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Your search keyword '"Parker, Alasdair"' showing total 212 results
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212 results on '"Parker, Alasdair"'

1. Classic ketogenic diet versus further antiseizure medicine in infants with drug-resistant epilepsy (KIWE): a UK, multicentre, open-label, randomised clinical trial

Author

Schoeler, Natasha E, Marston, Louise, Lyons, Laura, Halsall, Sally, Jain, Ruchika, Titre-Johnson, Siobhan, Balogun, Maryam, Heales, Simon J R, Eaton, Simon, Orford, Michael, Neal, Elizabeth, Reilly, Colin, Eltze, Christin, Stephen, Elma, Mallick, Andrew A, O’Callaghan, Finbar, Agrawal, Shakti, Parker, Alasdair, Kirkpatrick, Martin, Brunklaus, Andreas, McLellan, Ailsa, McCullagh, Helen, Samanta, Rajib, Kneen, Rachel, Tan, Hui Jeen, Devlin, Anita, Prasad, Manish, Rattihalli, Rohini, Basu, Helen, Desurkar, Archana, Williams, Ruth, Fallon, Penny, Nazareth, Irwin, Freemantle, Nick, and Cross, J Helen

Published
2023
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2. Genome sequencing and comprehensive rare-variant analysis of 465 families with neurodevelopmental disorders

Author

Sanchis-Juan, Alba, Megy, Karyn, Stephens, Jonathan, Armirola Ricaurte, Camila, Dewhurst, Eleanor, Low, Kayyi, French, Courtney E., Grozeva, Detelina, Stirrups, Kathleen, Erwood, Marie, McTague, Amy, Penkett, Christopher J., Shamardina, Olga, Tuna, Salih, Daugherty, Louise C., Gleadall, Nicholas, Duarte, Sofia T., Hedrera-Fernández, Antonio, Vogt, Julie, Ambegaonkar, Gautam, Chitre, Manali, Josifova, Dragana, Kurian, Manju A., Parker, Alasdair, Rankin, Julia, Reid, Evan, Wakeling, Emma, Wassmer, Evangeline, Woods, C. Geoffrey, Raymond, F. Lucy, and Carss, Keren J.

Published
2023
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4. Consensus recommendations for the assessment and management of idiopathic intracranial hypertension in children and young people

Author

Amin, Sam, primary, Monaghan, Marie, additional, Forrest, Katharine, additional, Harijan, Pooja, additional, Mehta, Vishal, additional, Moran, Matthew, additional, Mukhtyar, Bina, additional, Muthusamy, Brinda, additional, Parker, Alasdair, additional, Prabhakar, Prab, additional, Whitehouse, William P, additional, and Krishnakumar, Deepa, additional

Published
2024
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18. 397 Delphi consensus for the UK guideline for management and surveillance of Idiopathic Intracranial Hypertension in children and young people

Author

Amin, Sam, primary, Monaghan, Marie, additional, Moran, Matthew, additional, Forrest, Katharine, additional, Harijan, Pooja, additional, Mehta, Vishal, additional, Mukhtyar, Bina, additional, Muthusamy, Brinda, additional, Parker, Alasdair, additional, Prabhakar, Prab, additional, Whitehouse, William, additional, and Krishnakumar, Deepa, additional

Published
2022
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19. Refinements and considerations for trio whole-genome sequence analysis when investigating Mendelian diseases presenting in early childhood

Author

French, Courtney E., primary, Dolling, Helen, additional, Mégy, Karyn, additional, Sanchis-Juan, Alba, additional, Kumar, Ajay, additional, Delon, Isabelle, additional, Wakeling, Matthew, additional, Mallin, Lucy, additional, Agrawal, Shruti, additional, Austin, Topun, additional, Walston, Florence, additional, Park, Soo-Mi, additional, Parker, Alasdair, additional, Piyasena, Chinthika, additional, Bradbury, Kimberley, additional, Ellard, Sian, additional, Rowitch, David H., additional, and Raymond, F. Lucy, additional

Published
2022
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22. Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension

Author

Hadinnapola, Charaka, Bleda, Marta, Haimel, Matthias, Screaton, Nicholas, Swift, Andrew, Dorfmüller, Peter, Preston, Stephen D., Southwood, Mark, Hernandez-Sanchez, Jules, Martin, Jennifer, Treacy, Carmen, Yates, Katherine, Bogaard, Harm, Church, Colin, Coghlan, Gerry, Condliffe, Robin, Corris, Paul A., Gibbs, Simon, Girerd, Barbara, Holden, Simon, Humbert, Marc, Kiely, David G., Lawrie, Allan, Machado, Rajiv, MacKenzie Ross, Robert, Moledina, Shahin, Montani, David, Newnham, Michael, Peacock, Andrew, Pepke-Zaba, Joanna, Rayner-Matthews, Paula, Shamardina, Olga, Soubrier, Florent, Southgate, Laura, Suntharalingam, Jay, Toshner, Mark, Trembath, Richard, Noordegraaf, Anton Vonk, Wilkins, Martin R., Wort, Stephen J., Wharton, John, Gräf, Stefan, Morrell, Nicholas W., Aitman, Timothy, Bennett, David, Caulfield, Mark, Chinnery, Patrick, Gale, Daniel, Koziell, Ania, Kuijpers, Taco W, Laffan, Michael A, Maher, Eamonn, Markus, Hugh S, Ouwehand, Willem H, Perry, David, Raymond, F Lucy, Roberts, Irene, Smith, Kenneth, Thrasher, Adrian, Watkins, Hugh, Williamson, Catherine, Woods, Geoffrey, Ashford, Sofie, Bradley, John R, Fletcher, Debra, Hammerton, Tracey, James, Roger, Kingston, Nathalie, Ouwehand, Willem H, Penkett, Christopher J, Raymond, F Lucy, Stirrups, Kathleen, Veltman, Marijke, Young, Tim, Ashford, Sofie, Brown, Matthew, Clements-Brod, Naomi, Davis, John, Dewhurst, Eleanor, Erwood, Marie, Frary, Amy, Linger, Rachel, Papadia, Sofia, Rehnstrom, Karola, Stark, Hannah, Allsup, David, Austin, Steve, Bakchoul, Tamam, Bariana, Tadbir K, Bolton-Maggs, Paula, Chalmers, Elizabeth, Collins, Peter, Erber, Wendy N, Everington, Tamara, Favier, Remi, Freson, Kathleen, Furie, Bruce, Gattens, Michael, Gomez, Keith, Greene, Daniel, Greinacher, Andreas, Hart, Daniel, Heemskerk, Johan WM, Henskens, Yvonne, Kazmi, Rashid, Keeling, David, Kelly, Anne M, Laffan, Michael A, Lambert, Michele P, Lentaigne, Claire, Liesner, Ri, Mangles, Sarah, Mathias, Mary, Millar, Carolyn M, Mumford, Andrew, Nurden, Paquita, Ouwehand, Willem H, Papadia, Sofia, Payne, Jeanette, Pasi, John, Perry, David J, Peerlinck, Kathelijne, Richards, Michael, Rondina, Matthew, Roughley, Catherine, Schulman, Sol, Schulze, Harald, Scully, Marie, Sivapalaratnam, Suthesh, Tait, R Campbell, Talks, Kate, Thachil, Jecko, Turro, Ernest, Toh, Cheng-Hock, Van Geet, Chris, De Vries, Minka, Warner, Timothy Q, Westbury, Sarah, Furnell, Abigail, Mapeta, Rutendo, Simeoni, Ilenia, Staines, Simon, Stephens, Jonathan, Stirrups, Kathleen, Whitehorn, Deborah, Watt, Christopher, Attwood, Antony, Daugherty, Louise, Deevi, Sri VV, Halmagyi, Csaba, Hu, Fengyuan, James, Roger, Matser, Vera, Meacham, Stuart, Megy, Karyn, Penkett, Christopher J, Stirrups, Kathleen, Titterton, Catherine, Tuna, Salih, Yu, Ping, von Ziegenweldt, Julie, Astle, William, Carss, Keren, Greene, Daniel, Lango-Allen, Hana, Turro, Ernest, Astle, William, Greene, Daniel, Richardson, Sylvia, Turro, Ernest, Calleja, Paul, Rankin, Stuart, Turek, Wojciech, Bryson, Christine, Anderson, Julie, Fletcher, Debra, McJannet, Coleen, Stock, Sophie, Young, Tim, Wassmer, Evangeline, Sohal, Aman, Santra, Saikat, Vogt, Julie, Chitre, Manali, Krishnakumar, Deepa, Ambegaonkar, Gautum, Maw, Anna, Armstrong, Ruth, Park, Soo-Mi, Mehta, Sarju, Paterson, Joan, Carmichael, Jenny, Allen, Louise, Hensiek, Anke, Firth, Helen, Stein, Penelope, Deegan, Patrick, Doffinger, Rainer, Parker, Alasdair, Bitner-Glindzicz, Maria, Scott, Richard, Hurst, Jane, Rosser, Elisabeth, Lees, Melissa, Clement, Emma, Henderson, Robert, Thompson, Dorothy, Gardham, Alice, Gissen, Paul, Josifova, Dragana, Thomas, Ellen, Patch, Chris, Deshpande, Charu, Flinter, Frances, Holder, Muriel, Canham, Natalie, Wakeling, Emma, Holder, Susan, Ghali, Neeti, Brady, Angie, Clowes, Virginia, MacLaren, Robert, Webster, Andrew, Moore, Anthony, Arno, Gavin, Michaelides, Michel, Rankin, Julia, Kurian, Manju, Murphy, Elaine, Carss, Keren, Sanchis-Juan, Alba, Erwood, Marie, Dewhurst, Eleanor, Grozeva, Detelina, Raymond, F Lucy, Reid, Evan, Woods, Geoff, Tischkowitz, Marc, Sandford, Richard, Ali, Sonia, Creaser-Myers, Amanda, Cookson, Victoria, DaCosta, Rosa, Dormand, Natalie, Ghataorhe, Pavandeep K, Greenhalgh, Alan, Huis in’t Veld, Anna, Kennedy, Fiona, Mackenzie Ross, Rob, Masati, Larahmie, Meehan, Sharon, Othman, Shokri, Pollock, Val, Polwarth, Gary, Rhodes, Christopher J, Rue-Albrecht, Kevin, Schotte, Gwen, Shipley, Debbie, Tan, Yvonne, Wanjiku, Ivy, Wort, John, Smith, Kenneth, Kuijpers, Taco, Thrasher, Adrian, Thaventhiran, James, Brown, Matthew, Lango Allen, Hana, Simeoni, Ilenia, Staples, Emily, Samarghitean, Crina, Alachkar, Hana, Antrobus, Richard, Arumugakani, Gururaj, Bacchelli, Chiara, Baxendale, Helen, Bethune, Claire, Bibi, Shahnaz, Booth, Claire, Browning, Michael, Burns, Siobhan, Chandra, Anita, Cooper, Nichola, Davies, Sophie, Devlin, Lisa, Doffinger, Rainer, Drewe, Elizabeth, Edgar, David, Egner, William, Ghurye, Rohit, Gilmour, Kimberley, Goddard, Sarah, Gordins, Pavel, Grigoriadou, Sofia, Hackett, Scott, Hague, Rosie, Hayman, Grant, Herwadkar, Archana, Huissoon, Aarnoud, Jolles, Stephen, Kelleher, Peter, Kumararatne, Dinakantha, Lear, Sara, Longhurst, Hilary, Lorenzo, Lorena, Maimaris, Jesmeen, Manson, Ania, McDermott, Elizabeth, Murng, Sai, Nejentsev, Sergey, Noorani, Sadia, Oksenhendler, Eric, Ponsford, Mark, Qasim, Waseem, Quinti, Isabella, Richter, Alex, Sargur, Ravishankar, Savic, Sinisa, Seneviratne, Suranjith, Sewell, Carrock, Stauss, Hans, Thomas, Moira, Welch, Steve, Willcocks, Lisa, Yeatman, Nigel, and Yong, Patrick

Published
2017
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23. Refinements and considerations for trio whole-genome sequence analysis when investigating Mendelian diseases presenting in early childhood

Author

French, Courtney E, Dolling, Helen, Mégy, Karyn, Sanchis-Juan, Alba, Kumar, Ajay, Delon, Isabelle, Wakeling, Matthew, Mallin, Lucy, Agrawal, Shruti, Austin, Topun, Walston, Florence, Park, Soo-Mi, Parker, Alasdair, Piyasena, Chinthika, Bradbury, Kimberley, Next Generation Children’s Project Consortium, Ellard, Sian, Rowitch, David H, Raymond, F Lucy, Rowitch, David [0000-0002-0079-0060], and Apollo - University of Cambridge Repository

Subjects
paediatrics, rapid diagnostic whole genome, genomics, rare disease, mendelian disorders
Abstract

To facilitate early deployment of whole-genome sequencing (WGS) for severely ill children, a standardized pipeline for WGS analysis with timely turnaround and primary care pediatric uptake is needed. We developed a bioinformatics pipeline for comprehensive gene-agnostic trio WGS analysis of children suspected of having an undiagnosed monogenic disease that included detection and interpretation of primary genetic mechanisms of disease, including SNVs/indels, CNVs/SVs, uniparental disomy (UPD), imprinted genes, short tandem repeat expansions, mobile element insertions, SMN1/2 copy number calling, and mitochondrial genome variants. We assessed primary care practitioner experience and competence in a large cohort of 521 families (comprising 90% WGS trios). Children were identified by primary practitioners for recruitment, and we used the UK index of multiple deprivation to confirm lack of patient socio-economic status ascertainment bias. Of the 521 children sequenced, 176 (34%) received molecular diagnoses, with rates as high as 45% for neurology clinics. Twenty-three of the diagnosed cases (13%) required bespoke methods beyond routine SNV/CNV analysis. In our multidisciplinary clinician user experience assessment, both pediatricians and clinical geneticists expressed strong support for rapid WGS early in the care pathway, but requested further training in determining patient selection, consenting, and variant interpretation. Rapid trio WGS provides an efficacious single-pass screening test for children when deployed by primary practitioners in clinical settings that carry high a priori risk for rare pediatric disease presentations.

Published
2022
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24. Fifteen-minute consultation: The efficient investigation of infantile and childhood epileptic encephalopathies in the era of modern genomics.

Author

Perry, Luke Daniel, Hogg, Sarah Louise, Bowdin, Sarah, Ambegaonkar, Gautam, Parker, Alasdair P. J., and Parker, Alasdair Pj

Subjects
WHOLE genome sequencing, GENOMICS, PEOPLE with epilepsy, FAMILY counseling
Abstract

The investigation of children presenting with infantile and childhood epileptic encephalopathies (ICEE) is challenging due to diverse aetiologies, overlapping phenotypes and the relatively low diagnostic yield of MRI, electroencephalography (EEG) and biochemical investigations. Careful history and thorough examination remain essential as these may identify an acquired cause or indicate more targeted investigation for a genetic disorder. Whole exome sequencing (WES) with analysis of a panel of candidate epilepsy genes has increased the diagnostic yield. Whole genome sequencing (WGS), particularly as a trio with both parents' DNA, is likely to supersede WES. Modern genomic investigation impacts on the timing and necessity of other testing. We propose a structured approach for children presenting with ICEE where there is diagnostic uncertainty, emphasising the importance of WGS or, if unavailable, WES early in the investigative process. We note the importance of expert review of all investigations, including radiology, neurophysiology and biochemistry, to confirm the technique used was appropriate as well as the results. It is essential to counsel families on the risks associated with the procedures, the yield of the procedures, findings that are difficult to interpret and implication of 'negative' results. Where children remain without a diagnosis despite comprehensive investigation, we note the importance of ongoing multidisciplinary care. [ABSTRACT FROM AUTHOR]

Published
2022
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26. Editorial: Advances in Early Onset Epilepsies

Author

Parker, Alasdair Patrick John, Hartmann, Hans, and Van Bogaert, Patrick

Subjects
Editorial, Neurology, treatment, genomics, epilepsy, neurometabolic, MRI
Published
2021

30. Contributors

Author

Abzug, Mark J., Acharya, Krishna K., Adams, Denise M., Adelson, Stewart, Adrian, Molly C., Ahlfeld, Shawn K., Aiken, John J., Akdis, Cezmi A., Albokhari, Daniah, Alderman, Elizabeth M., Ali, Omar, Allen-Rhoades, Wendy A., Almutlaq, Nourah N., Amos, Louella B., Anari, Jason B., Anderson, Karl E., Anupindi, Sudha A., Appleby, Brian S., Ardoin, Stacy P., Arkader, Alexandre, Armangué, Thaís, Arndt, Carola A.S., Arnold, Danielle E., Artis, Adrianne R., Asher, David M., Asselin, Barbara L., Astley, Christina M., Atkinson, Norrell K., Augustine, Erika F., Augustyn, Marilyn C., Bacharier, Leonard B., Bacino, Carlos A., Bailey, Zinzi D., Balamuth, Frances B., Baldassano, Robert N., Baldwin, Keith D., Bales, Christina B., Balistreri, William F., Balwani, Manisha, Bamba, Vaneeta, Banerji, Aleena, Bang, Janet Y., Barai, Nikita, Baranowski, Katherine, Barclay, Sarah F., Barkoudah, Elizabeth, Barrero-Castillero, Alejandra, Barrett, Katherine J., Barron, Karyl S., Basel, Donald, Bass, Dorsey M., Bassett, Mary T., Bassiri, Hamid, Baum, Rebecca A., Behrens, Edward M., Bell, Michael J., Benjamin, Daniel K., Jr., Bennett, Amanda E., Bergerson, Jenna R.E., Bernstein, Daniel, Bernstein, Henry H., Bice-Urbach, Brittany J., Bielory, Brett P., Bielory, Leonard, Blanchard, Samra S., Blanchette, Eliza, Blatter, Joshua A., Bleyer, Archie, Boas, Steven R., Bock, Margret E., Boggs, Sarah R., Boivin, Michael J., Bonn, Julie, Bonthius, Daniel J., Boppana, Suresh B., Bordini, Brett J., Borst, Alexandra J., Bosse, Kristopher R., Boyer, Kenneth M., Brady, Patrick W., Brady, Rebecca C., Brady, Samuel L., Branchford, Brian R., Brandow, Amanda M., Brandsma, Erik, Breault, David T., Breuner, Cora Collette, Bridgemohan, Carolyn F., Britt, William J., Brower, Laura, Brown, Maria D., Brownell, Jefferson N., Browning, Meghen B., Brunetti-Pierri, Nicola, Bunyavanich, Supinda, Burstein, Danielle S., Bustinduy, Amaya L., Buyon, Jill P., Cabada, Miguel M., Cada, Michaela, Cairo, Mitchell S., Calello, Diane P., Cameron, Lindsay H., Campbell, Angela J.P., Candelaria, Margo, Cannon, Laura, Carlin, Rebecca F., Carlucci, James G., Carr, Michael R., Carrigan, Robert B., Carter, Rebecca G., Carter-Hamilton, Gail V., Case, Abigail, Chang, Pearl W., Chelimsky, Gisela G., Chelimsky, Thomas, Chemaitilly, Wassim, Chiotos, Kathleen, Chiu, Yvonne E., Chong, Hey Jin, Chou, Stella T., Christ, Lori A., Christenson, John C., Chugh, Ankur A., Cieslak, Theodore J., Claes, Donna J., Coates, Thomas D., Sánchez Códez, María I., Coffin, Susan E., Cohen, Mitchell B., Cohen, Susan S., Cole, F. Sessions, III, Collaco, J. Michael, Collins, James W., Jr., Congeni, Joseph A., Conrad, Máire A., Corcoran, Justin N., Corley, Alexandra M.S., Cox, Amanda L., Coyle, Anne M., Coyne-Beasley, Tamera, Craig, Sansanee S., Creighton, Sarah M., Crigger, Chad B., Crowe, James E., Jr., Culbert, Gabriel, Czinn, Steven J., Dalal, Aarti S., Dalmau, Josep, D’Andrea, Lynn A., Danziger-Isakov, Lara A., Darville, Toni, David, Richard J., Davidoff, Katharine, Davidson, Loren T., Davidson, Richard S., Davies, H. Dele, Davis, Stephanie D., Davis-Kankanamge, Christina, Daw, Najat C., Dean, Shannon L., DeBiasi, Roberta L., Delair, Shirley, DeLaroche, Amy M., De León-Crutchlow, Diva D., Oquendo Del Toro, Helen M., Del Valle Mojica, Coralee, DeMaso, David R., Dendrinos, Melina L., Dent, Arlene E., Desnick, Robert J., Deterding, Robin R., Devarajan, Prasad, deVeber, Gabrielle A., Dhar, Vineet K., Dhossche, Julie M., Diab, Liliane K., Di Carlo, Heather N., Dietz, Harry C., III, Dietze-Fiedler, Megan L., DiMeglio, Linda A., Dixon, Bradley P., DiVasta, Amy D., Dlamini, Nomazulu, Dobbs, Katherine R., Dodhia, Sonam N., Doerholt, Katja, Dolin, Cara D., Dominguez, Samuel R., Donohoue, Patricia A., Dow, Jennifer, Downes, Kevin J., Doyle, Daniel A., Doyle, Jefferson J., Dror, Yigal, Dubowitz, Howard, Dumler, J. Stephen, Duncan, Andrea F., Durant, Nefertiti H., Dvergsten, Jeffrey A., Earing, Michael G., Eberly, Col. Matthew D., Egan, Marie E., Eichenwald, Eric C., Elkadri, Abdul-Aziz K., Englander, Elizabeth, Ericson, Jessica E., Erkan, Elif, Etzel, Ruth A., Evans, Sarah Helen, Faherty, Erin, Falk, Marni J., Familiar-Lopez, Itziar, Fargo, John H., Feemster, Kristen A., Fehnel, Katie P., Feigelman, Susan, Feldman, Amy G., Feldman, Heidi M., Fels, Edward C., Felner, Eric I., Feng, Sing-Yi, Ferkol, Thomas W., Jr., Finberg, Karin E., Finder, Jonathan D., Fiorino, Kristin N., Fischer, Philip R., Fitzpatrick, Anne M., Flannery, Dustin D., Fleming, Nicholas L., Flood, Veronica H., Flores, Francisco X., Flynn, Joseph T., Flynn, Patricia M., Foglia, Elizabeth E., Forkey, Heather C., Forman, Joel A., Freeman, Alexandra F., Friedman, Deborah M., Friedman, Susan A., Friehling, Erika D., Fritz, Stephanie A., Frush, Donald P., Fuleihan, Ramsay L., Gahagan, Sheila, Gallagher, Patrick G., Galloway, David P., Gans, Hayley A., Garber, Andrea K., Gardiner, Paula M., Garibaldi, Luigi R., Gauthier, Gregory M., Gerber, Jeffrey S., Gershon, Anne A., Ghadersohi, Saied, Gibbs, Kathleen A., Gibson, Mark, Gigante, Joseph, Gigliotti, Francis, Gilley, Stephanie P., Gilliam, Walter S., Ginde, Salil, Girotto, John A., Goldfarb, Samuel B., Goldman, David L., Goldman, Stanton C., Gómez-Duarte, Oscar G., Good, Misty, Goodbody, Christine M., Goodman, Denise M., Goodman, Tracey, Goodyer, William R., Gordon, Catherine M., Gordon, Leslie B., Gordon, Rebecca J., Gordon-Lipkin, Eliza, Gorelik, Michael, Gower, W. Adam, Graber, Evan G., Graff, Zachary T., Graham, Robert J., Green, Cori M., Green, Michael, Greenbaum, Larry A., Greenbaum, V. Jordan, Greiner, Mary V., Griffiths, Anne G., Grizzle, Kenneth L., Groner, Judith A., Grumach, Anete Sevciovic, Gueye-Ndiaye, Seyni, Guz-Mark, Anat, Haamid, Fareeda, Haddad, Gabriel G., Haddad, Joseph, Jr., Haemer, Matthew A., Hagan, Joseph F., Jr., Haider, Suraiya K., Hakim, Hana, Haldeman-Englert, Chad R., Halstead, Scott B., Hamie, Lamiaa, Hammerschlag, Margaret R., Hammershaimb, E. Adrianne, Hampton, Elisa, Hamvas, Aaron, Hanchard, Neil A., Hanley, Patrick C., Hanna, Melisha G., Harijan, Pooja D., Harrison, Douglas J., Harstad, Elizabeth B., Haslam, David B., Hauck, Fern R., Havers, Fiona P., Hayes, Ericka V., Heard-Garris, Nia J., Hedrick, Holly L., Hemingway, Cheryl, Heneghan, Chelsea, Hernandez, Michelle L., Hernandez-Trujillo, Vivian P., Hernandez Tejada, Fiorela N., Herrick, Heidi M., Hershey, Andrew D., Herzog, Cynthia E., Heston, Sarah M., Hijazi, Ghada, Hill, Samantha V., Hochberg, Jessica, Hodes, Deborah, Hoefgen, Holly R., Holinger, Lauren D., Holland-Hall, Cynthia M., Hollenbach, Laura L., Holler-Managan, Yolanda F., Hooper, David K., Hooven, Thomas A., Hoover-Fong, Julie E., Hopper, Rachel K., Hord, Jeffrey D., Horn, B. David, Horstmann, Helen M., Hotez, Peter J., House, Samantha A., Howard, Ashley C., Howard, Mary Beth, Hsu, Evelyn K., Hsu, Katherine, Huddleston, Heather G., Huh, Winston W., Humphrey, Stephen R., Hunstad, David A., Hunger, Stephen P., Hunt, Carl E., Huppert, Stacey S., Huppler, Anna R., Hurt, Hallam, Izumi, Kosuke, Jackson, Allison M., Jackson, Mary Anne, Jaffe, Ashlee M., James, Kiera M., Janowski, Andrew B., Jenssen, Brian P., Jinnah, H.A., John, Chandy C., Johansen, Kari, Johnson, Susan L., Johnston, Brian D., Jongco, Artemio M., III, Josephson, Cassandra D., Joyce, Joel C., Jyonouchi, Soma, Kabbany, Mohammad Nasser, Kabbouche, Marielle, Kacperski, Joanne, Kadry, Nadia A., Kaj-Carbaidwala, Batul, Kalish, Jennifer M., Kamat, Deepak, Kansra, Alvina R., Kanter, David M., Kao, Carol M., Kapavarapu, Prasanna K., Kattan, Jacob, Kelly, Andrea, Kelly, Desmond P., Kelly, Matthew S., Kelly, Michael E., Kendi, Sadiqa, Kerem, Eitan, Kerr, Julie M., Khan, David A., Khan, Seema, Khatami, Ameneh, Khaytin, Ilya, Kier, Catherine, Kilinsky, Alexandra, Kim, Chong-Tae, Kim, Jung Won, Kim, Rosa K., King, J. Michael, Kirschen, Matthew P., Kishnani, Priya S., Klawonn, Meghan A., Klein, Bruce L., Klein, Bruce S., Kliegman, Alison S., Kliegman, Robert M., Kneyber, Martin C.J., Koch, William C., Kochanek, Patrick M., Kodish, Eric, Kohlhoff, Stephan A., Kortepeter, Mark G., Kotloff, Karen L., Koumbourlis, Anastassios C., Krause, Peter J., Krebs, Nancy F., Kreipe, Richard E., Krug, Steven E., Kwiatkowski, Janet L., Kwon, Jennifer M., Ladisch, Stephan, Lakser, Oren J., Lalor, Leah, Lam, Simon, Lambert, Michele P., Lampe, Christina, Landry, Gregory L., Lane, Wendy G., Larson, A. Noelle, LaRussa, Phillip S., Lawrence, J. Todd R., Lee, Brendan, Lee, Erica H., Leiding, Jennifer W., Lemmon, Monica E., Lesser, Daniel J., Lestrud, Steven O., Leung, Donald Y.M., Levas, Michael N., Liacouras, Chris A., Lipkin, Paul H., Liptzin, Deborah R., Liu, Andrew H., Lo, Mindy S., Lo, Stanley F., Long, Sarah S., Lord, Katherine, Macias, Charles G., Macias, Michelle M., Macumber, Ian R., Magnusson, Mark R., Magoulas, Pilar L., Maguire, Kathleen J., Mahajan, Prashant V., Majzoub, Joseph A., Mamula, Petar, Manak, Colleen K., Mangus, Courtney W., Manoli, Irini, Manzur, Adnan Y., Maqbool, Asim, Maranich, Col. Ashley M., Margetts, Miranda, Margolis, David, Marin, Mona, Marini, Joan C., Markowitz, Morri, Maroushek, Stacene R., Marsh, Justin D., Marshall, Trisha L., Martin, Kari L., Masson, Vicki K., Matalon, Dena R., Matalon, Reuben K., Mathijssen, Irene M.J., Reddy Matta, Sravan Kumar, Maxwell, Elizabeth C., Maybank, Aletha, McCabe, Megan E., McCain, Darla H., McColley, Susanna A., McConnico, Neena, McCormick, Elizabeth M., McDonald, Christine M., McGovern, Margaret M., McGrath-Morrow, Sharon A., McInerney, Alissa, McKinney, Jeffrey S., McLeod, Rima, McVay-Gillam, Marcene R., Meade, Julia C., Meehan, William P., III, Mejias, Asuncion, Melby, Peter C., Melzer-Lange, Marlene D., Merves, Jamie F., Messacar, Kevin B., Michaels, Marian G., Michniacki, Thomas F., Mikati, Mohamad A., Miller-Handley, Hilary E., Mink, Jonathan W., Mirasola, Karolyn, Mistovich, R. Justin, Mohr, Emma L., Montoya-Williams, Diana, Moon, Rachel Y., Morava, Eva, Moreno, Megan A., Morgan, Ryan W., Morrison, Peter E., Morrison, Wynne, Mukhopadhyay, Sagori, Munoz, Flor M., Munson, David A., Murphy, Timothy F., Murray, Karen F., Murray, Thomas S., Mutlu, Levent, Nagata, Jason M., Narula, Sona, Nataro, James P., Navsaria, Dipesh, Nduati, Ruth W., Nehus, Edward J., Nelson, Maureen R., Neri, Caitlin M., Nevin, Mary A., Newburger, Jane W., Newmark, Jonathan, Nield, Linda S., Niermeyer, Susan, Nocton, James J., Nogee, Lawrence M., Noje, Corina, Nowak-Wegrzyn, Anna H., Obaro, Stephen K., Obeid, Makram M., O’Callaghan, Kevin P., Oleszek, Joyce L., Olitsky, Scott E., Olsson, John M., O’Neill, Meghan E., Onigbanjo, Mutiat T., Opoka, Robert O., Orenstein, Walter A., Orkin, Sarah H., Orscheln, Rachel C., Ortega, Camile, O’Toole, Timothy R., Owens, Judith A., Ozen, Seza, Pach, Sophie, Pachter, Lee M., Padhye, Amruta, Pandurangi, Sindhu, Pak-Gorstein, Suzinne, Palla, John, Palmieri, Tina L., Palmieri, Jessica M., Pappas, Diane E., Parent, John J., Parga-Belinkie, Joanna J., Parikh, Bijal A., Parker, Alasdair P.J., Partridge, Emily A., Patel, Ami B., Patel, Trusha, Patrick, Stephen W., Patterson, Briana C., Pelosi, Emanuele, Permar, Sallie R., Perry, Michael, Perry, Tamara T., Peters, Mark J., Peters, Timothy R., Peterson, Stacy J.B., Phelan, Rachel A., Pinto, Anna L., Pipan, Mary, Player, Brittany, Prince, William Benjamin, Proctor, Mark R., Prozora, Stephanie, Pryor, Howard I., II, Pyles, Lee A., Quinn, Molly M., Quint, Elisabeth H., Rabinovich, C. Egla, Raffini, Leslie J., Ragoonanan, Dristhi S., Rahman, Shamima, Ralston, Shawn L., Ram, Sanjay, Ramilo, Octavio, Ramirez, Kacy A., Rand, Casey M., Rasmussen, Sonja A., Rathke, Kevin M., Ratner, Adam J., Ratner, Lee, Reed, Ann M., Reich, Patrick J., Reif, Shimon, Reller, Megan E., Remick, Katherine E., Remiker, Allison S., Reyes, Jorge D., Richardson, Katherine M., Rintoul, Natalie E., Ritchey, A. Kim, Robinson, Angela Byun, Rodrigues, Kristine Knuti, Rogers, Michael E., Romano, Mary E., Roosevelt, Genie E., Roper, Stephen M., Rosenthal, Stephen M., Ross, A. Catharine, Rossano, Joseph W., Rothman, Jennifer A., Rotta, Alexandre T., Rozenfeld, Ranna A., Russo, Michael E., Ryan, Kelsey S., Ryan, Monique M., Ryu, Julie, Sabbagh, Sara E., Sachdev, H.P.S., Sadarangani, Manish, Sadun, Rebecca E., Sahin, Mustafa, Saint-Cyr, Martine, Salata, Robert A., Salazar, José H., Salvana, Edsel Maurice T., Samelson-Jones, Benjamin J., Sammons, Julia S., Sampson, Hugh A., Samsel, Chase B., Sandora, Thomas J., Sankar, Wudbhav N., Sarnaik, Ashok P., Sato, Alice I., Satter, Lisa Forbes, Scaggs Huang, Felicia A., Schaffzin, Joshua K., Schechter, Michael S., Schilling, Samantha, Schleiss, Mark R., Schluter, W. William, Schondelmeyer, Amanda C., Schroeder, James W., Jr., Schulte, Elaine E., Schuster, Jennifer E., Schuster, Marcy, Schuster, Mark A., Scott, Daryl A., Scott, John P., Seaborg, Kristin A., Seed, Patrick C., Serwint, Janet R., Shah, Dheeraj, Shah, Samir S., Shah, Shivang S., Shamir, Raanan, Shanti, Christina M., Shapiro, Bruce K., Shaywitz, Bennett A., Shaywitz, Sally E., Shchelochkov, Oleg A., Shulman, Stanford T., Sicherer, Scott H., Simmons, Jeffrey M., Simões, Eric A.F., Simonsen, Kari A., Simpson, Tess S., Sinclair-McBride, Keneisha R., Singh, Arunjot, Sink, Jacquelyn R., Sisk, Bryan A., Sivaraman, Vidya, Slattery, Susan M., Slavotinek, Anne M., Smith, Jessica R., Smith-Whitley, Kim, Solensky, Roland, Son, Mary Beth F., Soranno, Danielle E., Sosa, Tina K., Soto-Rivera, Carmen L., Sosinsky, Laura Stout, Souder, Emily E., Souverbielle, Cristina Tomatis, Spearman, Paul, Spiegel, David A., Spinks-Franklin, Adiaha I.A., Sprecher, Alicia J., Squires, James E., Srivastava, Siddharth, St. Geme, Joseph W., III, St. John, Rachel D., Stambough, Kathryn C., Stanberry, Lawrence R., Starke, Jeffrey R., Starr, Taylor B., Steenhoff, Andrew P., Stein, Ronen E., Steinbach, William J., Stillwell, Terri L., Stone, Deborah L., Su, Stefani, Sucato, Gina S., Suchy, Frederick J., Sullivan, Kathleen E., Swami, Sanjeev K., Szafron, Vibha A., Szilagyi, Moira, Taha, Dalal, Tan, Libo, Tantisira, Kelan G., Taylor, Alex M., Tchapyjnikov, Dmitry, Tesini, Brenda L., Theobald, Jillian L., Thielen, Beth K., Thom, Christopher S., Thornburg, Courtney D., Tieder, Joel S., Tissières, Pierre, Tolentino, Victorio R., Jr., Topjian, Alexis A., Tower, Richard L., Trachtman, Rebecca, Triebwasser, Jourdan E., Trowbridge, Sara K., Truglio, Joseph M., Tubergen, David G., Turk, Margaret A., Tymon-Rosario, Joan R., Ufberg, Paul J., Ullrich, Christina, Ullrich, Nicole, Valika, Taher S., Van Hare, George F., Van Mater, Heather A., Varnell, Charles D., Jr., Vash-Margita, Alla, Vece, Timothy J., Vemana, Aarthi P., Venditti, Charles P., Vepraskas, Sarah, Verbsky, James W., Vermilion, Jennifer A., Vickery, Brian P., Vockley, Jerry, Voynow, Judith A., Walch, Abby, Waldrop, Stephanie W., Walker, David M., Walkovich, Kelly J., Walter, Heather J., Wambach, Jennifer A., Wamithi, Susan, Wang, Julie, Wang, Marie E., Wangler, Michael F., Ware, Stephanie M., Washam, Matthew C., Wasserman, Jonathan D., Wassner, Ari J., Watson, Andrew M., Wattier, Rachel L., Weber, David R., Webster, Jennifer, Weese-Mayer, Debra E., Weinberg, Jason B., Weinman, Jason P., Weisman, Steven J., Weiss, Anna K., Weiss, Scott L., Weiss, Pamela F., Weitzman, Carol C., Wells, Lawrence, Wen, Jessica W., Wendel, Danielle R., Werlin, Steven L., Wexler, Isaiah D., Whitaker, Alexander S., White, A. Clinton, Jr., White, Perrin C., Willoughby, Rodney E., Jr., Wilschanski, Michael, Wiley, Susan E., Williams, Brendan A., Wilson, Karen M., Wilson, Pamela E., Winell, Jennifer J., Witters, Peter, Wolf, Joshua, Wolfe, Joanne, Wolfgram, Peter M., Woods, Brandon T., Wright, Benjamin L., Wright, Terry W., Wu, Eveline Y., Yagupsky, Pablo, Yang, Edward, Yang, Kesi C., Yang, Ming, Yaron, Michael, Younger, Sarah B., Yuskaitis, Christopher J., Zachariah, Philip, Zafar, Muhammad S., Zahler, Stacey G., Zajac, Lauren M., Zaky, Wafik, Zaspel, Jennifer A., Zerra, Patricia E., Zhou, Amy, Zuckerman, Barry S., and Zur, Karen B.

Published
2025
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31. The SANAD II study of the effectiveness and cost-effectiveness of valproate versus levetiracetam for newly diagnosed generalised and unclassifiable epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial

Author

Marson, Anthony, Burnside, Girvan, Appleton, Richard, Smith, Dave, Leach, John Paul, Sills, Graeme, Tudur-Smith, Catrin, Plumpton, Catrin, Hughes, Dyfrig A, Williamson, Paula, Baker, Gus A, Balabanova, Silviya, Taylor, Claire, Brown, Richard, Hindley, Dan, Howell, Stephen, Maguire, Melissa, Mohanraj, Rajiv, Smith, Philip E, Lanyon, Karen, Manford, Mark, Chitre, Manali, Parker, Alasdair, Swiderska, Nina, Pauling, James, Hughes, Adrian, Gupta, Rajat, Hanif, Sadia, Awadh, Mostafa, Ragunathan, Sharmini, Cable, Nicola, Cooper, Paul, Hindley, Daniel, Rakshi, Karl, Molloy, Sophie, Reuber, Markus, Ayonrinde, Kunle, Wilson, Martin, Saladi, Satyanarayana, Gibb, John, Funston, Lesley-Ann, Cassidy, Damhait, Boyd, Jonathan, Ratnayaka, Mal, Faza, Hani, Sadler, Martin, Al-Moasseb, Hassan, Galtrey, Clare, Wren, Damien, Olabi, Anas, Fuller, Geraint, Khan, Muhammed, Kallappa, Chetana, Chinthapalli, Ravi, Aji, Baba, Davies, Rhys, Foster, Kathryn, Hitiris, Nikolas, Hussain, Nahin, Dowson, Simon, Ellison, Julie, Sharrack, Basil, Gandhi, Vandna, Powell, Rob, Tittensor, Phil, Summers, Beatrice, Shashikiran, Sastry, Dison, Penelope J, Samarasekera, Shanika, McCorry, Doug, White, Kathleen, Nithi, Kannan, Richardson, Martin, Page, Rupert, Deekollu, David, Slaght, Sean, Warriner, Stephen, Ahmed, Mansoor, Chaudhuri, Abhijit, Chow, Gabriel, Artal, Javier, Kucinskiene, Danute, Sreenivasa, Harish, Velmurugan, Singara, Zipitis, Christos S, McLean, Brendan, Lal, Vaithianathar, Gregoriou, Angelous, Maddison, Paul, Pickersgill, Trevor, Anderson, Joseph, Lawthom, Charlotte, Whitlingum, Gabriel, Rakowicz, Wojtek, Kinton, Lucy, McLellan, Alisa, Vora, Nitish, Zuberi, Sameer, Kelso, Andrew, Hughes, Imelda, Martland, John, Emsley, Hedley, de Goede, Christian, Singh, RP, Moor, Carl-Christian, Aram, Julia, Sakthivel, Kumar, Nelapatla, Suresh, Rittey, Chris, Pinto, Ashwin, Cock, Hannah, Richardson, Anna, Houston, Erika, Cooper, Christopher, Lawson, Geoff, Massarano, Albert, Burness, Christine, Wieshmann, Udo, Dey, Indranil, Sivakumar, Puthuval, Yeung, Lap-Kong, Smith, Philip, Bentur, Hemalata, Heafield, Tom, Mathew, Anna, Smith, David, and Jauhari, Praveen

Subjects
Pediatrics, medicine.medical_specialty, Levetiracetam, Cost effectiveness, Newly diagnosed, 030204 cardiovascular system & hematology, Minimisation (clinical trials), law.invention, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Randomized controlled trial, Alzheimer Disease, Seizures, law, medicine, Humans, 030212 general & internal medicine, Young adult, business.industry, Hazard ratio, Articles, General Medicine, medicine.disease, Anticonvulsants, business, medicine.drug
Abstract

Background: \ud Valproate is a first-line treatment for patients with newly diagnosed idiopathic generalised or difficult to classify epilepsy, but not for women of child-bearing potential because of teratogenicity. Levetiracetam is increasingly prescribed for these patient populations despite scarcity of evidence of clinical effectiveness or cost-effectiveness. We aimed to compare the long-term clinical effectiveness and cost-effectiveness of levetiracetam compared with valproate in participants with newly diagnosed generalised or unclassifiable epilepsy.\ud \ud Methods: \ud We did an open-label, randomised controlled trial to compare levetiracetam with valproate as first-line treatment for patients with generalised or unclassified epilepsy. Adult and paediatric neurology services (69 centres overall) across the UK recruited participants aged 5 years or older (with no upper age limit) with two or more unprovoked generalised or unclassifiable seizures. Participants were randomly allocated (1:1) to receive either levetiracetam or valproate, using a minimisation programme with a random element utilising factors. Participants and investigators were aware of treatment allocation. For participants aged 12 years or older, the initial advised maintenance doses were 500 mg twice per day for levetiracetam and valproate, and for children aged 5–12 years, the initial daily maintenance doses advised were 25 mg/kg for valproate and 40 mg/kg for levetiracetam. All drugs were administered orally. SANAD II was designed to assess the non-inferiority of levetiracetam compared with valproate for the primary outcome time to 12-month remission. The non-inferiority limit was a hazard ratio (HR) of 1·314, which equates to an absolute difference of 10%. A HR greater than 1 indicated that an event was more likely on valproate. All participants were included in the intention-to-treat (ITT) analysis. Per-protocol (PP) analyses excluded participants with major protocol deviations and those who were subsequently diagnosed as not having epilepsy. Safety analyses included all participants who received one dose of any study drug. This trial is registered with the ISRCTN registry, 30294119 (EudraCt number: 2012-001884-64).\ud \ud Findings: \ud 520 participants were recruited between April 30, 2013, and Aug 2, 2016, and followed up for a further 2 years. 260 participants were randomly allocated to receive levetiracetam and 260 participants to receive valproate. The ITT analysis included all participants and the PP analysis included 255 participants randomly allocated to valproate and 254 randomly allocated to levetiracetam. Median age of participants was 13·9 years (range 5·0–94·4), 65% were male and 35% were female, 397 participants had generalised epilepsy, and 123 unclassified epilepsy. Levetiracetam did not meet the criteria for non-inferiority in the ITT analysis of time to 12-month remission (HR 1·19 [95% CI 0·96–1·47]); non-inferiority margin 1·314. The PP analysis showed that the 12-month remission was superior with valproate than with levetiracetam. There were two deaths, one in each group, that were unrelated to trial treatments. Adverse reactions were reported by 96 (37%) participants randomly assigned to valproate and 107 (42%) participants randomly assigned to levetiracetam. Levetiracetam was dominated by valproate in the cost-utility analysis, with a negative incremental net health benefit of −0·040 (95% central range −0·175 to 0·037) and a probability of 0·17 of being cost-effectiveness at a threshold of £20 000 per quality-adjusted life-year. Cost-effectiveness was based on differences between treatment groups in costs and quality-adjusted life-years.\ud \ud Interpretation: \ud Compared with valproate, levetiracetam was found to be neither clinically effective nor cost-effective. For girls and women of child-bearing potential, these results inform discussions about benefit and harm of avoiding valproate.\ud \ud Funding: \ud National Institute for Health Research Health Technology Assessment Programme.

Published
2021

33. Diagnostic delays in paediatric stroke

Author

Mallick, Andrew A, Ganesan, Vijeya, Kirkham, Fenella J, Fallon, Penny, Hedderly, Tammy, McShane, Tony, Parker, Alasdair P, Wassmer, Evangeline, Wraige, Elizabeth, Amin, Samir, Edwards, Hannah B, and OʼCallaghan, Finbar J

Published
2015
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34. The SANAD II study of the effectiveness and cost-effectiveness of levetiracetam, zonisamide, or lamotrigine for newly diagnosed focal epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial

Author

Marson, Anthony, Burnside, Girvan, Appleton, Richard, Smith, Dave, Leach, John Paul, Sills, Graeme, Tudur-Smith, Catrin, Plumpton, Catrin, Hughes, Dyfrig A., Williamson, Paula, Baker, Gus A., Balabanova, Silviya, Taylor, Claire, Brown, Richard, Hindley, Dan, Howell, Stephen, Maguire, Melissa, Mohanraj, Rajiv, Smith, Philip E., Lanyon, Karen, Manford, Mark, Chitre, Manali, Parker, Alasdair, Swiderska, Nina, Pauling, James, Hughes, Adrian, Gupta, Rajat, Hanif, Sadia, Awadh, Mostafa, Ragunathan, Sharmini, Cable, Nicola, Cooper, Paul, Hindley, Daniel, Rakshi, Karl, Molloy, Sophie, Reuber, Markus, Ayonrinde, Kunle, Wilson, Martin, Saladi, Satyanarayana, Gibb, John, Funston, Lesley-Ann, Cassidy, Damhait, Boyd, Jonathan, Ratnayaka, Mal, Faza, Hani, Sadler, Martin, Al-Moasseb, Hassan, Galtrey, Clare, Wren, Damien, Olabi, Anas, Fuller, Geraint, Khan, Muhammed, Kallappa, Chetana, Chinthapalli, Ravi, Aji, Baba, Davies, Rhys, Foster, Kathryn, Hitiris, Nikolas, Hussain, Nahin, Dowson, Simon, Ellison, Julie, Sharrack, Basil, Gandhi, Vandna, Powell, Rob, Tittensor, Phil, Summers, Beatrice, Shashikiran, Sastry, Dison, Penelope J, Samarasekera, Shanika, McCorry, Doug, White, Kathleen, Nithi, Kannan, Richardson, Martin, Page, Rupert, Deekollu, David, Slaght, Sean, Warriner, Stephen, Ahmed, Mansoor, Chaudhuri, Abhijit, Chow, Gabriel, Artal, Javier, Kucinskiene, Danute, Sreenivasa, Harish, Velmurugan, Singara, Zipitis, Christos S., McLean, Brendan, Lal, Vaithianathar, Gregoriou, Angelous, Maddison, Paul, Pickersgill, Trevor, Anderson, Joseph, Lawthom, Charlotte, Whitlingum, Gabriel, Rakowicz, Wojtek, Kinton, Lucy, McLellan, Alisa, Vora, Nitish, Zuberi, Sameer, Kelso, Andrew, Hughes, Imelda, Martland, John, Emsley, Hedley, de Goede, Christian, Singh, RP, Moor, Carl-Christian, Aram, Julia, Sakthivel, Kumar, Nelapatla, Suresh, Rittey, Chris, Pinto, Ashwin, Cock, Hannah, Richardson, Anna, Houston, Erika, Cooper, Christopher, Lawson, Geoff, Massarano, Albert, Burness, Christine, Wieshmann, Udo, Dey, Indranil, Sivakumar, Puthuval, Yeung, Lap-Kong, Smith, Philip, Bentur, Hemalata, Heafield, Tom, Mathew, Anna, Smith, David, and Jauhari, Praveen

Subjects
Adult, Male, Pediatrics, medicine.medical_specialty, Levetiracetam, Adolescent, Cost effectiveness, Cost-Benefit Analysis, Zonisamide, Administration, Oral, 030204 cardiovascular system & hematology, Lamotrigine, law.invention, 03 medical and health sciences, Epilepsy, Young Adult, 0302 clinical medicine, Randomized controlled trial, law, medicine, Humans, 030212 general & internal medicine, Child, Aged, business.industry, Standard treatment, Hazard ratio, Articles, General Medicine, Middle Aged, medicine.disease, Treatment Outcome, Anticonvulsants, Female, Epilepsies, Partial, business, medicine.drug
Abstract

Background: \ud Levetiracetam and zonisamide are licensed as monotherapy for patients with focal epilepsy, but there is uncertainty as to whether they should be recommended as first-line treatments because of insufficient evidence of clinical effectiveness and cost-effectiveness. We aimed to assess the long-term clinical effectiveness and cost-effectiveness of levetiracetam and zonisamide compared with lamotrigine in people with newly diagnosed focal epilepsy.\ud \ud Methods: \ud This randomised, open-label, controlled trial compared levetiracetam and zonisamide with lamotrigine as first-line treatment for patients with newly diagnosed focal epilepsy. Adult and paediatric neurology services across the UK recruited participants aged 5 years or older (with no upper age limit) with two or more unprovoked focal seizures. Participants were randomly allocated (1:1:1) using a minimisation programme with a random element utilising factor to receive lamotrigine, levetiracetam, or zonisamide. Participants and investigators were not masked and were aware of treatment allocation. SANAD II was designed to assess non-inferiority of both levetiracetam and zonisamide to lamotrigine for the primary outcome of time to 12-month remission. Anti-seizure medications were taken orally and for participants aged 12 years or older the initial advised maintenance doses were lamotrigine 50 mg (morning) and 100 mg (evening), levetiracetam 500 mg twice per day, and zonisamide 100 mg twice per day. For children aged between 5 and 12 years the initial daily maintenance doses advised were lamotrigine 1·5 mg/kg twice per day, levetiracetam 20 mg/kg twice per day, and zonisamide 2·5 mg/kg twice per day. All participants were included in the intention-to-treat (ITT) analysis. The per-protocol (PP) analysis excluded participants with major protocol deviations and those who were subsequently diagnosed as not having epilepsy. Safety analysis included all participants who received one dose of any study drug. The non-inferiority limit was a hazard ratio (HR) of 1·329, which equates to an absolute difference of 10%. A HR greater than 1 indicated that an event was more likely on lamotrigine. The trial is registered with the ISRCTN registry, 30294119 (EudraCt number: 2012-001884-64).\ud \ud Findings: \ud 990 participants were recruited between May 2, 2013, and June 20, 2017, and followed up for a further 2 years. Patients were randomly assigned to receive lamotrigine (n=330), levetiracetam (n=332), or zonisamide (n=328). The ITT analysis included all participants and the PP analysis included 324 participants randomly assigned to lamotrigine, 320 participants randomly assigned to levetiracetam, and 315 participants randomly assigned to zonisamide. Levetiracetam did not meet the criteria for non-inferiority in the ITT analysis of time to 12-month remission versus lamotrigine (HR 1·18; 97·5% CI 0·95–1·47) but zonisamide did meet the criteria for non-inferiority in the ITT analysis versus lamotrigine (1·03; 0·83–1·28). The PP analysis showed that 12-month remission was superior with lamotrigine than both levetiracetam (HR 1·32 [97·5% CI 1·05 to 1·66]) and zonisamide (HR 1·37 [1·08–1·73]). There were 37 deaths during the trial. Adverse reactions were reported by 108 (33%) participants who started lamotrigine, 144 (44%) participants who started levetiracetam, and 146 (45%) participants who started zonisamide. Lamotrigine was superior in the cost-utility analysis, with a higher net health benefit of 1·403 QALYs (97·5% central range 1·319–1·458) compared with 1·222 (1·110–1·283) for levetiracetam and 1·232 (1·112, 1·307) for zonisamide at a cost-effectiveness threshold of £20 000 per QALY. Cost-effectiveness was based on differences between treatment groups in costs and QALYs.\ud \ud Interpretation: \ud These findings do not support the use of levetiracetam or zonisamide as first-line treatments for patients with focal epilepsy. Lamotrigine should remain a first-line treatment for patients with focal epilepsy and should be the standard treatment in future trials.\ud \ud Funding: \ud National Institute for Health Research Health Technology Assessment programme.

Published
2021

39. Publisher Correction:Whole-genome sequencing of a sporadic primary immunodeficiency cohort (Nature, (2020), 583, 7814, (90-95), 10.1038/s41586-020-2265-1)

Author

Thaventhiran, James E.D., Lango Allen, Hana, Burren, Oliver S., Rae, William, Greene, Daniel, Staples, Emily, Zhang, Zinan, Farmery, James H.R., Simeoni, Ilenia, Rivers, Elizabeth, Maimaris, Jesmeen, Penkett, Christopher J., Stephens, Jonathan, Deevi, Sri V.V., Sanchis-Juan, Alba, Gleadall, Nicholas S., Thomas, Moira J., Sargur, Ravishankar B., Gordins, Pavels, Baxendale, Helen E., Brown, Matthew, Tuijnenburg, Paul, Worth, Austen, Hanson, Steven, Linger, Rachel J., Buckland, Matthew S., Rayner-Matthews, Paula J., Gilmour, Kimberly C., Samarghitean, Crina, Seneviratne, Suranjith L., Sansom, David M., Lynch, Andy G., Megy, Karyn, Ellinghaus, Eva, Ellinghaus, David, Jorgensen, Silje F., Karlsen, Tom H., Stirrups, Kathleen E., Cutler, Antony J., Kumararatne, Dinakantha S., Chandra, Anita, Edgar, J. David M., Herwadkar, Archana, Cooper, Nichola, Grigoriadou, Sofia, Huissoon, Aarnoud P., Goddard, Sarah, Jolles, Stephen, Schuetz, Catharina, Boschann, Felix, Abbs, Stephen, Adhya, Zoe, Adlard, Julian, Afzal, Maryam, Ahmed, Irshad, Ahmed, Munaza, Ahmed, Saeed, Aitman, Timothy J., Alachkar, Hana, Alamelu, Jayanthi, Alikhan, Raza, Allen, Carl E., Allen, Louise, Allsup, David J., Alvi, Arif, Ambegaonkar, Gautam, Anantharachagan, Ariharan, Ancliff, Philip, Anderson, Julie, Antrobus, Richard, Armstrong, Ruth, Arno, Gavin, Arumugakani, Gururaj, Arya, Rita, Ashford, Sofie, Astle, William J., Attwood, Anthony, Austin, Steve, Aydinok, Yesim, Ayub, Waqar, Babbs, Christian, Bacchelli, Chiara, Baglin, Trevor, Bakchoul, Tamam, Bariana, Tadbir K., Barratt, Jonathan, Barwell, Julian, Baski, John, Bates, Rachel W., Batista, Joana, Baynam, Gareth, Bennett, David L., Bethune, Claire, Bhatnagar, Neha, Bibi, Shahnaz, Bierzynska, Agnieszka, Biss, Tina, Bitner-Glindzicz, Maria A.K., Bleda, Marta, Blesneac, Iulia, Boardman, Barbara, Boddana, Preetham, Bogaard, Harm J., Booth, Claire, Boyce, Sara, Bradley, John R., Brady, Angela, Breen, Gerome, Brennan, Paul, Brewer, Carole, Briley, Annette, Brown, Richard, Browning, Michael J., Brownlie, Mary, Bryson, Christine J., Buchan, Rachel J., Buck, Jackie, Bueser, Teofila, Diz, Carmen Bugarin, Burns, Siobhan O., Calleja, Paul, Carmichael, Jenny, Carr-White, Gerald, Carss, Keren J., Casey, Ruth, Chalmers, Elizabeth, Chambers, Jenny, Chambers, John, Chan, Melanie M.Y., Chan, Melissa V., Cheng, Floria, Chinn, Ivan K., Chinnery, Patrick F., Chitre, Manali, Chong, Sam, Christian, Martin T., Church, Colin, Clement, Emma M., Brod, Naomi Clements, Clifford, Hayley, Clowes, Virginia E., Coghlan, Gerry, Colby, Elizabeth, Cole, Trevor R.P., Collins, Janine H., Collins, Peter W., Condliffe, Robin, Cook, H. Terence, Cook, Stuart, Cookson, Victoria, Corris, Paul A., Creaser-Myers, Amanda, Crisp-Hihn, Abigail, Curry, Nicola S., Da Costa, Rosa, Danesino, Cesare, Daniels, Matthew J., Darby, Damaris, Daugherty, Louise C., Davies, E. G., Davies, Sophie, Davis, John, de Bree, Godelieve J., Deacock, Sarah, Deegan, Patrick B., Dempster, John, Dent, Timothy, Deshpande, Charu, Devlin, Lisa A., Dewhurst, Eleanor F., Dixit, Anand K., Dixon, Peter H., Doffinger, Rainer, Dolling, Helen, Dormand, Natalie, Downes, Kate, Drazyk, Anna M., Drewe, Elizabeth, Duarte, Daniel, Dutt, Tina, Edwards, Karen E., Egner, William, Ekani, Melanie N., El-Shanawany, Tariq, Elkhalifa, Shuayb, Elston, Tony, Emmerson, Ingrid, Erber, Wendy N., Erwood, Marie, Estiu, Maria C., Evans, Dafydd Gareth, Evans, Gillian, Everington, Tamara, Eyries, Mélanie, Favier, Remi, Firth, Helen V., Fitzpatrick, Maggie M., Fletcher, Debra, Flinter, Frances A., Fox, James C., Frary, Amy J., French, Courtney E., Freson, Kathleen, Frontini, Mattia, Furie, Bruce, Gale, Daniel P., Gall, Henning J., Gardham, Alice, Gaspar, H. Bobby, Gattens, Michael, Ghali, Neeti, Ghataorhe, Pavandeep K., Ghio, Stefano, Ghofrani, Hossein Ardeschir, Ghurye, Rohit, Gibbs, J. Simon R., Gilbert, Rodney D., Girerd, Barbara, Girling, Joanna C., Gissen, Paul, Gorman, Kathleen M., Gosal, David, Graf, Stefan, Grassi, Luigi, Greenhalgh, Alan J., Greenhalgh, Lynn, Greinacher, Andreas, Gresele, Paolo, Griffiths, Philip G., Griffiths, Sian, Grozeva, Detelina, Hackett, Scott J., Hadden, Robert D.M., Hadinnapola, Charaka, Hague, Rosie, Hague, William M., Haimel, Matthias, Hall, Matthew, Halmagyi, Csaba, Hammerton, Tracey, Hanson, Helen L., Harkness, Kirsty, Harper, Andrew R., Harper, Lorraine, Harris, Claire, Harrison, Claire, Hart, Daniel, Hassan, Ahamad, Hayman, Grant, Heemskerk, Johan W.M., Hegde, Shivaram, Henderson, Alex, Henderson, Robert H., Hensiek, Anke, Henskens, Yvonne M.C., Hodgson, Joshua, Hoffman, Jonathan, Holden, Simon, Holder, Muriel, Horvath, Rita, Houlden, Henry, Houweling, Arjan C., Howard, Luke S., Hu, Fengyuan, Hudson, Gavin, Hughes, Sean, Hughes, Stephen, Huis in ‘t Veld, Anna E., Humbert, Marc, Hurles, Matthew E., Hurst, Jane A., Irvine, Val, Izatt, Louise, James, Roger, Jeevaratnam, Praveen, Johnson, Mark, Johnson, Sally A., Jolley, Jennifer D., Jones, Bryony, Jones, Julie, Josifova, Dragana, Jurkute, Neringa, Karim, Yousuf M., Karoshi, Mahantesh A., Kasanicki, Mary A., Kazkaz, Hanadi, Kazmi, Rashid, Keeling, David, Kelleher, Peter, Kelly, Anne M., Kempster, Carly, Kennedy, Fiona, Kiani, Sorena, Kiely, David G., Kingston, Nathalie, Kinsey, Sally, Klein, Nigel, Klima, Robert, Knox, Ellen, Kostadima, Myrto A., Kovacs, Gabor, Koziell, Ania B., Kreuzhuber, Roman, Krishnakumar, Deepa, Kuijpers, Taco W., Kumar, Ajith, Kurian, Manju A., Laffan, James, Laffan, Michael A., Lalloo, Fiona, Lambert, Michele P., Lawman, Sarah H.A., Lawrie, Allan, Layton, D. Mark, Lear, Sara E., Lees, Melissa M., Lentaigne, Claire, Levine, Adam P., Lewington, Andrew J.P., Li, Wei, Liesner, Ri, Liu, Bin, Longhurst, Hilary, Lorenzo, Lorena E., Louka, Eleni, Hadeler, Silvia Lucato, Lyons, Paul A., Macdougall, Malcolm, Machado, Rajiv D., MacKenzie Ross, Robert V., Mackillop, Lucy H., MacLaren, Robert, Madan, Bella, Magee, Laura, Mahdi-Rogers, Mohamed, Maher, Eamonn R., Makris, Mike, Mangles, Sarah, Manson, Ania, Manzur, Adnan, Mapeta, Rutendo, Marchbank, Kevin J., Mark, Patrick B., Marks, Stephen, Markus, Hugh S., Marschall, Hanns Ulrich, Marshall, Andrew, Martin, Jennifer M., Masati, Larahmie, Mathias, Mary, Matser, Vera, Matthews, Emma L., Maw, Anna, Maxwell, Heather, McAlinden, Paul, McCarthy, Mark I., McDermott, Elizabeth M., McGowan, Simon J., McJannet, Coleen, McKinney, Harriet, Meacham, Stuart, Mead, Adam J., Castello, Ignacio Medina, Meehan, Sharon, Mehta, Sarju, Mercer, Catherine L., Michaelides, Michel, Michell, Anna C., Milford, David, Millar, Carolyn M., Millar, Hazel, Mistry, Anoop, Moenen, Floor, Moledina, Shahin, Montani, David, Moore, Anthony T., Moore, Jason, Morrell, Nicholas W., Morrisson, Valerie, Mozere, Monika, Muir, Keith W., Mumford, Andrew D., Murng, Sai H.K., Nasir, Iman, Nejentsev, Sergey, Newnham, Michael, Ng, Joanne, Ngoh, Adeline, Noorani, Sadia, Noori, Muna, Nurden, Paquita, O’Sullivan, Jennifer M., Obaji, Samya, Okoli, Steven, Oksenhendler, Eric, Olschewski, Andrea, Olschewski, Horst, Ong, Albert C.M., Ong, Kai Ren, Oram, Helen, Ormondroyd, Elizabeth, Othman, Shokri, Ouwehand, Willem H., Pantazis, Antonis, Papadia, Sofia, Papandreou, Apostolos, Park, Soo Mi, Parker, Alasdair P.J., Parry, David, Parsons, Georgina, Pasi, K. John, Paterson, Joan, Payne, Jeanette H., Peacock, Andrew J., Peerlinck, Kathelijne, Pepke-Zaba, Joanna, Perry, David, Petersen, Romina, Piechowski-Jozwiak, Bartlomiej, Pinto, Fernando, Polwarth, Gary J., Ponsford, Mark J., Prasad, Sanjay, Prokopenko, Inga, Psaila, Beth, Pyle, Angela, Qasim, Waseem, Quinn, Ellen, Quinti, Isabella, Raina, Sanjay, Ranganathan, Lavanya, Rankin, Julia, Rankin, Stuart, Rao, Anupama, Raymond, F. Lucy, Rehnstrom, Karola, Reid, Evan, Reilly, Mary M., Renton, Tara, Revel-Vilk, Shoshana, Rhodes, Christopher J., Rice, Andrew S.C., Richards, Emma E., Richards, Mike, Richardson, Sylvia, Richter, Alex, Robert, Leema, Roberts, Irene, Rondina, Matthew T., Rosser, Elisabeth, Rothwell, Peter, Roughley, Catherine, Roy, Noemi B., Rue-Albrecht, Kevin, Sadeghi-Alavijeh, Omid, Saleem, Moin A., Salmon, Richard M., Samani, Nilesh J., Sambrook, Jennifer G., Sandford, Richard, Santra, Saikat, Satchell, Simon C., Savic, Sinisa, Scelsi, Laura, Schotte, Gwen, Schulman, Sol, Schulze, Harald, Scott, Richard, Scully, Marie, Searle, Claire, Seeger, Werner, Sewell, W. A.Carrock, Seyres, Denis, Shackley, Fiona, Shamardina, Olga, Shapiro, Susan E., Sharma, Pankaj, Shehata, Hassan A., Shipley, Deborah, Shtoyerman, Rakefet, Sibson, Keith, Side, Lucy, Simpson, Michael, Sims, Matthew C., Sinha, Manish D., Sivapalaratnam, Suthesh, Skytte, Anne Bine, Smith, Kenneth G.C., Snape, Katie, Sneddon, Linda, Sohal, Aman, Soubrier, Florent, Southgate, Laura, Southwood, Mark, Splitt, Miranda, Staines, Simon, Stark, Hannah, Stauss, Hans, Steele, Cathal L., Stein, Daniel, Stein, Penelope E., Stock, Sophie, Stubbs, Matthew J., Suntharalingam, Jay, Swietlik, Emilia M., Symington, Emily, Tait, R. Campbell, Talks, Kate, Tan, Rhea Y.Y., Taylor, Gordon B., Thachil, Jecko, Themistocleous, Andreas C., Thomas, David C., Thomas, Ellen, Thomas, Patrick, Thompson, Dorothy A., Thomson, Kate, Thrasher, Adrian J., Thys, Chantal, Tilly, Tobias, Tischkowitz, Marc, Titterton, Catherine, Todd, John A., Toh, Cheng Hock, Tool, Anton T.J., Toshner, Mark R., Traylor, Matthew, Treacy, Carmen M., Treadaway, Paul, Trembath, Richard C., Trippier, Sarah, Tuna, Salih, Turek, Wojciech, Turro, Ernest, Upton, Paul D., Urniaz, Rafal, Vale, Tom, Van Geet, Chris, van Zuydam, Natalie, Vandersteen, Anthony M., Vazquez-Lopez, Marta, Veltman, Marijcke W.M., Vogt, Julie, von Ziegenweidt, Julie, Noordegraaf, Anton Vonk, Vora, Ajay, Vries, Minka J.A., Wakeling, Emma L., Walker, Neil, Walker, Suellen M., Walsh, Roddy, Wanjiku, Ivy, Ware, James S., Warner, Timothy Q., Wassmer, Evangeline, Watkins, Hugh, Watson, Henry G., Watt, Christopher, Waugh, Dean, Webb, Nick, Webster, Andrew R., Wei, Wei, Welch, Angela, Welch, Steven B., Werring, David, Wessels, Julie, Westbury, Sarah K., Westwood, John Paul W., Wharton, John, Whitehorn, Deborah, Whitworth, James, Wilkins, Martin R., Willcocks, Lisa, Williams, David J., Williamson, Catherine, Wong, Edwin K.S., Wood, Nicholas, Wood, Yvette, Woods, Christopher Geoffrey, Woodward, Emma R., Workman, Sarita, Wort, Stephen J., Yates, Katherine, Yeatman, Nigel, Yong, Patrick F.K., Young, Timothy, Yu, Ping, Yu-Wai-Man, Patrick, Zlamalova, Eliska, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, and ACS - Atherosclerosis & ischemic syndromes

Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2020

40. Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures

Author

Tang, Shan, Addis, Laura, Smith, Anna, Topp, Simon D., Pendziwiat, Manuela, Mei, Davide, Parker, Alasdair, Agrawal, Shakti, Hughes, Elaine, Lascelles, Karine, Williams, Ruth E., Fallon, Penny, Robinson, Robert, Cross, Helen J., Hedderly, Tammy, Eltze, Christin, Kerr, Tim, Desurkar, Archana, Hussain, Nahin, Kinali, Maria, Bagnasco, Irene, Vassallo, Grace, Whitehouse, William, Goyal, Sushma, Absoud, Michael, Møller, Rikke S., Helbig, Ingo, Weber, Yvonne G., Marini, Carla, Guerrini, Renzo, Simpson, Michael A., Pal, Deb K., Craiu, Dana, Davila, Carol, Obregia, Alexandru, De Jonghe, Peter, Lehesjoki, Anna‐Elina, Muhle, Hiltrud, Neubauer, Bernd, Selmer, Kaja, Stephani, Ulrich, Sterbova, Katalin, Striano, Pasquale, Talvik, Tiina, von Spiczak, Sarah, Weckhuysen, Sarah, Caglayan, Hande, Hoffman‐Zacharska, Dorota, Department of Medical and Clinical Genetics, Neuroscience Center, University of Helsinki, and EuroEPINOMICS-RES Consortium

Subjects
Male, 0301 basic medicine, Pediatrics, INTELLECTUAL DISABILITY, PROGNOSIS, Autism Spectrum Disorder, PROTEIN, Epilepsies, Myoclonic, VARIANTS, epilepsy/seizures, 3124 Neurology and psychiatry, Epilepsy, myoclonic astatic epilepsy, 0302 clinical medicine, OF-FUNCTION MUTATIONS, genetics, Age of Onset, Child, Exome, Doose syndrome, seizures, FEBRILE SEIZURES, Seizure types, Electroencephalography, 3. Good health, Phenotype, Neurology, Autism spectrum disorder, Child, Preschool, Epilepsy, Generalized, Female, medicine.medical_specialty, GENERALIZED EPILEPSY, Neuroimaging, 03 medical and health sciences, Exome Sequencing, medicine, Myoclonic atonic seizures, Humans, Generalized epilepsy, AUTISM, ASTATIC EPILEPSY, business.industry, 3112 Neurosciences, Infant, medicine.disease, 030104 developmental biology, Myoclonic astatic epilepsy, Attention Deficit Disorder with Hyperactivity, DE-NOVO MUTATIONS, Autism, epilepsy, Human medicine, Neurology (clinical), 3111 Biomedicine, business, 030217 neurology & neurosurgery
Abstract

OBJECTIVE: We aimed to describe the extent of neurodevelopmental impairments and identify the genetic etiologies in a large cohort of patients with epilepsy with myoclonic atonic seizures (MAE).METHODS: We deeply phenotyped MAE patients for epilepsy features, intellectual disability, autism spectrum disorder, and attention-deficit/hyperactivity disorder using standardized neuropsychological instruments. We performed exome analysis (whole exome sequencing) filtered on epilepsy and neuropsychiatric gene sets to identify genetic etiologies.RESULTS: We analyzed 101 patients with MAE (70% male). The median age of seizure onset was 34 months (range = 6-72 months). The main seizure types were myoclonic atonic or atonic in 100%, generalized tonic-clonic in 72%, myoclonic in 69%, absence in 60%, and tonic seizures in 19% of patients. We observed intellectual disability in 62% of patients, with extremely low adaptive behavioral scores in 69%. In addition, 24% exhibited symptoms of autism and 37% exhibited attention-deficit/hyperactivity symptoms. We discovered pathogenic variants in 12 (14%) of 85 patients, including five previously published patients. These were pathogenic genetic variants in SYNGAP1 (n = 3), KIAA2022 (n = 2), and SLC6A1 (n = 2), as well as KCNA2, SCN2A, STX1B, KCNB1, and MECP2 (n = 1 each). We also identified three new candidate genes, ASH1L, CHD4, and SMARCA2 in one patient each.SIGNIFICANCE: MAE is associated with significant neurodevelopmental impairment. MAE is genetically heterogeneous, and we identified a pathogenic genetic etiology in 14% of this cohort by exome analysis. These findings suggest that MAE is a manifestation of several etiologies rather than a discrete syndromic entity.

Published
2020

41. Whole-genome sequencing of a sporadic primary immunodeficiency cohort

Author

Thaventhiran, James E.D., Lango Allen, Hana, Burren, Oliver S., Rae, William, Greene, Daniel, Staples, Emily, Zhang, Zinan, Farmery, James H.R., Simeoni, Ilenia, Rivers, Elizabeth, Maimaris, Jesmeen, Penkett, Christopher J., Stephens, Jonathan, Deevi, Sri V.V., Sanchis-Juan, Alba, Gleadall, Nicholas S., Thomas, Moira J., Sargur, Ravishankar B., Gordins, Pavels, Baxendale, Helen E., Brown, Matthew, Tuijnenburg, Paul, Worth, Austen, Hanson, Steven, Linger, Rachel J., Buckland, Matthew S., Rayner-Matthews, Paula J., Gilmour, Kimberly C., Samarghitean, Crina, Seneviratne, Suranjith L., Sansom, David M., Lynch, Andy G., Megy, Karyn, Ellinghaus, Eva, Ellinghaus, David, Jorgensen, Silje F., Karlsen, Tom H., Stirrups, Kathleen E., Cutler, Antony J., Kumararatne, Dinakantha S., Chandra, Anita, Edgar, J. David M., Herwadkar, Archana, Cooper, Nichola, Grigoriadou, Sofia, Huissoon, Aarnoud P., Goddard, Sarah, Jolles, Stephen, Schuetz, Catharina, Boschann, Felix, Abbs, Stephen, Adhya, Zoe, Adlard, Julian, Afzal, Maryam, Ahmed, Irshad, Ahmed, Munaza, Ahmed, Saeed, Aitman, Timothy J., Alachkar, Hana, Alamelu, Jayanthi, Alikhan, Raza, Allen, Carl E., Allen, Louise, Allsup, David J., Alvi, Arif, Ambegaonkar, Gautam, Anantharachagan, Ariharan, Ancliff, Philip, Anderson, Julie, Antrobus, Richard, Armstrong, Ruth, Arno, Gavin, Arumugakani, Gururaj, Arya, Rita, Ashford, Sofie, Astle, William J., Attwood, Anthony, Austin, Steve, Aydinok, Yesim, Ayub, Waqar, Babbs, Christian, Bacchelli, Chiara, Baglin, Trevor, Bakchoul, Tamam, Bariana, Tadbir K., Barratt, Jonathan, Barwell, Julian, Baski, John, Bates, Rachel W., Batista, Joana, Baynam, Gareth, Bennett, David L., Bethune, Claire, Bhatnagar, Neha, Bibi, Shahnaz, Bierzynska, Agnieszka, Biss, Tina, Bitner-Glindzicz, Maria A.K., Bleda, Marta, Blesneac, Iulia, Boardman, Barbara, Boddana, Preetham, Bogaard, Harm J., Booth, Claire, Boyce, Sara, Bradley, John R., Brady, Angela, Breen, Gerome, Brennan, Paul, Brewer, Carole, Briley, Annette, Brown, Richard, Browning, Michael J., Brownlie, Mary, Bryson, Christine J., Buchan, Rachel J., Buck, Jackie, Bueser, Teofila, Diz, Carmen Bugarin, Burns, Siobhan O., Calleja, Paul, Carmichael, Jenny, Carr-White, Gerald, Carss, Keren J., Casey, Ruth, Chalmers, Elizabeth, Chambers, Jenny, Chambers, John, Chan, Melanie M.Y., Chan, Melissa V., Cheng, Floria, Chinn, Ivan K., Chinnery, Patrick F., Chitre, Manali, Chong, Sam, Christian, Martin T., Church, Colin, Clement, Emma M., Brod, Naomi Clements, Clifford, Hayley, Clowes, Virginia E., Coghlan, Gerry, Colby, Elizabeth, Cole, Trevor R.P., Collins, Janine H., Collins, Peter W., Condliffe, Robin, Cook, H. Terence, Cook, Stuart, Cookson, Victoria, Corris, Paul A., Creaser-Myers, Amanda, Crisp-Hihn, Abigail, Curry, Nicola S., Da Costa, Rosa, Danesino, Cesare, Daniels, Matthew J., Darby, Damaris, Daugherty, Louise C., Davies, E. G., Davies, Sophie, Davis, John, de Bree, Godelieve J., Deacock, Sarah, Deegan, Patrick B., Dempster, John, Dent, Timothy, Deshpande, Charu, Devlin, Lisa A., Dewhurst, Eleanor F., Dixit, Anand K., Dixon, Peter H., Doffinger, Rainer, Dolling, Helen, Dormand, Natalie, Downes, Kate, Drazyk, Anna M., Drewe, Elizabeth, Duarte, Daniel, Dutt, Tina, Edwards, Karen E., Egner, William, Ekani, Melanie N., El-Shanawany, Tariq, Elkhalifa, Shuayb, Elston, Tony, Emmerson, Ingrid, Erber, Wendy N., Erwood, Marie, Estiu, Maria C., Evans, Dafydd Gareth, Evans, Gillian, Everington, Tamara, Eyries, Mélanie, Favier, Remi, Firth, Helen V., Fitzpatrick, Maggie M., Fletcher, Debra, Flinter, Frances A., Fox, James C., Frary, Amy J., French, Courtney E., Freson, Kathleen, Frontini, Mattia, Furie, Bruce, Gale, Daniel P., Gall, Henning J., Gardham, Alice, Gaspar, H. Bobby, Gattens, Michael, Ghali, Neeti, Ghataorhe, Pavandeep K., Ghio, Stefano, Ghofrani, Hossein Ardeschir, Ghurye, Rohit, Gibbs, J. Simon R., Gilbert, Rodney D., Girerd, Barbara, Girling, Joanna C., Gissen, Paul, Gorman, Kathleen M., Gosal, David, Graf, Stefan, Grassi, Luigi, Greenhalgh, Alan J., Greenhalgh, Lynn, Greinacher, Andreas, Gresele, Paolo, Griffiths, Philip G., Griffiths, Sian, Grozeva, Detelina, Hackett, Scott J., Hadden, Robert D.M., Hadinnapola, Charaka, Hague, Rosie, Hague, William M., Haimel, Matthias, Hall, Matthew, Halmagyi, Csaba, Hammerton, Tracey, Hanson, Helen L., Harkness, Kirsty, Harper, Andrew R., Harper, Lorraine, Harris, Claire, Harrison, Claire, Hart, Daniel, Hassan, Ahamad, Hayman, Grant, Heemskerk, Johan W.M., Hegde, Shivaram, Henderson, Alex, Henderson, Robert H., Hensiek, Anke, Henskens, Yvonne M.C., Hodgson, Joshua, Hoffman, Jonathan, Holden, Simon, Holder, Muriel, Horvath, Rita, Houlden, Henry, Houweling, Arjan C., Howard, Luke S., Hu, Fengyuan, Hudson, Gavin, Hughes, Sean, Hughes, Stephen, Huis in ‘t Veld, Anna E., Humbert, Marc, Hurles, Matthew E., Hurst, Jane A., Irvine, Val, Izatt, Louise, James, Roger, Jeevaratnam, Praveen, Johnson, Mark, Johnson, Sally A., Jolley, Jennifer D., Jones, Bryony, Jones, Julie, Josifova, Dragana, Jurkute, Neringa, Karim, Yousuf M., Karoshi, Mahantesh A., Kasanicki, Mary A., Kazkaz, Hanadi, Kazmi, Rashid, Keeling, David, Kelleher, Peter, Kelly, Anne M., Kempster, Carly, Kennedy, Fiona, Kiani, Sorena, Kiely, David G., Kingston, Nathalie, Kinsey, Sally, Klein, Nigel, Klima, Robert, Knox, Ellen, Kostadima, Myrto A., Kovacs, Gabor, Koziell, Ania B., Kreuzhuber, Roman, Krishnakumar, Deepa, Kuijpers, Taco W., Kumar, Ajith, Kurian, Manju A., Laffan, James, Laffan, Michael A., Lalloo, Fiona, Lambert, Michele P., Lawman, Sarah H.A., Lawrie, Allan, Layton, D. Mark, Lear, Sara E., Lees, Melissa M., Lentaigne, Claire, Levine, Adam P., Lewington, Andrew J.P., Li, Wei, Liesner, Ri, Liu, Bin, Longhurst, Hilary, Lorenzo, Lorena E., Louka, Eleni, Hadeler, Silvia Lucato, Lyons, Paul A., Macdougall, Malcolm, Machado, Rajiv D., MacKenzie Ross, Robert V., Mackillop, Lucy H., MacLaren, Robert, Madan, Bella, Magee, Laura, Mahdi-Rogers, Mohamed, Maher, Eamonn R., Makris, Mike, Mangles, Sarah, Manson, Ania, Manzur, Adnan, Mapeta, Rutendo, Marchbank, Kevin J., Mark, Patrick B., Marks, Stephen, Markus, Hugh S., Marschall, Hanns Ulrich, Marshall, Andrew, Martin, Jennifer M., Masati, Larahmie, Mathias, Mary, Matser, Vera, Matthews, Emma L., Maw, Anna, Maxwell, Heather, McAlinden, Paul, McCarthy, Mark I., McDermott, Elizabeth M., McGowan, Simon J., McJannet, Coleen, McKinney, Harriet, Meacham, Stuart, Mead, Adam J., Castello, Ignacio Medina, Meehan, Sharon, Mehta, Sarju, Mercer, Catherine L., Michaelides, Michel, Michell, Anna C., Milford, David, Millar, Carolyn M., Millar, Hazel, Mistry, Anoop, Moenen, Floor, Moledina, Shahin, Montani, David, Moore, Anthony T., Moore, Jason, Morrell, Nicholas W., Morrisson, Valerie, Mozere, Monika, Muir, Keith W., Mumford, Andrew D., Murng, Sai H.K., Nasir, Iman, Nejentsev, Sergey, Newnham, Michael, Ng, Joanne, Ngoh, Adeline, Noorani, Sadia, Noori, Muna, Nurden, Paquita, O’Sullivan, Jennifer M., Obaji, Samya, Okoli, Steven, Oksenhendler, Eric, Olschewski, Andrea, Olschewski, Horst, Ong, Albert C.M., Ong, Kai Ren, Oram, Helen, Ormondroyd, Elizabeth, Othman, Shokri, Ouwehand, Willem H., Pantazis, Antonis, Papadia, Sofia, Papandreou, Apostolos, Park, Soo Mi, Parker, Alasdair P.J., Parry, David, Parsons, Georgina, Pasi, K. John, Paterson, Joan, Payne, Jeanette H., Peacock, Andrew J., Peerlinck, Kathelijne, Pepke-Zaba, Joanna, Perry, David, Petersen, Romina, Piechowski-Jozwiak, Bartlomiej, Pinto, Fernando, Polwarth, Gary J., Ponsford, Mark J., Prasad, Sanjay, Prokopenko, Inga, Psaila, Beth, Pyle, Angela, Qasim, Waseem, Quinn, Ellen, Quinti, Isabella, Raina, Sanjay, Ranganathan, Lavanya, Rankin, Julia, Rankin, Stuart, Rao, Anupama, Raymond, F. Lucy, Rehnstrom, Karola, Reid, Evan, Reilly, Mary M., Renton, Tara, Revel-Vilk, Shoshana, Rhodes, Christopher J., Rice, Andrew S.C., Richards, Emma E., Richards, Mike, Richardson, Sylvia, Richter, Alex, Robert, Leema, Roberts, Irene, Rondina, Matthew T., Rosser, Elisabeth, Rothwell, Peter, Roughley, Catherine, Roy, Noemi B., Rue-Albrecht, Kevin, Sadeghi-Alavijeh, Omid, Saleem, Moin A., Salmon, Richard M., Samani, Nilesh J., Sambrook, Jennifer G., Sandford, Richard, Santra, Saikat, Satchell, Simon C., Savic, Sinisa, Scelsi, Laura, Schotte, Gwen, Schulman, Sol, Schulze, Harald, Scott, Richard, Scully, Marie, Searle, Claire, Seeger, Werner, Sewell, W. A.Carrock, Seyres, Denis, Shackley, Fiona, Shamardina, Olga, Shapiro, Susan E., Sharma, Pankaj, Shehata, Hassan A., Shipley, Deborah, Shtoyerman, Rakefet, Sibson, Keith, Side, Lucy, Simpson, Michael, Sims, Matthew C., Sinha, Manish D., Sivapalaratnam, Suthesh, Skytte, Anne Bine, Smith, Kenneth G.C., Snape, Katie, Sneddon, Linda, Sohal, Aman, Soubrier, Florent, Southgate, Laura, Southwood, Mark, Splitt, Miranda, Staines, Simon, Stark, Hannah, Stauss, Hans, Steele, Cathal L., Stein, Daniel, Stein, Penelope E., Stock, Sophie, Stubbs, Matthew J., Suntharalingam, Jay, Swietlik, Emilia M., Symington, Emily, Tait, R. Campbell, Talks, Kate, Tan, Rhea Y.Y., Taylor, Gordon B., Thachil, Jecko, Themistocleous, Andreas C., Thomas, David C., Thomas, Ellen, Thomas, Patrick, Thompson, Dorothy A., Thomson, Kate, Thrasher, Adrian J., Thys, Chantal, Tilly, Tobias, Tischkowitz, Marc, Titterton, Catherine, Todd, John A., Toh, Cheng Hock, Tool, Anton T.J., Toshner, Mark R., Traylor, Matthew, Treacy, Carmen M., Treadaway, Paul, Trembath, Richard C., Trippier, Sarah, Tuna, Salih, Turek, Wojciech, Turro, Ernest, Upton, Paul D., Urniaz, Rafal, Vale, Tom, Van Geet, Chris, van Zuydam, Natalie, Vandersteen, Anthony M., Vazquez-Lopez, Marta, Veltman, Marijcke W.M., Vogt, Julie, von Ziegenweidt, Julie, Noordegraaf, Anton Vonk, Vora, Ajay, Vries, Minka J.A., Wakeling, Emma L., Walker, Neil, Walker, Suellen M., Walsh, Roddy, Wanjiku, Ivy, Ware, James S., Warner, Timothy Q., Wassmer, Evangeline, Watkins, Hugh, Watson, Henry G., Watt, Christopher, Waugh, Dean, Webb, Nick, Webster, Andrew R., Wei, Wei, Welch, Angela, Welch, Steven B., Werring, David, Wessels, Julie, Westbury, Sarah K., Westwood, John Paul W., Wharton, John, Whitehorn, Deborah, Whitworth, James, Wilkins, Martin R., Willcocks, Lisa, Williams, David J., Williamson, Catherine, Wong, Edwin K.S., Wood, Nicholas, Wood, Yvette, Woods, Christopher Geoffrey, Woodward, Emma R., Workman, Sarita, Wort, Stephen J., Yates, Katherine, Yeatman, Nigel, Yong, Patrick F.K., Young, Timothy, Yu, Ping, Yu-Wai-Man, Patrick, Zlamalova, Eliska, Wellcome Trust, Thaventhiran, James [0000-0001-8616-074X], Lango Allen, Hana [0000-0002-7803-8688], Burren, Oliver [0000-0002-3388-5760], Rae, William [0000-0003-0095-2514], Zhang, Zinan [0000-0003-3831-2272], Megy, Karyn [0000-0002-2826-3879], Johnson, Kathleen [0000-0002-6823-3252], Smith, Kenneth [0000-0003-3829-4326], Apollo - University of Cambridge Repository, University of St Andrews. School of Medicine, University of St Andrews. Statistics, University of St Andrews. Sir James Mackenzie Institute for Early Diagnosis, University of St Andrews. Cellular Medicine Division, Ege Üniversitesi, Experimental Immunology, Graduate School, AII - Inflammatory diseases, Infectious diseases, APH - Aging & Later Life, APH - Global Health, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Human genetics, APH - Quality of Care, ACS - Atherosclerosis & ischemic syndromes, Biochemie, RS: Carim - B03 Cell biochemistry of thrombosis and haemostasis, Faculteit FHML Centraal, MUMC+: DA CDL Algemeen (9), RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, MUMC+: MA Hematologie (9), Interne Geneeskunde, and Promovendi CD

Subjects
0301 basic medicine, Male, Protein Tyrosine Phosphatase, Non-Receptor Type 2/genetics, Genome-wide association study, VARIANTS, Regulatory Sequences, Nucleic Acid, medicine.disease_cause, Genome, Cohort Studies, 0302 clinical medicine, RARE, QR180 Immunology, Primary Immunodeficiency Consortium for the NIHR Bioresource, Genetics, Protein Tyrosine Phosphatase, Non-Receptor Type 2, Multidisciplinary, Suppressor of Cytokine Signaling 1 Protein/genetics, GENETIC-VARIATION, RNA-Binding Proteins, Primary Immunodeficiency Diseases/diagnosis, ASSOCIATION, Penetrance, Multidisciplinary Sciences, DEFICIENCY, QR180, Science & Technology - Other Topics, Female, General Science & Technology, Primary Immunodeficiency Diseases, Transcription Factors/genetics, Genomics, COMMON VARIABLE IMMUNODEFICIENCY, QH426 Genetics, Biology, Article, Actin-Related Protein 2-3 Complex, 03 medical and health sciences, Suppressor of Cytokine Signaling 1 Protein, SDG 3 - Good Health and Well-being, SUPPRESSOR, Actin-Related Protein 2-3 Complex/genetics, medicine, Humans, QH426, Whole genome sequencing, Science & Technology, Whole Genome Sequencing, Common variable immunodeficiency, DAS, Bayes Theorem, Immune dysregulation, Regulatory Sequences, Nucleic Acid/genetics, medicine.disease, RNA-Binding Proteins/genetics, STAT1 MUTATIONS, 030104 developmental biology, Primary immunodeficiency, IUIS PHENOTYPIC CLASSIFICATION, GAIN, 030215 immunology, Genome-Wide Association Study, Transcription Factors
Abstract

Primary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges. Although the most severe forms of PID are identified in early childhood, most patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent and up to 10% develop lymphoid malignancies1–3. Consequently, in sporadic (or non-familial) PID genetic diagnosis is difficult and the role of genetics is not well defined. Here we address these challenges by performing whole-genome sequencing in a large PID cohort of 1,318 participants. An analysis of the coding regions of the genome in 886 index cases of PID found that disease-causing mutations in known genes that are implicated in monogenic PID occurred in 10.3% of these patients, and a Bayesian approach (BeviMed4) identified multiple new candidate PID-associated genes, including IVNS1ABP. We also examined the noncoding genome, and found deletions in regulatory regions that contribute to disease causation. In addition, we used a genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization of—and interplay between—novel high-penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to the variable penetrance and phenotypic complexity that are observed in PID. Thus, using a cohort-based whole-genome-sequencing approach in the diagnosis of PID can increase diagnostic yield and further our understanding of the key pathways that influence immune responsiveness in humans. © 2020, The Author(s), under exclusive licence to Springer Nature Limited., Wellcome Trust, WT: 104807/Z/14/Z University College London, UCL: 100140/Z/12/Z, 107212/Z/15/Z, MR/L019027, 203141/Z/16/Z, 091157/Z/10/Z Bundesministerium für Bildung und Forschung, BMBF: 01ZX1306A University of Cambridge 201250/Z/16/Z 01ZX1709 Seventh Framework Programme, FP7 NIHR Bristol Biomedical Research Centre Deutsche Forschungsgemeinschaft, DFG Deutsche Forschungsgemeinschaft, DFG: EXC 2167-390884018 Juvenile Diabetes Research Foundation United Kingdom, JDRF: 9-2011-253, 5-SRA-2015-130-A-N National Institute for Health Research, NIHR: RG65966 Medical Research Council, MRC: RG95376, MR/L006197/1 Great Ormond Street Hospital for Children, GOSH, Acknowledgements The NBR-RD PID Consortium is part of the NIHR BioResource, for which funding was provided by the NIHR (NIHR, grant number RG65966). We acknowledge the participation of all NIHR BioResource volunteers, and thank the NIHR BioResource centre and staff for their contribution. J.E.D.T. is supported by the Medical Research Council (MRC) (RG95376 and MR/L006197/1); A.J.T. is supported by the Wellcome Trust (104807/Z/14/Z) and the NIHR Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London; K.G.C.S. is supported by the MRC (programme grant MR/L019027) and is a Wellcome Investigator; A.J.C. was supported by the Wellcome Trust (091157/Z/10/Z, 107212/Z/15/Z, 100140/Z/12/Z, 203141/Z/16/Z), JDRF (9-2011-253, 5-SRA-2015-130-A-N), NIHR Oxford Biomedical Research Centre and NIHR Cambridge Biomedical Research Centre; E.E. has received funding from the European Union Seventh Framework Programme (FP7-PEOPLE-2013-COFUND) under grant agreement number 609020-Scientia Fellows; E.R. is supported by the Wellcome Trust (201250/Z/16/Z); D.E. is supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (SysInflame grant 01ZX1306A; GB-XMAP grant 01ZX1709) and funded by the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation) under Germany’s Excellence Strategy (EXC 2167-390884018). The NIHR Cambridge Biomedical Research Centre (BRC) is a partnership between Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge, funded by the NIHR. This research was co-funded by the support listed above and the NIHR Cambridge BRC.

Published
2020

44. Clinical and radiological characterization of novel FIG4‐related combined system disease with neuropathy

Author

Wright, Georgia C., primary, Brown, Richard, additional, Grayton, Hannah, additional, Livingston, John H., additional, Park, Soo‐Mi, additional, Parker, Alasdair P.J., additional, Patel, Anjla, additional, Simonic, Ingrid, additional, Thomas, Adam G., additional, Vadlamani, Gayatri, additional, Horvath, Rita, additional, and Harijan, Pooja D., additional

Published
2020
Full Text
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46. Fifteen-minute consultation: Efficient investigation of the child with early developmental impairment in the era of genomic sequencing.

Author

Coysh, Thomas, Hogg, Sarah Louise, Parker, Alasdair P. J., and Parker, Alasdair Pj

Subjects
INVESTIGATIONS, FAMILY counseling, DISABILITIES, PEDIATRICIANS
Abstract

The investigation of children with early developmental impairment (EDI) is challenging in terms of selecting investigations and supporting families through the diagnostic pathway. Modern genomic sequencing has the potential to greatly improve yield of investigation, but produces challenges in terms of timing and explaining its strengths/weaknesses to families. We present an evidence-based and practical guideline to help the paediatrician through all stages of investigation. We emphasise the importance of a really good history and examination, allowing targeted investigation for specific disorders and outline an approach for isolated EDI when this is not possible. This prioritises genetic investigation- after appropriate counselling to families, and balances the very low yield of biochemical/radiological investigations in isolated EDI, with the need to detect extremely rare, but potentially treatable disorders. Collaboration with both families and regional specialists to ensure appropriate testing is likely to reduce parental and clinician anxiety. [ABSTRACT FROM AUTHOR]

Published
2020
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47. Efficacy and Tolerability of the New Antiepileptic Drugs: Commentary on the Recently Published Practice Parameters

Author

Panayiotopoulos, Chrysostomos P., Benbadis, Selim R., Covanis, Athanasios, Dulac, Olivier, Duncan, John S., Eeg-Olofsson, Orvar, Ferrie, Colin D., Grünewald, Richard A., Trenite, Dorothee G. A. Kasteleijn-Nolst, Koutroumanidis, Michael, Martinovic, Zarko, Newton, Richard W., Parker, Alasdair P., Salas-Puig, Janvier, Sander, JWAS, Shorvon, Simon, Watanabe, Kazuyoshi, Whitehouse, William P., and Youroukos, Sotirios

Published
2004

50. Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data

Author

Farmery, James H. R., Smith, Mike L., Lynch, Andy G., Huissoon, Aarnoud, Furnell, Abigail, Mead, Adam, Levine, Adam P., Manzur, Adnan, Thrasher, Adrian, Greenhalgh, Alan, Parker, Alasdair, Sanchis-Juan, Alba, Richter, Alex, Gardham, Alice, Lawrie, Allan, Sohal, Aman, Creaser-Myers, Amanda, Frary, Amy, Greinacher, Andreas, Themistocleous, Andreas, Peacock, Andrew J., Marshall, Andrew, Mumford, Andrew, Rice, Andrew, Webster, Andrew, Brady, Angie, Koziell, Ania, Manson, Ania, Chandra, Anita, Hensiek, Anke, in't Veld, Anna Huis, Maw, Anna, Kelly, Anne M., Moore, Anthony, Noordegraaf, Anton Vonk, Attwood, Antony, Herwadkar, Archana, Ghofrani, Ardi, Houweling, Arjan C., Girerd, Barbara, Furie, Bruce, Treacy, Carmen M., Millar, Carolyn M., Sewell, Carrock, Roughley, Catherine, Titterton, Catherine, Williamson, Catherine, Hadinnapola, Charaka, Deshpande, Charu, Heemskerk, Johan W. M., Biochemie, and RS: CARIM - R1.03 - Cell biochemistry of thrombosis and haemostasis

Abstract

Telomere length is a risk factor in disease and the dynamics of telomere length are crucial to our understanding of cell replication and vitality. The proliferation of whole genome sequencing represents an unprecedented opportunity to glean new insights into telomere biology on a previously unimaginable scale. To this end, a number of approaches for estimating telomere length from whole-genome sequencing data have been proposed. Here we present Telomerecat, a novel approach to the estimation of telomere length. Previous methods have been dependent on the number of telomeres present in a cell being known, which may be problematic when analysing aneuploid cancer data and non-human samples. Telomerecat is designed to be agnostic to the number of telomeres present, making it suited for the purpose of estimating telomere length in cancer studies. Telomerecat also accounts for interstitial telomeric reads and presents a novel approach to dealing with sequencing errors. We show that Telomerecat performs well at telomere length estimation when compared to leading experimental and computational methods. Furthermore, we show that it detects expected patterns in longitudinal data, repeated measurements, and cross-species comparisons. We also apply the method to a cancer cell data, uncovering an interesting relationship with the underlying telomerase genotype.

Published
2018

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