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Joint modeling of longitudinal autoantibody patterns and progression to type 1 diabetes: results from the TEDDY study

  • Original Article
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Abstract

Aims

The onset of clinical type 1 diabetes (T1D) is preceded by the occurrence of disease-specific autoantibodies. The level of autoantibody titers is known to be associated with progression time from the first emergence of autoantibodies to the onset of clinical symptoms, but detailed analyses of this complex relationship are lacking. We aimed to fill this gap by applying advanced statistical models.

Methods

We investigated data of 613 children from the prospective TEDDY study who were persistent positive for IAA, GADA and/or IA2A autoantibodies. We used a novel approach of Bayesian joint modeling of longitudinal and survival data to assess the potentially time- and covariate-dependent association between the longitudinal autoantibody titers and progression time to T1D.

Results

For all autoantibodies we observed a positive association between the titers and the T1D progression risk. This association was estimated as time-constant for IA2A, but decreased over time for IAA and GADA. For example the hazard ratio [95% credibility interval] for IAA (per transformed unit) was 3.38 [2.66, 4.38] at 6 months after seroconversion, and 2.02 [1.55, 2.68] at 36 months after seroconversion.

Conclusions

These findings indicate that T1D progression risk stratification based on autoantibody titers should focus on time points early after seroconversion. Joint modeling techniques allow for new insights into these associations.

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Funding

The TEDDY study was supported by U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, UC4 DK106955 and Contract No. HHSN267200700014C from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Child Health and Human Development (NICHD), National Institute of Environmental Health Sciences (NIEHS), Juvenile Diabetes Research Foundation (JDRF) and Centers for Disease Control and Prevention (CDC). Additionally this work was supported by funds from the Helmholtz International Research Group [HIRG-0018] and the Juvenile Diabetes Research Foundation (JDRF) [Grant Number 2-SRA-2015-13-Q-R] to AGZ, and the German Research Foundation DFG [Emmy Noether grant GR 3793/1-1] to SG. The funders had no impact on the design, implementation, analysis and interpretation of the data.

The TEDDY Study Group

Colorado Clinical Center

Marian Rewers, M.D., Ph.D., PI1,4,5,6,10,11, Kimberly Bautista12, Judith Baxter9,10,12,15, Ruth Bedoy2, Daniel Felipe-Morales, Kimberly Driscoll, Ph.D.9, Brigitte I. Frohnert, M.D.2,14, Patricia Gesualdo2,6,12,14,15, Michelle Hoffman12,13,14, Rachel Karban12, Edwin Liu, M.D.13, Jill Norris, Ph.D.2,3,12, Adela Samper-Imaz, Andrea Steck, M.D.3,14, Kathleen Waugh6,7,12,15, Hali Wright12. University of Colorado, Anschutz Medical Campus, Barbara Davis Center for Childhood Diabetes.

Finland Clinical Center

Jorma Toppari, M.D., Ph.D., PI¥^1,4,11,14, Olli G. Simell, M.D., Ph.D.¥^1,4,11,13, Annika Adamsson, Ph.D.^12, Suvi Ahonen*±§, Heikki Hyöty, M.D., Ph.D.*±6, Jorma Ilonen, M.D., Ph.D.¥ ¶3, Sanna Jokipuu^, Tiina Kallio^, Leena Karlsson^, Miia Kähönenµ¤, Mikael Knip, M.D., Ph.D.*±5, Lea Kovanen*±§, Mirva Koreasalo*±§2, Kalle Kurppa, M.D., Ph.D.*±13, Tiina Latva-ahoµ¤, Maria Lönnrot, M.D., Ph.D.*±6, Elina Mäntymäki^, Katja Multasuoµ¤, Juha Mykkänen, Ph.D.¥ 3, Tiina Niininen±*12, Sari Niinistö±§, Mia Nyblom*±, Petra Rajala^, Jenna Rautanen±§, Anne Riikonen*±§, Mika Riikonen^, Jenni Rouhiainen^, Minna Romo^, Tuula Simell, Ph.D., Ville Simell^¥13, Maija Sjöberg¥^12,14, Aino Steniusµ¤12, Maria Leppänen^, Sini Vainionpää^, Eeva Varjonen¥^12, Riitta Veijola, M.D., Ph.D.µ¤14, Suvi M. Virtanen, M.D., Ph.D.*±§2, Mari Vähä-Mäkilä^, Mari Åkerlund*±§, Katri Lindfors, Ph.D.*13 ¥University of Turku, *University of Tampere, µUniversity of Oulu, ^Turku University Hospital, Hospital District of Southwest Finland, ±Tampere University Hospital, ¤Oulu University Hospital, §National Institute for Health and Welfare, Finland, University of Kuopio.

Georgia/Florida Clinical Center

Jin-Xiong She, Ph.D., PI1,3,4,11, Desmond Schatz, M.D.*4,5,7,8, Diane Hopkins12, Leigh Steed12,13,14,15, Jamie Thomas*6,12, Janey Adams*12, Katherine Silvis2, Michael Haller, M.D.*14, Melissa Gardiner, Richard McIndoe, Ph.D., Ashok Sharma, Joshua Williams, Gabriela Young, Stephen W. Anderson, M.D.^, Laura Jacobsen, M.D.*14 Center for Biotechnology and Genomic Medicine, Augusta University. *University of Florida, ^Pediatric Endocrine Associates, Atlanta.

Germany Clinical Center

Anette-G. Ziegler, M.D., PI1,3,4,11, Andreas Beyerlein, Ph.D.2, Ezio Bonifacio Ph.D.*5, Michael Hummel, M.D.13, Sandra Hummel, Ph.D.2, Kristina Foterek¥2, Nicole Janz, Mathilde Kersting, Ph.D.¥2, Annette Knopff7, Sibylle Koletzko, M.D.¶13, Claudia Peplow12, Roswith Roth, Ph.D.9, Marlon Scholz, Joanna Stock9,12,14, Katharina Warncke, M.D.14, Lorena Wendel, Christiane Winkler, Ph.D.2,12,15. Forschergruppe Diabetes e.V. and Institute of Diabetes Research, Helmholtz Zentrum München, and Klinikum rechts der Isar, Technische Universität München. *Center for Regenerative Therapies, TU Dresden, Dr. von Hauner Children’s Hospital, Department of Gastroenterology, Ludwig-Maximilians-University Munich, ¥Research Institute for Child Nutrition, Dortmund.

Sweden Clinical Center

Åke Lernmark, Ph.D., PI1,3,4,5,6,8,10,11,15, Daniel Agardh, M.D., Ph.D.13, Carin Andrén Aronsson2,12,13, Maria Ask, Jenny Bremer, Ulla-Marie Carlsson, Corrado Cilio, Ph.D., M.D.5, Emelie Ericson-Hallström, Lina Fransson, Thomas Gard, Joanna Gerardsson, Rasmus Bennet, Monica Hansen, Gertie Hansson, Susanne Hyberg, Fredrik Johansen, Berglind Jonsdottir, M.D., Helena Elding Larsson, M.D., Ph.D. 6,14, Marielle Lindström, Markus Lundgren, M.D.14, Maria Månsson-Martinez, Maria Markan, Jessica Melin12, Zeliha Mestan, Karin Ottosson, Kobra Rahmati, Anita Ramelius, Falastin Salami, Sara Sibthorpe, Birgitta Sjöberg, Ulrica Swartling, Ph.D.9,12, Evelyn Tekum Amboh, Carina Törn, Ph.D. 3,15, Anne Wallin, Åsa Wimar12,14, Sofie Åberg. Lund University.

Washington Clinical Center

William A. Hagopian, M.D., Ph.D., PI1,3,4, 5, 6,7,11,13, 14, Michael Killian6,7,12,13, Claire Cowen Crouch12,14,15, Jennifer Skidmore2, Josephine Carson, Maria Dalzell, Kayleen Dunson, Rachel Hervey, Corbin Johnson, Rachel Lyons, Arlene Meyer, Denise Mulenga, Alexander Tarr, Morgan Uland, John Willis. Pacific Northwest Diabetes Research Institute.

Pennsylvania Satellite Center

Dorothy Becker, M.D., Margaret Franciscus, MaryEllen Dalmagro-Elias Smith2, Ashi Daftary, M.D., Mary Beth Klein, Chrystal Yates. Children’s Hospital of Pittsburgh of UPMC.

Data Coordinating Center

Jeffrey P. Krischer, Ph.D.,PI1,4,5,10,11, Michael Abbondondolo, Sarah Austin-Gonzalez, Maryouri Avendano, Sandra Baethke, Rasheedah Brown12,15, Brant Burkhardt, Ph.D.5,6, Martha Butterworth2, Joanna Clasen, David Cuthbertson, Christopher Eberhard, Steven Fiske9, Dena Garcia, Jennifer Garmeson, Veena Gowda, Kathleen Heyman, Francisco Perez Laras, Hye-Seung Lee, Ph.D.1,2,13,15, Shu Liu, Xiang Liu, Ph.D.2,3,9,14, Kristian Lynch, Ph.D. 5,6,9,15, Jamie Malloy, Cristina McCarthy12,15, Steven Meulemans, Hemang Parikh, Ph.D.3, Chris Shaffer, Laura Smith, Ph.D.9,12, Susan Smith12,15, Noah Sulman, Ph.D., Roy Tamura, Ph.D.1,2,13, Ulla Uusitalo, Ph.D.2,15, Kendra Vehik, Ph.D.4,5,6,14,15, Ponni Vijayakandipan, Keith Wood, Jimin Yang, Ph.D., R.D.2,15. Past staff: Lori Ballard, David Hadley, Ph.D., Wendy McLeod. University of South Florida.

Project scientist

Beena Akolkar, Ph.D.1,3,4,5,6,7,10,11. National Institutes of Diabetes and Digestive and Kidney Diseases.

Autoantibody Reference Laboratories

Liping Yu, M.D.^5, Dongmei Miao, M.D.^, Polly Bingley, M.D., FRCP*5, Alistair Williams*, Kyla Chandler*, Saba Rokni*, Claire Williams*, Rebecca Wyatt*, Gifty George*, Sian Grace*. ^Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, *School of Clinical Sciences, University of Bristol UK.

HLA Reference Laboratory

Henry Erlich, Ph.D.3, Steven J. Mack, Ph.D., Anna Lisa Fear. Center for Genetics, Children’s Hospital Oakland Research Institute.

Repository

Sandra Ke, Niveen Mulholland, Ph.D. NIDDK Biosample Repository at Fisher BioServices.

Other contributors

Kasia Bourcier, Ph.D.5, National Institutes of Allergy and Infectious Diseases. Thomas Briese, Ph.D.6,15, Columbia University. Suzanne Bennett Johnson, Ph.D.9,12, Florida State University. Eric Triplett, Ph.D.6, University of Florida.

Committees

1Ancillary Studies, 2Diet, 3Genetics, 4Human Subjects/Publicity/Publications, 5Immune Markers, 6Infectious Agents, 7Laboratory Implementation, 8Maternal Studies, 9Psychosocial, 10Quality Assurance, 11Steering, 12Study Coordinators, 13Celiac Disease, 14Clinical Implementation, 15Quality Assurance Subcommittee on Data Quality.

Author information

Authors and Affiliations

  1. Institute of Diabetes Research, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany

    Meike Köhler, Andreas Beyerlein, Anette-G. Ziegler & Eric Triplett

  2. Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Neuherberg, Germany

    Meike Köhler, Andreas Beyerlein & Anette-G. Ziegler

  3. Forschergruppe Diabetes e.V., Neuherberg, Germany

    Meike Köhler, Andreas Beyerlein & Anette-G. Ziegler

  4. Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA

    Kendra Vehik & Jeffrey P. Krischer

  5. Department of Statistics, Ludwig-Maximilians-Universität München, Munich, Germany

    Sonja Greven

  6. Department of Statistics, University of Innsbruck, Innsbruck, Austria

    Nikolaus Umlauf

  7. Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital SUS, Malmö, Sweden

    Åke Lernmark

  8. Pacific Northwest Diabetes Research Institute, Seattle, WA, USA

    William A. Hagopian

  9. Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Marian Rewers

  10. Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA

    Jin-Xiong She

  11. Department of Physiology Institute of Biomedicine, University of Turku, Turku, Finland

    Jorma Toppari

  12. Department of Pediatrics, Turku University Hospital, Turku, Finland

    Jorma Toppari

  13. National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA

    Beena Akolkar

  14. Center for Regenerative Therapies Dresden and Paul Langerhans Institute Dresden, Technische Universität Dresden, Dresden, Germany

    Ezio Bonifacio

Authors
  1. Meike Köhler
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  2. Andreas Beyerlein
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  3. Kendra Vehik
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  4. Sonja Greven
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  5. Nikolaus Umlauf
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  6. Åke Lernmark
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  7. William A. Hagopian
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  8. Marian Rewers
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  9. Jin-Xiong She
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  10. Jorma Toppari
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  11. Beena Akolkar
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  12. Jeffrey P. Krischer
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  13. Ezio Bonifacio
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  14. Anette-G. Ziegler
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Consortia

TEDDY study group

  • Marian Rewers
  • , Kimberly Bautista
  • , Judith Baxter
  • , Ruth Bedoy
  • , Daniel Felipe-Morales
  • , Kimberly Driscoll
  • , Brigitte I. Frohnert
  • , Patricia Gesualdo
  • , Michelle Hoffman
  • , Rachel Karban
  • , Edwin Liu
  • , Jill Norris
  • , Adela Samper-Imaz
  • , Andrea Steck
  • , Kathleen Waugh
  • , Hali Wright
  • , Jorma Toppari
  • , Olli G. Simell
  • , Annika Adamsson
  • , Suvi Ahonen
  • , Heikki Hyöty
  • , Jorma Ilonen
  • , Sanna Jokipuu
  • , Tiina Kallio
  • , Leena Karlsson
  • , Miia Kähönen
  • , Mikael Knip
  • , Lea Kovanen
  • , Mirva Koreasalo
  • , Kalle Kurppa
  • , Tiina Latva-aho
  • , Maria Lönnrot
  • , Elina Mäntymäki
  • , Katja Multasuo
  • , Juha Mykkänen
  • , Tiina Niininen
  • , Sari Niinistö
  • , Mia Nyblom
  • , Petra Rajala
  • , Jenna Rautanen
  • , Anne Riikonen
  • , Mika Riikonen
  • , Jenni Rouhiainen
  • , Minna Romo
  • , Tuula Simell
  • , Ville Simell
  • , Maija Sjöberg
  • , Aino Stenius
  • , Maria Leppänen
  • , Sini Vainionpää
  • , Eeva Varjonen
  • , Riitta Veijola
  • , Suvi M. Virtanen
  • , Mari Vähä-Mäkilä
  • , Mari Åkerlund
  • , Katri Lindfors
  • , Jin-Xiong She
  • , Desmond Schatz
  • , Diane Hopkins
  • , Leigh Steed
  • , Jamie Thomas
  • , Janey Adams
  • , Katherine Silvis
  • , Michael Haller
  • , Melissa Gardiner
  • , Richard McIndoe
  • , Ashok Sharma
  • , Joshua Williams
  • , Gabriela Young
  • , Stephen W. Anderson
  • , Laura Jacobsen
  • , Anette G. Ziegler
  • , Andreas Beyerlein
  • , Ezio Bonifacio
  • , Michael Hummel
  • , Sandra Hummel
  • , Kristina Foterek
  • , Nicole Janz
  • , Mathilde Kersting
  • , Annette Knopff
  • , Sibylle Koletzko
  • , Claudia Peplow
  • , Roswith Roth
  • , Marlon Scholz
  • , Joanna Stock
  • , Katharina Warncke
  • , Lorena Wendel
  • , Christiane Winkler
  • , Åke Lernmark
  • , Daniel Agardh
  • , Carin Andrén Aronsson
  • , Maria Ask
  • , Jenny Bremer
  • , Ulla-Marie Carlsson
  • , Corrado Cilio
  • , Emelie Ericson-Hallström
  • , Lina Fransson
  • , Thomas Gard
  • , Joanna Gerardsson
  • , Rasmus Bennet
  • , Monica Hansen
  • , Gertie Hansson
  • , Susanne Hyberg
  • , Fredrik Johansen
  • , Berglind Jonsdottir
  • , Helena Elding Larsson
  • , Marielle Lindström
  • , Markus Lundgren
  • , Maria Månsson-Martinez
  • , Maria Markan
  • , Jessica Melin
  • , Zeliha Mestan
  • , Karin Ottosson
  • , Kobra Rahmati
  • , Anita Ramelius
  • , Falastin Salami
  • , Sara Sibthorpe
  • , Birgitta Sjöberg
  • , Ulrica Swartling
  • , Evelyn Tekum Amboh
  • , Carina Törn
  • , Anne Wallin
  • , Åsa Wimar
  • , Sofie Åberg
  • , William A. Hagopian
  • , Michael Killian
  • , Claire Cowen Crouch
  • , Jennifer Skidmore
  • , Josephine Carson
  • , Maria Dalzell
  • , Kayleen Dunson
  • , Rachel Hervey
  • , Corbin Johnson
  • , Rachel Lyons
  • , Arlene Meyer
  • , Denise Mulenga
  • , Alexander Tarr
  • , Morgan Uland
  • , John Willis
  • , Dorothy Becker
  • , Margaret Franciscus
  • , MaryEllen Dalmagro-Elias Smith
  • , Ashi Daftary
  • , Mary Beth Klein
  • , Chrystal Yates
  • , Jeffrey P. Krischer
  • , Michael Abbondondolo
  • , Sarah Austin-Gonzalez
  • , Maryouri Avendano
  • , Sandra Baethke
  • , Rasheedah Brown
  • , Brant Burkhardt
  • , Martha Butterworth
  • , Joanna Clasen
  • , David Cuthbertson
  • , Christopher Eberhard
  • , Steven Fiske
  • , Dena Garcia
  • , Jennifer Garmeson
  • , Veena Gowda
  • , Kathleen Heyman
  • , Francisco PerezLaras
  • , Hye-Seung Lee
  • , Shu Liu
  • , Xiang Liu
  • , Kristian Lynch
  • , Jamie Malloy
  • , Cristina McCarthy
  • , Steven Meulemans
  • , Hemang Parikh
  • , Chris Shaffer
  • , Laura Smith
  • , Susan Smith
  • , Noah Sulman
  • , Roy Tamura
  • , Ulla Uusitalo
  • , Kendra Vehik
  • , Ponni Vijayakandipan
  • , Keith Wood
  • , Jimin Yang
  • , Lori Ballard
  • , David Hadley
  • , Wendy McLeod
  • , Beena Akolkar
  • , Liping Yu
  • , Dongmei Miao
  • , Polly Bingley
  • , Alistair Williams
  • , Kyla Chandler
  • , Saba Rokni
  • , Claire Williams
  • , Rebecca Wyatt
  • , Gifty George
  • , Sian Grace
  • , Henry Erlich
  • , Steven J. Mack
  • , Sandra Ke
  • , Niveen Mulholland
  • , Kasia Bourcier
  • , Thomas Briese
  • , Suzanne Bennett Johnson
  • , Eric Triplett
  • , Ancillary Studies
  • , Diet
  • , Genetics
  • , Human Subjects/Publicity/Publications
  • , Immune Markers
  • , Infectious Agents
  • , Laboratory Implementation
  • , Maternal Studies
  • , Psychosocial
  • , Quality Assurance
  • , Steering
  • , Study Coordinators
  • , Celiac Disease
  • , Clinical Implementation
  •  & Quality Assurance Subcommittee on Data Quality

Contributions

AGZ and EB designed this manuscript proposal. MK analyzed the data and wrote the first and final draft of the manuscript together with AB, SG and AGZ. EB and KV contributed to the interpretation of the results and to subsequent drafts of the manuscript. NU contributed to specific programming aspects. MR, WAH, JXS, AL, JT, BA, AGZ and JPK are principal investigators of the TEDDY study, contributed to conception and design of the TEDDY study, data acquisition and funding for TEDDY, reviewed the manuscript and contributed to subsequent drafts. This work is part of MK’s PhD thesis within the graduate school HELENA at the Helmholtz Zentrum München in collaboration with the Ludwig-Maximilians-Universität München, Germany.

Corresponding author

Correspondence to Anette-G. Ziegler.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Human and animal rights

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the 1975 Declaration of Helsinki, as revised in 2008 (5).

Informed consent

Informed consent was obtained from all patients for being included in the study.

Additional information

Managed by Massimo Porta.

Meike Köhler and Andreas Beyerlein: Shared first authorship.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 2120 kb)

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Köhler, M., Beyerlein, A., Vehik, K. et al. Joint modeling of longitudinal autoantibody patterns and progression to type 1 diabetes: results from the TEDDY study. Acta Diabetol 54, 1009–1017 (2017). https://doi.org/10.1007/s00592-017-1033-7

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  • DOI: https://doi.org/10.1007/s00592-017-1033-7

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