An Age-Related Exponential Decline in the Risk of Multiple Islet Autoantibody Seroconversion During Childhood
Authors: Bonifacio Ezio , Weiß Andreas , Winkler Christiane , Hippich Markus , Rewers Marian J. , Toppari Jorma , Lernmark Åke , She Jin-Xiong , Hagopian William A. , Krischer Jeffrey P. , Vehik Kendra , Schatz Desmond A. , Akolkar Beena , Ziegler Anette-Gabriele ,   TEDDY Study Group, Rewers Marian , Barbour Aaron , Bautista Kimberly , Baxter Judith , Felipe-Morales Daniel , Driscoll Kimberly , Frohnert Brigitte I. , Stahl Marisa , Gesualdo Patricia , Hoffman Michelle , Karban Rachel , Liu Edwin , Norris Jill , Peacock Stesha , Shorrosh Hanan , Steck Andrea , Stern Megan , Villegas Erica , Waugh Kathleen , Toppari Jorma , Simell Olli G. , Adamsson Annika , Ahonen Suvi , Åkerlund Mari , Hakola Leena , Hekkala Anne , Holappa Henna , Hyöty Heikki , Ikonen Anni , Ilonen Jorma , Jäminki Sinikka , Jokipuu Sanna , Karlsson Leena , Kero Jukka , Kähönen Miia , Knip Mikael , Koivikko Minna-Liisa , Koskinen Merja , Koreasalo Mirva , Kurppa Kalle , Kytölä Jarita , Laiho Jutta , Latva-aho Tiina , Lindfors Katri , Lönnrot Maria , Mäntymäki Elina , Mattila Markus , Miettinen Maija , Multasuo Katja , Mykkänen Teija , Niininen Tiina , Niinistö Sari , Nyblom Mia , Oikarinen Sami , Ollikainen Paula , Othmani Zhian , Pohjola Sirpa , Rajala Petra , Rautanen Jenna , Riikonen Anne , Riski Eija , Pekkola Miia , Romo Minna , Ruohonen Satu , Simell Satu , Sjöberg Maija , Stenius Aino , Tossavainen Päivi , Vähä-Mäkilä Mari , Vainionpää Sini , Varjonen Eeva , Veijola Riitta , Viinikangas Irene , Virtanen Suvi M. , She Jin-Xiong , Schatz Desmond , Hopkins Diane , Steed Leigh , Bryant Jennifer , Silvis Katherine , Haller Michael , Gardiner Melissa , McIndoe Richard , Sharma Ashok , Anderson Stephen W. , Jacobsen Laura , Marks John , Ziegler Anette G. , Bonifacio Ezio , Gezginci Cigdem , Heublein Anja , Hohoff Eva , Hummel Sandra , Knopff Annette , Koch Charlotte , Koletzko Sibylle , Ramminger Claudia , Roth Roswith , Schmidt Jennifer , Scholz Marlon , Stock Joanna , Warncke Katharina , Wendel Lorena , Winkler Christiane , Lernmark Åke , Agardh Daniel , Andrén Aronsson Carin , Ask Maria , Bennet Rasmus , Cilio Corrado , Dahlberg Susanne , Engqvist Helene , Ericson-Hallström Emelie , Björne Fors Annika , Fransson Lina , Gard Thomas , Hansen Monika , Jisser Hanna , Johansen Fredrik , Jonsdottir Berglind , Larsson Helena Elding , Lindström Marielle , Lundgren Markus , Maziarz Marlena , Månsson-Martinez Maria , Melin Jessica , Mestan Zeliha , Nilsson Caroline , Ottosson Karin , Rahmati Kobra , Ramelius Anita , Salami Falastin , Sjöberg Anette , Sjöberg Birgitta , Törn Carina , Wimar Åsa , Hagopian William A. , Killian Michael , Cowen Crouch Claire , Skidmore Jennifer , Chavoshi Masumeh , Meyer Arlene , Meyer Jocelyn , Mulenga Denise , Powell Nole , Radtke Jared , Romancik Matei , Roy Shreya , Schmitt Davey , Zink Sarah , Becker Dorothy , Franciscus Margaret , Dalmagro-Elias Smith MaryEllen , Daftary Ashi , Beth Klein Mary , Yates Chrystal , Krischer Jeffrey P. , Austin-Gonzalez Sarah , Avendano Maryouri , Baethke Sandra , Burkhardt Brant , Butterworth Martha , Clasen Joanna , Cuthbertson David , Eberhard Christopher , Fiske Steven , Garmeson Jennifer , Gowda Veena , Heyman Kathleen , Hsiao Belinda , Karges Christina , Perez Laras Francisco , Li Qian , Liu Shu , Liu Xiang , Lynch Kristian , Malloy Jamie , McCarthy Cristina , Parikh Hemang , Remedios Cassandra , Shaffer Chris , Smith Laura , Smith Susan , Sulman Noah , Tamura Roy , Tewey Dena , Toth Michael , Uusitalo Ulla , Vehik Kendra , Vijayakandipan Ponni , Yang Jimin , Abbondondolo Michael , Ballard Lori , Brown Rasheedah , Dankyi Stephen , Hadley David , Lee Hye-Seung , Maguire Colleen , McLeod Wendy , Merrell Aubrie , Meulemans Steven , Quigley Ryan , Akolkar Beena , Yu Liping , Miao Dongmei , Bingley Polly , Williams Alistair , Chandler Kyla , Kelland Ilana , Ben Khoud Yassin , Zahid Huma , Randell Matthew , Hagopian William , Chavoshi Masumeh , Radtke Jared , Zink Sarah , Erlich Henry , Mack Steven J. , Lisa Fear Anna , Rich Stephen S. , Chen Wei-Min , Onengut-Gumuscu Suna , Farber Emily , Roche Pickin Rebecca , Davis Jonathan , Davis Jordan , Gallo Dan , Bonnie Jessica , Campolieto Paul , Ke Sandra , Mulholland Niveen , Briese Thomas 
Published: February 2021

OBJECTIVE
Islet autoimmunity develops before clinical type 1 diabetes and includes multiple and single autoantibody phenotypes. The objective was to determine age-related risks of islet autoantibodies that reflect etiology and improve screening for presymptomatic type 1 diabetes.

RESEARCH DESIGN AND METHODS
The Environmental Determinants of Diabetes in the Young study prospectively monitored 8,556 genetically at-risk children at 3- to 6-month intervals from birth for the development of islet autoantibodies and type 1 diabetes. The age-related change in the risk of developing islet autoantibodies was determined using landmark and regression models.

RESULTS
The 5-year risk of developing multiple islet autoantibodies was 4.3% (95% CI 3.8–4.7) at 7.5 months of age and declined to 1.1% (95% CI 0.8–1.3) at a landmark age of 6.25 years (P &lt; 0.0001). Risk decline was slight or absent in single insulin and GAD autoantibody phenotypes. The influence of sex, HLA, and other susceptibility genes on risk subsided with increasing age and was abrogated by age 6 years. Highest sensitivity and positive predictive value of multiple islet autoantibody phenotypes for type 1 diabetes was achieved by autoantibody screening at 2 years and again at 5–7 years of age.

CONCLUSIONS
The risk of developing islet autoimmunity declines exponentially with age, and the influence of major genetic factors on this risk is limited to the first few years of life.