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2. Modeling Disease Progression Trajectories from Longitudinal Observational Data

Author

Kwon, Bum Chul, Achenbach, Peter, Dunne, Jessica L., Hagopian, William, Lundgren, Markus, Ng, Kenney, Veijola, Riitta, Frohnert, Brigitte I., Anand, Vibha, and Group, the T1DI Study

Subjects
Computer Science - Machine Learning
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., Comment: 9 pages, 5 figures, to be published in proceedings of AMIA Annual Symposium 2020

Published
2020

3. Distinct transcriptomic profiles in children prior to the appearance of type 1 diabetes-linked islet autoantibodies and following enterovirus infection

Author

Lin, Jake, Moradi, Elaheh, Salenius, Karoliina, Lehtipuro, Suvi, Häkkinen, Tomi, Laiho, Jutta E., Oikarinen, Sami, Randelin, Sofia, Parikh, Hemang M., Krischer, Jeffrey P., Toppari, Jorma, Lernmark, Åke, Petrosino, Joseph F., Ajami, Nadim J., She, Jin-Xiong, Hagopian, William A., Rewers, Marian J., Lloyd, Richard E., Rautajoki, Kirsi J., Hyöty, Heikki, and Nykter, Matti

Published
2023
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4. Longitudinal Metabolome-Wide Signals Prior to the Appearance of a First Islet Autoantibody in Children Participating in the TEDDY Study

Author

Li, Qian, Parikh, Hemang, Butterworth, Martha D, Lernmark, Åke, Hagopian, William, Rewers, Marian, She, Jin-Xiong, Toppari, Jorma, Ziegler, Anette-G, Akolkar, Beena, Fiehn, Oliver, Fan, Sili, Krischer, Jeffrey P, Barbour, Aaron, Bautista, Kimberly, Baxter, Judith, Felipe-Morales, Daniel, Driscoll, Kimberly, Frohnert, Brigitte I, Stahl, Marisa, Gesualdo, Patricia, Hoffman, Michelle, Karban, Rachel, Liu, Edwin, Norris, Jill, Peacock, Stesha, Shorrosh, Hanan, Steck, Andrea, Stern, Megan, Villegas, Erica, Waugh, Kathleen, Simell, Olli G, Adamsson, Annika, Ahonen, Suvi, Åkerlund, Mari, Hakola, Leena, Hekkala, Anne, Holappa, Henna, Hyöty, Heikki, Ikonen, Anni, Ilonen, Jorma, Jäminki, Sinikka, Jokipuu, Sanna, Karlsson, Leena, Kero, Jukka, Kähönen, Miia, Knip, Mikael, Koivikko, Minna-Liisa, Koskinen, Merja, Koreasalo, Mirva, Kurppa, Kalle, Kytölä, Jarita, Latva-aho, Tiina, Lindfors, Katri, Lönnrot, Maria, Mäntymäki, Elina, Mattila, Markus, Miettinen, Maija, Multasuo, Katja, Mykkänen, Teija, Niininen, Tiina, Niinistö, Sari, Nyblom, Mia, Oikarinen, Sami, Ollikainen, Paula, Othmani, Zhian, Pohjola, Sirpa, Rajala, Petra, Rautanen, Jenna, Riikonen, Anne, Riski, Eija, Pekkola, Miia, Romo, Minna, Ruohonen, Satu, Simell, Satu, Sjöberg, Maija, Stenius, Aino, Tossavainen, Päivi, Vähä-Mäkilä, Mari, Vainionpää, Sini, Varjonen, Eeva, Veijola, Riitta, Viinikangas, Irene, Virtanen, Suvi M, Schatz, Desmond, Hopkins, Diane, Steed, Leigh, Bryant, Jennifer, Silvis, Katherine, Haller, Michael, Gardiner, Melissa, McIndoe, Richard, Sharma, Ashok, Anderson, Stephen W, Jacobsen, Laura, Marks, John, and Towe, PD

Subjects
Pediatric, Autoimmune Disease, Diabetes, Prevention, Nutrition, Metabolic and endocrine, Alanine, Amino Acids, Branched-Chain, Autoantibodies, Child, Preschool, Dehydroascorbic Acid, Diabetes Mellitus, Type 1, Fatty Acids, Female, Genetic Predisposition to Disease, Glutamate Decarboxylase, Humans, Infant, Infant, Newborn, Insulin Antibodies, Longitudinal Studies, Male, Metabolome, Methionine, Phosphatidylethanolamines, Prodromal Symptoms, Proline, Risk, Triglycerides, gamma-Aminobutyric Acid, TEDDY Study Group, Medical and Health Sciences, Endocrinology & Metabolism
Abstract

Children at increased genetic risk for type 1 diabetes (T1D) after environmental exposures may develop pancreatic islet autoantibodies (IA) at a very young age. Metabolic profile changes over time may imply responses to exposures and signal development of the first IA. Our present research in The Environmental Determinants of Diabetes in the Young (TEDDY) study aimed to identify metabolome-wide signals preceding the first IA against GAD (GADA-first) or against insulin (IAA-first). We profiled metabolomes by mass spectrometry from children's plasma at 3-month intervals after birth until appearance of the first IA. A trajectory analysis discovered each first IA preceded by reduced amino acid proline and branched-chain amino acids (BCAAs), respectively. With independent time point analysis following birth, we discovered dehydroascorbic acid (DHAA) contributing to the risk of each first IA, and γ-aminobutyric acid (GABAs) associated with the first autoantibody against insulin (IAA-first). Methionine and alanine, compounds produced in BCAA metabolism and fatty acids, also preceded IA at different time points. Unsaturated triglycerides and phosphatidylethanolamines decreased in abundance before appearance of either autoantibody. Our findings suggest that IAA-first and GADA-first are heralded by different patterns of DHAA, GABA, multiple amino acids, and fatty acids, which may be important to primary prevention of T1D.

Published
2020

6. Metabolite-related dietary patterns and the development of islet autoimmunity.

Author

Johnson, Randi K, Vanderlinden, Lauren, DeFelice, Brian C, Kechris, Katerina, Uusitalo, Ulla, Fiehn, Oliver, Sontag, Marci, Crume, Tessa, Beyerlein, Andreas, Lernmark, Åke, Toppari, Jorma, Ziegler, Anette-G, She, Jin-Xiong, Hagopian, William, Rewers, Marian, Akolkar, Beena, Krischer, Jeffrey, Virtanen, Suvi M, Norris, Jill M, and TEDDY Study Group

Subjects
TEDDY Study Group
Abstract

The role of diet in type 1 diabetes development is poorly understood. Metabolites, which reflect dietary response, may help elucidate this role. We explored metabolomics and lipidomics differences between 352 cases of islet autoimmunity (IA) and controls in the TEDDY (The Environmental Determinants of Diabetes in the Young) study. We created dietary patterns reflecting pre-IA metabolite differences between groups and examined their association with IA. Secondary outcomes included IA cases positive for multiple autoantibodies (mAb+). The association of 853 plasma metabolites with outcomes was tested at seroconversion to IA, just prior to seroconversion, and during infancy. Key compounds in enriched metabolite sets were used to create dietary patterns reflecting metabolite composition, which were then tested for association with outcomes in the nested case-control subset and the full TEDDY cohort. Unsaturated phosphatidylcholines, sphingomyelins, phosphatidylethanolamines, glucosylceramides, and phospholipid ethers in infancy were inversely associated with mAb+ risk, while dicarboxylic acids were associated with an increased risk. An infancy dietary pattern representing higher levels of unsaturated phosphatidylcholines and phospholipid ethers, and lower sphingomyelins was protective for mAb+ in the nested case-control study only. Characterization of this high-risk infant metabolomics profile may help shape the future of early diagnosis or prevention efforts.

Published
2019

10. Telomere length is not a main factor for the development of islet autoimmunity and type 1 diabetes in the TEDDY study

Author

Törn, Carina, Liu, Xiang, Onengut-Gumuscu, Suna, Counts, Kevin M., Moreno, Jose Leonardo, Remedios, Cassandra L., Chen, Wei-Min, LeFaive, Jonathon, Butterworth, Martha D., Akolkar, Beena, Krischer, Jeffrey P., Lernmark, Åke, Rewers, Marian, She, Jin-Xiong, Toppari, Jorma, Ziegler, Anette-Gabriele, Ratan, Aakrosh, Smith, Albert V., Hagopian, William A., Rich, Stephen S., and Parikh, Hemang M.

Published
2022
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11. The influence of pubertal development on autoantibody appearance and progression to type 1 diabetes in the TEDDY study

Author

Warncke, Katharina, primary, Tamura, Roy, additional, Schatz, Desmond A, additional, Veijola, Riitta, additional, Steck, Andrea K, additional, Akolkar, Beena, additional, Hagopian, William, additional, Krischer, Jeffrey P, additional, Lernmark, Åke, additional, Rewers, Marian J, additional, Toppari, Jorma, additional, McIndoe, Richard, additional, Ziegler, Anette-G, additional, Vehik, Kendra, additional, Haller, Michael J, additional, and Elding Larsson, Helena, additional

Published
2024
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12. Associations of breastfeeding with childhood autoimmunity, allergies, and overweight: The Environmental Determinants of Diabetes in the Young (TEDDY) study

Author

Hummel, Sandra, Weiß, Andreas, Bonifacio, Ezio, Agardh, Daniel, Akolkar, Beena, Aronsson, Carin A, Hagopian, William A, Koletzko, Sibylle, Krischer, Jeffrey P, Lernmark, Åke, Lynch, Kristian, Norris, Jill M, Rewers, Marian J, She, Jin-Xiong, Toppari, Jorma, Uusitalo, Ulla, Vehik, Kendra, Virtanen, Suvi M, Beyerlein, Andreas, and Ziegler, Anette-G

Published
2021
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19. Clinical Prediction Models Combining Routine Clinical Measures Have High Accuracy in Identifying Youth-Onset Type 2 Diabetes Defined by Maintained Endogenous Insulin Secretion: The SEARCH for Diabetes in Youth Study

Author

Jones, Angus G., primary, Shields, Beverley M., additional, Oram, Richard A., additional, Dabelea, Dana M., additional, Hagopian, William A., additional, Lustigova, Eva, additional, Shah, Amy S., additional, Knupp, Julieanne, additional, Mottl, Amy K., additional, D’Agostino, Ralph B., additional, Williams, Adrienne, additional, Marcovina, Santica M., additional, Pihoker, Catherine, additional, Divers, Jasmin, additional, and Redondo, Maria J., additional

Published
2024
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20. Host autophagy mediates organ wasting and nutrient mobilization for tumor growth

Author

Khezri, Rojyar, Holland, Petter, Schoborg, Todd Andrew, Abramovich, Ifat, Takáts, Szabolcs, Dillard, Caroline, Jain, Ashish, O'Farrell, Fergal, Schultz, Sebastian Wolfgang, Hagopian, William M, Quintana, Eduardo Martin, Ng, Rachel, Katheder, Nadja Sandra, Rahman, Mohammed Mahidur, Teles Reis, José Gerardo, Brech, Andreas, Jasper, Heinrich, Rusan, Nasser M, Jahren, Anne Hope, Gottlieb, Eyal, and Rusten, Tor Erik

Published
2021
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22. Teplizumab (anti-CD3 mAb) treatment preserves C-peptide responses in patients with new-onset type 1 diabetes in a randomized controlled trial: metabolic and immunologic features at baseline identify a subgroup of responders.

Author

Herold, Kevan C, Gitelman, Stephen E, Ehlers, Mario R, Gottlieb, Peter A, Greenbaum, Carla J, Hagopian, William, Boyle, Karen D, Keyes-Elstein, Lynette, Aggarwal, Sudeepta, Phippard, Deborah, Sayre, Peter H, McNamara, James, Bluestone, Jeffrey A, and AbATE Study Team

Subjects
AbATE Study Team, Humans, Diabetes Mellitus, Type 1, C-Peptide, Adolescent, Adult, Child, Female, Male, Antibodies, Monoclonal, Humanized, Clinical Trials and Supportive Activities, Autoimmune Disease, Pediatric, Clinical Research, Diabetes, Metabolic and endocrine, Endocrinology & Metabolism, Medical and Health Sciences
Abstract

Trials of immune therapies in new-onset type 1 diabetes (T1D) have shown success, but not all subjects respond, and the duration of response is limited. Our aim was to determine whether two courses of teplizumab, an Fc receptor-nonbinding anti-CD3 monoclonal antibody, reduces the decline in C-peptide levels in patients with T1D 2 years after disease onset. We also set out to identify characteristics of responders. We treated 52 subjects with new-onset T1D with teplizumab for 2 weeks at diagnosis and after 1 year in an open-label, randomized, controlled trial. In the intent to treat analysis of the primary end point, patients treated with teplizumab had a reduced decline in C-peptide at 2 years (mean -0.28 nmol/L [95% CI -0.36 to -0.20]) versus control (mean -0.46 nmol/L [95% CI -0.57 to -0.35]; P = 0.002), a 75% improvement. The most common adverse events were rash, transient upper respiratory infections, headache, and nausea. In a post hoc analysis we characterized clinical responders and found that metabolic (HbA1c and insulin use) and immunologic features distinguished this group from those who did not respond to teplizumab. We conclude that teplizumab treatment preserves insulin production and reduces the use of exogenous insulin in some patients with new-onset T1D. Metabolic and immunologic features at baseline can identify a subgroup with robust responses to immune therapy.

Published
2013

27. Type 2 Diabetes: Evidence for Linkage on Chromosome 20 in 716 Finnish Affected Sib Pairs

Author

Ghosh, Soumitra, Watanabe, Richard M., Hauser, Elizabeth R., Valle, Timo, Magnuson, Victoria L., Erdos, Michael R., Langefeld, Carl D., Balow,, James, Ally, Delphine S., Kohtamaki, Kimmo, Chines, Peter, Birznieks, Gunther, Kaleta, Hong-Shi, Musick, Anjene, Te, Catherine, Tannenbaum, Joyce, Eldridge, William, Shapiro, Shane, Martin, Colin, Witt, Alyson, So, Alistair, Chang, Jennie, Shurtleff, Ben, Porter, Rachel, Kudelko, Kristina, Unni, Arun, Segal, Leonid, Sharaf, Ravi, Blaschak-Harvan, Jillian, Eriksson, Johan, Tenkula, Tuula, Vidgren, Gabriele, Ehnholm, Christian, Tuomilehto-Wolf, Eva, Hagopian, William, Buchanan, Thomas A., Tuomilehto, Jaakko, Bergman, Richard N., Collins, Francis S., and Boehnke, Michael

Published
1999

28. The human gut microbiome in early-onset type 1 diabetes from the TEDDY study

Author

Vatanen, Tommi, Franzosa, Eric A., Schwager, Randall, Tripathi, Surya, Arthur, Timothy D., Vehik, Kendra, Lernmark, Åke, Hagopian, William A., Rewers, Marian J., She, Jin-Xiong, Toppari, Jorma, Ziegler, Anette-G., Akolkar, Beena, Krischer, Jeffrey P., Stewart, Christopher J., Ajami, Nadim J., Petrosino, Joseph F., Gevers, Dirk, Lähdesmäki, Harri, Vlamakis, Hera, Huttenhower, Curtis, and Xavier, Ramnik J.

Published
2018
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29. Temporal development of the gut microbiome in early childhood from the TEDDY study

Author

Stewart, Christopher J., Ajami, Nadim J., O’Brien, Jacqueline L., Hutchinson, Diane S., Smith, Daniel P., Wong, Matthew C., Ross, Matthew C., Lloyd, Richard E., Doddapaneni, HarshaVardhan, Metcalf, Ginger A., Muzny, Donna, Gibbs, Richard A., Vatanen, Tommi, Huttenhower, Curtis, Xavier, Ramnik J., Rewers, Marian, Hagopian, William, Toppari, Jorma, Ziegler, Anette-G., She, Jin-Xiong, Akolkar, Beena, Lernmark, Ake, Hyoty, Heikki, Vehik, Kendra, Krischer, Jeffrey P., and Petrosino, Joseph F.

Published
2018
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30. Plasma protein biomarkers predict the development of persistent autoantibodies and type 1 diabetes 6 months prior to the onset of autoimmunity

Author

Nakayasu, Ernesto S., primary, Bramer, Lisa M., additional, Ansong, Charles, additional, Schepmoes, Athena A., additional, Fillmore, Thomas L., additional, Gritsenko, Marina A., additional, Clauss, Therese R., additional, Gao, Yuqian, additional, Piehowski, Paul D., additional, Stanfill, Bryan A., additional, Engel, Dave W., additional, Orton, Daniel J., additional, Moore, Ronald J., additional, Qian, Wei-Jun, additional, Sechi, Salvatore, additional, Frohnert, Brigitte I., additional, Toppari, Jorma, additional, Ziegler, Anette-G., additional, Lernmark, Åke, additional, Hagopian, William, additional, Akolkar, Beena, additional, Smith, Richard D., additional, Rewers, Marian J., additional, Webb-Robertson, Bobbie-Jo M., additional, and Metz, Thomas O., additional

Published
2023
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32. Abstract IA14: Host autophagy mediates organ wasting and nutrient mobilization for tumor growth

Author

Holland, Petter, primary, Schoborg, Todd Andrew, additional, Abramovich, Ifat, additional, Takáts, Szabolcs, additional, Dillard, Caroline, additional, Jain, Ashish, additional, O'Farrell, Fergal, additional, Schultz, Sebastian Wolfgang, additional, Hagopian, William M., additional, Quintana, Eduardo Martin, additional, Ng, Rachel, additional, Katheder, Nadja Sandra, additional, Rahman, Mohammed Mahidur, additional, Reis, José Gerardo Teles, additional, Brech, Andreas, additional, Jasper, Heinrich, additional, Rusan, Nasser M., additional, Jahren, Anne Hope, additional, Gottlieb, Eyal, additional, and Rusten, Tor Erik, additional

Published
2023
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33. Effects of Gluten Intake on Risk of Celiac Disease: A Case-Control Study on a Swedish Birth Cohort

Author

Rewers, Marian, Bautista, Kimberly, Baxter, Judith, Bedoy, Ruth, Felipe-Morales, Daniel, Frohnert, Brigitte I., Gesualdo, Patricia, Hoffman, Michelle, Karban, Rachel, Liu, Edwin, Norris, Jill, Samper-Imaz, Adela, Steck, Andrea, Waugh, Kathleen, Wright, Hali, She, Jin-Xiong, Schatz, Desmond, Hopkins, Diane, Steed, Leigh, Thomas, Jamie, Adams, Janey, Silvis, Katherine, Haller, Michael, Gardiner, Melissa, McIndoe, Richard, Sharma, Ashok, Williams, Joshua, Foghis, Gabriela, Anderson, Stephen W., Robinson, Richard, Ziegler, Anette G., Beyerlein, Andreas, Bonifacio, Ezio, Hummel, Michael, Hummel, Sandra, Foterek, Kristina, Kersting, Mathilde, Knopff, Annette, Koletzko, Sibylle, Peplow, Claudia, Roth, Roswith, Stock, Joanna, Strauss, Elisabeth, Warncke, Katharina, Winkler, Christiane, Toppari, Jorma, Simell, Olli G., Adamsson, Annika, Hyöty, Heikki, Ilonen, Jorma, Jokipuu, Sanna, Kallio, Tiina, Kähönen, Miia, Knip, Mikael, Koivu, Annika, Koreasalo, Mirva, Kurppa, Kalle, Lönnrot, Maria, Mäntymäki, Elina, Multasuo, Katja, Mykkänen, Juha, Niininen, Tiina, Nyblom, Mia, Rajala, Petra, Rautanen, Jenna, Riikonen, Anne, Romo, Minna, Simell, Satu, Simell, Tuula, Simell, Ville, Sjöberg, Maija, Stenius, Aino, Särmä, Maria, Vainionpää, Sini, Varjonen, Eeva, Veijola, Riitta, Virtanen, Suvi M., Vähä-Mäkilä, Mari, Åkerlund, Mari, Lernmark, Åke, Agardh, Daniel, Aronsson, Carin Andrén, Ask, Maria, Bremer, Jenny, Carlsson, Ulla-Marie, Cilio, Corrado, Ericson-Hallström, Emelie, Fransson, Lina, Gard, Thomas, Gerardsson, Joanna, Bennet, Rasmus, Hansen, Monica, Hansson, Gertie, Harmby, Cecilia, Hyberg, Susanne, Johansen, Fredrik, Jonasdottir, Berglind, Larsson, Helena Elding, Forss, Sigrid Lenrick, Lundgren, Markus, Månsson-Martinez, Maria, Markan, Maria, Melin, Jessica, Mestan, Zeliha, Rahmati, Kobra, Ramelius, Anita, Rosenquist, Anna, Salami, Falastin, Sibthorpe, Sara, Sjöberg, Birgitta, Swartling, Ulrica, Amboh, Evelyn Tekum, Trulsson, Erika, Törn, Carina, Wallin, Anne, Wimar, Åsa, Åberg, Sofie, Hagopian, William A., Killian, Michael, Crouch, Claire Cowen, Skidmore, Jennifer, Ayres, Stephen, Dunson, Kayleen, Hervey, Rachel, Johnson, Corbin, Lyons, Rachel, Meyer, Arlene, Mulenga, Denise, Scott, Elizabeth, Stabbert, Joshua, Tarr, Alexander, Uland, Morgan, Willis, John, Becker, Dorothy, Franciscus, Margaret, Smith, MaryEllen Dalmagro-Elias, Daftary, Ashi, Klein, Mary Beth, Yates, Chrystal, Krischer, Jeffrey P., Abbondondolo, Michael, Austin-Gonzalez, Sarah, Baethke, Sandra, Brown, Rasheedah, Burkhardt, Brant, Butterworth, Martha, Clasen, Joanna, Cuthbertson, David, Eberhard, Christopher, Fiske, Steven, Garcia, Dena, Garmeson, Jennifer, Gowda, Veena, Heyman, Kathleen, Laras, Francisco Perez, Lee, Hye-Seung, Liu, Shu, Liu, Xiang, Lynch, Kristian, Malloy, Jamie, McCarthy, Cristina, McLeod, Wendy, Meulemans, Steven, Shaffer, Chris, Smith, Laura, Smith, Susan, Sulman, Noah, Tamura, Roy, Uusitalo, Ulla, Vehik, Kendra, Vijayakandipan, Ponni, Wood, Keith, Yang, Jimin, Ballard, Lori, Hadley, David, Akolkar, Beena, Bourcier, Kasia, Briese, Thomas, Johnson, Suzanne Bennett, Triplett, Eric, Andrén Aronsson, Carin, and Norris, Jill M.

Published
2016
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34. Interaction Between Dietary Iron Intake and Genetically Determined Iron Overload:Risk of Islet Autoimmunity and Progression to Type 1 Diabetes in the TEDDY Study

Author

Ullitz Thorsen, Steffen, Liu, Xiang, Kataria, Yachana, Mandrup-poulsen, Thomas, Kaur, Simranjeet, Uusitalo, Ulla, Virtanen, Suvi M., Norris, Jill, Rewers, Marian, Hagopian, William, Yang, Jimin, She, Jin-xiong, Akolkar, Beena, Rich, Stephen S., Aronsson, Carin Andrén, Lernmark, Åke, Ziegler, Anette-gabriele, Toppari, Jorma, Krischer, Jeffrey P., Parikh, Hemang M., Ellervik, Christina, Svensson, Jannet, Barbour, Aaron, Bautista, Kimberly, Baxter, Judith, Felipe-morales, Daniel, Frohnert, Brigitte I., Stahl, Marisa, Gesualdo, Patricia, Hoffman, Michelle, Karban, Rachel, Liu, Edwin, Munoz, Alondra, O’donnell, Holly, Peacock, Stesha, Shorrosh, Hanan, Steck, Andrea, Stern, Megan, Waugh, Kathleen, Simell, Olli G., Adamsson, Annika, Ahonen, Suvi, Åkerlund, Mari, Anttila, Sirpa, Hakola, Leena, Hekkala, Anne, Agardh, Daniel, Ullitz Thorsen, Steffen, Liu, Xiang, Kataria, Yachana, Mandrup-poulsen, Thomas, Kaur, Simranjeet, Uusitalo, Ulla, Virtanen, Suvi M., Norris, Jill, Rewers, Marian, Hagopian, William, Yang, Jimin, She, Jin-xiong, Akolkar, Beena, Rich, Stephen S., Aronsson, Carin Andrén, Lernmark, Åke, Ziegler, Anette-gabriele, Toppari, Jorma, Krischer, Jeffrey P., Parikh, Hemang M., Ellervik, Christina, Svensson, Jannet, Barbour, Aaron, Bautista, Kimberly, Baxter, Judith, Felipe-morales, Daniel, Frohnert, Brigitte I., Stahl, Marisa, Gesualdo, Patricia, Hoffman, Michelle, Karban, Rachel, Liu, Edwin, Munoz, Alondra, O’donnell, Holly, Peacock, Stesha, Shorrosh, Hanan, Steck, Andrea, Stern, Megan, Waugh, Kathleen, Simell, Olli G., Adamsson, Annika, Ahonen, Suvi, Åkerlund, Mari, Anttila, Sirpa, Hakola, Leena, Hekkala, Anne, and Agardh, Daniel

Abstract

OBJECTIVE To examine whether iron intake and genetically determined iron overload interact in predisposing to the development of childhood islet autoimmunity (IA) and type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS In The Environmental Determinants of Diabetes in the Young (TEDDY) study, 7,770 genetically high-risk children were followed from birth until the development of IA and progression to T1D. Exposures included energy-adjusted iron intake in the first 3 years of life and a genetic risk score (GRS) for increased circulating iron. RESULTS We found a U-shaped association between iron intake and risk of GAD antibody as the first autoantibody. In children with GRS ≥2 iron risk alleles, high iron intake was associated with an increased risk of IA, with insulin as first autoantibody (adjusted hazard ratio 1.71 [95% CI 1.14; 2.58]) compared with moderate iron intake. CONCLUSIONS Iron intake may alter the risk of IA in children with high-risk HLA haplogenotypes.

Published
2023

35. Gastrointestinal Infections Modulate the Risk for Insulin Autoantibodies as the First-Appearing Autoantibody in the TEDDY Study.

Author

Lönnrot, Maria, Lynch, Kristian F., Rewers, Marian, Lernmark, Åke, Vehik, Kendra, Akolkar, Beena, Hagopian, William, Krischer, Jeffrey, McIndoe, Rickhard A., Toppari, Jorma, Ziegler, Anette-G., Petrosino, Joseph F., Lloyd, Richard, Hyöty, Heikki, TEDDY Study Group, Bautista, Kimberly, Baxter, Judith, Felipe-Morales, Daniel, Frohnert, Brigitte I., and Stahl, Marisa

Abstract

OBJECTIVE: To investigate gastrointestinal infection episodes (GIEs) in relation to the appearance of islet autoantibodies in The Environmental Determinants of Diabetes in the Young (TEDDY) cohort. RESEARCH DESIGN AND METHODS: GIEs on risk of autoantibodies against either insulin (IAA) or GAD (GADA) as the first-appearing autoantibody were assessed in a 10-year follow-up of 7,867 children. Stool virome was characterized in a nested case-control study. RESULTS: GIE reports (odds ratio [OR] 2.17 [95% CI 1.39–3.39]) as well as Norwalk viruses found in stool (OR 5.69 [1.36–23.7]) at <1 year of age were associated with an increased IAA risk at 2–4 years of age. GIEs reported at age 1 to <2 years correlated with a lower risk of IAA up to 10 years of age (OR 0.48 [0.35–0.68]). GIE reports at any other age were associated with an increase in IAA risk (OR 2.04 for IAA when GIE was observed 12–23 months prior [1.41–2.96]). Impacts on GADA risk were limited to GIEs <6 months prior to autoantibody development in children <4 years of age (OR 2.16 [1.54–3.02]). CONCLUSIONS: Bidirectional associations were observed. GIEs were associated with increased IAA risk when reported before 1 year of age or 12–23 months prior to IAA. Norwalk virus was identified as one possible candidate factor. GIEs reported during the 2nd year of life were associated with a decreased IAA risk. [ABSTRACT FROM AUTHOR]

Published
2023
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36. Dietary Intake and Body Mass Index Influence the Risk of Islet Autoimmunity in Genetically At-Risk Children: A Mediation Analysis Using the TEDDY Cohort

Author

Andrén Aronsson, Carin, primary, Tamura, Roy, additional, Vehik, Kendra, additional, Uusitalo, Ulla, additional, Yang, Jimin, additional, Haller, Michael J., additional, Toppari, Jorma, additional, Hagopian, William, additional, McIndoe, Richard A., additional, Rewers, Marian J., additional, Ziegler, Anette-G., additional, Akolkar, Beena, additional, Krischer, Jeffrey P., additional, Norris, Jill M., additional, Virtanen, Suvi M., additional, and Elding Larsson, Helena, additional

Published
2023
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38. Gluten-free diet adherence in children with screening-detected celiac disease using a prospective birth cohort study

Author

TEDDY Study Group, Mehta, Pooja, Li, Qian, Stahl, Marisa, Uusitalo, Ulla, Lindfors, Katri, Butterworth, Martha D., Kurppa, Kalle, Virtanen, Suvi, Koletzko, Sibylle, Aronsson, Carin, Hagopian, William A., Rewers, Marian J., Toppari, Jorma, Ziegler, Anette G., Akolkar, Beena, Krischer, Jeffrey P., Agardh, Daniel, Liu, Edwin, Tampere University, BioMediTech, Department of Paediatrics, Clinical Medicine, Seinäjoen keskussairaala VA, and Health Sciences

Subjects
Multidisciplinary, 3123 Gynaecology and paediatrics, 3121 Internal medicine, 3142 Public health care science, environmental and occupational health
Abstract

Background Celiac disease has an increasing incidence worldwide and is treated with lifelong adherence to a gluten-free diet. We aimed to describe gluten-free diet adherence rates in children with screening-identified celiac disease, determine adherence-related factors, and compare adherence to food records in a multinational prospective birth cohort study. Methods Children in The Environmental Determinants of Diabetes in the Young study with celiac disease were included. Subjects had at least annual measurement of adherence (parent-report) and completed 3-day food records. Descriptive statistics, t-tests, Kruskal-Wallis tests and multivariable logistic and linear regression were employed. Results Two hundred ninety (73%) and 199 (67%) of subjects were always adherent to a gluten-free diet at 2 and 5 years post celiac disease diagnosis respectively. The percentage of children with variable adherence increased from 1% at 2 years to 15% at 5 years. Children with a first-degree relative with celiac disease were more likely to be adherent to the gluten-free diet. Gluten intake on food records could not differentiate adherent from nonadherent subjects. Adherent children from the United States had more gluten intake based on food records than European children (P < .001 and P = .007 at 2 and 5 years respectively). Conclusion Approximately three-quarters of children with screening-identified celiac disease remain strictly adherent to a gluten-free diet over time. There are no identifiable features associated with adherence aside from having a first-degree relative with celiac disease. Despite good parent-reported adherence, children from the United States have more gluten intake when assessed by food records. Studies on markers of gluten-free diet adherence, sources of gluten exposure (particularly in the United States), and effects of adherence on mucosal healing are needed.

Published
2023

40. Respiratory infections are temporally associated with initiation of type 1 diabetes autoimmunity: the TEDDY study

Author

Lönnrot, Maria, Lynch, Kristian F., Elding Larsson, Helena, Lernmark, Åke, Rewers, Marian J., Törn, Carina, Burkhardt, Brant R., Briese, Thomas, Hagopian, William A., She, Jin-Xiong, Simell, Olli G., Toppari, Jorma, Ziegler, Anette-G., Akolkar, Beena, Krischer, Jeffrey P., Hyöty, Heikki, and on behalf of the TEDDY Study Group

Published
2017
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41. Refining the Definition of Stage 1 Type 1 Diabetes: An Ontology-Driven Analysis of the Heterogeneity of Multiple Islet Autoimmunity.

Author

Frohnert, Brigitte I., Ghalwash, Mohamed, Li, Ying, Ng, Kenney, Dunne, Jessica L., Lundgren, Markus, Hagopian, William, Lou, Olivia, Winkler, Christiane, Toppari, Jorma, Veijola, Riitta, Anand, Vibha, Ziegler, Anette G., Bonifacio, Ezio, Achenbach, Peter, Rewers, Marian, Norris, Jill, Steck, Andrea, Waugh, Kathleen, and Yu, Liping

Subjects
TYPE 1 diabetes, AUTOIMMUNITY, ISLANDS, AUTOANTIBODIES, HETEROGENEITY
Abstract

OBJECTIVE: To estimate the risk of progression to stage 3 type 1 diabetes based on varying definitions of multiple islet autoantibody positivity (mIA). RESEARCH DESIGN AND METHODS: Type 1 Diabetes Intelligence (T1DI) is a combined prospective data set of children from Finland, Germany, Sweden, and the U.S. who have an increased genetic risk for type 1 diabetes. Analysis included 16,709 infants-toddlers enrolled by age 2.5 years and comparison between groups using Kaplan-Meier survival analysis. RESULTS: Of 865 (5%) children with mIA, 537 (62%) progressed to type 1 diabetes. The 15-year cumulative incidence of diabetes varied from the most stringent definition (mIA/Persistent/2: two or more islet autoantibodies positive at the same visit with two or more antibodies persistent at next visit; 88% [95% CI 85–92%]) to the least stringent (mIA/Any: positivity for two islet autoantibodies without co-occurring positivity or persistence; 18% [5–40%]). Progression in mIA/Persistent/2 was significantly higher than all other groups (P < 0.0001). Intermediate stringency definitions showed intermediate risk and were significantly different than mIA/Any (P < 0.05); however, differences waned over the 2-year follow-up among those who did not subsequently reach higher stringency. Among mIA/Persistent/2 individuals with three autoantibodies, loss of one autoantibody by the 2-year follow-up was associated with accelerated progression. Age was significantly associated with time from seroconversion to mIA/Persistent/2 status and mIA to stage 3 type 1 diabetes. CONCLUSIONS: The 15-year risk of progression to type 1 diabetes risk varies markedly from 18 to 88% based on the stringency of mIA definition. While initial categorization identifies highest-risk individuals, short-term follow-up over 2 years may help stratify evolving risk, especially for those with less stringent definitions of mIA. [ABSTRACT FROM AUTHOR]

Published
2023
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42. HLA Genotype and Probiotics Modify the Association Between Timing of Solid Food Introduction and Islet Autoimmunity in the TEDDY Study.

Author

Uusitalo, Ulla, Mramba, Lazarus K., Aronsson, Carin Andrén, Vehik, Kendra, Yang, Jimin, Hummel, Sandra, Lernmark, Åke, Rewers, Marian, Hagopian, William, McIndoe, Richard, Toppari, Jorma, Ziegler, Anette-G., Akolkar, Beena, Krischer, Jeffrey P., Virtanen, Suvi M., and Norris, Jill M.

Subjects
BABY foods, PROPORTIONAL hazards models, TYPE 1 diabetes, GENOTYPES, PROBIOTICS, AUTOIMMUNITY, JUNK food
Abstract

OBJECTIVE: To study the interaction among HLA genotype, early probiotic exposure, and timing of complementary foods in relation to risk of islet autoimmunity (IA). RESEARCH DESIGN AND METHODS: The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively follows 8,676 children with increased genetic risk of type 1 diabetes. We used a Cox proportional hazards regression model adjusting for potential confounders to study early feeding and the risk of IA in a sample of 7,770 children. RESULTS: Any solid food introduced early (<6 months) was associated with increased risk of IA if the child had the HLA DR3/4 genotype and no probiotic exposure during the 1st year of life. Rice introduced at 4–5.9 months compared with later in the U.S. was associated with an increased risk of IA. CONCLUSIONS: Timing of solid food introduction, including rice, may be associated with IA in children with the HLA DR3/4 genotype not exposed to probiotics. The microbiome composition under these exposure combinations requires further study. [ABSTRACT FROM AUTHOR]

Published
2023
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44. Islet Autoantibody Levels Differentiate Progression Trajectories in Individuals With Presymptomatic Type 1 Diabetes

Author

Kwon, Bum Chul, primary, Achenbach, Peter, additional, Anand, Vibha, additional, Frohnert, Brigitte I., additional, Hagopian, William, additional, Hu, Jianying, additional, Koski, Eileen, additional, Lernmark, Åke, additional, Lou, Olivia, additional, Martin, Frank, additional, Ng, Kenney, additional, Toppari, Jorma, additional, and Veijola, Riitta, additional

Published
2022
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45. Physical Activity and the Development of Islet Autoimmunity and Type 1 Diabetes in 5- to 15-Year-Old Children Followed in the TEDDY Study.

Author

Liu, Xiang, Johnson, Suzanne Bennett, Lynch, Kristian F., Cordan, Kerry, Pate, Russell, Butterworth, Martha D., Lernmark, Åke, Hagopian, William A., Rewers, Marian J., McIndoe, Richard A., Toppari, Jorma, Ziegler, Anette-G., Akolkar, Beena, Krischer, Jeffrey P., Yang, Jimin, The TEDDY Study Group, Rewers, Marian, Bautista, Kimberly, Baxter, Judith, and Felipe-Morales, Daniel

Abstract

OBJECTIVE: This study investigated physical activity and its association with the development of islet autoimmunity and type 1 diabetes in genetically at-risk children aged 5–15 years. RESEARCH DESIGN AND METHODS: As part of the longitudinal Environmental Determinants of Diabetes in the Young (TEDDY) study, annual assessment of activity using accelerometry was conducted from age 5 years. Time-to-event analyses using Cox proportional hazard models were used to assess the association between time spent in moderate to vigorous physical activity per day and the appearance of one or several autoantibodies and progression to type 1 diabetes in three risk groups: 1) 3,869 islet autoantibody (IA)-negative children, of whom 157 became single IA positive; 2) 302 single IA–positive children, of whom 73 became multiple IA positive; and 3) 294 multiple IA–positive children, of whom 148 developed type 1 diabetes. RESULTS: No significant association was found in risk group 1 or risk group 2. A significant association was seen in risk group 3 (hazard ratio 0.920 [95% CI 0.856, 0.988] per 10-min increase; P = 0.021), particularly when glutamate decarboxylase autoantibody was the first autoantibody (hazard ratio 0.883 [95% CI 0.783, 0.996] per 10-min increase; P = 0.043). CONCLUSIONS: More daily minutes spent in moderate to vigorous physical activity was associated with a reduced risk of progression to type 1 diabetes in children aged 5–15 years who had developed multiple IAs. [ABSTRACT FROM AUTHOR]

Published
2023
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46. Interaction Between Dietary Iron Intake and Genetically Determined Iron Overload: Risk of Islet Autoimmunity and Progression to Type 1 Diabetes in the TEDDY Study.

Author

Thorsen, Steffen U., Liu, Xiang, Kataria, Yachana, Mandrup-Poulsen, Thomas, Kaur, Simranjeet, Uusitalo, Ulla, Virtanen, Suvi M., Norris, Jill M., Rewers, Marian, Hagopian, William, Yang, Jimin, She, Jin-Xiong, Akolkar, Beena, Rich, Stephen, Aronsson, Carin Andrén, Lernmark, Åke, Ziegler, Anette-Gabriele, Toppari, Jorma, Krischer, Jeffrey, and Parikh, Hemang M.

Subjects
TYPE 1 diabetes, IRON overload, FOOD consumption, IRON, DISEASE risk factors
Abstract

OBJECTIVE: To examine whether iron intake and genetically determined iron overload interact in predisposing to the development of childhood islet autoimmunity (IA) and type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: In The Environmental Determinants of Diabetes in the Young (TEDDY) study, 7,770 genetically high-risk children were followed from birth until the development of IA and progression to T1D. Exposures included energy-adjusted iron intake in the first 3 years of life and a genetic risk score (GRS) for increased circulating iron. RESULTS: We found a U-shaped association between iron intake and risk of GAD antibody as the first autoantibody. In children with GRS ≥2 iron risk alleles, high iron intake was associated with an increased risk of IA, with insulin as first autoantibody (adjusted hazard ratio 1.71 [95% CI 1.14; 2.58]) compared with moderate iron intake. CONCLUSIONS: Iron intake may alter the risk of IA in children with high-risk HLA haplogenotypes. [ABSTRACT FROM AUTHOR]

Published
2023
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49. 985-P: Prediction Models Combining Clinical Measures Identify Participants with Youth-Onset Diabetes Who Maintain Insulin Secretion

Author

JONES, ANGUS, primary, SHIELDS, BEVERLEY, additional, ORAM, RICHARD A., additional, DABELEA, DANA, additional, HAGOPIAN, WILLIAM, additional, LUSTIGOVA, EVA, additional, SHAH, AMY S., additional, MOTTL, AMY K., additional, DAGOSTINO, RALPH, additional, WILLIAMS, ADRIENNE H., additional, MARCOVINA, SANTICA M., additional, PIHOKER, CATHERINE, additional, DIVERS, JASMIN, additional, and REDONDO, MARIA J., additional

Published
2022
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