240 results on '"Hagopian W"'
Search Results
2. Quantifying the utility of islet autoantibody levels in the prediction of type 1 diabetes in children
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Ng, K. (Kenney), Anand, V. (Vibha), Stavropoulos, H. (Harry), Veijola, R. (Riitta), Toppari, J. (Jorma), Maziarz, M. (Marlena), Lundgren, M. (Markus), Waugh, K. (Kathy), Frohnert, B. I. (Brigitte I.), Martin, F. (Frank), Lou, O. (Olivia), Hagopian, W. (William), Achenbach, P. (Peter), f. t. (for the T1DI Study Group), Ng, K. (Kenney), Anand, V. (Vibha), Stavropoulos, H. (Harry), Veijola, R. (Riitta), Toppari, J. (Jorma), Maziarz, M. (Marlena), Lundgren, M. (Markus), Waugh, K. (Kathy), Frohnert, B. I. (Brigitte I.), Martin, F. (Frank), Lou, O. (Olivia), Hagopian, W. (William), Achenbach, P. (Peter), and f. t. (for the T1DI Study Group)
- Abstract
Aims/hypothesis: The aim of this study was to explore the utility of islet autoantibody (IAb) levels for the prediction of type 1 diabetes in autoantibody-positive children. Methods: Prospective cohort studies in Finland, Germany, Sweden and the USA followed 24,662 children at increased genetic or familial risk of developing islet autoimmunity and diabetes. For the 1403 who developed IAbs (523 of whom developed diabetes), levels of autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA) and insulinoma-associated antigen-2 (IA-2A) were harmonised for analysis. Diabetes prediction models using multivariate logistic regression with inverse probability censored weighting (IPCW) were trained using 10-fold cross-validation. Discriminative power for disease was estimated using the IPCW concordance index (C index) with 95% CI estimated via bootstrap. Results: A baseline model with covariates for data source, sex, diabetes family history, HLA risk group and age at seroconversion with a 10-year follow-up period yielded a C index of 0.61 (95% CI 0.58, 0.63). The performance improved after adding the IAb positivity status for IAA, GADA and IA-2A at seroconversion: C index 0.72 (95% CI 0.71, 0.74). Using the IAb levels instead of positivity indicators resulted in even better performance: C index 0.76 (95% CI 0.74, 0.77). The predictive power was maintained when using the IAb levels alone: C index 0.76 (95% CI 0.75, 0.76). The prediction was better for shorter follow-up periods, with a C index of 0.82 (95% CI 0.81, 0.83) at 2 years, and remained reasonable for longer follow-up periods, with a C index of 0.76 (95% CI 0.75, 0.76) at 11 years. Inclusion of the results of a third IAb test added to the predictive power, and a suitable interval between seroconversion and the third test was approximately 1.5 years, with a C index of 0.78 (95% CI 0.77, 0.78) at 10 years follow-up. Conclusions/interpretation: Consideration of quantitative patterns of IAb levels i
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- 2023
3. Screening for type 1 diabetes in the general population: a status report and perspective
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Sims EK, Besser REJ, Dayan C, C Geno Rasmussen, Greenbaum C, Griffin KJ, Hagopian W, Knip M, Long AE, Martin F, Mathieu C, Rewers M, Steck AK, Wentworth JM, Rich SS, Kordonouri O, Ziegler AG, and Herold KC
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General Economics, Econometrics and Finance - Published
- 2022
4. Non-HLA type 1 diabetes genes modulate disease risk together with HLA-DQ and islet autoantibodies
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Maziarz, M, Hagopian, W, Palmer, J P, Sanjeevi, C B, Kockum, I, Breslow, N, and Lernmark, Å
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- 2015
- Full Text
- View/download PDF
5. Two-age islet-autoantibody screening for childhood type 1 diabetes:a prospective cohort study
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Ghalwash, M. (Mohamed), Dunne, J. L. (Jessica L), Lundgren, M. (Markus), Rewers, M. (Marian), Ziegler, A.-G. (Anette-G), Anand, V. (Vibha), Toppari, J. (Jorma), Veijola, R. (Riitta), Hagopian, W. (William), Ghalwash, M. (Mohamed), Dunne, J. L. (Jessica L), Lundgren, M. (Markus), Rewers, M. (Marian), Ziegler, A.-G. (Anette-G), Anand, V. (Vibha), Toppari, J. (Jorma), Veijola, R. (Riitta), and Hagopian, W. (William)
- Abstract
Background: Early prediction of childhood type 1 diabetes reduces ketoacidosis at diagnosis and provides opportunities for disease prevention. However, only highly efficient approaches are likely to succeed in public health settings. We sought to identify efficient strategies for initial islet autoantibody screening in children younger than 15 years. Methods: We harmonised data from five prospective cohorts from Finland (DIPP), Germany (BABYDIAB), Sweden (DiPiS), and the USA (DAISY and DEW-IT) into the Type 1 Diabetes Intelligence (T1DI) cohort. 24 662 children at high risk of diabetes enrolled before age 2 years were included and followed up for islet autoantibodies and diabetes until age 15 years, or type 1 diabetes onset, whichever occurred first. Islet autoantibodies measured included those against glutamic acid decarboxylase, insulinoma antigen 2, and insulin. Main outcomes were sensitivity and positive predictive value (PPV) of detected islet autoantibodies, tested at one or two fixed ages, for diagnosis of clinical type 1 diabetes. Findings: Of the 24 662 participants enrolled in the Type 1 Diabetes Intelligence cohort, 6722 total were followed up to age 15 years or until onset of type 1 diabetes. Type 1 diabetes developed by age 15 years in 672 children, but did not develop in 6050 children. Optimal screening ages for two measurements were 2 years and 6 years, yielding sensitivity of 82% (95% CI 79–86) and PPV of 79% (95% CI 75–80) for diabetes by age 15 years. Autoantibody positivity at the beginning of each test age was highly predictive of diagnosis in the subsequent 2–5·99 year or 6–15-year age intervals. Autoantibodies usually appeared before age 6 years even in children diagnosed with diabetes much later in childhood. Interpretation: Our results show that initial screening for islet autoantibodies at two ages (2 years and 6 years) is sensitive and efficient for public health translation but might require adjustment by country on the basis of p
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- 2022
6. Islet autoantibody type-specific titer thresholds improve stratification of risk of progression to type 1 diabetes in children
- Author
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Ng, K. (Kenney), Stavropoulos, H. (Harry), Anand, V. (Vibha), Veijola, R. (Riitta), Toppari, J. (Jorma), Maziarz, M. (Marlena), Lundgren, M. (Markus), Waugh, K. (Kathy), Frohnert, B. I. (Brigitte I.), Martin, F. (Frank), Hagopian, W. (William), Achenbach, P. (Peter), Ng, K. (Kenney), Stavropoulos, H. (Harry), Anand, V. (Vibha), Veijola, R. (Riitta), Toppari, J. (Jorma), Maziarz, M. (Marlena), Lundgren, M. (Markus), Waugh, K. (Kathy), Frohnert, B. I. (Brigitte I.), Martin, F. (Frank), Hagopian, W. (William), and Achenbach, P. (Peter)
- Abstract
Objective: To use islet autoantibody titers to improve the estimation of future type 1 diabetes risk in children. Research design and methods: Prospective cohort studies in Finland, Germany, Sweden, and the U.S. followed 24,662 children at increased genetic or familial risk to develop islet autoimmunity and diabetes. For 1,604 children with confirmed positivity, titers of autoantibodies against insulin (IAA), GAD antibodies (GADA), and insulinoma-associated antigen 2 (IA-2A) were harmonized for diabetes risk analyses. Results: Survival analysis from time of confirmed positivity revealed markedly different 5-year diabetes risks associated with IAA (n = 909), GADA (n = 1,076), and IA-2A (n = 714), when stratified by quartiles of titer, ranging from 19% (GADA 1st quartile) to 60% (IA-2A 4th quartile). The minimum titer associated with a maximum difference in 5-year risk differed for each autoantibody, corresponding to the 58.6th, 52.4th, and 10.2nd percentile of children specifically positive for each of IAA, GADA, and IA-2A, respectively. Using these autoantibody type-specific titer thresholds in the 1,481 children with all autoantibodies tested, the 5-year risk conferred by single (n = 954) and multiple (n = 527) autoantibodies could be stratified from 6 to 75% (P < 0.0001). The thresholds effectively identified children with a ≥50% 5-year risk when considering age-specific autoantibody screening (57–65% positive predictive value and 56–74% sensitivity for ages 1–5 years). Multivariable analysis confirmed the significance of associations between the three autoantibody titers and diabetes risk, informing a childhood risk surveillance strategy. Conclusions: This study defined islet autoantibody type-specific titer thresholds that significantly improved type 1 diabetes risk stratification in children.
- Published
- 2022
7. HbA1c as a time predictive biomarker for an additional islet autoantibody and type 1 diabetes in seroconverted TEDDY children
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Salami, F. (Falastin), Tamura, R. (Roy), You, L. (Lu), Lernmark, Å. (Åke), Larsson, H. E. (Helena Elding), Lundgren, M. (Markus), Krischer, J. (Jeffrey), Ziegler, A.-G. (Anette-Gabriele), Toppari, J. (Jorma), Veijola, R. (Riitta), Rewers, M. (Marian), Haller, M. J. (Michael J.), Hagopian, W. (William), Akolkar, B. (Beena), Törn, C. (Carina), T. T. (The TEDDY Study Group), Salami, F. (Falastin), Tamura, R. (Roy), You, L. (Lu), Lernmark, Å. (Åke), Larsson, H. E. (Helena Elding), Lundgren, M. (Markus), Krischer, J. (Jeffrey), Ziegler, A.-G. (Anette-Gabriele), Toppari, J. (Jorma), Veijola, R. (Riitta), Rewers, M. (Marian), Haller, M. J. (Michael J.), Hagopian, W. (William), Akolkar, B. (Beena), Törn, C. (Carina), and T. T. (The TEDDY Study Group)
- Abstract
Objective: Increased level of glycated hemoglobin (HbA1c) is associated with type 1 diabetes onset that in turn is preceded by one to several autoantibodies against the pancreatic islet beta cell autoantigens; insulin (IA), glutamic acid decarboxylase (GAD), islet antigen-2 (IA-2) and zinc transporter 8 (ZnT8). The risk for type 1 diabetes diagnosis increases by autoantibody number. Biomarkers predicting the development of a second or a subsequent autoantibody and type 1 diabetes are needed to predict disease stages and improve secondary prevention trials. This study aimed to investigate whether HbA1c possibly predicts the progression from first to a subsequent autoantibody or type 1 diabetes in healthy children participating in the Environmental Determinants of Diabetes in the Young (TEDDY) study. Research Design and Methods: A joint model was designed to assess the association of longitudinal HbA1c levels with the development of first (insulin or GAD autoantibodies) to a second, second to third, third to fourth autoantibody or type 1 diabetes in healthy children prospectively followed from birth until 15 years of age. Results: It was found that increased levels of HbA1c were associated with a higher risk of type 1 diabetes (HR 1.82, 95% CI [1.57–2.10], p < 0.001) regardless of first appearing autoantibody, autoantibody number or type. A decrease in HbA1c levels was associated with the development of IA-2A as a second autoantibody following GADA (HR 0.85, 95% CI [0.75, 0.97], p = 0.017) and a fourth autoantibody following GADA, IAA and ZnT8A (HR 0.90, 95% CI [0.82, 0.99], p = 0.036). HbA1c trajectory analyses showed a significant increase of HbA1c over time (p < 0.001) and that the increase is more rapid as the number of autoantibodies increased from one to three (p < 0.001). Conclusion: In conclusion, increased HbA1c is a reliable time predictive marker for type 1 diabetes onset. The increased rate of increase of HbA1c from first to third autoant
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- 2022
8. Progression of type 1 diabetes from latency to symptomatic disease is predicted by distinct autoimmune trajectories
- Author
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Kwon, B. C. (Bum Chul), Anand, V. (Vibha), Achenbach, P. (Peter), Dunne, J. L. (Jessica L.), Hagopian, W. (William), Hu, J. (Jianying), Koski, E. (Eileen), Lernmark, Å. (Åke), Lundgren, M. (Markus), Ng, K. (Kenney), Toppari, J. (Jorma), Veijola, R. (Riitta), Frohnert, B. I. (Brigitte I.), the T1DI Study Group, Kwon, B. C. (Bum Chul), Anand, V. (Vibha), Achenbach, P. (Peter), Dunne, J. L. (Jessica L.), Hagopian, W. (William), Hu, J. (Jianying), Koski, E. (Eileen), Lernmark, Å. (Åke), Lundgren, M. (Markus), Ng, K. (Kenney), Toppari, J. (Jorma), Veijola, R. (Riitta), Frohnert, B. I. (Brigitte I.), and the T1DI Study Group
- Abstract
Development of islet autoimmunity precedes the onset of type 1 diabetes in children, however, the presence of autoantibodies does not necessarily lead to manifest disease and the onset of clinical symptoms is hard to predict. Here we show, by longitudinal sampling of islet autoantibodies (IAb) to insulin, glutamic acid decarboxylase and islet antigen-2 that disease progression follows distinct trajectories. Of the combined Type 1 Data Intelligence cohort of 24662 participants, 2172 individuals fulfill the criteria of two or more follow-up visits and IAb positivity at least once, with 652 progressing to type 1 diabetes during the 15 years course of the study. Our Continuous-Time Hidden Markov Models, that are developed to discover and visualize latent states based on the collected data and clinical characteristics of the patients, show that the health state of participants progresses from 11 distinct latent states as per three trajectories (TR1, TR2 and TR3), with associated 5-year cumulative diabetes-free survival of 40% (95% confidence interval [CI], 35% to 47%), 62% (95% CI, 57% to 67%), and 88% (95% CI, 85% to 91%), respectively (p < 0.0001). Age, sex, and HLA-DR status further refine the progression rates within trajectories, enabling clinically useful prediction of disease onset.
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- 2022
9. Prevalence of obesity was related to HLA-DQ in 2–4-year-old children at genetic risk for type 1 diabetes
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Yang, J, Lernmark, Å, Uusitalo, U M, Lynch, K F, Veijola, R, Winkler, C, Larsson, H E, Rewers, M, She, J-X, Ziegler, A G, Simell, O G, Hagopian, W A, Akolkar, B, Krischer, J P, and Vehik, K
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- 2014
- Full Text
- View/download PDF
10. Progression of type 1 diabetes from latency to symptomatic disease is predicted by distinct autoimmune trajectories
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Kwon BC, Anand V, Achenbach P, Dunne JL, Hagopian W, Hu J, Koski E, Lernmark AE, Lundgren M, Ng K, Toppari J, Veijola R, and Frohnert BI
- Subjects
Multidisciplinary ,Genotype ,General Physics and Astronomy ,Autoimmunity ,HLA-DR Antigens ,General Chemistry ,General Biochemistry, Genetics and Molecular Biology ,Islets of Langerhans ,Diabetes Mellitus, Type 1 ,Disease Progression ,Humans ,Child ,General Economics, Econometrics and Finance ,Autoantibodies - Abstract
Development of islet autoimmunity precedes the onset of type 1 diabetes in children, however, the presence of autoantibodies does not necessarily lead to manifest disease and the onset of clinical symptoms is hard to predict. Here we show, by longitudinal sampling of islet autoantibodies (IAb) to insulin, glutamic acid decarboxylase and islet antigen-2 that disease progression follows distinct trajectories. Of the combined Type 1 Data Intelligence cohort of 24662 participants, 2172 individuals fulfill the criteria of two or more follow-up visits and IAb positivity at least once, with 652 progressing to type 1 diabetes during the 15 years course of the study. Our Continuous-Time Hidden Markov Models, that are developed to discover and visualize latent states based on the collected data and clinical characteristics of the patients, show that the health state of participants progresses from 11 distinct latent states as per three trajectories (TR1, TR2 and TR3), with associated 5-year cumulative diabetes-free survival of 40% (95% confidence interval [CI], 35% to 47%), 62% (95% CI, 57% to 67%), and 88% (95% CI, 85% to 91%), respectively (p
- Published
- 2022
11. Type 1 diabetes can present before the age of 6 months and is characterized by autoimmunity and rapid loss of beta cells
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Domingo-Vila C, Dobbs R, Kashyap A. Patel, De Franco E, Hudson M, Killian M, Hagopian W, McDonald Tj, Johnson Mb, R. A. Oram, Sian Ellard, Suzanne Hammersley, Flanagan Se, Hattersley At, and Tree Tim
- Subjects
Type 1 diabetes ,medicine.medical_specialty ,Endocrinology ,business.industry ,Internal medicine ,medicine ,medicine.disease ,Beta (finance) ,medicine.disease_cause ,business ,Autoimmunity - Published
- 2021
12. Early probiotic supplementation and the risk of celiac disease in children at genetic risk
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Uusitalo, U. (Ulla), Aronsson, C. A. (Carin Andren), Liu, X. (Xiang), Kurppa, K. (Kalle), Yang, J. (Jimin), Liu, E. (Edwin), Skidmore, J. (Jennifer), Winkler, C. (Christiane), Rewers, M. J. (Marian J.), Hagopian, W. A. (William A.), She, J.-X. (Jin-Xiong), Toppari, J. (Jorma), Ziegler, A.-G. (Anette-G), Akolkar, B. (Beena), Norris, J. M. (Jill M.), Virtanen, S. M. (Suvi M.), Krischer, J. P. (Jeffrey P.), Agardh, D. (Daniel), Rewers, M. (Marian), Bautista, K. (Kimberly), Baxter, J. (Judith), Felipe-Morales, D. (Daniel), Driscoll, K. (Kimberly), Frohnert, B. I. (Brigitte, I), Gallant, M. (Marisa), Gesualdo, P. (Patricia), Hoffman, M. (Michelle), Karban, R. (Rachel), Norris, J. (Jill), Steck, A. (Andrea), Waugh, K. (Kathleen), Simell, O. G. (Olli G.), Adamsson, A. (Annika), Ahonen, S. (Suvi), Akerlund, M. (Mari), Hekkala, A. (Anne), Holappa, H. (Henna), Hyoty, H. (Heikki), Ikonen, A. (Anni), Ilonen, J. (Jorma), Jaminki, S. (Sinikka), Jokipuu, S. (Sanna), Karlsson, L. (Leena), Kahonen, M. (Miia), Knip, M. (Mikael), Koivikko, M.-L. (Minna-Liisa), Koreasalo, M. (Mirva), Kytola, J. (Jarita), Latva-aho, T. (Tiina), Lindfors, K. (Katri), Lonnrot, M. (Maria), Mantymaki, E. (Elina), Mattila, M. (Markus), Multasuo, K. (Katja), Mykkanenv, T. (Teija), Niininen, T. (Titha), Niinisto, S. (Sari), Nyblom, M. (Mia), Oikarinen, S. (Sami), Ollikainen, P. (Paula), Pohjola, S. (Sirpa), Rajala, P. (Petra), Rautanen, J. (Jenna), Riikonen, A. (Anne), Romo, M. (Minna), Ruohonen, S. (Suvi), Simell, S. (Satu), Sjoberg, M. (Maija), Stenius, A. (Aino), Tossavainen, P. (Paivi), Vaha-Makila, M. (Mari), Vainionpaa, S. (Sini), Varjonen, E. (Eeva), Veijola, R. (Riitta), Viinikangas, I. (Irene), Schatz, D. (Desmond), Hopkins, D. (Diane), Steed, L. (Leigh), Bryant, J. (Jennifer), Silvis, K. (Katherine), Haller, M. (Michael), Gardiner, M. (Melissa), Mclndoe, R. (Richard), Sharma, A. (Ashok), Anderson, S. W. (Stephen W.), Jacobsen, L. (Laura), Marks, J. (John), Towe, P. D. (P. D.), Ziegler, A. G. (Anette G.), Bonifacio, E. (Ezio), D'Angelo, M. (Miryam), Gavrisan, A. (Anita), Gezginci, C. (Cigdem), Heublein, A. (Anja), Hoffmann, V. (Verena), Hummel, S. (Sandra), Keimer, A. (Andrea), Knopff, A. (Annette), Koch, C. (Charlotte), Koletzko, S. (Sibylle), Ramminger, C. (Claudia), Roth, R. (Roswith), Scholz, M. (Marlon), Stock, J. (Joanna), Warncke, K. (Katharina), Wendel, L. (Lorena), Lernmark, A. (Ake), Ask, M. (Maria), Bremer, J. (Jenny), Cilio, C. (Corrado), Ericson-Hallstrom, E. (Emelie), Fors, A. (Annika), Fransson, L. (Lina), Gard, T. (Thomas), Bennet, R. (Rasmus), Hansen, M. (Monika), Hyberg, S. (Susanne), Jisser, H. (Hanna), Johansen, F. (Fredrik), Jonsdottir, B. (Berglind), Jovic, S. (Silvija), Larsson, H. E. (Helena Elding), Lindstrom, M. (Marielle), Lundgren, M. (Markus), Manson-Martinez, M. (Maria), Markan, M. (Maria), Melin, J. (Jessica), Mestan, Z. (Zeliha), Nilsson, C. (Caroline), Ottosson, K. (Karin), Rahmati, K. (Kobra), Ramelius, A. (Anita), Salami, F. (Falastin), Sjoberg, A. (Anette), Sjoberg, B. (Birgitta), Torn, C. (Carina), Wallin, A. (Anne), Wimar, A. (Asa), Aberg, S. (Sofie), Killian, M. (Michael), Crouch, C. C. (Claire Cowen), Akramoff, A. (Ashley), Chavoshi, M. (Masumeh), Dunson, K. (Kayleen), Hervey, R. (Rachel), Lyons, R. (Rachel), Meyer, A. (Arlene), Mulenga, D. (Denise), Radtke, J. (Jared), Romancik, M. (Matei), Schmitt, D. (Davey), Schwabe, J. (Julie), Zink, S. (Sarah), Becker, D. (Dorothy), Franciscus, M. (Margaret), Smith, M. D. (Maryellen Dalmagro-Elias), Daftary, A. (Ashi), Klein, M. B. (Mary Beth), Yates, C. (Chrystal), Austin-Gonzalez, S. (Sarah), Avendano, M. (Maryouri), Baethke, S. (Sandra), Brown, R. (Rasheedah), Burkhardt, B. (Brant), Butterworth, M. (Martha), Clasen, J. (Joanna), Cuthbertson, D. (David), Eberhard, C. (Christopher), Fiske, S. (Steven), Garmeson, J. (Jennifer), Gowda, V. (Veena), Heyman, K. (Kathleen), Hsiao, B. (Belinda), Karges, C. (Christina), Laras, F. P. (Francisco Perez), Lee, H.-S. (Hye-Seung), Li, Q. (Qian), Liu, S. (Shu), Lynch, K. (Kristian), Maguire, C. (Colleen), Malloy, J. (Jamie), McCarthy, C. (Cristina), Merrell, A. (Aubrie), Meulemans, S. (Steven), Parikh, H. (Hemang), Quigley, R. (Ryan), Remedios, C. (Cassandra), Shaffer, C. (Chris), Smith, L. (Laura), Smith, S. (Susan), Sulman, N. (Noah), Tamura, R. (Roy), Tewey, D. (Dena), Toth, M. (Michael), Vehik, K. (Kendra), Vijayakandipan, P. (Ponni), Wood, K. (Keith), Abbondondolo, M. (Michael), Ballard, L. (Lori), Hadley, D. (David), McLeod, W. (Wendy), Yu, L. (Liping), Miao, D. (Dongmei), Bingley, P. (Polly), Williams, A. (Alistair), Chandler, K. (Kyla), Ball, O. (Olivia), Kelland, I. (Ilana), Grace, S. (Sian), . (), Hagopian, W. (William), Erlich, H. (Henry), Mack, S. J. (Steven J.), Fear, A. L. (Anna Lisa), Ke, S. (Sandra), Mulholland, N. (Niveen), Bourcier, K. (Kasia), Briese, T. (Thomas), Johnson, S. B. (Suzanne Bennett), Triplett, E. (Eric), Uusitalo, U. (Ulla), Aronsson, C. A. (Carin Andren), Liu, X. (Xiang), Kurppa, K. (Kalle), Yang, J. (Jimin), Liu, E. (Edwin), Skidmore, J. (Jennifer), Winkler, C. (Christiane), Rewers, M. J. (Marian J.), Hagopian, W. A. (William A.), She, J.-X. (Jin-Xiong), Toppari, J. (Jorma), Ziegler, A.-G. (Anette-G), Akolkar, B. (Beena), Norris, J. M. (Jill M.), Virtanen, S. M. (Suvi M.), Krischer, J. P. (Jeffrey P.), Agardh, D. (Daniel), Rewers, M. (Marian), Bautista, K. (Kimberly), Baxter, J. (Judith), Felipe-Morales, D. (Daniel), Driscoll, K. (Kimberly), Frohnert, B. I. (Brigitte, I), Gallant, M. (Marisa), Gesualdo, P. (Patricia), Hoffman, M. (Michelle), Karban, R. (Rachel), Norris, J. (Jill), Steck, A. (Andrea), Waugh, K. (Kathleen), Simell, O. G. (Olli G.), Adamsson, A. (Annika), Ahonen, S. (Suvi), Akerlund, M. (Mari), Hekkala, A. (Anne), Holappa, H. (Henna), Hyoty, H. (Heikki), Ikonen, A. (Anni), Ilonen, J. (Jorma), Jaminki, S. (Sinikka), Jokipuu, S. (Sanna), Karlsson, L. (Leena), Kahonen, M. (Miia), Knip, M. (Mikael), Koivikko, M.-L. (Minna-Liisa), Koreasalo, M. (Mirva), Kytola, J. (Jarita), Latva-aho, T. (Tiina), Lindfors, K. (Katri), Lonnrot, M. (Maria), Mantymaki, E. (Elina), Mattila, M. (Markus), Multasuo, K. (Katja), Mykkanenv, T. (Teija), Niininen, T. (Titha), Niinisto, S. (Sari), Nyblom, M. (Mia), Oikarinen, S. (Sami), Ollikainen, P. (Paula), Pohjola, S. (Sirpa), Rajala, P. (Petra), Rautanen, J. (Jenna), Riikonen, A. (Anne), Romo, M. (Minna), Ruohonen, S. (Suvi), Simell, S. (Satu), Sjoberg, M. (Maija), Stenius, A. (Aino), Tossavainen, P. (Paivi), Vaha-Makila, M. (Mari), Vainionpaa, S. (Sini), Varjonen, E. (Eeva), Veijola, R. (Riitta), Viinikangas, I. (Irene), Schatz, D. (Desmond), Hopkins, D. (Diane), Steed, L. (Leigh), Bryant, J. (Jennifer), Silvis, K. (Katherine), Haller, M. (Michael), Gardiner, M. (Melissa), Mclndoe, R. (Richard), Sharma, A. (Ashok), Anderson, S. W. (Stephen W.), Jacobsen, L. (Laura), Marks, J. (John), Towe, P. D. (P. D.), Ziegler, A. G. (Anette G.), Bonifacio, E. (Ezio), D'Angelo, M. (Miryam), Gavrisan, A. (Anita), Gezginci, C. (Cigdem), Heublein, A. (Anja), Hoffmann, V. (Verena), Hummel, S. (Sandra), Keimer, A. (Andrea), Knopff, A. (Annette), Koch, C. (Charlotte), Koletzko, S. (Sibylle), Ramminger, C. (Claudia), Roth, R. (Roswith), Scholz, M. (Marlon), Stock, J. (Joanna), Warncke, K. (Katharina), Wendel, L. (Lorena), Lernmark, A. (Ake), Ask, M. (Maria), Bremer, J. (Jenny), Cilio, C. (Corrado), Ericson-Hallstrom, E. (Emelie), Fors, A. (Annika), Fransson, L. (Lina), Gard, T. (Thomas), Bennet, R. (Rasmus), Hansen, M. (Monika), Hyberg, S. (Susanne), Jisser, H. (Hanna), Johansen, F. (Fredrik), Jonsdottir, B. (Berglind), Jovic, S. (Silvija), Larsson, H. E. (Helena Elding), Lindstrom, M. (Marielle), Lundgren, M. (Markus), Manson-Martinez, M. (Maria), Markan, M. (Maria), Melin, J. (Jessica), Mestan, Z. (Zeliha), Nilsson, C. (Caroline), Ottosson, K. (Karin), Rahmati, K. (Kobra), Ramelius, A. (Anita), Salami, F. (Falastin), Sjoberg, A. (Anette), Sjoberg, B. (Birgitta), Torn, C. (Carina), Wallin, A. (Anne), Wimar, A. (Asa), Aberg, S. (Sofie), Killian, M. (Michael), Crouch, C. C. (Claire Cowen), Akramoff, A. (Ashley), Chavoshi, M. (Masumeh), Dunson, K. (Kayleen), Hervey, R. (Rachel), Lyons, R. (Rachel), Meyer, A. (Arlene), Mulenga, D. (Denise), Radtke, J. (Jared), Romancik, M. (Matei), Schmitt, D. (Davey), Schwabe, J. (Julie), Zink, S. (Sarah), Becker, D. (Dorothy), Franciscus, M. (Margaret), Smith, M. D. (Maryellen Dalmagro-Elias), Daftary, A. (Ashi), Klein, M. B. (Mary Beth), Yates, C. (Chrystal), Austin-Gonzalez, S. (Sarah), Avendano, M. (Maryouri), Baethke, S. (Sandra), Brown, R. (Rasheedah), Burkhardt, B. (Brant), Butterworth, M. (Martha), Clasen, J. (Joanna), Cuthbertson, D. (David), Eberhard, C. (Christopher), Fiske, S. (Steven), Garmeson, J. (Jennifer), Gowda, V. (Veena), Heyman, K. (Kathleen), Hsiao, B. (Belinda), Karges, C. (Christina), Laras, F. P. (Francisco Perez), Lee, H.-S. (Hye-Seung), Li, Q. (Qian), Liu, S. (Shu), Lynch, K. (Kristian), Maguire, C. (Colleen), Malloy, J. (Jamie), McCarthy, C. (Cristina), Merrell, A. (Aubrie), Meulemans, S. (Steven), Parikh, H. (Hemang), Quigley, R. (Ryan), Remedios, C. (Cassandra), Shaffer, C. (Chris), Smith, L. (Laura), Smith, S. (Susan), Sulman, N. (Noah), Tamura, R. (Roy), Tewey, D. (Dena), Toth, M. (Michael), Vehik, K. (Kendra), Vijayakandipan, P. (Ponni), Wood, K. (Keith), Abbondondolo, M. (Michael), Ballard, L. (Lori), Hadley, D. (David), McLeod, W. (Wendy), Yu, L. (Liping), Miao, D. (Dongmei), Bingley, P. (Polly), Williams, A. (Alistair), Chandler, K. (Kyla), Ball, O. (Olivia), Kelland, I. (Ilana), Grace, S. (Sian), . (), Hagopian, W. (William), Erlich, H. (Henry), Mack, S. J. (Steven J.), Fear, A. L. (Anna Lisa), Ke, S. (Sandra), Mulholland, N. (Niveen), Bourcier, K. (Kasia), Briese, T. (Thomas), Johnson, S. B. (Suzanne Bennett), and Triplett, E. (Eric)
- Abstract
Probiotics are linked to positive regulatory effects on the immune system. The aim of the study was to examine the association between the exposure of probiotics via dietary supplements or via infant formula by the age of 1 year and the development of celiac disease autoimmunity (CDA) and celiac disease among a cohort of 6520 genetically susceptible children. Use of probiotics during the first year of life was reported by 1460 children. Time-to-event analysis was used to examine the associations. Overall exposure of probiotics during the first year of life was not associated with either CDA (n = 1212) (HR 1.15; 95%CI 0.99, 1.35; p = 0.07) or celiac disease (n = 455) (HR 1.11; 95%CI 0.86, 1.43; p = 0.43) when adjusting for known risk factors. Intake of probiotic dietary supplements, however, was associated with a slightly increased risk of CDA (HR 1.18; 95%CI 1.00, 1.40; p = 0.043) compared to children who did not get probiotics. It was concluded that the overall exposure of probiotics during the first year of life was not associated with CDA or celiac disease in children at genetic risk.
- Published
- 2019
13. Next-generation sequencing for viruses in children with rapid-onset type 1 diabetes
- Author
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Lee, H.-S., Briese, T., Winkler, C., Rewers, M., Bonifacio, E., Hyoty, H., Pflueger, M., Simell, O., She, J. X., Hagopian, W., Lernmark, Å., Akolkar, B., Krischer, J. P., Ziegler, A. G., and the TEDDY study group
- Published
- 2013
- Full Text
- View/download PDF
14. Modeling Disease Progression Trajectories from Longitudinal Observational Data
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Kwon, B. C., Achenbach, P., Dunne, J. L., Hagopian, W., Markus Lundgren, Ng, K., Veijola, R., Frohnert, B. I., and Anand, V.
- Subjects
Models, Statistical ,Chronic Disease ,Disease Progression ,Humans ,Articles ,Markov Chains - Abstract
Analyzing disease progression patterns can provide useful insights into the disease processes of many chronic conditions. These analyses may help inform recruitment for prevention trials or the development and personalization of treatments for those affected. We learn disease progression patterns using Hidden Markov Models (HMM) and distill them into distinct trajectories using visualization methods. We apply it to the domain of Type 1 Diabetes (T1D) using large longitudinal observational data from the T1DI study group. Our method discovers distinct disease progression trajectories that corroborate with recently published findings. In this paper, we describe the iterative process of developing the model. These methods may also be applied to other chronic conditions that evolve over time.
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- 2021
15. The association between the PTPN22 1858C>T variant and type 1 diabetes depends on HLA risk and GAD65 autoantibodies
- Author
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Maziarz, M, Janer, M, Roach, J C, Hagopian, W, Palmer, J P, Deutsch, K, Sanjeevi, C B, Kockum, I, Breslow, N, and Lernmark, Å
- Published
- 2010
- Full Text
- View/download PDF
16. Genetic association of HLA DQB1 with CD4+CD25+high T-cell apoptosis in type 1 diabetes
- Author
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Glisic, S, Klinker, M, Waukau, J, Jailwala, P, Jana, S, Basken, J, Wang, T, Alemzadeh, R, Hagopian, W, and Ghosh, S
- Published
- 2009
- Full Text
- View/download PDF
17. Identification of non-HLA genes associated with development of islet autoimmunity and type 1 diabetes in the prospective TEDDY cohort
- Author
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Sharma, A., Liu, X., Hadley, D., Hagopian, W., Chen, W.M., Onengut-Gumuscu, S., Törn, C., Steck, A.K., Frohnert, B.I., Rewers, M., Ziegler, A.-G., Lernmark, A., Toppari, J., Krischer, J.P., Akolkar, B., Rich, S.S., She, J.X., and TEDDY Study Group (The Teddy Study Group)
- Subjects
Male ,Risk ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Genotype ,Immunology ,The Environmental Determinants of Diabetes in the Young ,Autoimmunity ,030209 endocrinology & metabolism ,Single-nucleotide polymorphism ,Human leukocyte antigen ,ta3111 ,Polymorphism, Single Nucleotide ,Article ,Cohort Studies ,PTPN22 ,Islets of Langerhans ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Immunology and Allergy ,Genetic Predisposition to Disease ,Prospective Studies ,Child ,Prospective cohort study ,Genetic Association Studies ,Autoantibodies ,Genetic association ,Type 1 diabetes ,Teddy Study ,Autoimmune Disorder ,Gene Mapping ,Susceptibility ,Type 1 Diabetes ,business.industry ,ta1184 ,Infant, Newborn ,Infant ,medicine.disease ,Diabetes Mellitus, Type 1 ,030104 developmental biology ,Child, Preschool ,Cohort ,Female ,business - Abstract
Traditional linkage analysis and genome-wide association studies have identified HLA and a number of non-HLA genes as genetic factors for islet autoimmunity (IA) and type 1 diabetes (T1D). However, the relative risk associated with previously identified non-HLA genes is usually very small as measured in cases/controls from mixed populations. Genetic associations for IA and T1D may be more accurately assessed in prospective cohorts. In this study, 5806 subjects from the TEDDY (The Environmental Determinants of Diabetes in the Young) study, an international prospective cohort study, were genotyped for 176,586 SNPs on the ImmunoChip. Cox proportional hazards analyses were performed to discover the SNPs associated with the risk for IA, T1D, or both. Three regions were associated with the risk of developing any persistent confirmed islet autoantibody: one known region near SH2B3 (HR = 1.35, p = 3.58 x 10(-7)) with Bonferroni-corrected significance and another known region near PTPN22 (HR = 1.46, p = 2.17 x 10(-6)) and one novel region near PPIL2 (HR = 2.47, p = 9.64 x 10(-7)) with suggestive evidence (p < 10(-5)). Two known regions (PTPN22: p = 2.25 x 10(-6), INS; p = 1.32 x 10(-7)) and one novel region (PXK/PDHB: p = 8.99 x 10(-6)) were associated with the risk for multiple islet autoantibodies. First appearing islet autoantibodies differ with respect to association. Two regions (INS: p = 5.67 x 10(-6) and TTC34/PROM16: 6.45 x 10(-6)) were associated if the fist appearing autoantibody was IAA and one region (RBFOXI: p = 8.02 x 10(-6)) was associated if the first appearing autoantibody was GADA. The analysis of T1D identified one region already known to be associated with T1D (INS: p = 3.13 x 10(-7)) and three novel regions (RNASET2, PLEKHA1, and PPIL2; 5.42 x 10(-6) > p > 2.31 x 10(-6)). These results suggest that a number of low frequency variants influence the risk of developing IA and/or T1D and these variants can be identified by large prospective cohort studies using a survival analysis approach. (C) 2017 Elsevier Ltd. All rights reserved.
- Published
- 2018
18. Relapsing and Remitting Severe Hypoglycemia due to a Monoclonal Anti-insulin Antibody Heralding a Case of Multiple Myeloma
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Waldron-Lynch, F., Inzucchi, S. E., Menard, L., Tai, N., Preston-Hurlburt, P., Hui, P., McClaskey, J., Hagopian, W. A., Meffre, E., Marks, P. W., Wen, L., and Herold, K. C.
- Published
- 2012
19. Country-specific birth weight and length in type 1 diabetes high-risk HLA genotypes in combination with prenatal characteristics
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Sterner, Y, Törn, C, Lee, H-S, Larsson, H, Winkler, C, McLeod, W, Lynch, K, Simell, O, Ziegler, A, Schatz, D, Hagopian, W, Rewers, M, She, J-X, Krischer, J P, Akolkar, B, and Lernmark, Å
- Published
- 2011
- Full Text
- View/download PDF
20. The association between the PTPN22 1858C> T variant and type 1 diabetes depends on HLA risk and GAD65 autoantibodies
- Author
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Maziarz, M, Janer, M, Roach, J C, Hagopian, W, Palmer, J P, Deutsch, K, Sanjeevi, C B, Kockum, I, Breslow, N, and Lernmark, Å
- Published
- 2010
- Full Text
- View/download PDF
21. Genetic association of HLA DQB1 with CD4+ CD25+high T-cell apoptosis in type 1 diabetes
- Author
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Glisic, S, Klinker, M, Waukau, J, Jailwala, P, Jana, S, Basken, J, Wang, T, Alemzadeh, R, Hagopian, W, and Ghosh, S
- Published
- 2009
22. Carboxypeptidase-H Autoantibodies Differentiate a More Latent Subset of Autoimmune Diabetes from Phenotypic Type 2 Diabetes among Chinese Adults
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Yang, L., Zhou, Z. G., Tan, S. Z., Huang, G., Jin, P., Yan, X., Li, X., Peng, H., and Hagopian, W.
- Published
- 2008
- Full Text
- View/download PDF
23. Maternal dietary supplement use and development of islet autoimmunity in the offspring: TEDDY study
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Silvis, K., Aronsson, C.A., Liu, X., Uusitalo, U., Yang, J., Tamura, R., Lernmark, A., Rewers, M., Hagopian, W., She, J.X., Simell, O., Toppari, J., Ziegler, A.-G., Akolkar, B., Krischer, J., Virtanen, S.M., Norris, J.M., and Teddy Study Group
- Subjects
Male ,Offspring ,Endocrinology, Diabetes and Metabolism ,The Environmental Determinants of Diabetes in the Young ,Physiology ,Autoimmunity ,030209 endocrinology & metabolism ,Article ,Islets of Langerhans ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,Germany ,Fatty Acids, Omega-3 ,Internal Medicine ,medicine ,Vitamin D and neurology ,Humans ,030212 general & internal medicine ,Vitamin D ,Family history ,Child ,Finland ,Autoantibodies ,Sweden ,Type 1 diabetes ,Glutamate Decarboxylase ,business.industry ,Hazard ratio ,Infant ,Maternal Nutritional Physiological Phenomena ,medicine.disease ,ta3123 ,United States ,Dietary Supplements ,Islet Autoimmunity ,Omega-3 Fatty Acids ,Diabetes Mellitus, Type 1 ,Child, Preschool ,Prenatal Exposure Delayed Effects ,Pediatrics, Perinatology and Child Health ,Cohort ,Female ,business - Abstract
Objective: We investigated the association between maternal use of vitamin D and omega-3 fatty acids (n-3 FAs) supplements during pregnancy and risk of islet autoimmunity (IA) in the offspring. Methods: The Environmental Determinants of Diabetes in the Young (TEDDY) Study is prospectively following 8676 children with increased genetic risk for type 1 diabetes in Finland, Germany, Sweden, and the United States. Blood samples were collected every 3 months between 3 and 48 months of age then every 6 months thereafter to determine persistent IA. Duration, frequency, and supplement dose during pregnancy were recalled by mothers at 3 to 4 months postpartum. Cumulative intakes of supplemental vitamin D and n-3 FAs were analyzed as continuous or binary variables. We applied time-to-event analysis to study the association between maternal supplement use and IA, adjusting for country, human leukocyte antigen-DR-DQ genotype, family history of type 1 diabetes and sex. Secondary outcomes included insulin autoantibodies (IAA) or glutamic acid decarboxylase (GADA) as the first appearing autoantibody. Results: As of February 2018, there were 747 (9.0%) children with IA. Vitamin D supplement intake during pregnancy (any vs none) was not associated with risk for IA (hazard ratio [HR] 1.11; 95% confidence interval [CI] 0.94, 1.31); neither was cumulative vitamin D supplement intake. Supplemental n-3 FA intake was similarly not associated with IA risk (HR: 1.19, 95% CI 0.98, 1.45). Similar lack of association was observed for either IAA or GADA as the first appearing autoantibody. Conclusions: The TEDDY cohort showed no evidence of benefit regarding IA risk for vitamin D or n-3 FA supplementation during pregnancy. (Less)
- Published
- 2019
24. Islet autoantibodies are associated with HLA-DQ genotypes in Han Chinese patients with type 1 diabetes and their relatives
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Wang, J.-P., Zhou, Z.-G., Lin, J., Huang, G., Zhang, C., Yang, L., Yuan, Y., Zhou, H.-F., Zhou, M., Hou, C., Zhou, W.-D., Peng, H., and Hagopian, W. A.
- Published
- 2007
25. A novel radioligand binding assay to determine diagnostic accuracy of isoform-specific glutamic acid decarboxylase antibodies in childhood IDDM
- Author
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Grubin, C. E., Daniels, T., Toivola, B., Landin-Olsson, M., Hagopian, W. A., Li, L., Karlsen, A. E., Boel, E., Michelsen, B., and Lernmark, Å.
- Published
- 1994
- Full Text
- View/download PDF
26. Predicting progression to type 1 diabetes from ages 3 to 6 in islet autoantibody positive TEDDY children
- Author
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Jacobsen, L. M. (Laura M.), Larsson, H. E. (Helena E.), Tamura, R. N. (Roy N.), Vehik, K. (Kendra), Clasen, J. (Joanna), Sosenko, J. (Jay), Hagopian, W. A. (William A.), She, J. (Jin‐Xiong), Steck, A. K. (Andrea K.), Rewers, M. (Marian), Simell, O. (Olli), Toppari, J. (Jorma), Veijola, R. (Riitta), Ziegler, A. G. (Anette G.), Krischer, J. P. (Jeffrey P.), Akolkar, B. (Beena), Haller, M. J. (Michael J.), t. T. (the TEDDY Study Group), Jacobsen, L. M. (Laura M.), Larsson, H. E. (Helena E.), Tamura, R. N. (Roy N.), Vehik, K. (Kendra), Clasen, J. (Joanna), Sosenko, J. (Jay), Hagopian, W. A. (William A.), She, J. (Jin‐Xiong), Steck, A. K. (Andrea K.), Rewers, M. (Marian), Simell, O. (Olli), Toppari, J. (Jorma), Veijola, R. (Riitta), Ziegler, A. G. (Anette G.), Krischer, J. P. (Jeffrey P.), Akolkar, B. (Beena), Haller, M. J. (Michael J.), and t. T. (the TEDDY Study Group)
- Abstract
Objective: The capacity to precisely predict progression to type 1 diabetes (T1D) in young children over a short time span is an unmet need. We sought to develop a risk algorithm to predict progression in children with high‐risk human leukocyte antigen (HLA) genes followed in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Methods: Logistic regression and 4‐fold cross‐validation examined 38 candidate predictors of risk from clinical, immunologic, metabolic, and genetic data. TEDDY subjects with at least one persistent, confirmed autoantibody at age 3 were analyzed with progression to T1D by age 6 serving as the primary endpoint. The logistic regression prediction model was compared to two non‐statistical predictors, multiple autoantibody status, and presence of insulinoma‐associated‐2 autoantibodies (IA‐2A). Results: A total of 363 subjects had at least one autoantibody at age 3. Twenty‐one percent of subjects developed T1D by age 6. Logistic regression modeling identified 5 significant predictors ‐ IA‐2A status, hemoglobin A1c, body mass index Z‐score, single‐nucleotide polymorphism rs12708716_G, and a combination marker of autoantibody number plus fasting insulin level. The logistic model yielded a receiver operating characteristic area under the curve (AUC) of 0.80, higher than the two other predictors; however, the differences in AUC, sensitivity, and specificity were small across models. Conclusions: This study highlights the application of precision medicine techniques to predict progression to diabetes over a 3‐year window in TEDDY subjects. This multifaceted model provides preliminary improvement in prediction over simpler prediction tools. Additional tools are needed to maximize the predictive value of these approaches.
- Published
- 2019
27. Antibodies to New Beta Cell Antigen ICA12 in Latvian Diabetes Patients
- Author
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SHTAUVERE-BRAMEUS, A., HAGOPIAN, W., RUMBA, I., and SANJEEVI, C. B.
- Published
- 2002
28. Prevalence of ICA-12 and Other Autoantibodies in North Indian Patients with Early-Onset Diabetes
- Author
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TANDON, N., SHTAUVERE-BRAMEUS, A., HAGOPIAN, W. A., and SANJEEVI, C. B.
- Published
- 2002
29. Reversion of β-Cell Autoimmunity Changes Risk of Type 1 Diabetes: TEDDY Study
- Author
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Vehik, K., Lynch, K.F., Schatz, D.A., Akolkar, B., Hagopian, W., Rewers, M., She, J.X., Simell, O., Toppari, J., Ziegler, A.-G., Lernmark, A., Bonifacio, E., Krischer, J.P., TEDDY Study Group (Beyerlein, A., Hummel, M., Hummel, S., Janz, N., Knopff, A., Peplow, C., Roth, R., Scholz, M., Stock, J., Strauss, E., Warncke, K., Wendel, L., and Winkler, C.)
- Subjects
Male ,0301 basic medicine ,Genotype ,Insulin Antibodies ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Autoimmunity ,030209 endocrinology & metabolism ,medicine.disease_cause ,Risk Assessment ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Insulin-Secreting Cells ,Diabetes mellitus ,Internal Medicine ,Humans ,Insulin ,Medicine ,Receptor-Like Protein Tyrosine Phosphatases, Class 8 ,Prospective Studies ,Epidemiology/Health Services Research ,Seroconversion ,Child ,Prospective cohort study ,Autoantibodies ,Advanced and Specialized Nursing ,Type 1 diabetes ,Glutamate Decarboxylase ,business.industry ,Autoantibody ,medicine.disease ,Diabetes Mellitus, Type 1 ,030104 developmental biology ,Child, Preschool ,Cohort ,Immunology ,Female ,business - Abstract
OBJECTIVE β-Cell autoantibodies are a feature of the preclinical phase of type 1 diabetes. Here, we asked how frequently they revert in a cohort of children at risk for type 1 diabetes and whether reversion has any effect on type 1 diabetes risk. RESEARCH DESIGN AND METHODS Children were up to 10 years of age and screened more than once for insulin autoantibody, GAD antibody, and insulinoma antigen-2 antibodies. Persistent autoantibody was defined as an autoantibody present on two or more consecutive visits and confirmed in two reference laboratories. Reversion was defined as two or more consecutive negative visits after persistence. Time-dependent Cox regression was used to examine how reversion modified the risk of development of multiple autoantibodies and type 1 diabetes. RESULTS Reversion was relatively frequent for autoantibodies to GAD65 (19%) and insulin (29%), but was largely restricted to children who had single autoantibodies (24%) and rare in children who had developed multiple autoantibodies ( CONCLUSIONS Type 1 diabetes risk remained high in children who had developed multiple β-cell autoantibodies even when individual autoantibodies reverted. We suggest that monitoring children with single autoantibodies for at least 1 year after seroconversion is beneficial for stratification of type 1 diabetes risk.
- Published
- 2016
30. Association between autoantibody markers and subtypes of DR4 and DR4-DQ in Swedish children with insulin-dependent diabetes reveals closer association of tyrosine pyrophosphatase autoimmunity with DR4 than DQ8
- Author
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Sanjeevi, C. B., Hagopian, W. A., Landin-Olsson, M., Kockum, I., Woo, W., Palmer, J. P., Lernmark, Å., and Dahlquist, G.
- Published
- 1998
31. Non-HLA type 1 diabetes genes modulate disease risk together with HLA-DQ and islet autoantibodies
- Author
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Maziarz, M., Hagopian, W., Palmer, J.P., Sanjeevi, C.B., Kockum, I., Breslow, N., Lernmark, A., Swedish Childhood Diabet Register, Diabet Incidence Sweden Study Grp, and T1DGC
- Subjects
Adult ,endocrine system ,endocrine system diseases ,Adolescent ,Receptor, ErbB-3 ,type 1 diabetes ,autoantibodies ,Immunology ,Single-nucleotide polymorphism ,Human leukocyte antigen ,Biology ,Polymorphism, Single Nucleotide ,Article ,PTPN22 ,Islets of Langerhans ,Young Adult ,HLA-DQ Antigens ,HLA-DQ ,Genetics ,medicine ,Humans ,Child ,Genetics (clinical) ,geography ,Type 1 diabetes ,geography.geographical_feature_category ,HLA-DQ Antigen ,autoimmunity ,Autoantibody ,Infant ,Protein Tyrosine Phosphatase, Non-Receptor Type 22 ,Islet ,medicine.disease ,3. Good health ,non-HLA genes ,Diabetes Mellitus, Type 1 ,Child, Preschool - Abstract
The possible interrelations between human leukocyte antigen (HLA)-DQ, non-HLA single-nucleotide polymorphisms (SNPs) and islet autoantibodies were investigated at clinical onset in 1-34-year-old type 1 diabetes (T1D) patients (n=305) and controls (n=203). Among the non-HLA SNPs reported by the Type 1 Diabetes Genetics Consortium, 24% were supported in this Swedish replication set including that the increased risk of minor PTPN22 allele and high-risk HLA was modified by GAD65 autoantibodies. The association between T1D and the minor AA+AC genotype in ERBB3 gene was stronger among IA-2 autoantibody-positive patients (comparison P=0.047). The association between T1D and the common insulin (AA) genotype was stronger among insulin autoantibody (IAA)-positive patients (comparison P=0.008). In contrast, the association between T1D and unidentified 26471 gene was stronger among IAA-negative (comparison P=0.049) and IA-2 autoantibody-negative (comparison P=0.052) patients. Finally, the association between IL2RA and T1D was stronger among IAA-positive than among IAA-negative patients (comparison P=0.028). These results suggest that the increased risk of T1D by non-HLA genes is often modified by both islet autoantibodies and HLA-DQ. The interactions between non-HLA genes, islet autoantibodies and HLA-DQ should be taken into account in T1D prediction studies as well as in prevention trials aimed at inducing immunological tolerance to islet autoantigens.
- Published
- 2015
32. Dietary intake of soluble fiber and risk of islet autoimmunity by 5 y of age: Results from the TEDDY study
- Author
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Beyerlein, A., Liu, X., Uusitalo, U.M., Harsunen, M.H., Norris, J.M., Foterek, K., Virtanen, S.M., Rewers, M.J., She, J.X., Simell, O., Lernmark, A., Hagopian, W., Akolkar, B., Ziegler, A.-G., Krischer, J.P., Hummel, S., TEDDY Study Group (Hummel, M., Knopff, A., Peplow, C., Roth, R., Stock, J., Strauss, E., Warncke, K., and Winkler, C.)
- Subjects
Type 1 diabetes ,medicine.medical_specialty ,geography ,endocrine system ,Nutrition and Dietetics ,geography.geographical_feature_category ,endocrine system diseases ,business.industry ,Autoantibody ,Teddy Study ,Autoimmunity ,Diet ,Soluble Fiber ,Type 1 Diabetes ,Medicine (miscellaneous) ,biochemical phenomena, metabolism, and nutrition ,medicine.disease ,Islet ,medicine.disease_cause ,Soluble fiber intake ,Endocrinology ,Immune system ,Diabetes mellitus ,Internal medicine ,medicine ,Soluble fiber ,business - Abstract
BACKGROUND: Deficient soluble fiber intake has been suggested to dysregulate the immune response either directly or through alterations of the microbial composition in the gut. OBJECTIVE: We hypothesized that a high intake of dietary soluble fiber in early childhood decreases the risk of type 1 diabetes (T1D)-associated islet autoimmunity. DESIGN: We analyzed 17,620 food records collected between age 9 and 48 mo from 3358 children from the United States and Germany prospectively followed in the TEDDY (The Environmental Determinants of Diabetes in the Young) study. HRs for the development of any/multiple islet autoantibodies (242 and 151 events, respectively) and T1D (71 events) by soluble fiber intake were calculated in Cox regression models and adjusted for potential confounders. RESULTS: There were no statistically significantly protective associations observed between a high intake of soluble fiber and islet autoimmunity or T1D. For example, the adjusted HRs (95% CIs) for high intake (highest vs. lowest quintile) at age 12 mo were 0.90 (0.55, 1.45) for any islet autoantibody, 1.20 (0.69, 2.11) for multiple islet autoantibodies, and 1.24 (0.57, 2.70) for T1D. In analyzing soluble fiber intake as a time-varying covariate, there were also no short-term associations between soluble fiber intake and islet autoimmunity development, with adjusted HRs of 0.85 (0.51, 1.42) for high intake and development of any islet autoantibody, for example. CONCLUSION: These results indicate that the intake level of dietary soluble fiber is not associated with islet autoimmunity or T1D in early life.
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- 2015
33. Methods, Quality Control and Specimen Management in an International Multi-Center Investigation of Type 1 Diabetes: TEDDY
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Vehik, K., Fiske, S.W., Logan, C.A., Agardh, D., Cilio, C.M., Hagopian, W., Simell, O., Roivainen, M., She, J.X., Briese, T., Oikarinen, S., Hyoty, H., Ziegler, A.-G., Rewers, M., Lernmark, A., Akolkar, B., Krischer, J.P., and Burkhardt, B.R.
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Quality Control ,Adolescent ,Infant, Newborn ,Infant ,Article ,Specimen Handling ,Feces ,Diabetes Mellitus, Type 1 ,Child, Preschool ,Data Integrity ,Stool Sample Preservation ,Rna ,Biomarker Stability ,Metabolic Biomarkers ,T-cell Viability ,Humans ,Longitudinal Studies ,RNA, Messenger ,Child ,Autoantibodies ,Biological Specimen Banks - Abstract
BACKGROUND: The vast array and quantity of longitudinal samples collected in The Environmental Determinants of Diabetes in the Young study present a series of challenges in terms of quality control procedures and data validity. To address this, pilot studies have been conducted to standardize and enhance both biospecimen collection and sample obtainment in terms of autoantibody collection, stool sample preservation, RNA, biomarker stability, metabolic biomarkers and T-cell viability. RESEARCH DESIGN AND METHODS: The Environmental Determinants of Diabetes in the Young is a multicentre, international prospective study (n = 8677) designed to identify environmental triggers of type 1 diabetes (T1D) in genetically at-risk children from ages 3 months until 15 years. The study is conducted through six primary clinical centres located in four countries. RESULTS: As of May 2012, over three million biological samples and 250 million total data points have been collected, which will be analysed to assess autoimmunity status, presence of inflammatory biomarkers, genetic factors, exposure to infectious agents, dietary biomarkers and other potentially important environmental exposures in relation to autoimmunity and progression to T1D. CONCLUSIONS: Detailed procedures were utilized to standardize both data harmonization and management when handling a large quantity of longitudinal samples obtained from multiple locations. In addition, a description of the available specimens is provided that serve as an invaluable repository for the elucidation of determinants in T1D focusing on autoantibody concordance and harmonization, transglutaminase autoantibody, inflammatory biomarkers (T-cells), genetic proficiency testing, RNA lab internal quality control testing, infectious agents (monitoring cross-contamination, virus preservation and nasal swab collection validity) and HbA1c testing.
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- 2013
34. Plasmid-Encoded Proinsulin Preserves C-Peptide While Specifically Reducing Proinsulin-Specific CD8+ T Cells in Type 1 Diabetes
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Steinman, L., Quan, J., Utz, P. J., Robinson, W. H., Hagopian, W. A., Abreu, J. R. F., von Herrath, M., Gottlieb, P. A., Leviten, M., Garren, H., Solvason, N., Yu, L., Roep, B. O., King, R. S., Harrison, L. C., Buse, J. B., and Eisenbarth, G. S.
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endocrine system ,endocrine system diseases - Abstract
In type 1 diabetes (T1D) an intense inflammatory response destroys β cells in the pancreas, where insulin is produced and released. A therapy for T1D that reduces the specific autoimmune response in this disease while leaving the remainder of the immune system intact has long been sought. Proinsulin is a major target of adaptive immunity in T1D. We hypothesized that an engineered DNA plasmid encoding proinsulin (BHT-3021) would preserve β cell function in T1D patients through reduction of insulin-specific T cells. We studied 80 subjects over 18 years of age who were diagnosed with T1D within 5 years. Subjects were randomized 2:1 to receive intramuscular injections of BHT-3021 or BHT-placebo, weekly for 12 weeks, and then monitored for safety and immune responses in a blinded fashion. Four dose levels of BHT-3021 were evaluated: 0.3, 1.0, 3.0, and 6.0 mg. C-peptide served as an exploratory measure of efficacy and safety. Islet-specific CD8+ T cell frequencies were assessed with multimers of monomeric human leukocyte antigen class I molecules loaded with peptides containing pancreatic or unrelated antigens. No serious adverse events related to BHT-3021 occurred. C-peptide levels improved relative to placebo at all doses, most notably at 1 mg at 15 weeks (+19.5% BHT-3021 versus −8.8% BHT-placebo, P < 0.026). Proinsulin-reactive CD8+ T cells, but not T cells against unrelated islet or foreign molecules, declined in the BHT-3021 arm (P < 0.006). Thus, we demonstrate that a plasmid encoding proinsulin reduces the frequency of CD8+ T cells reactive to proinsulin while preserving C-peptide over the course of dosing.
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- 2013
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35. Identification of autoantibody epitopes of glutamic acid decarboxylase in stiff-man syndrome patients
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Li, L., Hagopian, W. A., Brashear, H. R., Daniels, T., and Ake Lernmark
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Immunology ,Immunology and Allergy - Abstract
Stiff-man syndrome is a neurologic disorder characterized by progressive rigidity of skeletal muscles. Deficiency of the neurotransmitter gamma-aminobutyric acid and autoantibodies to glutamic acid decarboxylase (GAD), the enzyme synthesizing gamma-aminobutyric acid, are closely associated with the disorder, although the relevant antigenic epitopes have not been identified. In the present study, sera from two patients with SMS was used in an immunoblotting assay with recombinant GAD67 (M(r) 67,000) and GAD65 (M(r) 65,000) isoforms to test whether SMS sera can recognize specific epitopes. We found that both SMS sera recognized the GAD65, but not the GAD67, isoform. Using 13 different synthetic GAD peptides to block the autoantibodies, two GAD65 epitopes were identified. One epitope recognized by both patients' sera, was blocked by the peptide representing amino acid residues 354-368. In one patient only, blocking was also observed by a peptide representing residues 390-402, which includes the binding site of the GAD cofactor, pyridoxal 5'-phosphate. A single amino acid substitution in GAD65 at position 401 (leucine to proline) and representing the analogous GAD67 sequence in this region significantly reduced the peptide's inhibitory effect. These findings suggest that SMS GAD autoantibodies share distinct GAD65 linear epitopes and that some SMS patients' autoantibodies may block the active site, explaining SMS GABA deficiency.
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- 1994
36. Next-generation sequencing for viruses in children with rapid-onset type 1 diabetes
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Lee, H-S, Briese, T., Winkler, C., Rewers, M., Bonifacio, E., Hyoty, H., Pflueger, M., Simell, O., She, J. X., Hagopian, W., Lernmark, Åke, Akolkar, B., Krischer, J. P., Ziegler, A. G., Lee, H-S, Briese, T., Winkler, C., Rewers, M., Bonifacio, E., Hyoty, H., Pflueger, M., Simell, O., She, J. X., Hagopian, W., Lernmark, Åke, Akolkar, B., Krischer, J. P., and Ziegler, A. G.
- Abstract
Viruses are candidate causative agents in the pathogenesis of autoimmune (type 1) diabetes. We hypothesised that children with a rapid onset of type 1 diabetes may have been exposed to such agents shortly before the initiation of islet autoimmunity, possibly at high dose, and thus study of these children could help identify viruses involved in the development of autoimmune diabetes. We used next-generation sequencing to search for viruses in plasma samples and examined the history of infection and fever in children enrolled in The Environmental Determinants of Diabetes in the Young (TEDDY) study who progressed to type 1 diabetes within 6 months from the appearance of islet autoimmunity, and in matched islet-autoantibody-negative controls. Viruses were not detected more frequently in plasma from rapid-onset patients than in controls during the period surrounding seroconversion. In addition, infection histories were found to be similar between children with rapid-onset diabetes and control children, although episodes of fever were reported less frequently in children with rapid-onset diabetes. These findings do not support the presence of viraemia around the time of seroconversion in young children with rapid-onset type 1 diabetes.
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- 2013
37. Islet cell and glutamic acid decarboxylase antibodies present at diagnosis of diabetes predict the need for insulin treatment. A cohort study in young adults whose disease was initially labeled as type 2 or unclassifiable diabetes.
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Littorin, B, Sundkvist, G, Hagopian, W, Landin-Olsson, M, Lernmark, A, Ostman, J, Arnqvist, H J, Blohmé, G, Bolinder, J, Eriksson, Jan W, Lithner, F, Scherstén, B, Wibell, L, Littorin, B, Sundkvist, G, Hagopian, W, Landin-Olsson, M, Lernmark, A, Ostman, J, Arnqvist, H J, Blohmé, G, Bolinder, J, Eriksson, Jan W, Lithner, F, Scherstén, B, and Wibell, L
- Abstract
OBJECTIVE: To clarify the predictive value of islet cell antibody (ICA) and GAD65 antibody (GADA) present at diagnosis with respect to the need for insulin treatment 6 years after diagnosis in young adults initially considered to have type 2 or unclassifiable diabetes. RESEARCH DESIGN AND METHODS: The patient material was representative of the entire Swedish population, consisting of patients who were 15-34 years old at diagnosis of diabetes in 1987-1988 but were not considered to have type 1 diabetes at onset. At follow-up, 6 years after the diagnosis, it was noted whether the patient was treated with insulin. The presence of ICA was determined by an immunofluorescence assay, and GADAs were measured by a radioligand assay. RESULTS: Six years after diagnosis, 70 of 97 patients were treated with insulin, and 27 of 97 patients were treated with oral drugs or diet alone. At diagnosis, ICAs and GADAs were present in 41 (59%) of 70 patients and 41 (60%) of 68 patients, respectively, of those now treated with insulin, compared with only 1 (4%) of 26 patients and 2 (7%) of 27 patients who were still not treated with insulin. For either ICA or GADA, the corresponding frequencies were 50 (74%) of 68 for patients who were later treated with insulin and 3 (12%) of 26 for those who were still not treated with insulin, respectively. The sensitivity for later insulin treatment was highest (74%) for the presence of ICA or GADA, and the specificity was highest (100%) for ICA and GADA. The positive predictive value was 100% for the combination of ICA and GADA, 98% for ICA alone, and approximately 95% for GADA alone. CONCLUSIONS: Determination of the presence of ICA and GADA at diagnosis of diabetes improves the classification of diabetes and predicts the future need of insulin in young adults.
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- 1999
38. Islet cell and glutamic acid decarboxylase antibodies present at diagnosis of diabetes predict the need for insulin treatment.
- Author
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Littorin, B, Sundkvist, G, Hagopian, W, Landin-Olsson, M, Lernmark, Å, Östman, J, Blohmé, G, Bolinder, J, Eriksson, JW, Lithner, F, Scherstén, B, Wibell, L, Arnqvist, Hans, Littorin, B, Sundkvist, G, Hagopian, W, Landin-Olsson, M, Lernmark, Å, Östman, J, Blohmé, G, Bolinder, J, Eriksson, JW, Lithner, F, Scherstén, B, Wibell, L, and Arnqvist, Hans
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- 1999
39. TEDDY-The Environmental Determinants of Diabetes in the Young: An Observational Clinical Trial
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HAGOPIAN, W. A, primary, LERNMARK, A., additional, REWERS, M. J, additional, SIMELL, O. G, additional, SHE, J.-X., additional, ZIEGLER, A. G, additional, KRISCHER, J. P, additional, and AKOLKAR, B., additional
- Published
- 2006
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40. Prevalence of ICA-12 and Other Autoantibodies in North Indian Patients with Early-Onset Diabetes
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TANDON, N., primary, SHTAUVERE-BRAMEUS, A., additional, HAGOPIAN, W. A., additional, and SANJEEVI, C. B., additional
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- 2006
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41. Immunogenetic analysis suggests different pathogenesis for obese and lean African-Americans with diabetic ketoacidosis.
- Author
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Umpierrez, G E, primary, Woo, W, additional, Hagopian, W A, additional, Isaacs, S D, additional, Palmer, J P, additional, Gaur, L K, additional, Nepom, G T, additional, Clark, W S, additional, Mixon, P S, additional, and Kitabchi, A E, additional
- Published
- 1999
- Full Text
- View/download PDF
42. Islet cell and glutamic acid decarboxylase antibodies present at diagnosis of diabetes predict the need for insulin treatment. A cohort study in young adults whose disease was initially labeled as type 2 or unclassifiable diabetes.
- Author
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Littorin, B, primary, Sundkvist, G, additional, Hagopian, W, additional, Landin-Olsson, M, additional, Lernmark, A, additional, Ostman, J, additional, Arnqvist, H J, additional, Blohmé, G, additional, Bolinder, J, additional, Eriksson, J W, additional, Lithner, F, additional, Scherstén, B, additional, and Wibell, L, additional
- Published
- 1999
- Full Text
- View/download PDF
43. A large sample of finnish diabetic sib-pairs reveals no evidence for a non-insulin-dependent diabetes mellitus susceptibility locus at 2qter.
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Ghosh, S, primary, Hauser, E R, additional, Magnuson, V L, additional, Valle, T, additional, Ally, D S, additional, Karanjawala, Z E, additional, Rayman, J B, additional, Knapp, J I, additional, Musick, A, additional, Tannenbaum, J, additional, Te, C, additional, Eldridge, W, additional, Shapiro, S, additional, Musick, T, additional, Martin, C, additional, So, A, additional, Witt, A, additional, Harvan, J B, additional, Watanabe, R M, additional, Hagopian, W, additional, Eriksson, J, additional, Nylund, S J, additional, Kohtamaki, K, additional, Tuomilehto-Wolf, E, additional, and Boehnke, M, additional
- Published
- 1998
- Full Text
- View/download PDF
44. Genetic and Immunological Findings in Patients With Newly Diagnosed Insulin-Dependent Diabetes Mellitus
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Kockum, Ingrid, primary, Lernmark, Å., additional, Dahlquist, Gisela, additional, Falorni, A., additional, Hagopian, W., additional, Landin-Olsson, Mona, additional, Li, L., additional, Luthman, H., additional, Palmer, J., additional, Sanjeevi, C., additional, Sundkvist, G., additional, and Östman, J., additional
- Published
- 1996
- Full Text
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45. Glutamate decarboxylase-, insulin-, and islet cell-antibodies and HLA typing to detect diabetes in a general population-based study of Swedish children.
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Hagopian, W A, primary, Sanjeevi, C B, additional, Kockum, I, additional, Landin-Olsson, M, additional, Karlsen, A E, additional, Sundkvist, G, additional, Dahlquist, G, additional, Palmer, J, additional, and Lernmark, A, additional
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- 1995
- Full Text
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46. Differential detection of rat islet and brain glutamic acid decarboxylase (GAD) isoforms with sequence-specific peptide antibodies.
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Li, L, primary, Jiang, J, additional, Hagopian, W A, additional, Karlsen, A E, additional, Skelly, M, additional, Baskin, D G, additional, and Lernmark, A, additional
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- 1995
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47. Analysis of antibody markers, DRB1, DRB5, DQA1 and DQB1 genes and modeling of DR2 molecules in DR2-positive patients with insulin-dependent diabetes mellitus
- Author
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Sanjeevi, C. B., primary, Lybrand, T. P., additional, Landin-Olsson, M., additional, Kockum, I., additional, Dahlquist, G., additional, Hagopian, W. A., additional, Palmer, J. P., additional, and Lernmark, Å., additional
- Published
- 1994
- Full Text
- View/download PDF
48. Islet cell antibodies, but not glutamic acid decarboxylase antibodies, are decreased by plasmapheresis in patients with newly diagnosed insulin-dependent diabetes mellitus.
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Sundkvist, G, primary, Hagopian, W A, additional, Landin-Olsson, M, additional, Lernmark, A, additional, Ohlsson, L, additional, Ericsson, C, additional, and Ahlmén, J, additional
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- 1994
- Full Text
- View/download PDF
49. Regulation of glutamic acid decarboxylase diabetes autoantigen expression in highly purified isolated islets from Macaca nemestrina.
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Hagopian, W A, primary, Karlsen, A E, additional, Petersen, J S, additional, Teague, J, additional, Gervassi, A, additional, Jiang, J, additional, Fujimoto, W, additional, and Lernmark, A, additional
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- 1993
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50. Autoantibodies in IDDM primarily recognize the 65,000-M(r) rather than the 67,000-M(r) isoform of glutamic acid decarboxylase
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Hagopian, W. A., primary, Michelsen, B., additional, Karlsen, A. E., additional, Larsen, F., additional, Moody, A., additional, Grubin, C. E., additional, Rowe, R., additional, Petersen, J., additional, McEvoy, R., additional, and Lernmark, A., additional
- Published
- 1993
- Full Text
- View/download PDF
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