Time-Resolved Autoantibody Profiling Facilitates Stratification of Preclinical Type 1 Diabetes in Children
Authors: Endesfelder David , zu Castell Wolfgang , Bonifacio Ezio , Rewers Marian , Hagopian William A. , She Jin-Xiong , Lernmark Åke , Toppari Jorma , Vehik Kendra , Williams Alistair J.K. , Yu Liping , Akolkar Beena , Krischer Jeffrey P. , Ziegler Anette-G. , Achenbach Peter ,   TEDDY Study Group, Rewers Marian , Bautista Kimberly , Baxter Judith , Felipe-Morales Daniel , Driscoll Kimberly , Frohnert Brigitte I. , Gallant Marisa , Gesualdo Patricia , Hoffman Michelle , Karban Rachel , Liu Edwin , Norris Jill , Samper-Imaz Adela , Steck Andrea , Waugh Kathleen , Wright Hali , Toppari Jorma , Simell Olli G. , Adamsson Annika , Ahonen Suvi , Hyöty Heikki , Ilonen Jorma , Jokipuu Sanna , Karlsson Leena , Kähönen Miia , Knip Mikael , Koreasalo Mirva , Kurppa Kalle , Latva-aho Tiina , Lönnrot Maria , Mattila Markus , Mäntymäki Elina , Multasuo Katja , Niininen Tiina , Niinistö Sari , Nyblom Mia , Ollikainen Paula , Rajala Petra , Rautanen Jenna , Riikonen Anne , Romo Minna , Ruohonen Suvi , Rönkä Juulia , Simell Satu , Simell Tuula , Sjöberg Maija , Stenius Aino , Vainionpää Sini , Varjonen Eeva , Veijola Riitta , Virtanen Suvi M. , Vähä-Mäkilä Mari , Åkerlund Mari , Lindfors Katri , She Jin-Xiong , Schatz Desmond , Hopkins Diane , Steed Leigh , Bryant Jennifer , Adams Janey , Silvis Katherine , Haller Michael , Gardiner Melissa , McIndoe Richard , Sharma Ashok , Anderson Stephen W. , Jacobsen Laura , Marks John , Towe P.D. , Ziegler Anette G. , Beyerlein Andreas , Bonifacio Ezio , Gavrisan Anita , Gezginci Cigdem , Heublein Anja , Hummel Michael , Hummel Sandra , Knopff Annette , Koch Charlotte , Koletzko Sibylle , Ramminger Claudia , Roth Roswith , Scholz Marlon , Stock Joanna , Warncke Katharina , Wendel Lorena , Winkler Christiane , Lernmark Åke , Agardh Daniel , Aronsson Carin Andrén , Ask Maria , Bremer Jenny , Carlsson Ulla-Marie , Cilio Corrado , Ericson-Hallström Emelie , Fors Annika , Fransson Lina , Gard Thomas , Bennet Rasmus , Hansson Carina , Hyberg Susanne , Jisser Hanna , Johansen Fredrik , Jonsdottir Berglind , Jovic Silvija , Larsson Helena Elding , Lindström Marielle , Lundgren Markus , Månsson-Martinez Maria , Markan Maria , Melin Jessica , Mestan Zeliha , Nilsson Caroline , Ottosson Karin , Rahmati Kobra , Ramelius Anita , Salami Falastin , Sibthorpe Sara , Sjöberg Anette , Sjöberg Birgitta , Törn Carina , Wallin Anne , Wimar Åsa , Åberg Sofie , Hagopian William A. , Killian Michael , Crouch Claire Cowen , Skidmore Jennifer , Akramoff Ashley , Banjanin Jana , Chavoshi Masumeh , Dunson Kayleen , Hervey Rachel , Lyons Rachel , Meyer Arlene , Mulenga Denise , Radtke Jared , Schmitt Davey , Schwabe Julie , Zink Sarah , Becker Dorothy , Franciscus Margaret , Dalmagro-Elias Smith MaryEllen , Daftary Ashi , Klein Mary Beth , Yates Chrystal , Krischer Jeffrey P. , Austin-Gonzalez Sarah , Avendano Maryouri , Baethke Sandra , Brown Rasheedah , Burkhardt Brant , Butterworth Martha , Clasen Joanna , Cuthbertson David , Eberhard Christopher , Fiske Steven , Garcia Dena , Garmeson Jennifer , Gowda Veena , Heyman Kathleen , Hsiao Belinda , Laras Francisco Perez , Lee Hye-Seung , Liu Shu , Liu Xiang , Lynch Kristian , Maguire Colleen , Malloy Jamie , McCarthy Cristina , Merrell Aubrie , Meulemans Steven , Parikh Hemang , Quigley Ryan , Remedios Cassandra , Shaffer Chris , Smith Laura , Smith Susan , Sulman Noah , Tamura Roy , Uusitalo Ulla , Vehik Kendra , Vijayakandipan Ponni , Wood Keith , Yang Jimin , Yu Liping , Miao Dongmei , Bingley Polly , Williams Alistair , Chandler Kyla , Ball Olivia , Kelland Ilana , Grace Sian , Gillard Ben , Hagopian William , Chavoshi Masumeh , Radtke Jared , Schwabe Julie , Erlich Henry , Mack Steven J. , Fear Anna Lisa , Ke Sandra , Mulholland Niveen , Akolkar Beena , Bourcier Kasia , Briese Thomas , Johnson Suzanne Bennett , Triplett Eric 
Published: October 2018

Progression to clinical type 1 diabetes varies among children who develop β-cell autoantibodies. Differences in autoantibody patterns could relate to disease progression and etiology. Here we modeled complex longitudinal autoantibody profiles by using a novel wavelet-based algorithm. We identified clusters of similar profiles associated with various types of progression among 600 children from The Environmental Determinants of Diabetes in the Young (TEDDY) birth cohort study; these children developed persistent insulin autoantibodies (IAA), GAD autoantibodies (GADA), insulinoma-associated antigen 2 autoantibodies (IA-2A), or a combination of these, and they were followed up prospectively at 3- to 6-month intervals (median follow-up 6.5 years). Children who developed multiple autoantibody types (n = 370) were clustered, and progression from seroconversion to clinical diabetes within 5 years ranged between clusters from 6% (95% CI 0, 17.4) to 84% (59.2, 93.6). Children who seroconverted early in life (median age &lt;2 years) and developed IAA and IA-2A that were stable-positive on follow-up had the highest risk of diabetes, and this risk was unaffected by GADA status. Clusters of children who lacked stable-positive GADA responses contained more boys and lower frequencies of the HLA-DR3 allele. Our novel algorithm allows refined grouping of β-cell autoantibody–positive children who distinctly progressed to clinical type 1 diabetes, and it provides new opportunities in searching for etiological factors and elucidating complex disease mechanisms.