Acta Diabetologica

, Volume 54, Issue 11, pp 1009–1017 | Cite as

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

  • Meike Köhler
  • Andreas Beyerlein
  • Kendra Vehik
  • Sonja Greven
  • Nikolaus Umlauf
  • Åke Lernmark
  • William A. Hagopian
  • Marian Rewers
  • Jin-Xiong She
  • Jorma Toppari
  • Beena Akolkar
  • Jeffrey P. Krischer
  • Ezio Bonifacio
  • Anette-G. Ziegler
  • TEDDY study group
Original Article

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.

Keywords

Autoantibodies Joint modeling Type 1 diabetes 

Notes

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 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.

Compliance with ethical standards

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.

Supplementary material

592_2017_1033_MOESM1_ESM.pdf (2.1 mb)
Supplementary material 1 (PDF 2120 kb)

References

  1. 1.
    Patterson CC, Dahlquist GG, Gyurus E, Green A, Soltesz G, Eurodiab Study Group (2009) Incidence trends for childhood type 1 diabetes in Europe during 1989–2003 and predicted new cases 2005–2020: a multicentre prospective registration study. Lancet 373(9680):2027–2033. doi: 10.1016/S0140-6736(09)60568-7 CrossRefPubMedGoogle Scholar
  2. 2.
    Parikka V, Nanto-Salonen K, Saarinen M, Simell T, Ilonen J, Hyoty H, Veijola R, Knip M, Simell O (2012) Early seroconversion and rapidly increasing autoantibody concentrations predict prepubertal manifestation of type 1 diabetes in children at genetic risk. Diabetologia 55(7):1926–1936. doi: 10.1007/s00125-012-2523-3 CrossRefPubMedGoogle Scholar
  3. 3.
    Ziegler AG, Bonifacio E, Babydiab-Babydiet Study Group (2012) Age-related islet autoantibody incidence in offspring of patients with type 1 diabetes. Diabetologia 55(7):1937–1943. doi: 10.1007/s00125-012-2472-x CrossRefPubMedGoogle Scholar
  4. 4.
    Ziegler AG, Rewers M, Simell O, Simell T, Lempainen J, Steck A, Winkler C, Ilonen J, Veijola R, Knip M, Bonifacio E, Eisenbarth GS (2013) Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA, J Am Med Assoc 309(23):2473–2479. doi: 10.1001/jama.2013.6285 CrossRefGoogle Scholar
  5. 5.
    Achenbach P, Warncke K, Reiter J, Naserke HE, Williams AJ, Bingley PJ, Bonifacio E, Ziegler AG (2004) Stratification of type 1 diabetes risk on the basis of islet autoantibody characteristics. Diabetes 53(2):384–392CrossRefPubMedGoogle Scholar
  6. 6.
    Steck AK, Johnson K, Barriga KJ, Miao D, Yu L, Hutton JC, Eisenbarth GS, Rewers MJ (2011) Age of islet autoantibody appearance and mean levels of insulin, but not GAD or IA-2 autoantibodies, predict age of diagnosis of type 1 diabetes: diabetes autoimmunity study in the young. Diabetes Care 34(6):1397–1399. doi: 10.2337/dc10-2088 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Steck AK, Vehik K, Bonifacio E, Lernmark A, Ziegler AG, Hagopian WA, She J, Simell O, Akolkar B, Krischer J, Schatz D, Rewers MJ, TEDDY Study Group (2015) Predictors of progression from the appearance of islet autoantibodies to early childhood diabetes: the environmental determinants of diabetes in the young (TEDDY). Diabetes Care 38(5):808–813. doi: 10.2337/dc14-2426 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Steck AK, Dong F, Waugh K, Frohnert BI, Yu L, Norris JM, Rewers MJ (2016) Predictors of slow progression to diabetes in children with multiple islet autoantibodies. J Autoimmun 72:113–117. doi: 10.1016/j.jaut.2016.05.010 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Endesfelder D, Hagen M, Winkler C, Haupt F, Zillmer S, Knopff A, Bonifacio E, Ziegler AG, Zu Castell W, Achenbach P (2016) A novel approach for the analysis of longitudinal profiles reveals delayed progression to type 1 diabetes in a subgroup of multiple-islet-autoantibody-positive children. Diabetologia. doi: 10.1007/s00125-016-4050-0 PubMedGoogle Scholar
  10. 10.
    Krischer JP, Lynch KF, Schatz DA, Ilonen J, Lernmark Å, Hagopian WA, Rewers MJ, She J-X, Simell OG, Toppari J, Ziegler A-G, Akolkar B, Bonifacio E, Group tTS (2015) The 6 year incidence of diabetes-associated autoantibodies in genetically at-risk children: the TEDDY study. Diabetologia 58:980–987. doi: 10.1007/s00125-015-3514-y CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Teddy Study Group (2007) The environmental determinants of diabetes in the young (TEDDY) study: study design. Pediatr Diabetes 8(5):286–298. doi: 10.1111/j.1399-5448.2007.00269.x CrossRefGoogle Scholar
  12. 12.
    Asar O, Ritchie J, Kalra PA, Diggle PJ (2015) Joint modelling of repeated measurement and time-to-event data: an introductory tutorial. Int J Epidemiol 44(1):334–344. doi: 10.1093/ije/dyu262 CrossRefPubMedGoogle Scholar
  13. 13.
    Teddy Study Group (2008) The environmental determinants of diabetes in the young (TEDDY) Study. Ann N Y Acad Sci 1150:1–13. doi: 10.1196/annals.1447.062 CrossRefPubMedCentralGoogle Scholar
  14. 14.
    Hagopian WA, Erlich H, Lernmark A, Rewers M, Ziegler AG, Simell O, Akolkar B, Vogt R Jr, Blair A, Ilonen J, Krischer J, She J, Group TS (2011) The environmental determinants of diabetes in the young (TEDDY): genetic criteria and international diabetes risk screening of 421 000 infants. Pediatr diabetes 12(8):733–743. doi: 10.1111/j.1399-5448.2011.00774.x CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    American Diabetes Association (2011) Executive summary: standards of medical care in diabetes—2011. Diabetes Care 34(Suppl 1):S4–S10. doi: 10.2337/dc11-S004 Google Scholar
  16. 16.
    Rizopoulos D (2012) Joint models for longitudinal and time-to-event data, with applications in R. Chapman and Hall/CRC, Boca RatonCrossRefGoogle Scholar
  17. 17.
    Köhler M, Umlauf N, Beyerlein A, Winkler C, Ziegler A-G, Greven S (2017) Flexible Bayesian additive joint models with an application to type 1 diabetes research. Biom J. doi: 10.1002/bimj.201600224
  18. 18.
    Umlauf N, Klein N, Zeileis A (2017) BAMLSS: Bayesian additive models for location, scale and shape (and beyond). Working Paper 2017-05. Working Papers in Economics and Statistics, Research Platform Empirical and Experimental Economics, Universität Innsbruck. http://EconPapers.RePEc.org/RePEc:inn:wpaper:2017-05
  19. 19.
    R Core Team (2016) R: a language and environment for statistical computing. R Foundation for Statistical Computing, ViennaGoogle Scholar
  20. 20.
    Mrena S, Virtanen SM, Laippala P, Kulmala P, Hannila M-L, Åkerblom HK, Knip M, Group tCDiFS (2006) Models for predicting type 1 diabetes in siblings of affected children. Diabetes Care 29(3):662–667. doi: 10.2337/diacare.29.03.06.dc05-0774 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Italia S.r.l. 2017

Authors and Affiliations

  • Meike Köhler
    • 1
    • 2
    • 3
  • Andreas Beyerlein
    • 1
    • 2
    • 3
  • Kendra Vehik
    • 4
  • Sonja Greven
    • 5
  • Nikolaus Umlauf
    • 6
  • Åke Lernmark
    • 7
  • William A. Hagopian
    • 8
  • Marian Rewers
    • 9
  • Jin-Xiong She
    • 10
  • Jorma Toppari
    • 11
    • 12
  • Beena Akolkar
    • 13
  • Jeffrey P. Krischer
    • 4
  • Ezio Bonifacio
    • 14
  • Anette-G. Ziegler
    • 1
    • 2
    • 3
  • TEDDY study group
  1. 1.Institute of Diabetes Research, Helmholtz Zentrum München NeuherbergGermany
  2. 2.Forschergruppe Diabetes, Klinikum rechts der IsarTechnische Universität MünchenNeuherbergGermany
  3. 3.Forschergruppe Diabetes e.V.NeuherbergGermany
  4. 4.Health Informatics Institute, Morsani College of MedicineUniversity of South FloridaTampaUSA
  5. 5.Department of StatisticsLudwig-Maximilians-Universität MünchenMunichGermany
  6. 6.Department of StatisticsUniversity of InnsbruckInnsbruckAustria
  7. 7.Department of Clinical SciencesLund University/CRC, Skåne University Hospital SUSMalmöSweden
  8. 8.Pacific Northwest Diabetes Research InstituteSeattleUSA
  9. 9.Barbara Davis Center for Childhood DiabetesUniversity of Colorado Anschutz Medical CampusAuroraUSA
  10. 10.Center for Biotechnology and Genomic Medicine, Medical College of GeorgiaGeorgia Regents UniversityAugustaUSA
  11. 11.Department of Physiology Institute of BiomedicineUniversity of TurkuTurkuFinland
  12. 12.Department of PediatricsTurku University HospitalTurkuFinland
  13. 13.National Institute of Diabetes and Digestive and Kidney DiseasesBethesdaUSA
  14. 14.Center for Regenerative Therapies Dresden and Paul Langerhans Institute DresdenTechnische Universität DresdenDresdenGermany

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