TY - JOUR
T1 - Joint modeling of longitudinal autoantibody patterns and progression to type 1 diabetes
T2 - results from the TEDDY study
AU - Ancillary Studies
AU - Diet
AU - Genetics
AU - Human Subjects/Publicity/Publications
AU - Immune Markers
AU - Infectious Agents
AU - Laboratory Implementation
AU - Maternal Studies
AU - Psychosocial
AU - Quality Assurance
AU - Steering
AU - Study Coordinators
AU - Celiac Disease
AU - Clinical Implementation
AU - TEDDY study group
AU - Köhler, Meike
AU - Beyerlein, Andreas
AU - Vehik, Kendra
AU - Greven, Sonja
AU - Umlauf, Nikolaus
AU - Lernmark, Åke
AU - Hagopian, William A.
AU - Rewers, Marian
AU - She, Jin-Xiong
AU - Toppari, Jorma
AU - Akolkar, Beena
AU - Krischer, Jeffrey P.
AU - Bonifacio, Ezio
AU - Ziegler, Anette G.
AU - Bautista, Kimberly
AU - Baxter, Judith
AU - Bedoy, Ruth
AU - Felipe-Morales, Daniel
AU - Driscoll, Kimberly
AU - Frohnert, Brigitte I.
AU - Gesualdo, Patricia
AU - Hoffman, Michelle
AU - Karban, Rachel
AU - Liu, Edwin
AU - Norris, Jill
AU - Samper-Imaz, Adela
AU - Steck, Andrea
AU - Waugh, Kathleen
AU - Wright, Hali
AU - Simell, Olli G.
AU - Adamsson, Annika
AU - Ahonen, Suvi
AU - Hyöty, Heikki
AU - Ilonen, Jorma
AU - Jokipuu, Sanna
AU - Kallio, Tiina
AU - Karlsson, Leena
AU - Kähönen, Miia
AU - Knip, Mikael
AU - Kovanen, Lea
AU - Koreasalo, Mirva
AU - Kurppa, Kalle
AU - Latva-aho, Tiina
AU - Lönnrot, Maria
AU - Mäntymäki, Elina
AU - Multasuo, Katja
AU - Mykkänen, Juha
AU - Niininen, Tiina
AU - Niinistö, Sari
AU - McIndoe, Richard A
N1 - Funding Information:
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.
Publisher Copyright:
© 2017, Springer-Verlag Italia S.r.l.
PY - 2017/11/1
Y1 - 2017/11/1
N2 - 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.
AB - 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.
KW - Autoantibodies
KW - Joint modeling
KW - Type 1 diabetes
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U2 - 10.1007/s00592-017-1033-7
DO - 10.1007/s00592-017-1033-7
M3 - Article
C2 - 28856522
AN - SCOPUS:85028622724
SN - 0940-5429
VL - 54
SP - 1009
EP - 1017
JO - Acta Diabetologica
JF - Acta Diabetologica
IS - 11
ER -