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Yield of a Public Health Screening of Children for Islet Autoantibodies in Bavaria, Germany

Educational Objective
To learn about autoimmunity and progression to clinical diabetes.
1 Credit CME
Key Points

Question  What is the yield of primary care–based screening of children for islet autoantibodies?

Findings  In a program that screened 90 632 children aged 2 to 5 years in Bavaria, Germany, during primary care visits, 280 children (0.31%) had 2 or more islet autoantibodies, among whom 62 developed clinical type 1 diabetes and 2 had mild or moderate diabetic ketoacidosis. Mothers of children with presymptomatic type 1 diabetes reported more symptoms of depression at diagnosis than mothers of children without islet autoantibodies (median psychological stress score of 3 vs 2).

Meaning  These findings may inform considerations of population-based screening of children for islet autoantibodies.

Abstract

Importance  Public health screening for type 1 diabetes in its presymptomatic stages may reduce disease severity and burden on a population level.

Objective  To determine the prevalence of presymptomatic type 1 diabetes in children participating in a public health screening program for islet autoantibodies and the risk for progression to clinical diabetes.

Design, Setting, and Participants  Screening for islet autoantibodies was offered to children aged 1.75 to 5.99 years in Bavaria, Germany, between 2015 and 2019 by primary care pediatricians during well-baby visits. Families of children with multiple islet autoantibodies (presymptomatic type 1 diabetes) were invited to participate in a program of diabetes education, metabolic staging, assessment of psychological stress associated with diagnosis, and prospective follow-up for progression to clinical diabetes until July 31, 2019.

Exposures  Measurement of islet autoantibodies.

Main Outcomes and Measures  The primary outcome was presymptomatic type 1 diabetes, defined by 2 or more islet autoantibodies, with categorization into stages 1 (normoglycemia), 2 (dysglycemia), or 3 (clinical) type 1 diabetes. Secondary outcomes were the frequency of diabetic ketoacidosis and parental psychological stress, assessed by the Patient Health Questionnaire-9 (range, 0-27; higher scores indicate worse depression; ≤4 indicates no to minimal depression; >20 indicates severe depression).

Results  Of 90 632 children screened (median [interquartile range {IQR}] age, 3.1 [2.1-4.2] years; 48.5% girls), 280 (0.31%; 95% CI, 0.27-0.35) had presymptomatic type 1 diabetes, including 196 (0.22%) with stage 1, 17 (0.02%) with stage 2, 26 (0.03%) with stage 3, and 41 who were not staged. After a median (IQR) follow-up of 2.4 (1.0-3.2) years, another 36 children developed stage 3 type 1 diabetes. The 3-year cumulative risk for stage 3 type 1 diabetes in the 280 children with presymptomatic type 1 diabetes was 24.9% ([95% CI, 18.5%-30.7%]; 54 cases; annualized rate, 9.0%). Two children had diabetic ketoacidosis. Median (IQR) psychological stress scores were significantly increased at the time of metabolic staging in mothers of children with presymptomatic type 1 diabetes (3 [1-7]) compared with mothers of children without islet autoantibodies (2 [1-4]) (P = .002), but declined after 12 months of follow-up (2 [0-4]) (P < .001).

Conclusions and Relevance  Among children aged 2 to 5 years in Bavaria, Germany, a program of primary care–based screening showed an islet autoantibody prevalence of 0.31%. These findings may inform considerations of population-based screening of children for islet autoantibodies.

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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Corresponding Author: Anette-Gabriele Ziegler, MD, Institute of Diabetes Research, Helmholtz Zentrum München, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany (anette-g.ziegler@helmholtz-muenchen.de).

Accepted for Publication: December 12, 2019.

Author Contributions: Dr Ziegler had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Ziegler, Bonifacio, Dunstheimer, Lang, Warncke, Lange, Assfalg, Winkler, Achenbach.

Acquisition, analysis, or interpretation of data: Ziegler, Kick, Bonifacio, Haupt, Hippich, Laub, Lange, Jolink, Winkler, Achenbach.

Drafting of the manuscript: Ziegler, Bonifacio, Hippich, Winkler.

Critical revision of the manuscript for important intellectual content: Ziegler, Kick, Bonifacio, Haupt, Dunstheimer, Lang, Laub, Warncke, Lange, Assfalg, Jolink, Winkler, Achenbach.

Statistical analysis: Ziegler, Bonifacio, Hippich, Lange, Jolink, Winkler.

Obtained funding: Ziegler, Bonifacio.

Administrative, technical, or material support: Ziegler, Bonifacio, Haupt, Hippich, Dunstheimer, Lang, Warncke, Lange, Assfalg, Jolink, Winkler, Achenbach.

Supervision: Ziegler, Bonifacio, Achenbach.

Conflict of Interest Disclosures: Dr Bonifacio reported receiving grants from Deutsche Forschungsgemeinschaft during the conduct of the study. No other disclosures were reported.

Funding/Support: The Fr1da study was supported by grants from LifeScience-Stiftung (HMGU 2014.01 and HMGU 2016.01), Juvenile Diabetes Research Foundation International (1-SRA-2014-310-M-R and 3-SRA-2015-72-M-R), the Bavarian State Ministry of Health and Care (Gesund.Leben.Bayern, LP00228), The Leona M and Harry B Helmsley Charitable Trust (G-1911-03274), Deutsche Diabetes-Stiftung (364/11/14), Landesverband Bayern der Betriebskrankenkassen, B. Braun-Stiftung (BBST-D-15-00016), Deutsche Diabetes Hilfe, and the German Federal Ministry of Education and Research to the German Center for Diabetes Research (DZD e.V.). The DiMelli study was funded by the Competence Network Diabetes Mellitus, the Federal Ministry of Education and Research (FKZ01GI0805), and the German Center for Diabetes Research (DZD e.V.).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

The Fr1da Study Group Members: Fr1da Coordinating Center (Institute of Diabetes Research, Helmholtz Zentrum München):Principle investigator: Anette-Gabriele Ziegler, MD; Study coordination: Kerstin Kick, PhD; Robin Assfalg, PhD; Logistics and database development: Florian Haupt, PhD; Andreas Beyerlein, PhD; Database management: Christiane Winkler, PhD; Manja Jolink, MSc; Nana-Adjoa Kwarteng, MSc. Teaching, metabolic staging, care, and follow-up of children with presymptomatic type 1 diabetes: Anna Hofelich, MD; Franziska Reinmüller, MD; Tiziana Welzhofer, MD; Claudia Ramminger; Joanna Stock, Dipl; Anja Heublein, MSc; Charlotte Koch, BSc; Annette Knopff; Administrative and Scientific Management: Ramona Lickert, PhD; Islet autoantibody determination, sample processing, and methodology development: Peter Achenbach, MD; Ezio Bonifacio, PhD; Susanne Wittich, Katharina Gestrich, Marlon Scholz, Claudia Matzke; Genotyping: Markus Hippich, PhD; Data analysis: Anette-Gabriele Ziegler, MD; Christiane Winkler, PhD; Ezio Bonifacio, PhD; Markus Hippich, PhD; Analytical support: Andreas Weiss, PhD; Peter Achenbach, MD; Manja Jolink, MSc; Nana-Adjoa Kwarteng, MSc. Dissemination, information, and public relations: Peter Achenbach, MD, Cordula Falk, Mona Walter.

Fr1da Clinical Centers:Teaching, metabolic staging, care, and follow-up of children with presymptomatic type 1 diabetes: Susanne Bechtold-Dalla Pozza, MD (Dr. von Hauner Children’s Hospital LMU, Munich); Dominik Böcker, MD (Nuremberg Hospital South, Nuremberg); Sonja Braig, MD (Pediatric Clinic of the Bayreuth Hospital, Bayreuth); Desiree Dunstheimer, MD (Augsburg Hospital, Augsburg); Uwe Ermer, MD (St Elisabeth Klinik, Neuburg/Donau); Antonia Gavazzeni, MD (Munich); Eva-Maria Gerstl, MD (Children’s Hospital Dritter Orden, Passau); Ursula Kuhnle-Krahl, MD (Diabetes Center, Gauting); Herbert Müller, MD (Hospital Kempten, Kempten); Nicole Nellen-Hellmuth, MD (Würzburg); Christian Ockert, MD (RoMed Hospital, Rosenheim); Christian Renner, MD (Deggendorf); Marina Sindichakis, MD (Hospital Traunstein, Traunstein); Stefanie Tretter, MD (Hospital Weiden, Weiden); Katharina Warncke, MD (Department of Pediatrics, Klinikum rechts der Isar, TUM, Munich).

Fr1da Primary Care Pediatricians:Obtaining informed consent of parents, and blood samples from Fr1da study participants: Simon Abendroth, MD (Landsberg am Lech); Renate Abt, MD (Wendelstein); Klaus Adams, MD (Lindau); Melanie Adelhardt, MD; Verena Schuster, MD (Hersbruck); Georg Aderbauer, MD (Weiden); Judith Aderbauer, MD; Frank Scharnowski-Fischer, MD (Weiden); Bettina Aichholzer, MD (Bad Endorf); Ina Albrich, MD (Dorfen); Stephan Arenz, MD (Pfaffenhofen); Imam Arslan, MD (München); Olga Arzberger, MD (Sünching); Ärztezentrum Hammelburg (Hammelburg); Bernd Aulinger, MD (Burglengenfeld); Thomas Autenrieth, MD (Saulgrub); Glenn Averbeck, MD (Pfaffenhofen); Andrea Bachmeyr, MD (München); Erika Bahn, MD (Nürnberg); Georg Baier, MD (Schwabach); Ana-Maria Baitanu, MD (Selb); Elmar Barthel, MD (Gemünden); Susanne Barthel, MD; Katrin Kinzel, MD (Oberstdorf); Marina Bascone-Fricke, MD (Aidenbach); Stefanie Batz, MD; Michael Hubmann, MD (Zirndorf); Rolf Bauer, MD (Roth); Yvonna Bauer, MD (Augsburg); Matthias Bauer, MD (Beilngries); Gunhild Bauer-Niedermaier, MD (Zirndorf); Larissa Baumgärtner, MD (Heilsbronn); Michael Bäzner, MD (Sonthofen); Wolfgang Beck, MD; Albert Baier, MD; Petra Mussar, MD (Donauwörth); Axel Becker, MD (Haar); Christian Becker, MD (Bad Aibling); Elisabeth Beer, MD; Hubert Schirmer, MD (Marktredwitz); Arman Behdjati-Lindner, MD; Christian Rein, MD (Haßfurt); Lutz Bellingrath, MD (Bamberg); Reiner Benckendorff, MD (Augsburg); Julia Berg, MD (Neumarkt); Monika Berger, MD (Haimhausen); Annerose Bergner, MD (München); Alexander Bernhart, MD; Christine Wieland, MD (München); Martina Bertholl, MD (Donaustauf); Florian Berz, MD (München); Oliver Beste, MD; Nikolaus Hosemann, MD (Dachau); Reinhard Beuthan, MD (Dingolfing); Katrin Biebach, MD (München); Matthias Bierler, MD; Jens Keppler, MD; Sabine Beer, MD (Amberg); Helene Biermann-Franke, MD; Michael Trinczek, MD (Erlangen); Klaus Binder, MD; Markus Redenbacher, MD; Stefan Zink, MD (Nürnberg); Georg Black, MD (Dietfurt); Elisabeth Blaettner, MD (Augsburg); Maria-Magdalena Blauditschek, MD (Würzburg); Jörg Blume, MD (Schweinfurt); Waltraud Blümel-Eiber, MD; Manfred Rösch, MD (Nürnberg); Andreas Blüml, MD (Trostberg); Jens Böhm, MD/Nilgün Durmus, MD (Wettstetten); Mirko Böhme, MD (Sulzberg); Sabine Böhm-Vogt, MD (Ottobrunn); Elisabeth Boretzki, MD; Thomas Boretzki, MD (Eichstätt); Karola Börzsönyi, MD (Freising); Nadja Bösel, MD (Neumarkt Opf.); Stephan Böse-O'Reilly, MD (München); Diana Boudova, MD (Neunburg vorm Wald); Michael Brack, MD (Urspringen); Malte Bräutigam, MD (Eichstätt); Walter Breiner, MD (Marktoberdorf); Ulrike Brendel, MD (Parsberg); Michael Brijnen von Oldershausen, MD (München); Christian Brückmann, MD (Brannenburg); Wolfgang Brunnhölzl, MD; Matthias Grimberg, MD (München); Halina Eva Buchalik, MD (Lauf an der Pegnitz); Franz Bundscherer, MD (Geretsried); Anna Bürcky, MD (Ochsenfurt); Edeltraud Burg, MD; Rita Berger, MD (Straubing); Peter Büttner, MD; Petra May, MD (Memmingen); Barbara Capelle, MD (Unterhaching); Mona Castrop, MD (Regensburg); Bernd Chittka, MD; Franz-Josef Kordowich, MD; Thomas Eltermann, MD (Karlstadt); Barbara Christl, MD (Wegscheid); Alina Cocos, MD (Markt Schwaben); Isabel Cordes, MD; Denis Gebhard, MD (Nürnberg); Christoph Daffner, MD (Nürnberg); Claudia Delles, MD (Nürnberg); Arcan Demircioglu, MD (München); Jost Dieckerhoff, MD (Rosenheim); Karolin Diergarten, MD (Germering); Karolin Diergarten, MD (Eching); Peter Dietl, MD (München); Elmar Dietmair, MD (Bobingen); Lutz Dietrich, MD (Hof); Maximilian Dietrich, MD; Thomas Bihler, MD (Aichach); Brigitte Dietz, MD (Taufkirchen); Christian Döbig, MD (Erlangen); Bernadette Donath, MD; Andreas Kammermeier, MD (Passau); Sylvia Döpfer, MD (München); Jürgen Dörrer, MD (Freyung); Ragnar Dörrfuss, MD (Nürnberg); Monika Drexel, MD (Rehau); Bettina Düll, MD (Ippesheim); Elke Düll-Schiller, MD (Neumarkt); Désirée Dunstheimer, MD (Augsburg); Stefan Eber, MD (München); Thomas Ebert, MD (Veitsbronn/Siegelsdorf); Christoph Ebert, MD (Ebersberg); Christina Eder, MD (Bayreuth); Eibl, MD (Beratzhausen); Claudia Eichwald, MD (Ingolstadt); Annette Eiden, MD (Gauting); Hans-Dieter Eisner, MD (Kronach); Claus Engelhardt, MD (Nürnberg); Anja Engelmann, MD (Dinkelscherben); Georg Engl, MD (München); Uta Enzensberger, MD, (Mering); Alois Epp, MD (Kaufbeuren); Petra Erhardt, MD (Bamberg); Patricia Erlinger, MD (Postbauer-Heng); Uwe Ermer, MD (Neuburg a.d. Donau); Kirsten Exl, MD (München); Florian Fackler, MD (Erlangen); Edgar Fath, MD (München); Andreas Fauser, MD; Alexandra Sand, MD; Lothar Karolyi, MD; Dominic Hegele, MD (Dillingen); Peter Feiereisen, MD (München); Daniela Felsl, MD (Wolnzach); Maria Fischer, MD (Lappersdorf); Cordula Fischer-Trüstedt, MD (München); Gudrun Fleck, MD; Alfred Heihoff, MD (Regensburg); Katrin Flögel, MD (Gundelfingen); Katrin Flögel, MD (Günzburg); Anna-Maria Frangoulis, MD (Gilching); Katrin Franke-Augustin, MD (Bayreuth); Harald Frantzmann, MD (Memmingen); Rudolf Franz, MD (München); Alexandra Fraundorfer, MD (Michelsneukirchen); Susanne Freislederer-Caccia, MD (München); Claudia Frey, MD (Augsburg); Karl Fromme, MD (Coburg); Dominik Fürsich, MD (Altdorf); Ulrich Gandela, MD (Furth im Wald); Susanne Gandenberger-Bachem, MD (München); Markus Gauer, MD (Vöhringen); Antonia Gavazzeni, MD (München); Bernhard Geck, MD (Nürnberg); Edeltraud Gerber, MD (Kolbermoor); Martin Gerlich, MD (Dinkelsbühl); Elke Gerlitz, MD (Herzogenaurach); Julia Gerstl, MD (Hauzenberg); Michael Gerstmayr, MD (Ingolstadt); Jürgen Geuder, MD (Freilassing); Johannes Gilles, MD (Gunzenhausen); Rainer Gillessen, MD (Ottobrunn); Elisabeth Gimpl, MD (Schweinfurt); Cornelia Gläßel, MD (Fürth); Judith Glöckner-Pagel, MD (Regensburg); Elke Gloger, MD (Ochsenfurt); Birgit Goldschmitt-Wuttge, MD (München); Michaela Göttler, MD (Muhr am See); Martin Götz, MD (Elisabethzell); Elif Götz, MD; Ulrike Sautier, MD (Pullach); Wolfgang Graser, MD (Nürnberg); Marion Grau, MD (Nürnberg); Martin Griebel, MD (Poing); Anette Groethuysen, MD (München); Wilma Großkopf, MD; Josef Großkopf, MD (Wallerfing); Angelika Gruber-Müller, MD (Ingolstadt); Martin Grundhuber, MD (Bad Tölz); Dietrich Grunert, MD (Kempten); Mehmet Güler, MD (Neuendettelsau); Christian Haas, MD (München); Richard Haaser, MD (Feucht); Hanne Habelt-Bock, MD (Happurg); Caroline Haberl, MD (Starnberg); Ulrich Hagen, MD (Friedberg); Henrik Halboni, MD (München); Verner Hallmen, MD (München); Emma Halwas, MD (Geisenfeld); Stefan Hammann, MD (München); Georg Handwerker, MD (Passau); Matthias Hartig, MD (Vilsbiburg); Marcus Härtle, MD (Krumbach); Conny Hartmann, MD (Bad Wörishofen); Ingrid Hartmann, MD (Lichtenfels); Christian Hartnik, MD (Bad Staffelstein); Matthias Hasenpusch, MD (Schierling); Ulrike Haun, MD (Vilshofen); Gabi Haus, MD (München); Marita Häußlein, MD; Susanne Joha, MD; Michael Deckelmann, MD (Würzburg); Rudolf Havla, MD (Hof); Johannes Havla, MD (Pegnitz); Gabriele Hecht, MD (Peiting); Birgit Heck-Buchhorn, MD; Susanne Willnow, MD (Kösching); Holger Hedderich, MD; Josef Seidl, MD (Füssen); Bernhard Heeren, MD (Langenzenn); Ralph Heidingsfelder, MD (Ansbach); Christine Heinemeyer, MD (Nordheim); Markus Helmreich, MD (Schweinfurt); Tanja Hemmers, MD (Augsburg); Andreas Henning, MD (Lauf); Johannes Herrmann, MD (Schweinfurt); Holger Hertzberg, MD (Schwabach); Sigrid Hesse, MD (Straubing); Daniela Heuschmann, MD; Dominik Ewald, MD (Regensburg); Andreas Hickmann, MD (Schneeberg); Ulrich Hilber, MD (Höchstadt); Bernward Hinkes, MD; Thorsten Fröhlich, MD (Forchheim); Andrea Hinnawi, MD (Großostheim); Ladislaus Hochschau, MD (Regensburg); Cornelia Hoegen, MD (Herrsching); Reinhard Hoffmann, MD (Landshut); Klaus Hoffmann, MD (Niederwerrn); Steffen Hoffmann-Baldus, MD (Haar); Gerhard Hofmann, MD (Würzburg); Meike Hofmann, MD (Mitterteich); Andrea Högl, MD; Gregor Zuj, MD (Schwandorf); Sabina Hohn, MD (Nürnberg); Marie-Luise Holler, MD (Rain am Lech); Martina Hoog, MD (Uffenheim); Kirsten Höper, MD (Augsburg); Gabriele Hopf, MD (Ingolstadt); Jörg Horcher, MD (Straubing); Alexia Horelt-Ernou, MD (München); Michael Horn, MD (Schönau am Königssee); Birgit Hortig-Nevelö, MD (Regenstauf); Annette Hovestadt, MD (München); Gottfried Huber, MD (München); Benedikta Huber-Lederer, MD (Fürstenzell); Irene Hummel, MD (Bamberg); Peter Hußlein, MD (Grassau); Wolfgang Hüttner, MD (Coburg); Anna Maria Iarrapino-Demmel, MD (München); Birgit Indlekofer, MD (Tutzing); Anneliese Intemann, MD (München); Margarete Jäger, MD (München); Christine Janello, MD (Neubiberg); Stephan Jarosch, MD; Manuel Langer, MD (Würzburg); Stefan Jobst, MD (Bayreuth); Janina Joiko, MD (München); Birgit Jork-Käferlein, MD (Prien); Guido Judex, MD (Regensburg); Guido Judex, MD; Monika Corbacioglu, MD; Sabrina Lindner, MD; Bastian Baumgartner, MD (Regensburg); Ronny Jung, MD (Roth); Imme Kaiser, MD (Puchheim); Laura Kallmann, MD; Lyn Kohl, MD (München); Andreas Kalmutzki, MD (Schwabach); Ludwig Kamhuber, MD (Kraiburg am Inn); Vanadis Kamm-Kohl, MD (Nürnberg); Lampros Kampouridis, MD (Baldham); Michael Kandler, MD (Nürnberg); Susanne Kastl, MD (Bayreuth); Walther Kaufmann, MD (Nürnberg); Bernhard Keck, MD (Augsburg); Ursula Keicher, MD (Neubiberg); Peter Kellner, MD (Vilsbiburg); Lars Kellner, MD (Gräfelfing); Beate Kevekordes-Stade, MD (Neunkirchen am Brand); Ghassan Khazim, MD (Hammelburg); Christiane Kiefer, MD (Straßlach); Werner Kienle, MD (Feldkirchen-Westerham); Gunhild Kilian-Kornell, MD (Starnberg); Christa Kitz, MD (Veitshöchheim); Annegret Klein, MD (Oberaudorf); Arno Klein, MD (Vilsbiburg); Wolfgang Klein, MD; Dominik Kutter, MD (Augsburg); Kristina Klemp, MD (Burgkunstadt); Jörg Klepper, MD (Aschaffenburg); Margreth Knebel, MD (München); Harald Knee, MD; Astrid Treude, MD (Peißenberg); Norbert Knieß, MD; Oliver Kolonko, MD (Ingolstadt); Daniela Kober, MD; Irmgard Spannagel, MD (Gmund); Andreas Koch, MD; Christoph Gerdemann, MD; Silke Kimpel, MD (Erlangen); Katalin Köhler-Vajta, MD (Grünwald); Herbert Kollaschinski, MD (Marktredwitz); Cornelia Komm, MD (Waldkraiburg); Nikos Konstantopoulos, MD (München); Cosima Köring, MD (Altötting); Christian Korzinek, MD (Wolnzach9; Renate Kramer, MD (München); Guido Krandick, MD (Deisenhofen); Barbara Krappatsch, MD (Viechtach); Karla Krause, MD; Olga Stepanowa, MD; Cornelia Kiani, MD (Bayreuth); Berndt Kreisberger, MD (Ismaning); Stefan Krell, MD (Tirschenreuth); Gabriela Kreller-Laugwitz, MD (Adelsdorf); Ulrike Kreuels, MD (Nürnberg); Michaela Krieger, MD (Germering); Andreas Kronwitter, MD (München); Matthias Krueger, MD (Klingenberg); Danylo Kubryk, MD; Günther Döring, MD (Aschheim); Thomas Kuchenbauer, MD (München); Lisa Kuchler, MD (Stallwang); Heinrich Küffner, MD (Bad Windsheim); Karl Kugler, MD; Christian Mühe, MD (München); Stephan Küntzer, MD (Kitzingen); Wolfgang Künzer, MD (Regensburg); Beate Kusser, MD (München); Wolfgang Küver, MD (München); Franz Lachner, MD (Ruhpolding); Christof Land, MD (Gauting); Wolfgang Landendörfer, MD (Nürnberg); Martin Lang, MD (Augsburg); Christina Lang, MD (Nürnberg); Carolin Lang, MD; Britta Zötl, MD (Bad Tölz); Bettina Lang-Negretto, MD (München); Otto Laub, MD (Rosenheim); Annette Laub, MD (Bergen); Peter Lautenbach, MD (Herzogenaurach); Gerhard Legat, MD (Amberg); Ulrike Lehnert, MD (Erlangen); Stefan Leidig, MD; Heiko von Goessel, MD (Lauf); Christian Leitner, MD (Pfaffenhofen an der Ilm); Gabriele Lenz, MD; Christian Wander, MD (Piding); Katrin Leuchtenberger, MD (Kelheim); Ildiko Leuthe-Vogel, MD (Neu-Ulm); Karin Leykauf, MD (Bayreuth); Hans Lichtenstern, MD; Monika Muhr, MD; Tobias Busse, MD; Birgit Siegl, MD (Pocking); Werner Lick, MD (Würzburg); Gabriele Lieb, MD (Würzburg); Bärbel Liebezeit, MD (Mühldorf am Inn); Armin Liebscher, MD (Eckental); Katharina Lindel, MD (Rain am Lech); Michaela Lindenau-Maier, MD (Pfaffenhofen); Susanne Linder, MD (Grafrath); Katharina Lindhorst, MD; Daniel Seng, MD; Thomas Schuch, MD (Unterschleißheim); Hubertus Lindner, MD (Pegnitz); Ruth Lindner-Gajek, MD; Soyoun Maisch, MD (München); Janusz Lipinski, MD; Kirsten Mende, MD; Susanne Kirtscher, MD (Lindenberg); Barbara List, MD (Siegsdorf); Harald Lodes, MD; Kathrin Rosenthal, MD (Neumarkt); Markus Loeff, MD (Landsberg am Lech); Andreas Lorenz, MD (Krumbach); Petra Lorenzini, MD (Heideck); Martin Löw, MD (Memmingen); Ulf Lüdicke, MD (Rödental); Anna Elisabeth Lüdtke, MD (Neu-Ulm); Renata Lysy, MD (Möhrendorf); Eva Maas-Doyle, MD (Erlangen-Tennenlohe); Jarmilla Mahlmeister, MD; Anita Conze, MD (Schondra); Peter Maier, MD; Heiko Weerda, MD (Pfaffenhofen); Brigitte Maier-Brandt, MD (Stein); Selma Maierhofer, MD (Adlkofen); Soyoun Maisch, MD (München); Sibylle Manstein-Heueis, MD (Icking); Birgit Marquardt, MD (Oy-Mittelberg); Stefanie Marr, MD (Ingolstadt); Sigrid Martin, MD; Margarete Schilder, MD (Schrobenhausen); Helmuth Mauer, MD (Lichtenberg); Monika Maurus, MD (Memmingen); Peter Mayr, MD (Memmingen); Ernst Georg Mayr, MD (Murnau); Jeanette Mederer, MD (Laaber); Barbara Meiler, MD (Grafrath); Udo Meißner, MD (Bamberg); Norbert Meister, MD (Bindlach); Juan-Carlos Menendez-Castro, MD (Bad Kissingen); Steffi Menzel, MD (München); Susanne Merget, MD (Germering); Manfred Meßmer, MD (Augsburg); Jürgen Messner, MD (Lohr); Roland Metzner, MD (Würzburg); Petra Sibyl Meyer, MD (Augsburg); Oliver Michael, MD (Murnau); Wolfgang Moll, MD (Reichertshausen); Wolfgang Moser, MD (Schondorf); Kathrin Mothes, MD (Schwandorf); Miriam Mrach, MD (München); Sabine Mühlbauer, MD (München); Udo Mulitze, MD (Mainburg); Ulrich Müller, MD (Gauting); Daniel Müller, MD (Amberg); Herbert Müller, MD (Kempten); Wolfgang Müller, MD; Martin Wilken, MD; Andrea Schürmann, MD (Naila); Müller-Ntokas, MD (Sulzbach-Rosenberg); Patrick Muzzolini, MD (Kulmbach); Sabine Nagel, MD (Neustadt/Donau); Dieter Nagel, MD (Freyung); Karsten Naumann, MD (Erlangen); Nicole Nellen-Hellmuth, MD (Würzburg); Klaus Neumann, MD (Höhenkirchen-Siegertsbrunn); Christiane Neumeir, MD (Königsbrunn); Hans-Peter Niedermeier, MD (Erding); Maria Nitsch, MD (Wolnzach); Maike Nordmann, MD (Fürstenfeldbruck); Jochen Noss, MD (München); Andreas Nowack, MD (Siegsdorf); Barbara Nowitzky, MD (Peißenberg); Thomas Nowotny, MD (Stephanskirchen); Marcus Oberkötter, MD (Hohenwarth); Stefan Oberle, MD (Höchstadt); Jutta Oberndorfer, MD (Schonungen); Barbara Oberneder, MD (Gräfelfing); Christine Olbrich, MD (Augsburg); Angela Olze, MD (München); Dilek Önaldi-Gildein, MD (München); Michael Osang, MD; Petra Pudenz, MD (München); Jürgen Pannenbecker, MD; Anette Hein, MD (Gerbrunn); Nicola Pape-Feußner, MD (Berg); Barbara Parhofer, MD; Rüdiger Wiß, MD (Dachau); Michael Pätzold, MD (Marktoberdorf); Christine Pauli, MD; Stephan von Hornstein, MD (Olching); Michaela Pausenberger, MD (Lauf a.d. Pegnitz); Matthias Peisler, MD (Forchheim); Sonja Pemsl, MD (Nürnberg); Josivania Maria Pereira da Silva, MD (Hof); Wolfgang Peter, MD (Zeitlarn); Christine Pfaller, MD (Frasdorf); Angela Pfeffer, MD (Regen); Dominik Pfister, MD (Obing); Bergit Pfleger, MD (Neuendettelsau); Angelika Plank-Wihr, MD (Kallmünz); Stefan Platzer, MD (Osterhofen); Bernhard Pleyer, MD (Rückersdorf); Annette Pohl-Koppe, MD (München); Heike Polster, MD; Judit Kainzinger, MD (Dingolfing); Andreas Pontz, MD; Konrad Wimmer, MD (Passau); Martin Poschenrieder, MD (Vohenstrauß); Rudolf Poschenrieder, MD; Gudrun Korzenietz, MD (Vohenstrauß); Manfred Praun, MD (Gilching); Constanze Preis, MD; Wolfgang Preis, MD (Bischberg); Eberhard Preissler, MD; Zuhal Tomas, MD; Wolfgang Theil, MD (Gersthofen); Verena Printz, MD (Fürstenfeldbruck); Gabriele Prinz, MD; Eva Maria Sedlacek, MD (Burgau); Anke Prothmann, MD (Gröbenzell); Barbara Przyklenk, MD (München); Georg Puchner, MD (Regensburg); Stefan Putz, MD (Iggensbach); Norbert Raabe, MD (Weißenburg); Gertraud Raber-Webhofer, MD (München); Wolfgang Rahner, MD (Friesenried); Marco Ramella Pezza, MD (Meitingen); Udo Rampf, MD; Angela Lautner, MD (Freising); Jürgen Ratay, MD (Freising); Jürgen Ratay, MD (Hallbergmoos); Heribert Rauch, MD (Hengersberg); Angela Rausch, MD (Traunstein); Karla Rauschning-Sikora, MD (Mainaschaff); Christiane Razeghi, MD (Miesbach); Angela Reber, MD (Pfaffenhofen); Anja Regenfus, MD (Nürnberg); Brigitte Reichstein, MD (Ingolstadt); Evelyn Reineke, MD (Karlshuld); Tobias Reinhardt, MD (Feuchtwangen); Gertrud Reiter, MD (Neusäß); Michaela Reitz, MD; Johannes Pawlak, MD (Rosenheim); Christian Renner, MD (Deggendorf); Roland Renz, MD; Claudia Lauterbach, MD (Weiden); Tobias Reploh, MD (Bad Tölz); Volkmar Reschke, MD; Stella Exner, MD (Kaufbeuren); Gert Reutter-Simon, MD (Nürnberg); Michael Richter, MD; Mina Mameghanian, MD (München); Bernhard Riedl, MD (Wenzenbach); Mustafa Rihawi, MD (Kronach); Norbert Rindle, MD (Königsbrunn); Claudia Ringert-Esmaeili, MD; Beate Winters, MD (Alzenau); Carsten Rinker, MD (München); Kristina Risse, MD (Ingolstadt); Isabel Ritz, MD (München); Fritz Robitzsch, MD (Bodenmais); Gisela Rodorff, MD (Ichenhausen); Ingrid Rohland, MD (Erding); Herbert Rohr, MD (Fürstenfeldbruck); Alexander Roithmaier, MD (München); Maria Römmelt, MD (Schwanfeld); Stefanie Rosam, MD; Philip Wintermeyer, MD (München); Mark Rosenthal, MD; Anke Lütkemeyer, MD (Unterschleißheim); Walter Rößler, MD (Weiden); Christian Rothascher, MD; Ursula Shane, MD; Peter Beierlein, MD (Schnaittach); Anne Katrin Rothe, MD (München); Christian Rudolf, MD (Bad Neustadt); Sebastian Rühl, MD (Nürnberg); Irene Rühlemann, MD (München); Ramon Rümler, MD (Dachau); Paulina Ruppel, MD (Hof); Frank Rüßmann, MD; Evagelia Rüßmann-Tzilini, MD (München); Uwe Sack, MD; Silvia Glotzbach-Sack, MD; Margarethe Kozuschek, MD (Würzburg); Renate Sacker, MD (München); Reinhard Sailer, MD; Margit Kosoko, MD (Vilsbiburg); Sirin Salik, MD (Nürnberg); Franziska Schaaff, MD; Jan-Helge Höpner, MD (Eckental-Eschenau); Gabriele Schall, MD (Bad Wörishofen); Sigrid Scharrer-Bothner, MD (Nördlingen); Hans-Ulrich Schatz, MD (München); Carolus Schenke, MD (Neustadt a.d. Aisch); Barbara Scherer, MD (München); Gabriele Scheuerer, MD; Andrea Schimmer-Eidenschink, MD (München); Holger Schiffmann, MD (Feucht); Birgit Schilling, MD (Passau); Ute Schindler, MD (Kelheim); Ralf Schipper, MD (Monheim); Lydia Schlak, MD (Sulzbach-Rosenberg); Josef Schleibinger, MD (Pfaffenhofen); Ewald Schlereth, MD (Oberthulba); Andreas Schlossbauer, MD (Bad Kissingen); Stefan Schmid, MD (Riedenburg); Ludwig Schmid, MD (München); Petra Schmid-Seibold, MD; Georg Leipold, MD (Regensburg); Stefan Schmidt, MD (Rosenheim); Volker Schmidt, MD (Kempten); Wolfram Schmidt, MD (Bad Königshofen); Dorothea Schmidt-Colberg, MD (Erlangen); Annelies Schmölz-Hefele, MD (Kaufbeuren); Stephan Schneider, MD (Schweinfurt); Ulrich Schneider, MD (Biberbach); Klaus Schneider, MD (Hohenthann); Klaus Schnell, MD; Katja Nillies, MD (Coburg); Martin Scholz, MD; Dunja Scholz-Kühn, MD (Deggendorf); Monika Schömig-Spingler, MD (Würzburg); Patric Schön, MD (Oberschleißheim); Volker Schönecker, MD (Kaufering); Martin Schöniger, MD (Weilheim); Roland Schöniger, MD (Rotthalmünster); Philipp Schoof, MD (München); Eduard Schreglmann, MD (Kirchenthumbach); Cristian Schröter, MD (München); Franziskus Schuhböck, MD (Kirchheim); Carola Schum, MD (Parsberg); Brigitte Schwager, MD (Eckental); Kirsten Schwarz, MD (Regenstauf); Axel Schweighart, MD (München); Christine Schweikl, MD (Eggenfelden); Rosemarie Schwertner, MD (Germering); Julia Seemann, MD; Stephanie Bosch, MD; Rudolf Loibl-Keimler, MD (Deggendorf); Christian Seidel, MD; Gabriele Hopf, MD; Stephanie Marr, MD; Brigitte Reichstein, MD (Ingolstadt); Monika Seidt, MD (München); Andrea Seiler, MD; Jasmin Pletl-Maar, MD; Katja Gaßmann, MD (Erlangen); Horst Seithe, MD (Nürnberg); Nina Sellerer, MD; Roman Polanetz, MD (München); Marko Senjor, MD (Wasserburg am Inn); Ursula Shane, MD (Lauf a.d. Pegnitz); Kathrin Simmel, MD (Holzkirchen); Berta Simon, MD (Zwiesel); Marina Sindichakis, MD (Traunstein); Manfred Singer, MD (Forchheim); Cornelia Singer, MD (Wessling); Simon Sitter, MD (Bechhofen); Claudia Söhngen, MD (Traunreut); Anita Sommer, MD; Barbara Domes, MD (Karlsfeld); Bernhard Sondermaier, MD (Ampfing); Wilfried Späth, MD (Weißenhorn); Michael Sperlich, MD (Ampfing); Claudia Spieß, MD; Anke Robert, MD (Neuburg); Claudia Spooren, MD; Nurcan Incekara, MD (Senden); Sabine Sprich, MD; Rudolf Sprich, MD (Biessenhofen); Johannes Stadler, MD (Gerolzhofen); Helmut Stadler, MD (Straubing); Wilhelm Stechl, MD (Raubling); Wolfgang Steck, MD (Immenstadt); Christa Steenpaß, MD (Aschaffenburg); Marko Stein, MD (München); Wolfgang Steinbach, MD (Scheßlitz); Gerhard Steinberg, MD; Christopher Hauser, MD; Gertraude Klötzer, MD (Mittenwald); Gerhard Steinberg, MD; Johanna Wiese, MD; Ulrike Fulda-Rohlfs, MD; Christopher Hauser, MD (Garmisch-Partenkirchen); Constanze Steinborn, MD (Sauerlach); Andreas Steiner, MD (Landsberg); Bernd Steinkirchner, MD (Neufahrn); Paul Steinocher, MD (Augsburg); Stefan Stellwag, MD (München); Frank Steppberger, MD (Oberasbach); Heiko Stern, MD; Ullrich Fakler, MD (Gauting); Rosa Stettner-Gloning, MD; Slim Saadi, MD (München); Anke Steuerer, MD (Augsburg); Elisabeth Stöckhert, MD; Ingeborg Meyer, MD (Fürth); Christoph Stöhr-Sökefeld, MD (Neubiberg); Anette Stratmann, MD; Matthias Ensslen, MD (Holzkirchen); Dominik Stricker, MD (Lappersdorf); Annette Strobel, MD (Erlangen); Michael Strobelt, MD (Bruckmühl); Gesine Strohbach, MD (Nürnberg); Thomas Sturm, MD (Fürstenfeldbruck); Raphael Sturm, MD (Affing); Ursula Tchassem Tagny, MD (Neuburg a.d. Donau); Harald Tegtmeyer-Metzdorf, MD (Lindau); Vita Teichler, MD (München); Hans-Georg Terbrack, MD (Abensberg); Günter Theurer, MD; Günter Steidle, MD (Traunstein); Claus-Dieter Thiem, MD (Salzweg); Barbara Thumann, MD (Dietfurt); Uta Tielker, MD (Eichenau); Achim Timnik, MD; Gertrud Reiter, MD (Neusäß); Michael Torbahn, MD (Nürnberg); Regina Trammer, MD (Planegg); German Tretter, MD (Altenstadt/Waldnaab); Barbara Tröger, MD (Rain); Burkhard Trusen, MD (Bamberg); Martin Ulbrich, MD (Otterfing); Stephan Unkelbach, MD (Volkach); Reiner Valentin, MD (Grafing); Michael Veh-Hölzlein, MD (Fürth); Erhard Vetter, MD (Schönthal); Oliver Viethen, MD (Traunstein); Michael Vogel, MD (München); Hartmut Vogel, MD (Roth); Christian J. Voigt, MD (Stadtbergen); Victor von Arnim, MD (Roding); Eleonore von der Schulenburg, MD (München); Heike von Pigenot, MD (Ottobrunn); Katharina von Saurma, MD (München); Patrik von Schoenaich, MD (Neusäss); Olaf Vorbeck, MD (Moosburg); Christoph Wachenfeld-Wahl, MD (Augsburg); Roland Wagner, MD (Nittendorf); Gabriele Wagner, MD (Haag an der Amper); Alexander Wagner, MD (Kitzingen); Roland Wagner, MD (Regensburg); Hans Josef Wainryb, MD (Jesenwang); Edgar Waldmann, MD (Bamberg); Karin Waldmann, MD (Memmelsdorf); Heike Walessa, MD (Gars am Inn); Irene Walser, MD (Wolnzach); Susanne Wawatschek, MD; Olga Stroh, MD (Diedorf); Helke Weber, MD (Holzkirchen); Annette Weber-Pöhlmann, MD (Selb); Claudia Wegener, MD (München); Stefan Weickardt, MD (Straubing); Josef Weidinger, MD (Nabburg); Johannes Weigel, MD (Augsburg); Christine Weigmann-Popp, MD; Ulrike Ege-Mirzai, MD (Bamberg); Philipp Weinert, MD (Obergünzburg); Benedikt Weiß, MD (Bad Kötzting); Michael Weiß, MD (Kempten); Anika Wels, MD (Stegaurach); Mathias Wendeborn, MD (München); Beatrix Wenzel, MD; Simon Then, MD (Lichtenfels); Joachim Westphal, MD (Taufkirchen/Vils); Oliver Wiese, MD (Landsberg am Lech); Andreas Wiesheu, MD; Matthias Buckl, MD; Elisabeth Paul, MD; Corinna Popp, MD (Landshut); Margit Wiessner-Straßer, MD; Tobias Eisenhut, MD (München); Anke Wilberg, MD (Schwarzenbach am Wald); Martin Wilken, MD; Andrea Schürmann, MD; Lidia Steigerwald, MD (Hof); Karolin Wilman, MD (Friedberg); Jochen Winkler, MD (Schwabmünchen); Tobias Winter, MD (Teisendorf); Christina Wirth, MD; Jürgen Kleinhenz, MD; Jürgen Streit, MD (Brückenau); Christian Wittmann, MD (Fürth); Hermann Wittrock, MD (Mering); Anton Wohlfart, MD (Ehekirchen); Daniela Wohlmann, MD (Garmisch-Partenkirchen); Paul Wolf, MD (Erlangen); Marco Wölfel, MD; Hans Georg Schatz, MD (Bayreuth); Lothar Wurzer, MD (Oberstdorf); Christof Zang, MD (Haibach); Claudia Zapillon, MD (München); Alexander Zeiss, MD (München); Stefan Zeller, MD (Kempten); Roland Zeller, MD (Aschaffenburg); Stephan Zieher, MD (Marktheidenfeld); Sabine Ziemer, MD; Amalia Herineanu, MD (Nürnberg); Mathias Zimmer, MD (Coburg); Thomas Zimmermann, MD (Hirschaid); Thomas Zimmermann, MD (Burgebrach); Lothar Zimmermann, MD (Aichach); Stefan Zink, MD (Nürnberg); Dorothea Zitzmann, MD (Burgheim); Andreas Zurmühl, MD (Penzberg); Kristin Zwenzner, MD (Bayreuth); Kristin Zwenzner, MD (Neudrossenfeld).

Psychological consulting (Hannover Medical School, Hannover, Germany):Developing and performing the psychological assessment analysis: Karin Lange, PhD, Iris Müller, PhD, Rosanna Rodriguez, BSc, Mirjam Bassy, MD.

Data Sharing Statement: The data set analyzed in this paper is available from the corresponding author on reasonable request, and with appropriate additional ethical approvals, where necessary.

Additional Contributions: We thank Minister of State Melanie Huml, MD, who acted as the honorary patron of the Fr1da study.

Additional Information: Fr1da clinical centers received reimbursement for the clinical care of individuals undergoing metabolic staging and follow-up (ranging from 10€ to 130€ per visit). Primary care pediatricians received reimbursement of 10€ per study participant for consenting, collecting the screening sample and completing the questionnaire.

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