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1. Genetic sex validation for sample tracking in next-generation sequencing clinical testing

Author

Jianhong Hu, Viktoriya Korchina, Hana Zouk, Maegan V. Harden, David Murdock, Alyssa Macbeth, Steven M. Harrison, Niall Lennon, Christie Kovar, Adithya Balasubramanian, Lan Zhang, Gauthami Chandanavelli, Divya Pasham, Robb Rowley, Ken Wiley, Maureen E. Smith, Adam Gordon, Gail P. Jarvik, Patrick Sleiman, Melissa A. Kelly, Harris T. Bland, Mullai Murugan, Eric Venner, Eric Boerwinkle, the eMERGE III consortium, Cynthia Prows, Lisa Mahanta, Heidi L. Rehm, Richard A. Gibbs, and Donna M. Muzny

Subjects
Next-generation sequencing (NGS), Clinical testing, Sex concordance, SNP genotyping, Medicine, Biology (General), QH301-705.5, Science (General), Q1-390
Abstract

Abstract Objective Data from DNA genotyping via a 96-SNP panel in a study of 25,015 clinical samples were utilized for quality control and tracking of sample identity in a clinical sequencing network. The study aimed to demonstrate the value of both the precise SNP tracking and the utility of the panel for predicting the sex-by-genotype of the participants, to identify possible sample mix-ups. Results Precise SNP tracking showed no sample swap errors within the clinical testing laboratories. In contrast, when comparing predicted sex-by-genotype to the provided sex on the test requisition, we identified 110 inconsistencies from 25,015 clinical samples (0.44%), that had occurred during sample collection or accessioning. The genetic sex predictions were confirmed using additional SNP sites in the sequencing data or high-density genotyping arrays. It was determined that discrepancies resulted from clerical errors (49.09%), samples from transgender participants (3.64%) and stem cell or bone marrow transplant patients (7.27%) along with undetermined sample mix-ups (40%) for which sample swaps occurred prior to arrival at genome centers, however the exact cause of the events at the sampling sites resulting in the mix-ups were not able to be determined.

Published
2024
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2. Evaluation of the Access Bio CareStart rapid SARS-CoV-2 antigen test in asymptomatic individuals tested at a community mass-testing program in Western Massachusetts

Author

Sara Suliman, Wilfredo R. Matias, Isabel R. Fulcher, Francisco J. Molano, Shannon Collins, Elizabeth Uceta, Jack Zhu, Ryan M. Paxton, Sean F. Gonsalves, Maegan V. Harden, Marissa Fisher, Jim Meldrim, Stacey Gabriel, Molly F. Franke, Deborah T. Hung, Sandra C. Smole, Lawrence C. Madoff, and Louise C. Ivers

Subjects
Medicine, Science
Abstract

Abstract Point-of-care antigen-detecting rapid diagnostic tests (RDTs) to detect Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) represent a scalable tool for surveillance of active SARS-CoV-2 infections in the population. Data on the performance of these tests in real-world community settings are paramount to guide their implementation to combat the COVID-19 pandemic. We evaluated the performance characteristics of the CareStart COVID-19 Antigen test (CareStart) in a community testing site in Holyoke, Massachusetts. We compared CareStart to a SARS-CoV-2 reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) reference, both using anterior nasal swab samples. We calculated the sensitivity, specificity, and the expected positive and negative predictive values at different SARS-CoV-2 prevalence estimates. We performed 666 total tests on 591 unique individuals. 573 (86%) were asymptomatic. There were 52 positive tests by RT-qPCR. The sensitivity of CareStart was 49.0% (95% Confidence Interval (CI) 34.8–63.4) and specificity was 99.5% (95% CI 98.5–99.9). Among positive RT-qPCR tests, the median cycle threshold (Ct) was significantly lower in samples that tested positive on CareStart. Using a Ct ≤ 30 as a benchmark for positivity increased the sensitivity of the test to 64.9% (95% CI 47.5–79.8). Our study shows that CareStart has a high specificity and moderate sensitivity. The utility of RDTs, such as CareStart, in mass implementation should prioritize use cases in which a higher specificity is more important, such as triage tests to rule-in active infections in community surveillance programs.

Published
2022
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3. Molecular profiling identifies targeted therapy opportunities in pediatric solid cancer

Author

Alanna J. Church, Laura B. Corson, Pei-Chi Kao, Alma Imamovic-Tuco, Deirdre Reidy, Duong Doan, Wenjun Kang, Navin Pinto, Luke Maese, Theodore W. Laetsch, AeRang Kim, Susan I. Colace, Margaret E. Macy, Mark A. Applebaum, Rochelle Bagatell, Amit J. Sabnis, Daniel A. Weiser, Julia L. Glade-Bender, Alan C. Homans, John Hipps, Haley Harris, Danielle Manning, Alyaa Al-Ibraheemi, Yvonne Li, Hersh Gupta, Andrew D. Cherniack, Ying-Chun Lo, Gianna R. Strand, Lobin A. Lee, R. Seth Pinches, Lorena Lazo De La Vega, Maegan V. Harden, Niall J. Lennon, Seong Choi, Hannah Comeau, Marian H. Harris, Suzanne J. Forrest, Catherine M. Clinton, Brian D. Crompton, Junne Kamihara, Laura E. MacConaill, Samuel L. Volchenboum, Neal I. Lindeman, Eliezer Van Allen, Steven G. DuBois, Wendy B. London, and Katherine A. Janeway

Subjects
Adult, Adolescent, Infant, Newborn, High-Throughput Nucleotide Sequencing, Infant, Genomics, General Medicine, General Biochemistry, Genetics and Molecular Biology, Young Adult, Child, Preschool, Neoplasms, Biomarkers, Tumor, Humans, Molecular Targeted Therapy, Prospective Studies, Child
Abstract

To evaluate the clinical impact of molecular tumor profiling (MTP) with targeted sequencing panel tests, pediatric patients with extracranial solid tumors were enrolled in a prospective observational cohort study at 12 institutions. In the 345-patient analytical population, median age at diagnosis was 12 years (range 0-27.5); 298 patients (86%) had 1 or more alterations with potential for impact on care. Genomic alterations with diagnostic, prognostic or therapeutic significance were present in 61, 16 and 65% of patients, respectively. After return of the results, impact on care included 17 patients with a clarified diagnostic classification and 240 patients with an MTP result that could be used to select molecularly targeted therapy matched to identified alterations (MTT). Of the 29 patients who received MTT, 24% had an objective response or experienced durable clinical benefit; all but 1 of these patients received targeted therapy matched to a gene fusion. Of the diagnostic variants identified in 209 patients, 77% were gene fusions. MTP with targeted panel tests that includes fusion detection has a substantial clinical impact for young patients with solid tumors.

Published
2022
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4. Neptune: an environment for the delivery of genomic medicine

Author

Venner Eric, Victoria Yi, David Murdock, Sara E. Kalla, Tsung-Jung Wu, Aniko Sabo, Shoudong Li, Qingchang Meng, Xia Tian, Mullai Murugan, Michelle Cohen, Christie Kovar, Wei-Qi Wei, Wendy K. Chung, Chunhua Weng, Georgia L. Wiesner, Gail P. Jarvik, Donna Muzny, Richard A. Gibbs, Debra Abrams, Samuel E. Adunyah, Ladia Albertson-Junkans, Berta Almoguera, Darren C. Ames, Paul Appelbaum, Samuel Aronson, Sharon Aufox, Lawrence J. Babb, Adithya Balasubramanian, Hana Bangash, Melissa Basford, Lisa Bastarache, Samantha Baxter, Meckenzie Behr, Barbara Benoit, Elizabeth Bhoj, Suzette J. Bielinski, Sarah T. Bland, Carrie Blout, Kenneth Borthwick, Erwin P. Bottinger, Mark Bowser, Harrison Brand, Murray Brilliant, Wendy Brodeur, Pedro Caraballo, David Carrell, Andrew Carroll, Lisa Castillo, Victor Castro, Gauthami Chandanavelli, Theodore Chiang, Rex L. Chisholm, Kurt D. Christensen, Wendy Chung, Christopher G. Chute, Brittany City, Beth L. Cobb, John J. Connolly, Paul Crane, Katherine Crew, David R. Crosslin, Jyoti Dayal, Mariza De Andrade, Jessica De la Cruz, Josh C. Denny, Shawn Denson, Tim DeSmet, Ozan Dikilitas, Michael J. Dinsmore, Sheila Dodge, Phil Dunlea, Todd L. Edwards, Christine M. Eng, David Fasel, Alex Fedotov, Qiping Feng, Mark Fleharty, Andrea Foster, Robert Freimuth, Christopher Friedrich, Stephanie M. Fullerton, Birgit Funke, Stacey Gabriel, Vivian Gainer, Ali Gharavi, Andrew M. Glazer, Joseph T. Glessner, Jessica Goehringer, Adam S. Gordon, Chet Graham, Robert C. Green, Justin H. Gundelach, Heather S. Hain, Hakon Hakonarson, Maegan V. Harden, John Harley, Margaret Harr, Andrea Hartzler, M. Geoffrey Hayes, Scott Hebbring, Nora Henrikson, Andrew Hershey, Christin Hoell, Ingrid Holm, Kayla M. Howell, George Hripcsak, Jianhong Hu, Elizabeth Duffy Hynes, Joy C. Jayaseelan, Yunyun Jiang, Yoonjung Yoonie Joo, Sheethal Jose, Navya Shilpa Josyula, Anne E. Justice, Divya Kalra, Elizabeth W. Karlson, Brendan J. Keating, Melissa A. Kelly, Eimear E. Kenny, Dustin Key, Krzysztof Kiryluk, Terrie Kitchner, Barbara Klanderman, Eric Klee, David C. Kochan, Viktoriya Korchina, Leah Kottyan, Emily Kudalkar, Alanna Kulchak Rahm, Iftikhar J. Kullo, Philip Lammers, Eric B. Larson, Matthew S. Lebo, Magalie Leduc, Ming Ta (Michael) Lee, Niall J. Lennon, Kathleen A. Leppig, Nancy D. Leslie, Rongling Li, Wayne H. Liang, Chiao-Feng Lin, Jodell E. Linder, Noralane M. Lindor, Todd Lingren, James G. Linneman, Cong Liu, Wen Liu, Xiuping Liu, John Lynch, Hayley Lyon, Alyssa Macbeth, Harshad Mahadeshwar, Lisa Mahanta, Bradley Malin, Teri Manolio, Maddalena Marasa, Keith Marsolo, Michelle L. McGowan, Elizabeth McNally, Jim Meldrim, Frank Mentch, Hila Milo Rasouly, Jonathan Mosley, Shubhabrata Mukherjee, Thomas E. Mullen, Jesse Muniz, David R. Murdock, Shawn Murphy, Melanie F. Myers, Bahram Namjou, Yizhao Ni, Robert C. Onofrio, Aniwaa Owusu Obeng, Thomas N. Person, Josh F. Peterson, Lynn Petukhova, Cassandra J. Pisieczko, Siddharth Pratap, Cynthia A. Prows, Megan J. Puckelwartz, Ritika Raj, James D. Ralston, Arvind Ramaprasan, Andrea Ramirez, Luke Rasmussen, Laura Rasmussen-Torvik, Soumya Raychaudhuri, Heidi L. Rehm, Marylyn D. Ritchie, Catherine Rives, Beenish Riza, Dan M. Roden, Elisabeth A. Rosenthal, Avni Santani, Schaid Dan, Steven Scherer, Stuart Scott, Aaron Scrol, Soumitra Sengupta, Ning Shang, Himanshu Sharma, Richard R. Sharp, Rajbir Singh, Patrick M.A. Sleiman, Kara Slowik, Joshua C. Smith, Maureen E. Smith, Duane T. Smoot, Jordan W. Smoller, Sunghwan Sohn, Ian B. Stanaway, Justin Starren, Mary Stroud, Jessica Su, Casey Overby Taylor, Kasia Tolwinski, Sara L. Van Driest, Sean M. Vargas, Matthew Varugheese, David Veenstra, Eric Venner, Miguel Verbitsky, Gina Vicente, Michael Wagner, Kimberly Walker, Theresa Walunas, Liwen Wang, Qiaoyan Wang, Scott T. Weiss, Quinn S. Wells, Peter S. White, Ken L. Wiley, Janet L. Williams, Marc S. Williams, Michael W. Wilson, Leora Witkowski, Laura Allison Woods, Betty Woolf, Julia Wynn, Yaping Yang, Ge Zhang, Lan Zhang, and Hana Zouk

Subjects
Computer science, business.industry, Process (engineering), MEDLINE, High-Throughput Nucleotide Sequencing, Genomics, Data science, Article, Personalization, Variety (cybernetics), Workflow, Neptune, Pharmacogenomics, Health care, Electronic Health Records, Humans, business, Software, Genetics (clinical)
Abstract

Genomic medicine holds great promise for improving health care, but integrating searchable and actionable genetic data into electronic health records (EHRs) remains a challenge. Here we describe Neptune, a system for managing the interaction between a clinical laboratory and an EHR system during the clinical reporting process. We developed Neptune and applied it to two clinical sequencing projects that required report customization, variant reanalysis, and EHR integration. Neptune has been applied for the generation and delivery of over 15,000 clinical genomic reports. This work spans two clinical tests based on targeted gene panels that contain 68 and 153 genes respectively. These projects demanded customizable clinical reports that contained a variety of genetic data types including single-nucleotide variants (SNVs), copy-number variants (CNVs), pharmacogenomics, and polygenic risk scores. Two variant reanalysis activities were also supported, highlighting this important workflow. Methods are needed for delivering structured genetic data to EHRs. This need extends beyond developing data formats to providing infrastructure that manages the reporting process itself. Neptune was successfully applied on two high-throughput clinical sequencing projects to build and deliver clinical reports to EHR systems. The software is open source and available at https://gitlab.com/bcm-hgsc/neptune .

Published
2021
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5. Returning integrated genomic risk and clinical recommendations: the eMERGE study

Author

Jodell E. Linder, Aimee Allworth, Sarah T. Bland, Pedro J. Caraballo, Rex L. Chisholm, Ellen Wright Clayton, David R. Crosslin, Ozan Dikilitas, Alanna DiVietro, Edward D. Esplin, Sophie Forman, Robert R. Freimuth, Adam S. Gordon, Richard Green, Maegan V. Harden, Ingrid A. Holm, Gail P. Jarvik, Elizabeth W. Karlson, Sofia Labrecque, Niall J. Lennon, Nita A. Limdi, Kathleen F. Mittendorf, Shawn N. Murphy, Lori Orlando, Cynthia A. Prows, Luke V. Rasmussen, Laura Rasmussen-Torvik, Robb Rowley, Konrad Teodor Sawicki, Tara Schmidlen, Shannon Terek, David Veenstra, Digna R. Velez Edwards, Devin Absher, Noura S. Abul-Husn, Jorge Alsip, Hana Bangash, Mark Beasley, Jennifer E. Below, Eta S. Berner, James Booth, Wendy K. Chung, James J. Cimino, John Connolly, Patrick Davis, Beth Devine, Stephanie M. Fullerton, Candace Guiducci, Melissa L. Habrat, Heather Hain, Hakon Hakonarson, Margaret Harr, Eden Haverfield, Valentina Hernandez, Christin Hoell, Martha Horike-Pyne, George Hripcsak, Marguerite R. Irvin, Christopher Kachulis, Dean Karavite, Eimear E. Kenny, Atlas Khan, Krzysztof Kiryluk, Bruce Korf, Leah Kottyan, Iftikhar J. Kullo, Katie Larkin, Cong Liu, Edyta Malolepsza, Teri A. Manolio, Thomas May, Elizabeth M. McNally, Frank Mentch, Alexandra Miller, Sean D. Mooney, Priyanka Murali, Brenda Mutai, Naveen Muthu, Bahram Namjou, Emma F. Perez, Megan J. Puckelwartz, Tejinder Rakhra-Burris, Dan M. Roden, Elisabeth A. Rosenthal, Seyedmohammad Saadatagah, Maya Sabatello, Dan J. Schaid, Baergen Schultz, Lynn Seabolt, Gabriel Q. Shaibi, Richard R. Sharp, Brian Shirts, Maureen E. Smith, Jordan W. Smoller, Rene Sterling, Sabrina A. Suckiel, Jeritt Thayer, Hemant K. Tiwari, Susan B. Trinidad, Theresa Walunas, Wei-Qi Wei, Quinn S. Wells, Chunhua Weng, Georgia L. Wiesner, Ken Wiley, Josh F. Peterson, Adam Gordon, Agboade Sobowale, Akshar Patel, Alanna Strong, Alborz Sherafati, Alborz Sherfati, Alex Bick, Alka Chandel, Alyssa Rosenthal, Amit Khera, Amy Kontorovich, Andrew Beck, Andy Beck, Angelica Espinoza, Anna Lewis, Anya Prince, Ayuko Iverson, Bahram Namjou Khales, Barbara Benoit, Becca Hernan, Ben Kallman, Ben Kerman, Ben Shoemaker, Benjamin Satterfield, Bethany Etheridge, Blake Goff, Bob Freimuth, Bob Grundmeier, Brenae Collier, Brett Harnett, Brian Chang, Brian Piening, Brittney Davis, Candace Patterson, Carmen Demetriou, Casey Ta, Catherine Hammack, Catrina Nelson, Caytie Gascoigne, Chad Dorn, Chad Moretz, Chris Kachulis, Christie Hoell, Christine Cowles, Christoph Lange, Cindy Prows, Cole Brokamp, Courtney Scherr, Crystal Gonzalez, Cynthia Ramirez, Daichi Shimbo, Dan Roden, Daniel Schaid, Dave Kaufman, David Crosslin, David Kochan, Davinder Singh, Debbie Abrams, Digna Velez Edwards, Eduardo Morales, Edward Esplin, Ehsan Alipour, Eimear Kenny, Elisabeth Rosenthal, Eliza Duvall, Elizabeth McNally, Elizabeth Bhoj, Elizabeth Cohn, Elizabeth Hibler, Elizabeth Karlson, Ellen Clayton, Emily Chesnut, Emily DeFranco, Emily Gallagher, Emily Soper, Emma Perez, Erin Cash, Eta Berner, Fei Wang, Firas Wehbe, Francisco Ricci, Gabriel Shaibi, Gail Jarvik, George Hahn, Georgia Wiesner, Gillian Belbin, Gio Davogustto, Girish Nadkarni, Haijun Qiu, Hannah Beasley, Hao Liu, Heide Aungst, Hemant Tiwari, Hillary Duckham, Hope Thomas, Iftikhar Kullo, Ingrid Holm, Isabelle Allen, Iuliana Ionita-Laza, Jacklyn Hellwege, Jacob Petrzelka, Jacqueline Odgis, Jahnavi Narula, Jake Petrzelka, Jalpa Patel, James Cimino, James Meigs, James Snyder, Janet Olson, Janet Zahner, Jeff Pennington, Jen Pacheco, Jennifer Allen Pacheco, Jennifer Morse, Jeremy Corsmo, Jim Cimino, Jingheng Chen, Jocelyn Fournier, Jodell Jackson, Joe Glessner, Joel Pacyna, Johanna Smith, John Lynch, John Shelley, Jonathan Mosley, Jordan Nestor, Jordan Smoller, Joseph Kannry, Joseph Sutton, Josh Peterson, Joshua Smith, Julia Galasso, Julia Smith, Julia Wynn, Justin Gundelach, Justin Starren, Karmel Choi, Kate Mittendorf, Katherine Anderson, Katherine Bonini, Kathleen Leppig, Kathleen Muenzen, Kelsey Stuttgen, Kenny Nguyen, Kevin Dufendach, Kiley Atkins, Konrad Sawicki, Kristjan Norland, Laura Beskow, Li Hsu, Lifeng Tian, Lisa Mahanta, Lisa Martin, Lisa Wang, Lizbeth Gomez, Lorenzo Thompson, Lucas Richter, Luke Rasmussen, Lynn Petukhova, Madison O’Brien, Maegan Harden, Malia Fullerton, Marta Guindo, Martha Horike, Marwah Abdalla, Marwan Hamed, Mary Beth Terry, Mary Maradik, Matt Wyatt, Matthew Davis, Matthew Lebo, Maureen Smith, Maya del Rosario, Meckenzie Behr, Meg Roy-Puckelwartz, Mel Habrat, Melanie Myers, Meliha Yetisgen, Merve Iris, Michael DaSilva, Michael Preuss, Michelle McGowan, Mingjian Shi, Minoli Perera, Minta Thomas, Mitch Elkind, Mohammad Abbass, Mohammad Saadatagah, Molly Hess, Molly Maradik, Nataraja 'RJ' Vaitinadin, Nataraja Vaitinadin, Neil Netherly, Niall Lennon, Ning Shang, Nita Limdi, Noah Forrest, Noheli Romero, Nora Robinson, Noura Abul-Husn, Omar Elsekaily, Patricia Kovatch, Paul Appelbaum, Paul Francaviglia, Paul O’Reilly, Paulette Chandler, Pedro Caraballo, Peter Tarczy-Hornoch, Pierre Shum, Priya Marathe, Qiping Feng, Quinn Wells, Rachel Atchley, Radhika Narla, Rene Barton, Rex Chisholm, Richard Sharp, Riki Peters, Rita Kukafka, Robert Freimuth, Robert Green, Robert Winter, Roger Mueller, Ruth Loos, Ryan Irvin, Sabrina Suckiel, Sajjad Hussain, Samer Sharba, Sandy Aronson, Sarah Jones, Sarah Knerr, Scott Nigbur, Scott Weiss, Sean Mooney, Sharon Aufox, Sharon Nirenberg, Shawn Murphy, Sheila O’Byrne, Shing Wang (Sam) Choi, Sienna Aguilar, S.T. Bland, Stefanie Rodrigues, Stephanie Ledbetter, Stephanie Rutledge, Stuart James Booth, Su Xian, Susan Brown Trinidad, Suzanne Bakken, Teri Manolio, Tesfaye Mersha, Thevaa Chandereng, Tian Ge, Todd Edwards, Tom Kaszemacher, Valerie Willis, Vemi Desai, Vimi Desai, Virginia Lorenzi, Vivian Gainer, Wendy Chung, Wu-Chen Su, Xiao Chang, Yiqing Zhao, Yuan Luo, and Yufeng Shen

Subjects
Genetics (clinical)
Abstract

Assessing the risk of common, complex diseases requires consideration of clinical risk factors as well as monogenic and polygenic risks, which in turn may be reflected in family history. Returning risks to individuals and providers may influence preventive care or use of prophylactic therapies for those individuals at high genetic risk.To enable integrated genetic risk assessment, the eMERGE (electronic MEdical Records and GEnomics) network is enrolling 25,000 diverse individuals in a prospective cohort study across 10 sites. The network developed methods to return cross-ancestry polygenic risk scores (PRS), monogenic risks, family history, and clinical risk assessments via a Genome Informed Risk Assessment (GIRA) report and will assess uptake of care recommendations after return of results.GIRAs include summary care recommendations for 11 conditions, education pages, and clinical laboratory reports. The return of high-risk GIRA to individuals and providers includes guidelines for care and lifestyle recommendations. Assembling the GIRA required infrastructure and workflows for ingesting and presenting content from multiple sources. Recruitment began in February 2022.Return of a novel report for communicating monogenic, polygenic, and family history based risk factors will inform the benefits of integrated genetic risk assessment for routine health care.

Published
2022

6. Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network

Author

Ian B. Stanaway, Dan M. Roden, Divya Kalra, Dustin Key, Debra J. Abrams, David Fasel, Victor Castro, Brad Malin, Berta Almoguera, Beenish Riza, Meckenzie A. Behr, Eric Venner, Christine M. Eng, Joy Jayaseelan, Scott J. Hebbring, Michelle L. McGowan, Steven E. Scherer, Theresa L. Walunas, Mark Bowser, James D. Ralston, Wei-Qi Wei, Liwen Wang, David R. Murdock, Wayne H. Liang, Julia Wynn, Nancy D. Leslie, Laura J. Rasmussen-Torvik, Ming Ta (Michael) Lee, Frank D. Mentch, Lan Zhang, Alanna Kulchak Rahm, Josh F. Peterson, Jodell E. Linder, Joshua C. Smith, Soumitra Sengupta, Brendan J. Keating, Gina Vicente, Andrew Carroll, Nora B. Henrikson, Anne E. Justice, Heather S. Hain, Wen Liu, Andrea H. Ramirez, Matthew S. Lebo, Hana Zouk, Georgia L. Wiesner, Andrea L. Hartzler, Cassandra J. Pisieczko, Catherine M. Rives, Jessica Goehringer, Maegan V. Harden, John Lynch, Chiao-Feng Lin, Peter White, Phil Dunlea, Shawn N. Murphy, Mullai Murugan, Harshad Mahadeshwar, Mark Fleharty, Andrea Foster, Arvind Ramaprasan, Christopher A. Friedrich, Justin H. Gundelach, Hayley Lyon, Niall J. Lennon, Eric W. Klee, David R. Crosslin, Ge Zhang, Rongling Li, Ozan Dikilitas, Xiuping Liu, Christin Hoell, Aniwaa Owusu Obeng, Katherine D. Crew, Lisa M. Castillo, Justin Starren, Jonathan D. Mosley, Carrie L. Blout, Himanshu Sharma, Elizabeth M. McNally, Sarah T. Bland, Megan J. Puckelwartz, Matthew Varugheese, Keith Marsolo, Betty Woolf, Sharon Aufox, Janet L. Williams, Kimberly Walker, Murray H. Brilliant, Birgit Funke, Laura Allison Woods, Marylyn D. Ritchie, Brittany City, Todd Lingren, Hila Milo Rasouly, Lawrence J. Babb, Alex Fedotov, Robert C. Onofrio, Margaret Harr, Suzette J. Bielinski, Michael W. Wilson, Shubhabrata Mukherjee, Robert R. Freimuth, Chet Graham, Todd L. Edwards, Quinn S. Wells, Marc S. Williams, Jordan W. Smoller, Wendy K. Chung, Avni Santani, Paul K. Crane, George Hripcsak, QiPing Feng, Ali G. Gharavi, Yizhao Ni, Iftikhar J. Kullo, Michael Wagner, Philip E. Lammers, Michael J. Dinsmore, Thomas N. Person, Victoria Yi, Samuel E. Adunyah, Tim DeSmet, Eric B. Larson, Elizabeth Hynes, David C. Kochan, Eimear E. Kenny, Magalie S. Leduc, Lisa Mahanta, David Carrell, Paul S. Appelbaum, Viktoriya Korchina, Beth L. Cobb, Lynn Petukhova, Jessica De la Cruz, Patrick M. A. Sleiman, Stuart A. Scott, Tsung-Jung Wu, Gail P. Jarvik, Erwin P. Bottinger, Ken Wiley, Josh C. Denny, Melissa A. Basford, Samuel J. Aronson, David L. Veenstra, Yaping Yang, Kayla Marie Howell, John J. Connolly, Jessica Su, Yoonjung Yoonie Joo, Miguel Verbitsky, Sean M. Vargas, Cong Liu, Barbara Benoit, Andrew Hershey, Richard A. Gibbs, Cynthia A. Prows, Hana Bangash, Wendy Brodeur, Gauthami Chandanavelli, Sara L. Van Driest, Kurt D. Christensen, Elizabeth J. Bhoj, Vivian S. Gainer, Adam S. Gordon, Robert C. Green, Hakon Hakonarson, Krzysztof Kiryluk, Elisabeth A. Rosenthal, Rajbir Singh, James G. Linneman, Harrison Brand, Theodore Chiang, Sheila Dodge, Ingrid A. Holm, M. Geoffrey Hayes, Yunyun Jiang, Ning Shang, Samantha Baxter, Noralane M. Lindor, Kathleen A. Leppig, Teri A. Manolio, Sara E. Kalla, Pedro J. Caraballo, Ritika Raj, Aaron Scrol, Jyoti G. Dayal, Richard R. Sharp, Christie Kovar, Soumya Raychaudhuri, Sunghwan Sohn, Emily Kudalkar, Maddalena Marasa, Stacey Gabriel, Dan Schaid, Ladia Albertson-Junkans, Rex L. Chisholm, Maureen E. Smith, Donna M. Muzny, Casey Overby Taylor, Jianhong Hu, Elizabeth W. Karlson, Lisa Bastarache, Darren C. Ames, Joseph T. Glessner, Leora Witkowski, Siddharth Pratap, Qiaoyan Wang, Melissa A. Kelly, Adithya Balasubramanian, Kara Slowik, Terrie Kitchner, Barbara J. Klanderman, Shawn Denson, Mary Stroud, Alyssa Macbeth, Melanie F. Myers, Jesse Muniz, Kasia Tolwinski, Scott T. Weiss, Chunhua Weng, Stephanie M. Fullerton, John B. Harley, Christopher G. Chute, Heidi L. Rehm, Sheethal Jose, Andrew M. Glazer, Navya Shilpa Josyula, Kenneth M. Borthwick, Thomas E. Mullen, Mariza de Andrade, Leah C. Kottyan, Luke V. Rasmussen, James Meldrim, and Bahram Namjou

Subjects
0301 basic medicine, Standardization, Test data generation, business.industry, Computer science, Sequence Analysis, DNA, 030105 genetics & heredity, Precision medicine, Data science, Clinical decision support system, Biobank, Article, 3. Good health, Data sharing, 03 medical and health sciences, 030104 developmental biology, Genetics, Humans, Genetic Testing, Prospective Studies, Sample collection, Personalized medicine, Precision Medicine, business, Genetics (clinical)
Abstract

The advancement of precision medicine requires new methods to coordinate and deliver genetic data from heterogeneous sources to physicians and patients. The eMERGE III Network enrolled >25,000 participants from biobank and prospective cohorts of predominantly healthy individuals for clinical genetic testing to determine clinically actionable findings. The network developed protocols linking together the 11 participant collection sites and 2 clinical genetic testing laboratories. DNA capture panels targeting 109 genes were used for testing of DNA and sample collection, data generation, interpretation, reporting, delivery, and storage were each harmonized. A compliant and secure network enabled ongoing review and reconciliation of clinical interpretations, while maintaining communication and data sharing between clinicians and investigators. A total of 202 individuals had positive diagnostic findings relevant to the indication for testing and 1,294 had additional/secondary findings of medical significance deemed to be returnable, establishing data return rates for other testing endeavors. This study accomplished integration of structured genomic results into multiple electronic health record (EHR) systems, setting the stage for clinical decision support to enable genomic medicine. Further, the established processes enable different sequencing sites to harmonize technical and interpretive aspects of sequencing tests, a critical achievement toward global standardization of genomic testing. The eMERGE protocols and tools are available for widespread dissemination.

Published
2019
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7. Close association of olfactory placode precursors and cranial neural crest cells does not predestine cell mixing

Author

Jochen Wittbrodt, Megana K. Prasad, Andrew S. McCallion, Kathleen E. Whitlock, Mirana Ramialison, Maegan V. Harden, and Luisa Pereiro

Subjects
Olfactory system, Cell type, Embryo, Nonmammalian, Cell division, SOX10, Article, Animals, Genetically Modified, Cranial neural crest, Animals, Zebrafish, In Situ Hybridization, Homeodomain Proteins, biology, SOXE Transcription Factors, Neural crest, Cell migration, Olfactory Pathways, Anatomy, Zebrafish Proteins, biology.organism_classification, Immunohistochemistry, Cell biology, Neural Crest, Trans-Activators, Developmental Biology
Abstract

Vertebrate sensory organs originate from both cranial neural crest cells (CNCCs) and placodes. Previously, we have shown that the olfactory placode (OP) forms from a large field of cells extending caudally to the premigratory neural crest domain, and that OPs form through cell movements and not cell division. Concurrent with OP formation, CNCCs migrate rostrally to populate the frontal mass. However, little is known about the interactions between CNCCs and the placodes that form the olfactory sensory system. Previous reports suggest that the OP can generate cell types more typical of neural crest lineages such as neuroendocrine cells and glia, thus marking the OP as an unusual sensory placode. One possible explanation for this exception is that the neural crest origin of glia and neurons has been overlooked due to the intimate association of these two fields during migration. Using molecular markers and live imaging, we followed the development of OP precursors and of dorsally migrating CNCCs in zebrafish embryos. We generated a six4b:mCherry line (OP precursors) that, with a sox10:EGFP line (CNCCs), was used to follow cell migration. Our analyses showed that CNCCs associate with and eventually surround the forming OP with limited cell mixing occurring during this process. Developmental Dynamics 241:1143–1154, 2012. V C 2012 Wiley Periodicals, Inc.

Published
2012

8. A role for foxd3 and sox10 in the differentiation of gonadotropin-releasing hormone (GnRH) cells in the zebrafish Danio rerio

Author

Hannah Kim, Kalmia M. Smith, Maegan V. Harden, and Kathleen E. Whitlock

Subjects
Nervous system, Male, endocrine system, medicine.medical_specialty, Embryo, Nonmammalian, SOX10, Hypothalamus, Gonadotropin-releasing hormone, Biology, Midbrain, Gonadotropin-Releasing Hormone, Cranial neural crest, Mesencephalon, Internal medicine, medicine, Animals, Molecular Biology, Zebrafish, SOXE Transcription Factors, Neural tube, Cranial Nerves, High Mobility Group Proteins, Neural crest, Cell Differentiation, Forkhead Transcription Factors, Zebrafish Proteins, Cell biology, Endocrinology, medicine.anatomical_structure, Neural Crest, Mutation, Terminal nerve, Female, Carrier Proteins, hormones, hormone substitutes, and hormone antagonists, Developmental Biology
Abstract

Gonadotropin-releasing hormone (GnRH) is found in a wide range of vertebrate tissues, including the nervous system. In general, GnRH has two functions: endocrine, acting as a releasing hormone; and neuromodulatory,affecting neural activity in the peripheral and central nervous system. The best understood population of GnRH cells is that of the hypothalamus, which is essential for reproduction. Less well understood are the populations of GnRH cells found in the terminal nerve and midbrain, which appear to be neuromodulatory in function. The GnRH-containing cells of the midbrain are proposed to arise from the mesencephalic region of the neural tube. Previously, we showed that neuromodulatory GnRH cells of the terminal nerve arise from cranial neural crest. To test the hypothesis that neuromodulatory GnRH cells of the midbrain also arise from neural crest, we used gene knockdown experiments in zebrafish to disrupt neural crest development. We demonstrate that decrement of the function of foxd3 and/or sox10, two genes important for the development and specification of neural crest, resulted in a reduction and/or loss of GnRH cells of the midbrain, as well as a reduction in the number of terminal nerve GnRH cells. Therefore, our data support a neural crest origin for midbrain GnRH cells. Additionally, we demonstrate that knockdown of kallmann gene function resulted in the loss of endocrine GnRH cells of the hypothalamus, but not of neuromodulatory GnRH cells of the midbrain and terminal nerve, thus providing additional evidence for separate pathways controlling the development of neuromodulatory and endocrine GnRH cells.

Published
2005

9. UNC-6/netrin and SLT-1/slit guidance cues orient axon outgrowth mediated by MIG-10/RIAM/lamellipodin

Author

William G. Wadsworth, Christopher C. Quinn, Elizabeth F. Ryder, Maegan V. Harden, Megan K. Gavin, Elizabeth L. Stovall, Douglas S. Pfeil, Martha C. Soto, Esteban Chen, and Wayne C. Forrester

Subjects
animal structures, Nerve Tissue Proteins, Cell Growth Processes, Nervous System, General Biochemistry, Genetics and Molecular Biology, MOLNEURO, Netrin, Extracellular, medicine, Animals, Axon, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Actin, Agricultural and Biological Sciences(all), biology, Biochemistry, Genetics and Molecular Biology(all), fungi, Signal transducing adaptor protein, Anatomy, biology.organism_classification, Slit, Axons, Cell biology, medicine.anatomical_structure, nervous system, Intercellular Signaling Peptides and Proteins, Netrins, Lamellipodium, General Agricultural and Biological Sciences
Abstract

Summary Background Axon migrations are guided by extracellular cues that can act as repellants or attractants. However, the logic underlying the manner through which attractive and repulsive responses are determined is unclear. Many extracellular guidance cues, and the cellular components that mediate their signals, have been implicated in both types of responses. Results Genetic analyses indicate that MIG-10/RIAM/lamellipodin, a cytoplasmic adaptor protein, functions downstream of the attractive guidance cue UNC-6/netrin and the repulsive guidance cue SLT-1/slit to direct the ventral migration of the AVM and PVM axons in C. elegans . Furthermore, overexpression of MIG-10 in the absence of UNC-6 and SLT-1 induces a multipolar phenotype with undirected outgrowths. Addition of either UNC-6 or SLT-1 causes the neurons to become monopolar. Moreover, the ability of UNC-6 or SLT-1 to direct the axon ventrally is enhanced by the MIG-10 overexpression. We also demonstrate that an interaction between MIG-10 and UNC-34, a protein that promotes actin-filament extension, is important in the response to guidance cues and that MIG-10 colocalizes with actin in cultured cells, where it can induce the formation of lamellipodia. Conclusions We conclude that MIG-10 mediates the guidance of AVM and PVM axons in response to the extracellular UNC-6 and SLT-1 guidance cues. The attractive and repulsive guidance cues orient MIG-10-dependant axon outgrowth to cause a directional response.

Published
2005

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