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