests. Hence, considering the high frequency of coeliac-specific HLA genotypes, no cost savings could be expected. Furthermore, 7 (2.1%) of the 280 HLA-negative patients in our study even had biopsy-proven disease. Similar numbers of HLA-DQ2 and/or HLA-DQ8 negative coeliac patients were described in a large European study of 1008 coeliac patients. Many of the patients carrying neither HLA-DQ2 nor HLA-DQ8 have been reported to encode just one chain of the DQ2 heterodimer.28 29 Nevertheless, most of these cases present early-onset disease and total mucosal atrophy.28 According to the ESPGHAN guidelines, such patients would not receive any further evaluation if HLA genotyping alone was performed as a first-line test. One might, therefore, question whether HLA genotyping is indeed useful as the first-line screening method for CD in patients with T1D. A very high number of patients would have to undergo further diagnostic testing and CD could not be completely excluded even in HLA-negative patients as discussed previously.30

    In our study, 13.4% of the study population had positive tests for coeliac-specific antibodies against tTG, endomysium and/or gliadin. Even if we look exclusively at the subgroup of HLA-positive patients, serological antibody testing was positive only in 30.6%. The vast majority, nevertheless, had no antibodies and therefore needed no further exploration in the form of HLA genotyping or biopsy. Such patients should be monitored annually or every 2 years by screening for antibodies against tTG or endomysium in accordance with the ISPAD guidelines.17 Due to the relatively low number of patients with HLA screening in our study, one might speculate that the majority of paediatric endocrinologists in Germany, Austria, Luxembourg and Switzerland question the benefit of the ESPGHAN recommendation of HLA screening in patients with T1D as a first-line test for CD and follow ISPAD guidelines in their routine clinical care.

    Costs analyses may differ across countries and healthcare systems, but calculations by research groups from Austria, the Netherlands and Scotland have shown that HLA genotyping is more expensive than anti-tTG IgA testing.23–25 Moreover, HLA genotyping is not necessarily available at smaller hospitals and the alternative of sending blood samples to specialised laboratories would be time-consuming and costly.

    The increased risk of an additional autoimmune disease such as CD in patients with T1D is well understood. One has to take into account that the detection of certain HLA genotypes, and, hence, the predisposition to develop CD could cause additional concern for asymptomatic paediatric patients with T1D and their parents. This could lead to insecurity and anxiety, potentially resulting in additional psychological burden for the majority of patients while providing reassurance to only a few. In the PreventCD study, unfavourable HLA results of children were related with negative feelings in the parents, but had no influence of quality of life in their offspring. In general, families support HLA typing for genetic risk determination, even though a large percentage misinterpreted favourable results instead of being relieved.31

    The strength of our survey lies in the high number of patients, recruited from a large number of centres in four Central European countries. The DPV data reflect a ‘real-life setting’ and show how paediatric diabetologists deal with the diagnosis of diabetes-associated diseases, particularly CD. Even though DPV is used in a broad spectrum of paediatric facilities including small-sized and tertiary university centres, a certain bias leading to under-reporting or over-reporting of coeliac diagnosis cannot be completely excluded since this analysis does not constitute a full survey.

    In conclusion, our results clearly indicate that the vast majority of patients with T1D have positive coeliac-specific HLA genotypes, while only approximately 3% have biopsy-proven CD. Therefore, one has to question whether HLA genotyping as recommended by ESPGHAN as a first-line screening test in asymptomatic T1D individuals at risk for CD really is an efficient and cost-effective method to identify patients requiring additional diagnostic evaluation to exclude or confirm the diagnosis of the gluten-sensitive enteropathy. For the above-mentioned reasons (practicability, lack of cost-effectiveness and potential psychological burden) and the fact of biopsy-proven CD in HLA-negative patients, we agree with recently published data32 that HLA genotyping is not a constructive screening method in patients with T1D. We would propose that annual or biannual antibody screening followed by biopsy in case of positive results seems the most effective way to diagnose CD in patients with T1D.

    Acknowledgments

    Special thanks to A Hungele and R Ranz for support and development of the DPV documentation software and K Fink and E Bollow for the DPV data management and statistical analysis (in each case clinical data manager, Ulm University). The authors acknowledge the long-standing collaboration with all participating treatment centres in Germany, Austria, Switzerland and Luxembourg and thank all DPV centres who contributed data for this analysis. In detail: Aachen—Innere RWTH, Aachen—Uni-Kinderklinik RWTH, Aalen Kinderklinik, Ahlen St. Franziskus Kinderklinik, Aidlingen Praxisgemeinschaft, Altötting Zentrum Inn-Salzach, Altötting-Burghausen Innere Medizin, Amberg Kinderklinik St. Marien, Amstetten Klinikum Mostviertel Kinderklinik, Arnsberg-Hüsten Karolinenhosp. Kinderabteilung, Asbach Kamillus-Klinik Innere, Aue Helios Kinderklink, Augsburg IV. Med. Klinik, Augsburg Josefinum Kinderklinik, Augsburg Kinderklinik Zentralklinikum, Aurich Kinderklinik, Bad Aibling Internist. Praxis, Bad Driburg/Bad Hermannsborn Innere, Bad Hersfeld Innere, Bad Hersfeld Kinderklinik, Bad Kreuznach-St.Marienwörth-Innere, Bad Kreuznach-Viktoriastift, Bad Kösen Median Kinderklinik, Bad Lauterberg Diabeteszentrum Innere, Bad Mergentheim—Diabetesfachklinik, Bad Mergentheim—Gemeinschaftspraxis DM-dorf Althausen, Bad Oeynhausen Herz-und Diabeteszentrum NRW, Bad Orb Spessart Klinik, Bad Orb Spessart Klinik Reha, Bad Reichenhall Kreisklinik Innere Med., Bad Salzungen Kinderklinik, Bad Säckingen Hochrheinklinik Innere, Bad Waldsee Kinderarztpraxis, Bautzen Oberlausitz KK, Bayreuth Innere Medizin, Berchtesgaden CJD, Berchtesgaden MVZ Innere Med, Berlin DRK-Kliniken Mitte Innere, Berlin DRK-Kliniken Pädiatrie, Berlin Endokrinologikum, Berlin Evang. Krankenhaus Königin Elisabeth, Berlin Klinik St. Hedwig Innere, Berlin Lichtenberg—Kinderklinik, Berlin Oskar Zieten Krankenhaus Innere, Berlin Parkklinik Weissensee, Berlin Schlosspark-Klinik Innere, Berlin St. Josephskrankenhaus Innere, Berlin Virchow-Kinderklinik, Berlin Vivantes Hellersdorf Innere, Bern Universitätsklinik Inselspital Innere Medizin, Bielefeld Kinderarztpraxis, Bielefeld Kinderklinik Gilead, Bocholt Kinderklinik, Bochum Universitäts St. Josef, Bochum Universitätskinderklinik St. Josef, Bonn Uni-Kinderklinik, Bottrop Kinderklinik, Bottrop Knappschaftskrankenhaus Innere, Braunfels-Wetzlar Innere, Braunschweig Kinderarztpraxis, Bremen—Kinderklinik Nord, Bremen—Mitte Innere, Bremen Zentralkrankenhaus Kinderklinik, Bremerhaven Kinderklinik, Bruchweiler Edelsteinklinik Kinder-Reha, Böblingen Kinderklinik, Castrop-Rauxel Evangelisches Krankenhaus, Castrop-Rauxel Rochus-Hospital, Celle Klinik für Kinder- und Jugendmedizin, Chemnitz Kinderklinik, Chemnitz-Hartmannsdorf Innere Medizin—DIAKOMED-1, Coburg Innere Medizin, Coburg Kinderklinik, Coesfeld Kinderklinik, Coesfeld/Dülmen Innere Med., Darmstadt Innere Medizin, Darmstadt Kinderklinik Prinz. Margaret, Datteln Vestische Kinderklinik, Deggendorf Gemeinschaftspraxis, Deggendorf Kinderklinik, Deggendorf Medizinische Klinik II, Deggendorf Pädiatrie-Praxis, Delmenhorst Kinderklinik, Dessau Kinderklinik, Detmold Kinderklinik, Dinslaken Kinderklinik, Dornbirn Innere Medizin, Dornbirn Kinderklinik, Dortmund Kinderklinik, Dortmund Knappschaftskrankenhaus Innere, Dortmund Medizinische Kliniken Nord, Dortmund-Hombruch Marienhospital, Dortmund-St. Josefshospital Innere, Dortmund-West Innere, Dresden Neustadt Kinderklinik, Dresden Uni-Kinderklinik, Duisburg Evang. und Johanniter Krhs Innere, Duisburg Malteser Rhein-Ruhr St. Anna Innere, Duisburg Malteser St. Johannes, Duisburg Sana Kinderklinik, Duisburg-Huckingen, Duisburg-Huckingen Malteser Rhein-Ruhr ST. Johannes, Duisburg-St.Johannes Helios, Düren-Birkesdorf Kinderklinik, Düsseldorf Uni-Kinderklinik, Eberswalde Klinikum Barnim Werner Forßmann—Innere, Eisleben Lutherstadt Helios-Klinik, Erfurt Kinderklinik, Erlangen Uni Innere Medizin,Erlangen Uni-Kinderklinik,Essen Diabetes-Schwerpunktpraxis,Essen Elisabeth Kinderklinik, Essen Kinderarztpraxis, Essen Uni-Kinderklinik, Esslingen Klinik für Kinder und Jugendliche, Eutin Kinderklinik, Eutin St.-Elisabeth Innere, Feldkirch Kinderklinik, Filderstadt Kinderklinik, Flensburg Diakonissen Kinderklinik, Forchheim Diabeteszentrum SPP, Frankenthal Kinderarztpraxis, Frankfurt Diabeteszentrum Rhein-Main Erwachsenendiabetologie (Bürgerhospital), Frankfurt Diabeteszentrum Rhein-Main-pädiat. Diabetologie (Clementine-Hospital), Frankfurt Uni-Kinderklinik, Frankfurt Uni-Klinik Innere, Frankfurt Uni-Klinik Innere, Frankfurt-Sachsenhausen Innere, Frankfurt-Sachsenhausen Innere MVZ, Freiburg Kinder-MVZ, Freiburg St. Josef Kinderklinik, Freiburg Uni Innere, Freiburg Uni-Kinderklinik, Freudenstadt Kinderklinik, Friedberg Innere Klinik, Friedrichshafen Kinderklinik, Fulda Innere Medizin, Fulda Kinderklinik, Fürth Kinderklinik, Gaissach Fachklinik der Deutschen Rentenversicherung Bayern Süd, Garmisch-Partenkirchen Kinderklinik, Geislingen Klinik Helfenstein Innere, Gelnhausen Innere, Gelnhausen Kinderklinik, Gelsenkirchen Kinderklinik Marienhospital, Gera Kinderklinik, Gießen Ev. Krankenhaus Mittelhessen, Gießen Uni-Kinderklinik, Graz Uni Innere, Graz Uni-Kinderklinik, Greifswald Uni-Kinderklinik, Göppingen Innere Medizin, Göppingen Kinderklinik am Eichert, Görlitz Städtische Kinderklinik, Göttingen Uni Gastroenterologie, Göttingen Uni-Kinderklinik, Güstrow Innere, Hachenburg Kinderpraxis, Hagen Kinderklinik, Halberstadt Innere Med. AMEOS Klinik, Halberstadt Kinderklinik AMEOS, Halle Uni-Kinderklinik, Halle-Dölau Städtische Kinderklinik, Hamburg Altonaer Kinderklinik, Hamburg Endokrinologikum, Hamburg Kinderklinik Wilhelmstift, Hamburg-Nord Kinder-MVZ, Hameln Kinderklinik, Hamm Kinderklinik, Hanau Kinderklinik, Hanau St. Vincenz—Innere, Hannover DM-SPP, Hannover Henriettenstift—Innere, Hannover Kinderklinik MHH, Hannover Kinderklinik auf der Bult, Haren Kinderarztpraxis, Heide Kinderklinik, Heidelberg St. Josefskrankenhaus, Heidelberg Uni-Kinderklinik, Heidelberg Uniklinik Innere, Heidenheim Kinderklinik, Heilbronn Innere Klinik, Heilbronn Kinderklinik, Herdecke Kinderklinik, Herford Innere Med I, Herford Kinderarztpraxis, Herford Klinikum Kinder & Jugendliche, Heringsdorf Inselklinik, Hermeskeil Kinderpraxis, Herne Evan. Krankenhaus Innere, Herten St. Elisabeth Innere Medizin, Herzberg Kreiskrankenhaus Innere, Hildesheim GmbH—Innere, Hildesheim Kinderarztpraxis, Hildesheim Kinderklinik, Hinrichsegen-Bruckmühl Diabetikerjugendhaus, Hof Kinderklinik, Homburg Uni-Kinderklinik Saarland, Idar Oberstein Innere, Ingolstadt Klinikum Innere, Innsbruck Uni-Kinderklinik, Innsbruck Universitätsklinik Innere, Iserlohn Innere Medizin, Itzehoe Kinderklinik, Jena Uni-Kinderklinik, Kaiserslautern Kinderarztpraxis, Kaiserslautern-Westpfalzklinikum Kinderklinik, Kamen Klinikum Westfalen Hellmig Krankenhaus, Karlsburg Klinik für Diabetes & Stoffwechsel, Karlsruhe Städtische Kinderklinik, Kassel Klinikum Kinder- und Jugendmedizin, Kassel Rot-Kreuz-Krankenhaus Innere, Kassel Städtische Kinderklinik, Kaufbeuren Innere Medizin, Kempen Heilig Geist—Innere, Kempten Oberallgäu Kinderklinik, Kiel Städtische Kinderklinik, Kiel Universitäts-Kinderklinik, Kirchen DRK Krankenhaus Kinderklinik, Kirchheim-Nürtingen Innere, Klagenfurt Innere Med I, Kleve Innere Medizin, Koblenz Kemperhof 1. Med. Klinik, Koblenz Kinderklinik Kemperhof, Konstanz Innere Klinik, Konstanz Kinderklinik, Krefeld Innere Klinik, Krefeld Kinderklinik, Krefeld-Uerdingen St. Josef Innere, Kreischa-Zscheckwitz Klinik Bavaria, Köln Kinderklinik Amsterdamerstrasse, Köln Uni-Kinderklinik, Landau Innere, Landshut Kinderklink, Lappersdorf Kinderarztpraxis, Leer Klinikum—Klinik Kinder & Jugendmedizin, Leipzig Uni-Kinderklinik, Leoben LKH Kinderklinik, Leverkusen Kinderklinik, Lienz BKH Kinderklinik, Lienz Diabetesschwerpunktpraxis für Kinder und Jugendliche, Lilienthal Diabeteszentrum, Limburg Innere Medizin, Lindenfels Luisenkrankenhaus Innere, Lindenfels Luisenkrankenhaus Innere 2, Lingen Kinderklinik St. Bonifatius, Linz KUK/Med Campus IV Kinderklinik, Linz Krankenhaus Barmherzige Schwestern Kardiologie Abt. Int. II, Linz Krankenhaus der Barmherzigen Schwestern Kinderklinik, Lippstadt Evangelische Kinderklinik, Ludwigsburg Innere Medizin, Ludwigsburg Kinderklinik, Ludwigshafen Kinderklinik St.Anna-Stift, Ludwigshafen diabetol. SPP, Luxembourg—Centre Hospitalier, Lübeck Uni-Kinderklinik, Lübeck Uni-Klinik Innere Medizin, Lüdenscheid Hilfswerk Kinder & Jugendliche, Lüdenscheid Märkische Kliniken—Kinder & Jugendmedizin, Magdeburg Städtisches Klinikum Innere, Magdeburg Uni-Kinderklinik, Mainz Uni-Kinderklinik, Mannheim Uni-Kinderklinik, Mannheim Uniklinik Innere Medizin, Marburg—UKGM Endokrinologie & Diabetes, Marburg Uni-Kinderklinik, Marburg Uni-Kinderklinik, Marktredwitz Innere Medizin, Mechernich Kinderklinik, Meissen Kinderklinik Elblandklinikum, Memmingen Internistische Praxis, Memmingen Kinderklinik, Merzig Kinderklinik, Minden Kinderklinik, Moers - St. Josefskrankenhaus Innere, Moers Kinderklinik, Murnau am Staffelsee - diabetol. SPP, Mutterstadt Kinderarztpraxis, Mödling Kinderklinik, Mönchengladbach Kinderklinik Rheydt Elisabethkrankenhaus, Mühlacker Enzkreiskliniken Innere, Mühldorf am Inn Kinderarztpraxis, München 3. Orden Kinderklinik, München Diabetes-Zentrum Süd, München Kinderarztpraxis diabet. SPP, München Schwerpunktpraxis, München von Haunersche Kinderklinik, München-Gauting Kinderarztzentrum, München-Harlaching Kinderklinik, München-Schwabing Kinderklinik, Münster Herz Jesu Innere, Münster Ludgerus-Kliniken GmbH, Münster St. Franziskus Kinderklinik, Münster Uni-Kinderklinik, Münster pädiat. Schwerpunktpraxis, Münsterlingen Kinderklinik, Nagold Kreiskrankenhaus Innere, Nauen Havellandklinik, Neuburg Kinderklinik, Neumarkt Innere, Neunkirchen Innere Medizin, Neunkirchen Marienhausklinik Kohlhof Kinderklinik, Neuruppin Kinderklinik, Neuss Lukas-Krankenhaus Kinderklinik, Neuss Lukaskrankenhaus Kinderklinik, Neuwied Kinderklinik Elisabeth, Neuwied Marienhaus Klinikum St. Elisabeth Innere, Nürnberg Cnopfsche Kinderklinik, Nürnberg Med. Klinik 4, Nürnberg Zentrum f Neugeb./Kinder & Jugendl., Oberhausen Innere, Oberhausen Kinderklinik, Oberhausen Kinderpraxis, Oberhausen St.Clemens Hospitale Sterkrade, Oberndorf Gastroenterologische Praxis Schwerpunkt Diabetologie, Oberwart - Burgenländische Krankenanstalten Pädiatrie, Offenbach/Main Innere Medizin, Offenbach/Main Kinderklinik, Offenburg Kinderklinik, Oldenburg Kinderklinik, Oldenburg Schwerpunktpraxis, Olpe pädiatrische Gemeinschaftspraxis, Oschersleben MEDIGREIF Bördekrankenhaus, Osnabrück Christliches Kinderhospital, Osterkappeln Innere, Ottobeuren Kreiskrankenhaus, Oy-Mittelberg Hochgebirgsklinik Kinder-Reha, Paderborn St. Vincenz Kinderklinik, Papenburg Marienkrankenhaus Kinderklinik, Passau Kinderarztpraxis, Passau Kinderklinik, Pforzheim Kinderklinik, Pfullendorf Innere Medizin, Pirmasens Städtisches Krankenhaus Innere, Plauen Vogtlandklinikum, Prenzlau Krankenhaus Innere, Rastatt Gemeinschaftspraxis, Rastatt Kreiskrankenhaus Innere, Ravensburg Kinderklink St. Nikolaus, Recklinghausen Dialysezentrum Innere, Regensburg Kinderklinik St. Hedwig, Remscheid Kinderklinik, Rendsburg Kinderklinik, Reutlingen Kinderarztpraxis, Reutlingen Kinderklinik, Reutlingen Klinikum Steinenberg Innere, Reutte/Tirol BKH Kinderklinik, Rheine Mathiasspital Kinderklinik, Ried Innkreis Barmherzige Schwestern, Rodalben St. Elisabeth, Rosenheim Innere Medizin, Rosenheim Kinderklinik, Rosenheim Schwerpunktpraxis, Rostock Uni-Kinderklinik, Rostock Universität Innere Medizin, Rotenburg/Wümme Agaplesion Diakonieklinikum Kinderabteilung, Rüsselsheim Kinderklinik, Saaldorf-Surheim Diabetespraxis, Saalfeld Thüringenklinik Kinderklinik, Saarbrücken Kinderklinik Winterberg, Saarbrücken Kinderklinik Winterberg 2, Saarlouis Kinderklinik, Salzburg Universitäts-Kinderklinik, Scheibbs Landesklinikum, Scheidegg Prinzregent Luitpold, Scheidegg Reha-Kinderklinik Maximilian, Schw. Gmünd Stauferklinik Kinderklinik, Schweinfurt Kinderklinik, Schwerin Innere Medizin, Schwerin Kinderklinik, Schwäbisch Hall Diakonie Innere Medizin, Schwäbisch Hall Diakonie Kinderklinik, Siegen Kinderklinik, Singen—Hegauklinik Kinderklinik, Singen Kinderarztpraxis, Sinsheim Innere, Spaichingen Innere, Speyer Diakonissen Stiftungskrankenhaus Pädiatrie, St. Augustin Kinderklinik, St. Johann Tirol Kinderklinik, St. Pölten Universitäts-Kinderklinik, St. Pölten Universitätsklinik Innere, Stade Kinderklinik, Stockerau Landeskrankenhaus, Stolberg Kinderklinik, Stuttgart Olgahospital Kinderklinik, Suhl Kinderklinik, Sylt Rehaklinik, Tettnang Innere Medizin, Timmendorfer Strand, Traunstein Kinderklinik, Traunstein diabetol. Schwerpunktpraxis, Trier Kinderklinik der Borromäerinnen, Trostberg Innere, Tübingen Uni-Kinderklinik, Ulm Endokrinologikum2, Ulm Schwerpunktpraxis Bahnhofsplatz, Ulm Uni Innere Medizin, Ulm Uni-Kinderklinik, Vechta Kinderklinik, Viersen Kinderkrankenhaus St. Nikolaus, Villach Kinderklinik, Villingen-Schwenningen Schwarzwald Baar Klinikum Kinderklinik, Villingen-Schwenningen Schwarzwald-Baar-Klinikum Innere, Vöcklabruck Kinderklinik, Waldshut Kinderpraxis, Waldshut-Tiengen Kinderpraxis Biberbau, Wangen Oberschwabenklinik Innere Medizin, Waren-Müritz Kinderklinik, Weiden Kinderklinik, Weingarten Kinderarztpraxis, Weisswasser Kreiskrankenhaus, Wels Klinikum Pädiatrie, Wernberg-Köblitz SPP, Wesel Marienhospital Kinderklinik, Wetzlar Schwerpunkt-Praxis, Wien 3. Med. Hietzing Innere, Wien Preyersches Kinderspital, Wien Rudolfstiftung, Wien SMZ Ost Donauspital, Wien Uni Innere Med III, Wien Uni-Kinderklinik, Wien Wilhelminenspital 5. Med. Abteilung, Wiesbaden Helios Horst-Schmidt-Kinderkliniken, Wiesbaden Kinderklinik DKD, Wilhelmshaven Klinikum Kinderklinik, Wilhelmshaven St. Willehad Innere, Winnenden Rems-Murr Kinderklinik, Wismar Kinderklinik, Wittenberg Innere Medizin, Wittenberg Kinderklinik, Wolgast Innere Medizin, Worms—Weierhof, Worms Kinderklinik, Wuppertal Kinderklinik, Würzburg Kinderarztpraxis, Zweibrücken Ev. KH. Innere, Zweibrücken Kinderarztpraxis, Zwettl Landesklinikum Gmünd-Waidhofen Kinderklinik.

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    Footnotes

    • Contributors We confirm that all authors have participated in the concept and design, analysis and interpretation of the data and have approved this submitted version of the manuscript and take full responsibility for the manuscript. EB, NP and RWH collected and researched the data, wrote and edited the manuscript. TR, CD, WM, UO, HS-H, US, HS and EEF-R contributed to data collection and interpretation and edited the manuscript. NP and RWH performed statistical analyses.

    • Funding The DPV initiative is funded by the German Ministry of Education and Research (BMBF) as part of the German Center for Diabetes Research (DZD, grant number: 82DZD0017G). Additional funding was provided by the German Diabetes Association (DDG) and the European Foundation for the Study of Diabetes (EFSD). Furthermore, funding was available from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement number: 115797 (INNODIA) supported by the European Union’s Horizon 2020 research and innovation programme and ‘EFPIA’, ‘JDRF’ and ‘The Leona M. and Harry B. Helmsley Charitable Trust’.

    • Competing interests None declared.

    • Patient consent Not required.

    • Ethics approval Approved by the local ethics committee of University Ulm, Germany.

    • Provenance and peer review Not commissioned; externally peer reviewed.