A combined risk score enhances prediction of type 1 diabetes among susceptible children

Lauric A Ferrat; Kendra Vehik; Seth A Sharp; Åke Lernmark; Marian J Rewers; Jin-Xiong She; Anette-G Ziegler; Jorma Toppari; Beena Akolkar; Jeffrey P Krischer; Michael N Weedon; Richard A Oram; William A Hagopian; TEDDY Study Group

doi:10.1038/s41591-020-0930-4

A combined risk score enhances prediction of type 1 diabetes among susceptible children

Nat Med. 2020 Aug;26(8):1247-1255. doi: 10.1038/s41591-020-0930-4. Epub 2020 Aug 7.

Authors

Lauric A Ferrat¹, Kendra Vehik², Seth A Sharp¹, Åke Lernmark³, Marian J Rewers⁴, Jin-Xiong She⁵, Anette-G Ziegler^{6

7

8}, Jorma Toppari^{9

10}, Beena Akolkar¹¹, Jeffrey P Krischer², Michael N Weedon¹, Richard A Oram^#^{1

12}, William A Hagopian^#¹³; TEDDY Study Group

Collaborators

TEDDY Study Group:
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, 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, 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, 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, P D Towe, 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, 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, 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, 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, Colleen Maguire, Jamie Malloy, Cristina McCarthy, Hemang Parikh, Cassandra Remedios, Chris Shaffer, Laura Smith, Susan Smith, Noah Sulman, Roy Tamura, Dena Tewey, Michael Toth, Ulla Uusitalo, Ponni Vijayakandipan, Keith Wood, Jimin Yang, Liping Yu, Dongmei Miao, Polly Bingley, Alistair Williams, Kyla Chandler, Ilana Kelland, Yassin Ben Khoud, Huma Zahid, Matthew Randell, Masumeh Chavoshi, Jared Radtke, Sarah Zink, Sandra Ke, Niveen Mulholland, Stephen S Rich, Wei-Min Chen, Suna Onengut-Gumuscu, Emily Farber, Rebecca Roche Pickin, Jonathan Davis, Jordan Davis, Dan Gallo, Jessica Bonnie, Paul Campolieto, Joseph F Petrosino, Nadim J Ajami, Richard E Lloyd, Matthew C Ross, Jacqueline L O'Brien, Diane S Hutchinson, Daniel P Smith, Matthew C Wong, Xiangjun Tian, Tulin Ayvaz, Auriole Tamegnon, Nguyen Truong, Hannah Moreno, Lauren Riley, Eduardo Moreno, Tonya Bauch, Lenka Kusic, Ginger Metcalf, Donna Muzny, Harshavardhan Doddapaneni, Richard Gibbs, Kasia Bourcier, Thomas Briese, Suzanne Bennett Johnson, Eric Triplett, Anette G Ziegler, Roy Tamura, Jill Norris, Suvi M Virtanen, Brigitte I Frohnert, Patricia Gesualdo, Mirva Koreasalo, Maija Miettinen, Sari Niinistö, Anne Riikonen, Katherine Silvis, Eva Hohoff, Sandra Hummel, Christiane Winkler, Carin Andrén Aronsson, Jennifer Skidmore, MaryEllen Dalmagro-Elias Smith, Martha Butterworth, Qian Li, Xiang Liu, Roy Tamura, Ulla Uusitalo, Jimin Yang, Stephen S Rich, Jill Norris, Andrea Steck, Jorma Ilonen, Anette G Ziegler, Carina Törn, Qian Li, Xiang Liu, Hemang Parikh, Henry Erlich, Wei-Min Chen, Suna Onengut-Gumuscu, Desmond Schatz, Anette G Ziegler, Corrado Cilio, Ezio Bonifacio, Mikael Knip, Desmond Schatz, Brant Burkhardt, Kristian Lynch, Liping Yu, Polly Bingley, Kasia Bourcier, Heikki Hyöty, Eric Triplett, Richard Lloyd, Patricia Gesualdo, Kathleen Waugh, Maria Lönnrot, Daniel Agardh, Corrado Cilio, Helena Elding Larsson, Michael Killian, Brant Burkhardt, Kristian Lynch, Thomas Briese, Kathleen Waugh, Desmond Schatz, Michael Killian, Suzanne Bennett Johnson, Roswith Roth, Judith Baxter, Kimberly Driscoll, Desmond Schatz, Joanna Stock, Steven Fiske, Xiang Liu, Kristian Lynch, Laura Smith, Judith Baxter, Åke Lernmark, Judith Baxter, Michael Killian, Kimberly Bautista, Patricia Gesualdo, Michelle Hoffman, Rachel Karban, Jill Norris, Kathleen Waugh, Annika Adamsson, Miia Kähönen, Tiina Niininen, Aino Stenius, Eeva Varjonen, Diane Hopkins, Leigh Steed, Jennifer Bryant, Melissa Gardiner, John Marks, Claudia Ramminger, Joanna Stock, Christiane Winkler, Carin Andrén Aronsson, Berglind Jonsdottir, Jessica Melin, Michael Killian, Claire Cowen Crouch, Denise Mulenga, Cristina McCarthy, Laura Smith, Susan Smith, Roy Tamura, Suzanne Bennett Johnson, Daniel Agardh, Edwin Liu, Sibylle Koletzko, Kalle Kurppa, Marisa Stahl, Michelle Hoffman, Kalle Kurppa, Katri Lindfors, Satu Simell, Leigh Steed, Carin Andrén Aronsson, Michael Killian, Roy Tamura, Michael Haller, Helena Elding Larsson, Brigitte I Frohnert, Patricia Gesualdo, Michelle Hoffman, Andrea Steck, Miia Kähönen, Riitta Veijola, Leigh Steed, Laura Jacobsen, John Marks, Joanna Stock, Katharina Warncke, Markus Lundgren, Åsa Wimar, Claire Cowen Crouch, Xiang Liu, Roy Tamura

Affiliations

¹ Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
² Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
³ Department of Clinical Sciences, Lund University and Skåne University Hospital, Malmö, Sweden.
⁴ Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO, USA.
⁵ Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA.
⁶ Institute of Diabetes Research, Helmholtz Zentrum München, Munich, Germany.
⁷ Forschergruppe Diabetes, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
⁸ Forschergruppe Diabetes e.V., Munich, Germany.
⁹ Department of Pediatrics, Turku University Hospital, Turku, Finland.
¹⁰ Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland.
¹¹ National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
¹² Academic Renal Unit, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
¹³ Pacific Northwest Research Institute, Seattle, WA, USA. [email protected].

^# Contributed equally.

Abstract

Type 1 diabetes (T1D)-an autoimmune disease that destroys the pancreatic islets, resulting in insulin deficiency-often begins early in life when islet autoantibody appearance signals high risk¹. However, clinical diabetes can follow in weeks or only after decades, and is very difficult to predict. Ketoacidosis at onset remains common^2,3 and is most severe in the very young^4,5, in whom it can be life threatening and difficult to treat^6-9. Autoantibody surveillance programs effectively prevent most ketoacidosis^10-12 but require frequent evaluations whose expense limits public health adoption¹³. Prevention therapies applied before onset, when greater islet mass remains, have rarely been feasible¹⁴ because individuals at greatest risk of impending T1D are difficult to identify. To remedy this, we sought accurate, cost-effective estimation of future T1D risk by developing a combined risk score incorporating both fixed and variable factors (genetic, clinical and immunological) in 7,798 high-risk children followed closely from birth for 9.3 years. Compared with autoantibodies alone, the combined model dramatically improves T1D prediction at ≥2 years of age over horizons up to 8 years of age (area under the receiver operating characteristic curve ≥ 0.9), doubles the estimated efficiency of population-based newborn screening to prevent ketoacidosis, and enables individualized risk estimates for better prevention trial selection.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Autoantibodies / blood*
Autoantibodies / immunology
Autoimmunity / genetics
Child
Child, Preschool
Diabetes Mellitus, Type 1 / blood
Diabetes Mellitus, Type 1 / epidemiology*
Diabetes Mellitus, Type 1 / immunology
Female
Genetic Predisposition to Disease
Humans
Infant
Infant, Newborn
Insulin / deficiency
Insulin / immunology
Islets of Langerhans / immunology
Islets of Langerhans / pathology
Ketosis / blood*
Ketosis / immunology
Male
Neonatal Screening
Risk Assessment*
Risk Factors

Substances

Autoantibodies
Insulin

Abstract

Publication types

MeSH terms

Substances

Grants and funding