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2. Benchmarking UMI-aware and standard variant callers for low frequency ctDNA variant detection.

Author

Maruzani, Rugare, Brierley, Liam, Jorgensen, Andrea, and Fowler, Anna

Subjects
CELL-free DNA, NUCLEOTIDE sequencing, EARLY detection of cancer, SENSITIVITY & specificity (Statistics), TUMOR classification
Abstract

Background: Circulating tumour DNA (ctDNA) is a subset of cell free DNA (cfDNA) released by tumour cells into the bloodstream. Circulating tumour DNA has shown great potential as a biomarker to inform treatment in cancer patients. Collecting ctDNA is minimally invasive and reflects the entire genetic makeup of a patient's cancer. ctDNA variants in NGS data can be difficult to distinguish from sequencing and PCR artefacts due to low abundance, particularly in the early stages of cancer. Unique Molecular Identifiers (UMIs) are short sequences ligated to the sequencing library before amplification. These sequences are useful for filtering out low frequency artefacts. The utility of ctDNA as a cancer biomarker depends on accurate detection of cancer variants. Results: In this study, we benchmarked six variant calling tools, including two UMI-aware callers for their ability to call ctDNA variants. The standard variant callers tested included Mutect2, bcftools, LoFreq and FreeBayes. The UMI-aware variant callers benchmarked were UMI-VarCal and UMIErrorCorrect. We used both datasets with known variants spiked in at low frequencies, and datasets containing ctDNA, and generated synthetic UMI sequences for these datasets. Variant callers displayed different preferences for sensitivity and specificity. Mutect2 showed high sensitivity, while returning more privately called variants than any other caller in data without synthetic UMIs – an indicator of false positive variant discovery. In data encoded with synthetic UMIs, UMI-VarCal detected fewer putative false positive variants than all other callers in synthetic datasets. Mutect2 showed a balance between high sensitivity and specificity in data encoded with synthetic UMIs. Conclusions: Our results indicate UMI-aware variant callers have potential to improve sensitivity and specificity in calling low frequency ctDNA variants over standard variant calling tools. There is a growing need for further development of UMI-aware variant calling tools if effective early detection methods for cancer using ctDNA samples are to be realised. [ABSTRACT FROM AUTHOR]

Published
2024
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4. An Interpretable Classification Model Using Gluten-Specific TCR Sequences Shows Diagnostic Potential in Coeliac Disease

Author

Fowler, Anna, primary, FitzPatrick, Michael, additional, Shanmugarasa, Aberami, additional, Ibrahim, Amro Sayed Fadel, additional, Kockelbergh, Hannah, additional, Yang, Han-Chieh, additional, Williams-Walker, Amelia, additional, Luu Hoang, Kim Ngan, additional, Evans, Shelley, additional, Provine, Nicholas, additional, Klenerman, Paul, additional, and Soilleux, Elizabeth J., additional

Published
2023
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7. Genetic Insights from Consanguineous Cardiomyopathy Families

Author

Maurer, Constance, primary, Boleti, Olga, additional, Najarzadeh Torbati, Paria, additional, Norouzi, Farzaneh, additional, Fowler, Anna Nicole Rebekah, additional, Minaee, Shima, additional, Salih, Khalid Hama, additional, Taherpour, Mehdi, additional, Birjandi, Hassan, additional, Alizadeh, Behzad, additional, Salih, Aso Faeq, additional, Bijari, Moniba, additional, Houlden, Henry, additional, Pittman, Alan Michael, additional, Maroofian, Reza, additional, Almashham, Yahya H., additional, Karimiani, Ehsan Ghayoor, additional, Kaski, Juan Pablo, additional, Faqeih, Eissa Ali, additional, Vakilian, Farveh, additional, and Jamshidi, Yalda, additional

Published
2023
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10. Utility of Bulk T-Cell Receptor Repertoire Sequencing Analysis in Understanding Immune Responses to COVID-19

Author

Kockelbergh, Hannah, Evans, Shelley, Deng, Tong, Clyne, Ella, Kyriakidou, Anna, Economou, Andreas, Luu Hoang, Kim Ngan, Woodmansey, Stephen, Foers, Andrew, Fowler, Anna, Soilleux, Elizabeth J, Evans, Shelley [0000-0003-3242-6017], Clyne, Ella [0000-0001-8945-4508], Kyriakidou, Anna [0000-0001-8964-8345], Economou, Andreas [0000-0002-3305-5804], Luu Hoang, Kim Ngan [0000-0001-5670-1832], Foers, Andrew [0000-0002-5036-7906], Soilleux, Elizabeth J [0000-0002-4032-7249], Apollo - University of Cambridge Repository, and Soilleux, Elizabeth [0000-0002-4032-7249]

Subjects
T-cell receptor repertoire, immunological memory, machine learning, SARS-CoV-2, immunoreceptor, antibody, Clinical Biochemistry, coronavirus, COVID-19, immune response, diversity
Abstract

Measuring immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 19 (COVID-19), can rely on antibodies, reactive T cells and other factors, with T-cell-mediated responses appearing to have greater sensitivity and longevity. Because each T cell carries an essentially unique nucleic acid sequence for its T-cell receptor (TCR), we can interrogate sequence data derived from DNA or RNA to assess aspects of the immune response. This review deals with the utility of bulk, rather than single-cell, sequencing of TCR repertoires, considering the importance of study design, in terms of cohort selection, laboratory methods and analysis. The advances in understanding SARS-CoV-2 immunity that have resulted from bulk TCR repertoire sequencing are also be discussed. The complexity of sequencing data obtained by bulk repertoire sequencing makes analysis challenging, but simple descriptive analyses, clonal analysis, searches for specific sequences associated with immune responses to SARS-CoV-2, motif-based analyses, and machine learning approaches have all been applied. TCR repertoire sequencing has demonstrated early expansion followed by contraction of SARS-CoV-2-specific clonotypes, during active infection. Maintenance of TCR repertoire diversity, including the maintenance of diversity of anti-SARS-CoV-2 response, predicts a favourable outcome. TCR repertoire narrowing in severe COVID-19 is most likely a consequence of COVID-19-associated lymphopenia. It has been possible to follow clonotypic sequences longitudinally, which has been particularly valuable for clonotypes known to be associated with SARS-CoV-2 peptide/MHC tetramer binding or with SARS-CoV-2 peptide-induced cytokine responses. Closely related clonotypes to these previously identified sequences have been shown to respond with similar kinetics during infection. A possible superantigen-like effect of the SARS-CoV-2 spike protein has been identified, by means of observing V-segment skewing in patients with severe COVID-19, together with structural modelling. Such a superantigen-like activity, which is apparently absent from other coronaviruses, may be the basis of multisystem inflammatory syndrome and cytokine storms in COVID-19. Bulk TCR repertoire sequencing has proven to be a useful and cost-effective approach to understanding interactions between SARS-CoV-2 and the human host, with the potential to inform the design of therapeutics and vaccines, as well as to provide invaluable pathogenetic and epidemiological insights.

Published
2022
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14. Classification of intestinal T-cell receptor repertoires using machine learning methods can identify patients with coeliac disease regardless of dietary gluten status

Author

Foers, Andrew D, Shoukat, M Saad, Welsh, Oliver E, Donovan, Killian, Petry, Russell, Evans, Shelley C, FitzPatrick, Michael Eb, Collins, Nadine, Klenerman, Paul, Fowler, Anna, Soilleux, Elizabeth J, Soilleux, Elizabeth J [0000-0002-4032-7249], and Apollo - University of Cambridge Repository

Subjects
T-cell receptor repertoire, Adult, Male, T-lymphocyte, TRG, fungi, Receptors, Antigen, T-Cell, gamma-delta, duodenum, Middle Aged, Machine Learning, Celiac Disease, Diet, Gluten-Free, gluten, Intestine, Small, Humans, TRD, Female, coeliac disease, clustering
Abstract

In coeliac disease (CeD), immune-mediated small intestinal damage is precipitated by gluten, leading to variable symptoms and complications, occasionally including aggressive T-cell lymphoma. Diagnosis, based primarily on histopathological examination of duodenal biopsies, is confounded by poor concordance between pathologists and minimal histological abnormality if insufficient gluten is consumed. CeD pathogenesis involves both CD4+ T-cell-mediated gluten recognition and CD8+ and γδ T-cell-mediated inflammation, with a previous study demonstrating a permanent change in γδ T-cell populations in CeD. We leveraged this understanding and explored the diagnostic utility of bulk T-cell receptor (TCR) sequencing in assessing duodenal biopsies in CeD. Genomic DNA extracted from duodenal biopsies underwent sequencing for TCR-δ (TRD) (CeD, n = 11; non-CeD, n = 11) and TCR-γ (TRG) (CeD, n = 33; non-CeD, n = 21). We developed a novel machine learning-based analysis of the TCR repertoire, clustering samples by diagnosis. Leave-one-out cross-validation (LOOCV) was performed to validate the classification algorithm. Using TRD repertoire, 100% (22/22) of duodenal biopsies were correctly classified, with a LOOCV accuracy of 91%. Using TCR-γ (TRG) repertoire, 94.4% (51/54) of duodenal biopsies were correctly classified, with LOOCV of 87%. Duodenal biopsy TRG repertoire analysis permitted accurate classification of biopsies from patients with CeD following a strict gluten-free diet for at least 6 months, who would be misclassified by current tests. This result reflects permanent changes to the duodenal γδ TCR repertoire in CeD, even in the absence of gluten consumption. Our method could complement or replace histopathological diagnosis in CeD and might have particular clinical utility in the diagnostic testing of patients unable to tolerate dietary gluten, and for assessing duodenal biopsies with equivocal features. This approach is generalisable to any TCR/BCR locus and any sequencing platform, with potential to predict diagnosis or prognosis in conditions mediated or modulated by the adaptive immune response. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Published
2021

17. Classification of intestinal T ‐cell receptor repertoires using machine learning methods can identify patients with coeliac disease regardless of dietary gluten status

Author

Foers, Andrew D, primary, Shoukat, M Saad, additional, Welsh, Oliver E, additional, Donovan, Killian, additional, Petry, Russell, additional, Evans, Shelley C, additional, FitzPatrick, Michael EB, additional, Collins, Nadine, additional, Klenerman, Paul, additional, Fowler, Anna, additional, and Soilleux, Elizabeth J, additional

Published
2021
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20. Statistics at The Zoo

Author

Holmes, Lisa, primary, Edwards, Katie, additional, Moss, Andy, additional, Tollington, Simon, additional, Fowler, Anna, additional, Hughes, David, additional, and Sudell, Maria, additional

Published
2020
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22. All Bottled Up: Hazard Assessment of an Historic Pharmaceutical Collection

Author

Fowler, Anna, Koss Schrager, Kerith, and Ravenel, Nancie

Abstract

Shelburne Museum’s extensive pharmaceutical collection, located in northwestern Vermont, USA, has been the subject of a multi-year inventory project partially funded by the Institute of Museum and Library Services (IMLS) grant. Amounting to over 9,000 objects, 5,000 to 6,000 of which are unique products, the collection has been largely untouched since its acquisition circa 1947 to 1970. Housed in a historic general store and custom annex, the collection encompasses roughly 200 years of American pharmaceutical, veterinary, and cosmetic history. This article explores the discovery, research, triage, and disposal of the hazards found within the collection during the inventory.

Published
2024
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24. B cell repertoire dynamics after sequential Hepatitis B vaccination, and evidence for cross-reactive B cell activation

Author

Galson, Jacob D, Trück, Johannes, Clutterbuck, Elizabeth A, Fowler, Anna, Cerundolo, Vincenzo, Pollard, Andrew J, Lunter, Gerton, Kelly, Dominic F, University of Zurich, and Galson, Jacob D

Subjects
2716 Genetics (clinical), Research, Vaccination, 610 Medicine & health, Hepatitis B, Polyreactive, 1311 Genetics, 10036 Medical Clinic, B-cell repertoire, 1313 Molecular Medicine, VDJ, Genetics, 1312 Molecular Biology, Molecular Medicine, Genetics(clinical), Molecular Biology, Antibody
Abstract

Background A diverse B-cell repertoire is essential for recognition and response to infectious and vaccine antigens. High-throughput sequencing of B-cell receptor (BCR) genes can now be used to study the B-cell repertoire at great depth and may shed more light on B-cell responses than conventional immunological methods. Here, we use high-throughput BCR sequencing to provide novel insight into B-cell dynamics following a primary course of hepatitis B vaccination. Methods Nine vaccine-naïve participants were administered three doses of hepatitis B vaccine (months 0, 1, and 2 or 7). High-throughput Illumina sequencing of the total BCR repertoire was combined with targeted sequencing of sorted vaccine antigen-enriched B cells to analyze the longitudinal response of both the total and vaccine-specific repertoire after each vaccine. ELISpot was used to determine vaccine-specific cell numbers following each vaccine. Results Deconvoluting the vaccine-specific from total BCR repertoire showed that vaccine-specific sequence clusters comprised

Published
2016

25. In-Depth Assessment of Within-Individual and Inter-Individual Variation in the B Cell Receptor Repertoire

Author

Galson, Jacob D, Trück, Johannes, Fowler, Anna, Münz, Márton, Cerundolo, Vincenzo, Pollard, Andrew J, Lunter, Gerton, Kelly, Dominic F, University of Zurich, and Galson, Jacob D

Subjects
B cell receptor repertoire, 2403 Immunology, B cell, antibody diversity, Immunology, 610 Medicine & health, VDJ recombination, immunoglobulin repertoire, immunoglobulin gene, 10036 Medical Clinic, genetic variation, 2723 Immunology and Allergy, reproducibility, Original Research
Abstract

High-throughput sequencing of the B cell receptor (BCR) repertoire can provide rapid characterization of the B cell response in a wide variety of applications in health, after vaccination and in infectious, inflammatory and immune-driven disease, and is starting to yield clinical applications. However, the interpretation of repertoire data is compromised by a lack of studies to assess the intra and inter-individual variation in the BCR repertoire over time in healthy individuals. We applied a standardized isotype-specific BCR repertoire deep sequencing protocol to a single highly sampled participant, and then evaluated the method in 9 further participants to comprehensively describe such variation. We assessed total repertoire metrics of mutation, diversity, VJ gene usage and isotype subclass usage as well as tracking specific BCR sequence clusters. There was good assay reproducibility (both in PCR amplification and biological replicates), but we detected striking fluctuations in the repertoire over time that we hypothesize may be due to subclinical immune activation. Repertoire properties were unique for each individual, which could partly be explained by a decrease in IgG2 with age, and genetic differences at the immunoglobulin locus. There was a small repertoire of public clusters (0.5, 0.3, and 1.4% of total IgA, IgG, and IgM clusters, respectively), which was enriched for expanded clusters containing sequences with suspected specificity toward antigens that should have been historically encountered by all participants through prior immunization or infection. We thus provide baseline BCR repertoire information that can be used to inform future study design, and aid in interpretation of results from these studies. Furthermore, our results indicate that BCR repertoire studies could be used to track changes in the public repertoire in and between populations that might relate to population immunity against infectious diseases, and identify the characteristics of inflammatory and immunological diseases.

Published
2015

27. An Exploration of Identification Practices for Twice-Exceptional Students in the Early Years of Schooling

Author

Fowler, Anna C

Subjects
twice-exceptional students, identification, comprehensive assessment
Abstract

Twice-exceptional learners are difficult to identify in educational settings. In turn, it is challenging for educators to support the unique learning needs of these students in their classrooms. With a co-occurrence of high potential and disability, twice-exceptional learners require specific supports to address their unique needs, such as differentiated instruction, intervention support for their disabilities, and/or acceleration for advanced abilities. Without accurate identification, twice-exceptional students may not receive appropriate educational programming and provisions, further exacerbating educational difficulties where students are unable to reach their full potential. Approaches to identification, the timing and purpose of chosen tools, along with educator knowledge, all impact on the identification (or lack of identification) of twice-exceptional learners. Previous research has suggested that key influences on accurate and timely identification of these learners are early identification, a comprehensive identification approach, and increased teacher education. This qualitative exploratory case study into early identification practices involved one Queensland state school and considered the suitability of practices for identifying both exceptions (giftedness and disabilities) for these students. The theoretical lens of the bioecological systems theory (Bronfenbrenner & Morris, 2006), synthesised with Gagné’s differentiating model of giftedness and talent, created a unique lens to frame the exploration through the developing twice-exceptional child’s bioecological system. Data were gathered through a four-stage process with document reviews and two interviews with one specialist educator participant. A hybrid inductive-deductive, reflexive thematic analysis approach was used to construct meaning from the data. Findings, presented through the synthesised theoretical lens, provide insight into a comprehensive assessment approach and collaborative processes, which in turn provide the ability for both exceptions to be identified, with further investigation into possible twice-exceptional learners taking place. The case study school’s local policy initiative to identify gifted learners was found to be responsible for much of the success of practices within that site. This success also came from support given by the principal and the unique role of the specialist educator of gifted learners in driving local practice. Key recommendations include the instalment of state policy for identifying gifted learners across all schools in Queensland, with this case presenting a possible framework for identification practices. Further recommendations include increased education for principals, and professional development and preservice education for teachers for identifying and providing for twice-exceptional learners. Future research is suggested into identification practices taking place at other local schools across the state, along with the development of an appropriate Australian-based tool to identify gifted and twice-exceptional learners.

Published
2023

32. Analysis of B Cell Repertoire Dynamics Following Hepatitis B Vaccination in Humans, and Enrichment of Vaccine-specific Antibody Sequences

Author

Galson, Jacob D., primary, Trück, Johannes, additional, Fowler, Anna, additional, Clutterbuck, Elizabeth A., additional, Münz, Márton, additional, Cerundolo, Vincenzo, additional, Reinhard, Claudia, additional, van der Most, Robbert, additional, Pollard, Andrew J., additional, Lunter, Gerton, additional, and Kelly, Dominic F., additional

Published
2015
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33. Long-term disability after lacunar stroke

Author

Dhamoon, Mandip S., primary, McClure, Leslie A., additional, White, Carole L., additional, Lakshminarayan, Kamakshi, additional, Benavente, Oscar R., additional, Elkind, Mitchell S.V., additional, Benavente, Oscar, additional, Hart, Robert, additional, Pergola, Pablo, additional, Palacio, Santiago, additional, Castro, Irma, additional, Farias, Arlene, additional, Roldan, Ana, additional, Kase, Carlos, additional, Gavras, Irene, additional, Lau, Helena, additional, Ogrodnik, Matt, additional, Allen, Nancy, additional, Meissner, Irene, additional, Graves, John, additional, Herzig, Deb, additional, Covalt, Jody, additional, Meyer, Brett, additional, Jackson, Christy, additional, Gamble, Paul, additional, Kelly, Nancy, additional, Warner, Janet, additional, Bell, Jo, additional, Demaerschalk, Bart, additional, Hogan, Michael, additional, Wochos, Daniel, additional, Wieser, Judith, additional, Cleary, Barbara, additional, Wood, Lori, additional, Hanna, Joseph, additional, Zipp, Thomas, additional, Bailey, Scott, additional, Cook, Dana, additional, Liskay, Alice, additional, Simcox, Dana, additional, Kappler, Joan, additional, Anderson, David, additional, Grimm, Richard, additional, Brauer, Donna, additional, Pettigrew, Creed, additional, Vaishnov, Anand, additional, Sawaya, Peter, additional, Fowler, Anna, additional, Hughes, Nedda, additional, Rice, Johnya, additional, Vanderpool, Kathy, additional, Cruz-Flores, Salvador, additional, Walden, H Douglas, additional, Holzemer, Eve, additional, Santhakumar, Sunitha, additional, Van Stavern, Renee, additional, Chatuverdi, Seemant, additional, Flack, John, additional, Mada, Flicia, additional, Wiseman, David, additional, Berlow, Elizabeth, additional, Klinker, Julie, additional, Chiu, David, additional, Taylor, Addison, additional, Katz, Larry, additional, Coull, Bruce, additional, Howard, Lien, additional, Malekniazi, Mina, additional, VanSkiver, Melissa, additional, Bruck, Denise, additional, Redman, Stacey, additional, Logan, William, additional, Carpenter, David, additional, Schroer, Sally, additional, Katramados, Angelo, additional, Silver, Brian, additional, Yee, Jerry, additional, Aiello, Krisy, additional, Wilson, Kathleen, additional, McCarthy, Sharon, additional, Dandapani, Bhuvaneswari, additional, Spies, C Peter, additional, Vasile, Carole, additional, Anthony, Betty, additional, Ferguson, Jennifer, additional, Krubel, Sharon, additional, Synman, Amanda, additional, Andrews, Natalie, additional, Kirshner, Howard, additional, Sussman, Craig, additional, Brown, Diane, additional, Elkind, Mitch, additional, Crew, Russell John, additional, Radhakrishan, Jai, additional, Corporan, Tania E., additional, Diaz, Julisa, additional, Aragon, Rebeca, additional, Slivka, Andrew, additional, Spetie, Dan, additional, Agriesti, Julie, additional, Notstein, Peggy, additional, Naritoku, Dean, additional, Zweifler, Richard, additional, Culpepper, Michael, additional, Parnell, Mel, additional, Yunker, Robin, additional, Boots, Kelly, additional, Drinkard, Renay, additional, Backlin, Rachel, additional, Benesch, Curtis, additional, Bisognano, John, additional, Leonhardt, Ann, additional, Zentner, Justine, additional, Hildreth, Molly, additional, Johnson, Mark, additional, Liu, Yinghui, additional, Goldsteen, Robert, additional, Blair, April, additional, Wright, Gregg, additional, Gathua, Naomie, additional, Book, Diane, additional, Eapen, Sunu, additional, Grimm, Clarence, additional, Blaney, Barbara, additional, Rozman, Stephanie, additional, Gaertner, Linda, additional, Bradenburg, Erin, additional, Loomis, Laura, additional, Cotton, Jolene Monarch-, additional, Ravavelli-Meyer, Jean, additional, Golembieski, Anna, additional, Burgin, Scott W., additional, Hollander, Joshua, additional, Polashenski, Walter, additional, Wallace, Patricia, additional, Weber, Cheryl, additional, Lutsep, Helmi, additional, Girard, Don, additional, Seisler, Kali, additional, Cingel, Megan, additional, Ross, Megan, additional, Stone, Rachel, additional, Larsen, Darren, additional, Doherty, Ann, additional, Lefkowitz, David, additional, Pavel, Levy, additional, Buchheimer, Nancy, additional, Vaughn, Sara, additional, Smith, Emily, additional, Satterfield, Jean, additional, Tirschwell, David, additional, Logar, Christine, additional, Ryan, Michael, additional, Schubert, Glenn, additional, Tanzai, Patricia, additional, Mirsen, Tom, additional, McAllister, Susan, additional, Bastien, Arnaud, additional, Niblack, Patricia, additional, Frey, James, additional, Darbonne, Carol, additional, Karanjia, Percy, additional, Murali, Narayana, additional, Dart, Richard, additional, Mancl, Kathleen, additional, Atkinson, Richard, additional, Lieberman, Roger, additional, Carter, Teresa, additional, Zrelak, Pat, additional, Kenney, Nola, additional, Jacoby, Michael, additional, Jones, David, additional, DeFrancisco, Jeffrey, additional, Hamm, Theresa, additional, Romano, José, additional, Ortiz, Gustavo, additional, Carmen Lichtenberger, Maria del, additional, Linas, Rafael, additional, Kravet, Steven, additional, Alt, Janice, additional, Sundararajan, Sophia, additional, Rahman, Mahboob, additional, Horvath, Tom, additional, Korosec, David, additional, Murphy, Chris, additional, Greenberg, Jason, additional, Lennihan, Laura, additional, King, Marjorie, additional, Tenteromano, Laura, additional, Frankel, Michael, additional, Doyle, Joyce, additional, Braimah, Janet, additional, Pereira, Lorainne, additional, Ching, Marilou, additional, Sawyer, Robert, additional, Parkes, Kathy, additional, Conover, Cheryl, additional, Albakri, Erfan, additional, Ramirez, German, additional, Segal, Stephenie, additional, Taylor, Kathy, additional, Jackson, Judy, additional, Helgason, Kathy, additional, Hillmann, Maureen, additional, Ringel, Robert, additional, Fleming, Nicholas, additional, Mckown, Bunny, additional, Cohen, Stanley, additional, Jenders, Robert, additional, Singh, Ravinder, additional, La, Minh-Thu, additional, Trinh, Khanhphong, additional, Weinberger, Jesse, additional, Wright, Lewis, additional, Burch, Dorothy, additional, Horowitz, Ronnie, additional, Atlas, Steven, additional, Augustine, Sandra, additional, Brown, Angela, additional, Serna, Jannie, additional, Newgent, Jill, additional, Naylor, Julie, additional, Carpenter, Laura, additional, Warwick, Tanya, additional, Stoltz, Steven, additional, Garcia, Rebekah, additional, Scheck, Michael, additional, Chadwick, Linda, additional, Fleck, James, additional, Weinberger, Myron, additional, Sears, Alison, additional, Fanale, Chris, additional, Neeper, Lenden, additional, Fisk, Paula, additional, Sabry, Daniel, additional, Phoenix, Ron, additional, Tong, David, additional, Garcia, Madelleine, additional, Mackey, Ariane, additional, Morin, Jovette, additional, Haché, Annette, additional, Lessard, Claudette, additional, Côté, Robert, additional, Green, Laurence, additional, Wadup, Lisa, additional, Fontaine, Anne-Marie, additional, Gubitz, Gordon, additional, Rebello, Rosario, additional, Dean, Tim, additional, Reidy, Yvette, additional, Sharma, Mukul, additional, Stotts, Grant, additional, Clark, Heather, additional, Mortensen, Melodie, additional, Sauve, Jenniffer, additional, Sharma, Doris, additional, Savage, Michelle, additional, Minuk, Jeffrey, additional, Trudeau, Luc, additional, Schanz, Claudia, additional, Berger, Leo, additional, Brunet, Sylvain, additional, Pontbriand, Johanne, additional, Mainville, Martine, additional, Racicot, Denise, additional, Hill, Michael, additional, Fischer, Karyn, additional, Cole-Kaskayne, Andrea, additional, Keeney, Carol, additional, Shuab, Ashfaq, additional, Khan, Khurshid, additional, Dean, Naeen, additional, Herbert, Frederika, additional, Kastelic, Karen, additional, Pretell, Edwin Javier, additional, Valdivia, José, additional, Pretell, Marissa, additional, Brutto, Oscar del, additional, Santibáñez, Rocio, additional, Lara, Joffre, additional, Zambrano, Mauricio, additional, Arauz, Antonio, additional, Cervantes, G Amin, additional, Leyva, Adolfo, additional, Camacho, Itzel, additional, Ruiz Sandoval, José Luis, additional, Vásquez, Eduardo Salcido, additional, Ruiz, Carmen, additional, Brito, Carlos Cantú, additional, Fernández, Margarita, additional, Góngora-Rivera, Juan Fernándo, additional, Escamilla, Juan Manuel, additional, Moxica, Joaquín, additional, Arciniega, Genny, additional, Gonzalez, Wendy Joana, additional, Matamala, Gonzalo, additional, Goecke, Helmut, additional, Parra, Marcela, additional, Pozo, Jessica, additional, Tapia, Jorge, additional, Godoy, Ivan Esteban, additional, Valdes, Marcela, additional, Estol, Conrado, additional, Peralta, Cecilia, additional, Ellenberg, Adriana, additional, Chezzio, Daniela, additional, Fernández Pardal, Manuel M., additional, Trimachi, Hernan, additional, Bonardo, Pablo, additional, Mazziotti, Julieta, additional, Rey, Raul Carlos, additional, Caruso, Gustavo, additional, Melamud, Luciana, additional, Lepera, Sandra, additional, Stilman, Ana Paula, additional, Ameriso, Sebastian, additional, Sánchez, Ramiro, additional, Bruera, Guadalupe, additional, Moschini, Javier, additional, Ramírez, Maria J., additional, Bueri, José A., additional, Sevilla, Sebastián, additional, de Ambrosi, Bruno, additional, Marinsalta, Gabriela, additional, Rubio, Francisco, additional, Krupinski, Yurek, additional, Carvajal, Ana, additional, Roquer, Jaume, additional, Serrano, Ana Oliveras, additional, Conde, Jordi Jiménez, additional, Rodríguez, Ana, additional, Romeral, Gemma, additional, Arboix, Adrià, additional, Pelegrí, Antoni, additional, Blanco, Lorena, additional, Vergé, David Cánovas, additional, Herrero, Jordi Estela, additional, Gómez, Ana, additional, Leal, Joaquín Serena, additional, Castellanos, Mar, additional, Cruz, Verónica, additional, Cepeda, Mercè, additional, Gomis, Meritxell, additional, Arenillas, Juan, additional, Dávalos, Antonio, additional, Suñol, Ana, additional, Reverté, Silvia, additional, Martí-Villalta, José Lluis, additional, Martínez, Sergio, additional, Marín, Rebeca, additional, Sánchez, José Castillo, additional, González, Miguel Blanco, additional, Rodríguez, Manuel, additional, Jiménez, Isabel, additional, Rodríguez, Jaime, additional, Tejedor, Exuperio Díez, additional, Martínez, Patricia, additional, Fuentes, Blanca, additional, Singla, Lluis Soler, additional, Balaguer, Ernest, additional, Izquierdo, Joan, additional, Soler, Cristina, additional, Armenteros, Maria, additional, Shepherd, Alexander, additional, Benavente, Marie-France, additional, White, Carole, additional, Robu, Camilla, additional, Kelly, Che, additional, Talbert, Robert, additional, Martinez, Eduardo, additional, Bazan, Carlos, additional, Pergola, Gabriela, additional, Pearce, Lesly, additional, Costello, Raymond, additional, Jacova, Claudia, additional, Camelia, Luisa, additional, Mendoza, Crystal, additional, Pratt, Brandy, additional, Kin, B., additional, Holliday, Steve, additional, McClure, Leslie, additional, Coffey, Christopher, additional, Szychowski, Jeff, additional, Howard, George, additional, Katholi, Charles, additional, Zhang, Yu, additional, Peri, Kalyani, additional, Allcorn, Charles, additional, Mailhot, Richard, additional, Irby, Lisa, additional, Guyton, Fekisha, additional, Sewell, Mary Jo, additional, Ringer, Robert, additional, Raisch, Dennis, additional, Hunt, Dave, additional, Rosso, Clara M., additional, Martin, Ariadna, additional, Sanllorente, Mireia, additional, Arabetti, Celso, additional, Fernández, José Luis, additional, Cremona, Maria Julia, additional, Capece, Ana, additional, Benavente, Marie, additional, Conwit, Robin, additional, Elkind, Mitchell, additional, Moy, Claudia, additional, Aguilar, Maria, additional, Sherman, David, additional, Nasco, Elaine, additional, Blackshear, Joe, additional, Chung, Mina, additional, Fayad, Pierre, additional, Gage, Brian, additional, Johnston, Clay, additional, Kernan, Walter, additional, Leira, Enrique, additional, Merino, Jose, additional, Roman, Gustavo, additional, Sila, Cathy, additional, Sung, Gene, additional, van Walraven, Carl, additional, Stern, Barney, additional, Welch, K. Michael, additional, Clarke, William, additional, Cutler, Jeffrey, additional, Furie, Karen, additional, Johnston, Karen, additional, and Mayo, Matthew, additional

Published
2015
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36. Inferring B cell specificity for vaccines using a Bayesian mixture model

Author

Dominic F. Kelly, Gerton Lunter, Jacob D. Galson, Anna Fowler, Johannes Trück, University of Zurich, and Fowler, Anna

Subjects
Immune repertoire, lcsh:QH426-470, lcsh:Biotechnology, B-cell receptor, 610 Medicine & health, Computational biology, Biology, 03 medical and health sciences, 0302 clinical medicine, Immune system, 1311 Genetics, Antigen, Immunity, lcsh:TP248.13-248.65, Influenza, Human, Genetics, medicine, Humans, B cell, 030304 developmental biology, B-Lymphocytes, Vaccines, 0303 health sciences, High-throughput sequencing, B cell receptor, Methodology Article, Vaccination, Models, Immunological, breakpoint cluster region, Bayes Theorem, Hepatitis B, lcsh:Genetics, medicine.anatomical_structure, 10036 Medical Clinic, 1305 Biotechnology, biology.protein, Antibody, 030215 immunology, Biotechnology
Abstract

Background Vaccines have greatly reduced the burden of infectious disease, ranking in their impact on global health second only after clean water. Most vaccines confer protection by the production of antibodies with binding affinity for the antigen, which is the main effector function of B cells. This results in short term changes in the B cell receptor (BCR) repertoire when an immune response is launched, and long term changes when immunity is conferred. Analysis of antibodies in serum is usually used to evaluate vaccine response, however this is limited and therefore the investigation of the BCR repertoire provides far more detail for the analysis of vaccine response. Results Here, we introduce a novel Bayesian model to describe the observed distribution of BCR sequences and the pattern of sharing across time and between individuals, with the goal to identify vaccine-specific BCRs. We use data from two studies to assess the model and estimate that we can identify vaccine-specific BCRs with 69% sensitivity. Conclusion Our results demonstrate that statistical modelling can capture patterns associated with vaccine response and identify vaccine specific B cells in a range of different data sets. Additionally, the B cells we identify as vaccine specific show greater levels of sequence similarity than expected, suggesting that there are additional signals of vaccine response, not currently considered, which could improve the identification of vaccine specific B cells.

Published
2020

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