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1. MetaBayesDTA: Codeless Bayesian meta-analysis of test accuracy, with or without a gold standard

Author

Cerullo, Enzo, Sutton, Alex J., Jones, Hayley E., Wu, Olivia, Quinn, Terry J., and Cooper, Nicola J.

Subjects
Statistics - Applications
Abstract

Introduction: Despite their applicability, statistical models used for the meta-analysis of test accuracy require specialised knowledge to implement, with the necessary level of expertise having recently increased. This is due to the development and recommendation to use more sophisticated methods; such as those in Version 2 of the Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy. This paper describes a web-based application that extends the functionality of previous applications, making many advanced analysis methods more accessible. Methods: We sought to create an extended, stand-alone, Bayesian version of MetaDTA, which (i) has the benefits of previously proposed applications and addresses key limitations of them, (ii) is accessible to researchers who do not have the specific expertise required to fit such models, and (iii) is suitable for experienced analysts. We created the application using Shiny and Stan. Results: We created MetaBayesDTA (https://crsu.shinyapps.io/MetaBayesDTA/), which allows users to conduct meta-analysis of test accuracy, with or without a gold standard. The application addresses several key limitations of other applications. For instance, for the bivariate model, one can conduct subgroup analysis, univariate meta-regression, and comparative test accuracy evaluation. Meanwhile, for the model which does not assume a perfect gold standard, the application can account for the fact that studies use different reference tests. Conclusions: Due to its user-friendliness and broad array of features, MetaBayesDTA should appeal to a wide variety of researchers. We anticipate that the application will encourage wider use of more advanced methods, which ultimately should improve the quality of test accuracy reviews.

Published
2022

3. The NightLife study — the clinical and cost-effectiveness of thrice-weekly, extended, in-centre nocturnal haemodialysis versus daytime haemodialysis using a mixed methods approach: study protocol for a randomised controlled trial

Author

Hull, Katherine L., Bramham, Kate, Brookes, Cassandra L., Cluley, Victoria, Conefrey, Carmel, Cooper, Nicola J., Eborall, Helen, Fotheringham, James, Graham-Brown, Matthew P. M., Gray, Laura J., Mark, Patrick B., Mitra, Sandip, Murphy, Gavin J., Quann, Niamh, Rooshenas, Leila, Warren, Madeleine, and Burton, James O.

Published
2023
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5. Meta-Analysis of Dichotomous and Ordinal Tests with an Imperfect Gold Standard

Author

Cerullo, Enzo, Jones, Hayley E., Carter, Olivia, Quinn, Terry J., Cooper, Nicola J., and Sutton, Alex J.

Abstract

Standard methods for the meta-analysis of medical tests, without assuming a gold standard, are limited to dichotomous data. Multivariate probit models are used to analyse correlated dichotomous data, and can be extended to model ordinal data. Within the context of an imperfect gold standard, they have previously been used for the analysis of dichotomous and ordinal test data from a single study, and for the meta-analysis of dichotomous tests. However, they have not previously been used for the meta-analysis of ordinal tests. In this article, we developed a Bayesian multivariate probit latent class model for the simultaneous meta-analysis of ordinal and dichotomous tests without assuming a gold standard, which also allows one to obtain summary estimates of joint test accuracy. We fitted the models using the software Stan, which uses a state-of-the-art Hamiltonian Monte Carlo algorithm, and we applied the models to a dataset in which studies evaluated the accuracy of tests, and test combinations, for deep vein thrombosis. We demonstrate the issues with dichotomising ordinal test accuracy data in the presence of an imperfect gold standard, before applying and comparing several variations of our proposed model which do not require the data to be dichotomised. The models proposed will allow researchers to more appropriately meta-analyse ordinal and dichotomous tests without a gold standard, potentially leading to less biased estimates of test accuracy. This may lead to a better understanding of which tests, and test combinations, should be used for any given medical condition.

Published
2022
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7. Meta-analysis of dichotomous and ordinal tests without a gold standard

Author

Cerullo, Enzo, Jones, Hayley E., Carter, Olivia, Quinn, Terry J., Cooper, Nicola J., and Sutton, Alex J.

Subjects
Statistics - Applications
Abstract

Standard methods for the meta-analysis of medical tests without a gold standard are limited to dichotomous data. Multivariate probit models are used to analyze correlated binary data, and can be extended to multivariate ordered probit models to model ordinal data. Within the context of an imperfect gold standard, they have previously been used for the analysis of dichotomous and ordinal tests in a single study, and for the meta-analysis of dichotomous tests. In this paper, we developed a hierarchical, latent class multivariate probit model for the simultaneous meta-analysis of ordinal and dichotomous tests without assuming a gold standard. The model can accommodate a hierarchical partial pooling model on the conditional within-study correlations, enabling one to obtain summary estimates of joint test accuracy. Dichotomous tests use probit regression likelihoods and ordinal tests use ordered probit regression likelihoods. We fitted the models using Stan, which uses a state-of-the-art Hamiltonian Monte Carlo algorithm. We applied the models to a dataset in which studies evaluated the accuracy of tests, and test combinations, for deep vein thrombosis. We first demonstrated the issues with dichotomising test accuracy data a priori without a gold standard by fitting models which dichotomised the ordinal test data, and then we applied models which do not dichotomise the data. Furthermore, we fitted and compared a variety of other models, including those which assumed conditional independence and dependence between tests, and those assuming perfect and an imperfect gold standard.

Published
2021

8. Biallelic CRELD1 variants cause a multisystem syndrome, including neurodevelopmental phenotypes, cardiac dysrhythmias, and frequent infections

Author

Borras, Silvia, Clark, Caroline, Dean, John, Miedzybrodzka, Zosia, Ross, Alison, Tennant, Stephen, Dabir, Tabib, Donnelly, Deirdre, Humphreys, Mervyn, Magee, Alex, McConnell, Vivienne, McKee, Shane, McNerlan, Susan, Morrison, Patrick J., Rea, Gillian, Stewart, Fiona, Cole, Trevor, Cooper, Nicola, Cooper-Charles, Lisa, Cox, Helen, Islam, Lily, Jarvis, Joanna, Keelagher, Rebecca, Lim, Derek, McMullan, Dominic, Morton, Jenny, Naik, Swati, O’Driscoll, Mary, Ong, Kai-Ren, Osio, Deborah, Ragge, Nicola, Turton, Sarah, Vogt, Julie, Williams, Denise, Bodek, Simon, Donaldson, Alan, Hills, Alison, Low, Karen, Newbury-Ecob, Ruth, Norman, Andrew M., Roberts, Eileen, Scurr, Ingrid, Smithson, Sarah, Tooley, Madeleine, Abbs, Steve, Armstrong, Ruth, Dunn, Carolyn, Holden, Simon, Park, Soo-Mi, Paterson, Joan, Raymond, Lucy, Reid, Evan, Sandford, Richard, Simonic, Ingrid, Tischkowitz, Marc, Woods, Geoff, Bradley, Lisa, Comerford, Joanne, Green, Andrew, Lynch, Sally, McQuaid, Shirley, Mullaney, Brendan, Berg, Jonathan, Goudie, David, Mavrak, Eleni, McLean, Joanne, McWilliam, Catherine, Reavey, Eleanor, Azam, Tara, Cleary, Elaine, Jackson, Andrew, Lam, Wayne, Lampe, Anne, Moore, David, Porteous, Mary, Baple, Emma, Baptista, Júlia, Brewer, Carole, Castle, Bruce, Kivuva, Emma, Owens, Martina, Rankin, Julia, Shaw-Smith, Charles, Turner, Claire, Turnpenny, Peter, Tysoe, Carolyn, Bradley, Therese, Davidson, Rosemarie, Gardiner, Carol, Joss, Shelagh, Kinning, Esther, Longman, Cheryl, McGowan, Ruth, Murday, Victoria, Pilz, Daniela, Tobias, Edward, Whiteford, Margo, Williams, Nicola, Barnicoat, Angela, Clement, Emma, Faravelli, Francesca, Hurst, Jane, Jenkins, Lucy, Jones, Wendy, Ajith Kumar, V.K., Lees, Melissa, Loughlin, Sam, Male, Alison, Morrogh, Deborah, Rosser, Elisabeth, Scott, Richard, Wilson, Louise, Beleza, Ana, Deshpande, Charu, Flinter, Frances, Holder, Muriel, Irving, Melita, Izatt, Louise, Josifova, Dragana, Mohammed, Shehla, Molenda, Aneta, Robert, Leema, Roworth, Wendy, Ruddy, Deborah, Ryten, Mina, Yau, Shu, Bennett, Christopher, Blyth, Moira, Campbell, Jennifer, Coates, Andrea, Dobbie, Angus, Hewitt, Sarah, Hobson, Emma, Jackson, Eilidh, Jewell, Rosalyn, Kraus, Alison, Prescott, Katrina, Sheridan, Eamonn, Thomson, Jenny, Bradshaw, Kirsty, Dixit, Abhijit, Eason, Jacqueline, Haines, Rebecca, Harrison, Rachel, Mutch, Stacey, Sarkar, Ajoy, Searle, Claire, Shannon, Nora, Sharif, Abid, Suri, Mohnish, Vasudevan, Pradeep, Canham, Natalie, Ellis, Ian, Greenhalgh, Lynn, Howard, Emma, Stinton, Victoria, Swale, Andrew, Weber, Astrid, Banka, Siddharth, Breen, Catherine, Briggs, Tracy, Burkitt-Wright, Emma, Chandler, Kate, Clayton-Smith, Jill, Donnai, Dian, Douzgou, Sofia, Gaunt, Lorraine, Jones, Elizabeth, Kerr, Bronwyn, Langley, Claire, Metcalfe, Kay, Smith, Audrey, Wright, Ronnie, Bourn, David, Burn, John, Fisher, Richard, Hellens, Steve, Henderson, Alex, Montgomery, Tara, Splitt, Miranda, Straub, Volker, Wright, Michael, Zwolinski, Simon, Allen, Zoe, Bernhard, Birgitta, Brady, Angela, Brooks, Claire, Busby, Louise, Clowes, Virginia, Ghali, Neeti, Holder, Susan, Ibitoye, Rita, Wakeling, Emma, Blair, Edward, Carmichael, Jenny, Cilliers, Deirdre, Clasper, Susan, Gibbons, Richard, Kini, Usha, Lester, Tracy, Nemeth, Andrea, Poulton, Joanna, Price, Sue, Shears, Debbie, Stewart, Helen, Wilkie, Andrew, Albaba, Shadi, Baker, Duncan, Balasubramanian, Meena, Johnson, Diana, Parker, Michael, Quarrell, Oliver, Stewart, Alison, Willoughby, Josh, Crosby, Charlene, Elmslie, Frances, Homfray, Tessa, Jin, Huilin, Lahiri, Nayana, Mansour, Sahar, Marks, Karen, McEntagart, Meriel, Saggar, Anand, Tatton-Brown, Kate, Butler, Rachel, Clarke, Angus, Corrin, Sian, Fry, Andrew, Kamath, Arveen, McCann, Emma, Mugalaasi, Hood, Pottinger, Caroline, Procter, Annie, Sampson, Julian, Sansbury, Francis, Varghese, Vinod, Baralle, Diana, Callaway, Alison, Cassidy, Emma J., Daniels, Stacey, Douglas, Andrew, Foulds, Nicola, Hunt, David, Kharbanda, Mira, Lachlan, Katherine, Mercer, Catherine, Side, Lucy, Temple, I. Karen, Wellesley, Diana, Ambrose, J.C., Arumugam, P., Baple, E.L., Bleda, M., Boardman-Pretty, F., Boissiere, J.M., Boustred, C.R., Caulfield, M.J., Chan, G.C., Craig, C.E.H., Daugherty, L.C., de Burca, A., Devereau, A., Elgar, G., Foulger, R.E., Fowler, T., FurióTarí, P., Hackett, J.M., Halai, D., Hamblin, A., Henderson, S., Holman, J.E., Hubbard, T.J.P., Ibáñez, K., Jackson, R., Jones, L.J., Kasperaviciute, D., Kayikci, M., Lahnstein, L., Lawson, K., Leigh, S.E.A., Leong, I.U.S., Lopez, F.J., MaleadyCrowe, F., Mason, J., McDonagh, E.M., Moutsianas, L., Mueller, M., Murugaesu, N., Need, A.C., Odhams, C.A., Patch, C., Perez-Gil, D., Polychronopoulos, D., Pullinger, J., Rahim, T., Rendon, A., Riesgo-Ferreiro, P., Rogers, T., Ryten, M., Savage, K., Sawant, K., Scott, R.H., Siddiq, A., Sieghart, A., Smedley, D., Smith, K.R., Sosinsky, A., Spooner, W., Stevens, H.E., Stuckey, A., Sultana, R., Thomas, E.R.A., Thompson, S.R., Tucci, A., Walsh, E., Watters, S.A., Welland, M.J., Williams, E., Witkowska, K., Acosta, Maria T., Adam, Margaret, Adams, David R., Agrawal, Pankaj B., Alejandro, Mercedes E., Alvey, Justin, Amendola, Laura, Andrews, Ashley, Ashley, Euan A., Azamian, Mahshid S., Bacino, Carlos A., Bademci, Guney, Baker, Eva, Balasubramanyam, Ashok, Baldridge, Dustin, Bale, Jim, Bamshad, Michael, Barbouth, Deborah, Bayrak-Toydemir, Pinar, Beck, Anita, Beggs, Alan H., Behrens, Edward, Bejerano, Gill, Bennet, Jimmy, Berg-Rood, Beverly, Bernstein, Jonathan A., Berry, Gerard T., Bican, Anna, Bivona, Stephanie, Blue, Elizabeth, Bohnsack, John, Bonnenmann, Carsten, Bonner, Devon, Botto, Lorenzo, Boyd, Brenna, Briere, Lauren C., Brokamp, Elly, Brown, Gabrielle, Burke, Elizabeth A., Burrage, Lindsay C., Butte, Manish J., Byers, Peter, Byrd, William E., Carey, John, Carrasquillo, Olveen, Peter Chang, Ta Chen, Chanprasert, Sirisak, Chao, Hsiao-Tuan, Clark, Gary D., Coakley, Terra R., Cobban, Laurel A., Cogan, Joy D., Coggins, Matthew, Cole, F. Sessions, Colley, Heather A., Cooper, Cynthia M., Craigen, William J., Crouse, Andrew B., Cunningham, Michael, D'Souza, Precilla, Dai, Hongzheng, Dasari, Surendra, Davids, Mariska, Dayal, Jyoti G., Deardorff, Matthew, Dell'Angelica, Esteban C., Dhar, Shweta U., Dipple, Katrina, Doherty, Daniel, Dorrani, Naghmeh, Douine, Emilie D., Draper, David D., Duncan, Laura, Earl, Dawn, Eckstein, David J., Emrick, Lisa T., Eng, Christine M., Esteves, Cecilia, Estwick, Tyra, Falk, Marni, Fernandez, Liliana, Ferreira, Carlos, Fieg, Elizabeth L., Findley, Laurie C., Fisher, Paul G., Fogel, Brent L., Forghani, Irman, Fresard, Laure, Gahl, William A., Glass, Ian, Godfrey, Rena A., Golden-Grant, Katie, Goldman, Alica M., Goldstein, David B., Grajewski, Alana, Groden, Catherine A., Gropman, Andrea L., Gutierrez, Irma, Hahn, Sihoun, Hamid, Rizwan, Hanchard, Neil A., Hassey, Kelly, Hayes, Nichole, High, Frances, Hing, Anne, Hisama, Fuki M., Holm, Ingrid A., Hom, Jason, Horike-Pyne, Martha, Huang, Alden, Huang, Yong, Isasi, Rosario, Jamal, Fariha, Jarvik, Gail P., Jarvik, Jeffrey, Jayadev, Suman, Johnston, Jean M., Karaviti, Lefkothea, Kelley, Emily G., Kennedy, Jennifer, Kiley, Dana, Kohane, Isaac S., Kohler, Jennefer N., Krakow, Deborah, Krasnewich, Donna M., Kravets, Elijah, Korrick, Susan, Koziura, Mary, Krier, Joel B., Lalani, Seema R., Lam, Byron, Lam, Christina, Lanpher, Brendan C., Lanza, Ian R., Lau, C. Christopher, LeBlanc, Kimberly, Lee, Brendan H., Lee, Hane, Levitt, Roy, Lewis, Richard A., Lincoln, Sharyn A., Liu, Pengfei, Liu, Xue Zhong, Longo, Nicola, Loo, Sandra K., Loscalzo, Joseph, Maas, Richard L., Macnamara, Ellen F., MacRae, Calum A., Maduro, Valerie V., Majcherska, Marta M., Mak, Bryan, Malicdan, May Christine V., Mamounas, Laura A., Manolio, Teri A., Mao, Rong, Maravilla, Kenneth, Markello, Thomas C., Marom, Ronit, Marth, Gabor, Martin, Beth A., Martin, Martin G., Martínez-Agosto, Julian A., Marwaha, Shruti, McCauley, Jacob, McCormack, Colleen E., McCray, Alexa T., McGee, Elisabeth, Mefford, Heather, Merritt, J. Lawrence, Might, Matthew, Mirzaa, Ghayda, Morava, Eva, Moretti, Paolo M., Morimoto, Marie, Mulvihill, John J., Murdock, David R., Nakano-Okuno, Mariko, Nath, Avi, Nelson, Stan F., Newman, John H., Nicholas, Sarah K., Nickerson, Deborah, Nieves-Rodriguez, Shirley, Novacic, Donna, Oglesbee, Devin, Orengo, James P., Pace, Laura, Pak, Stephen, Pallais, J. Carl, Papp, Jeanette C., Parker, Neil H., Phillips, John A., Posey, Jennifer E., Potocki, Lorraine, Pusey, Barbara N., Quinlan, Aaron, Raskind, Wendy, Raja, Archana N., Rao, Deepak A., Renteria, Genecee, Reuter, Chloe M., Rives, Lynette, Robertson, Amy K., Rodan, Lance H., Rosenfeld, Jill A., Rosenwasser, Natalie, Ruzhnikov, Maura, Sacco, Ralph, Sampson, Jacinda B., Samson, Susan L., Saporta, Mario, Scott, C. Ron, Schaechter, Judy, Schedl, Timothy, Scott, Daryl A., Sharma, Prashant, Shin, Jimann, Signer, Rebecca, Sillari, Catherine H., Silverman, Edwin K., Sinsheimer, Janet S., Sisco, Kathy, Smith, Edward C., Smith, Kevin S., Solem, Emily, Solnica-Krezel, Lilianna, Stoler, Joan M., Stong, Nicholas, Sullivan, Jennifer A., Sun, Angela, Sutton, Shirley, Sweetser, David A., Sybert, Virginia, Tabor, Holly K., Tamburro, Cecelia P., Tekin, Mustafa, Telischi, Fred, Thorson, Willa, Tifft, Cynthia J., Toro, Camilo, Tran, Alyssa A., Tucker, Brianna M., Urv, Tiina K., Vanderver, Adeline, Velinder, Matt, Viskochil, Dave, Vogel, Tiphanie P., Wahl, Colleen E., Wallace, Stephanie, Walley, Nicole M., Walsh, Chris A., Walker, Melissa, Wambach, Jennifer, Wan, Jijun, Wang, Lee-Kai, Wangler, Michael F., Ward, Patricia A., Wegner, Daniel, Wener, Mark, Wenger, Tara, Perry, Katherine Wesseling, Westerfield, Monte, Wheeler, Matthew T., Whitlock, Jordan, Wolfe, Lynne A., Woods, Jeremy D., Yamamoto, Shinya, Yang, John, Yu, Guoyun, Zastrow, Diane B., Zhao, Chunli, Zuchner, Stephan, Jeffries, Lauren, Mis, Emily K., McWalter, Kirsty, Donkervoort, Sandra, Brodsky, Nina N., Carpier, Jean-Marie, Ji, Weizhen, Ionita, Cristian, Roy, Bhaskar, Morrow, Jon S., Darbinyan, Armine, Iyer, Krishna, Aul, Ritu B., Chao, Katherine R., Cobbold, Laura, Cohen, Stacey, Custodio, Helena M., Drummond-Borg, Margaret, Finanger, Erika, Hainline, Bryan E., Helbig, Ingo, Hewson, Stacy, Hu, Ying, Jackson, Adam, Konstantino, Monica, Leach, Meganne E., McCormick, David, Nelson, Stanley, Nguyen, Joanne, Nugent, Kimberly, Ortega, Lucy, Goodkin, Howard P., Roeder, Elizabeth, Roy, Sani, Sapp, Katie, Saade, Dimah, Sisodiya, Sanjay M., Stals, Karen, Towner, Shelley, Wilson, William, Khokha, Mustafa K., Bönnemann, Carsten G., Lucas, Carrie L., and Lakhani, Saquib A.

Published
2024
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9. Evaluating the effect of a digital health intervention to enhance physical activity in people with chronic kidney disease (Kidney BEAM): a multicentre, randomised controlled trial in the UK

Author

Greenwood, Sharlene A, Young, Hannah M L, Briggs, Juliet, Castle, Ellen M, Walklin, Christy, Haggis, Lynda, Balkin, Caitlin, Asgari, Elham, Bhandari, Sunil, Burton, James O, Billany, Roseanne E, Bishop, Nicolette C, Bramham, Kate, Campbell, Jackie, Chilcot, Joseph, Cooper, Nicola J, Deelchand, Vashist, Graham-Brown, Matthew P M, Hamilton, Alexander, Jesky, Mark, Kalra, Philip A, Koufaki, Pelagia, McCafferty, Kieran, Nixon, Andrew C, Noble, Helen, Saynor, Zoe, Taal, Maarten W, Tollit, James, Wheeler, David C, Wilkinson, Thomas J, Worboys, Hannah, and Macdonald, Jamie H

Published
2024
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11. The development and internal pilot trial of a digital physical activity and emotional well-being intervention (Kidney BEAM) for people with chronic kidney disease

Author

Young, Hannah M. L., Castle, Ellen M., Briggs, Juliet, Walklin, Christy, Billany, Roseanne E., Asgari, Elham, Bhandari, Sunil, Bishop, Nicolette, Bramham, Kate, Burton, James O., Campbell, Jackie, Chilcot, Joseph, Cooper, Nicola, Deelchand, Vashist, Graham-Brown, Matthew P. M., Haggis, Lynda, Hamilton, Alexander, Jesky, Mark, Kalra, Philip A., Koufaki, Pelagia, Macdonald, Jamie, McCafferty, Kieran, Nixon, Andrew C., Noble, Helen, Saynor, Zoe L., Taal, Maarten W., Tollitt, James, Wheeler, David C., Wilkinson, Thomas J., and Greenwood, Sharlene A.

Published
2024
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15. WCN24-1556 The clinical and health economic effect of a 6-month physical activity digital health intervention on health-related quality of life in people with chronic kidney disease

Author

Greenwood, Sharlene, primary, Young, Hannah, additional, Briggs, Juliet, additional, Walklin, Christy, additional, Mangahis, Emmanuel, additional, Billany, Roseanne, additional, Cooper, Nicola, additional, Worboys, Hannah, additional, Castle, Ellen, additional, Campbell, Jackie, additional, Bramham, Kate, additional, and Macdonald, Jamie, additional

Published
2024
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17. Graphical Enhancements to Summary Receiver Operating Characteristic Plots to Facilitate the Analysis and Reporting of Meta-Analysis of Diagnostic Test Accuracy Data

Author

Patel, Amit, Cooper, Nicola, Freeman, Suzanne, and Sutton, Alex

Abstract

Diagnostic test accuracy (DTA) systematic reviews are conducted to summarize evidence on the accuracy of a diagnostic test including a critical evaluation of the primary studies. Where appropriate, the evidence is meta-analyzed to obtain pooled estimates of effectiveness. In this study, we reviewed and critiqued three DTA guidance documents with respect to the graphical presentation of DTA meta-analysis results. All three documents recommended the use of two forms of graphical presentation: (a) forest plots displaying meta-analysis results for sensitivity (ie, the true positive rate) and specificity (ie, true negative rate) separately, and (b) Summary Receiver Operating Characteristic (SROC) curve to provide a global summary of test performance. Two primary shortcomings were identified: (a) lack of incorporation of quality assessment results into the main analysis and; (b) ambiguity with which the contribution of individual studies is represented on SROC curves. In response, two alternative graphical approaches were developed: (1) A quality assessment enhanced SROC plot which displays the results from individual studies in the meta-analysis with multiple indicators of quality assessed using QUADAS-2; and (2) A percentage study weights enhanced SROC plot which accurately portrays the percentage contribution each study makes to the meta-analysis. The proposed enhanced SROC curves facilitate the exploration of DTA data, leading to a deeper understanding of the primary studies included in a DTA meta-analysis including identifying reasons for between study heterogeneity and why specific study results may be divergent. Both plots can easily be produced in the free online interactive application, MetaDTA (https://crsu.shinyapps.io/dta_ma/).

Published
2021
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18. Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy

Author

O’Donnell-Luria, Anne H, Pais, Lynn S, Faundes, Víctor, Wood, Jordan C, Sveden, Abigail, Luria, Victor, Jamra, Rami Abou, Accogli, Andrea, Amburgey, Kimberly, Anderlid, Britt Marie, Azzarello-Burri, Silvia, Basinger, Alice A, Bianchini, Claudia, Bird, Lynne M, Buchert, Rebecca, Carre, Wilfrid, Ceulemans, Sophia, Charles, Perrine, Cox, Helen, Culliton, Lisa, Currò, Aurora, Study, Deciphering Developmental Disorders, McRae, Jeremy F, Clayton, Stephen, Fitzgerald, Tomas W, Kaplanis, Joanna, Prigmore, Elena, Rajan, Diana, Sifrim, Alejandro, Aitken, Stuart, Akawi, Nadia, Alvi, Mohsan, Ambridge, Kirsty, Barrett, Daniel M, Bayzetinova, Tanya, Jones, Philip, Jones, Wendy D, King, Daniel, Krishnappa, Netravathi, Mason, Laura E, Singh, Tarjinder, Tivey, Adrian R, Ahmed, Munaza, Anjum, Uruj, Archer, Hayley, Armstrong, Ruth, Awada, Jana, Balasubramanian, Meena, Banka, Siddharth, Baralle, Diana, Barnicoat, Angela, Batstone, Paul, Baty, David, Bennett, Chris, Berg, Jonathan, Bernhard, Birgitta, Bevan, A Paul, Bitner-Glindzicz, Maria, Blair, Edward, Blyth, Moira, Bohanna, David, Bourdon, Louise, Bourn, David, Bradley, Lisa, Brady, Angela, Brent, Simon, Brewer, Carole, Brunstrom, Kate, Bunyan, David J, Burn, John, Canham, Natalie, Castle, Bruce, Chandler, Kate, Chatzimichali, Elena, Cilliers, Deirdre, Clarke, Angus, Clasper, Susan, Clayton-Smith, Jill, Clowes, Virginia, Coates, Andrea, Cole, Trevor, Colgiu, Irina, Collins, Amanda, Collinson, Morag N, Connell, Fiona, Cooper, Nicola, Cresswell, Lara, Cross, Gareth, Crow, Yanick, D’Alessandro, Mariella, Dabir, Tabib, Davidson, Rosemarie, Davies, Sally, de Vries, Dylan, Dean, John, Deshpande, Charu, Devlin, Gemma, Dixit, Abhijit, and Dobbie, Angus

Subjects
Biological Sciences, Genetics, Autism, Neurosciences, Brain Disorders, Neurodegenerative, Intellectual and Developmental Disabilities (IDD), Pediatric, Clinical Research, Epilepsy, Mental Health, Aetiology, 2.1 Biological and endogenous factors, Neurological, Adolescent, Adult, Child, Child, Preschool, DNA-Binding Proteins, Female, Genetic Variation, Haploinsufficiency, Heterozygote, Humans, Infant, Male, Neurodevelopmental Disorders, Pedigree, Phenotype, Young Adult, Deciphering Developmental Disorders (DDD) Study, H3K4 methylation, KMT2E, autism, epilepsy, epileptic encephalopathy, global developmental delay, intellectual disability, neurodevelopmental disorder, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

Published
2019

19. MetaInsight: An Interactive Web-Based Tool for Analyzing, Interrogating, and Visualizing Network Meta-Analyses Using R-Shiny and Netmeta

Author

Owen, Rhiannon K., Bradbury, Naomi, Xin, Yiqiao, Cooper, Nicola, and Sutton, Alex

Abstract

Background: Network meta-analysis (NMA) is a powerful analysis method used to identify the best treatments for a condition and is used extensively by health care decision makers. Although software routines exist for conducting NMA, they require considerable statistical programming expertise to use, which limits the number of researchers able to conduct such analyses. Objectives: To develop a web-based tool allowing users with only standard internet browser software to be able to conduct NMAs using an intuitive "point and click" interface and present the results using visual plots. Methods: Using the existing netmeta and Shiny packages for R to conduct the analyses, and to develop the user interface, we created the "MetaInsight" tool which is freely available to use via the web. Results: A package was created for conducting NMA which satisfied our objectives, and this is described, and its application demonstrated, using an illustrative example. Conclusions: We believe that many researchers will find our package helpful for facilitating NMA as well as allowing decision makers to scrutinize presented results visually and in real time. This will impact on the relevance of statistical analyses for health care decision making and sustainably increase capacity by empowering informed nonspecialists to be able to conduct more clinically relevant reviews. It is also hoped that others will be inspired to create similar tools for other advanced specialist analyses methods using the freely available technologies we have adopted.

Published
2019
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21. De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder

Author

Reijnders, Margot RF, Miller, Kerry A, Alvi, Mohsan, Goos, Jacqueline AC, Lees, Melissa M, de Burca, Anna, Henderson, Alex, Kraus, Alison, Mikat, Barbara, de Vries, Bert BA, Isidor, Bertrand, Kerr, Bronwyn, Marcelis, Carlo, Schluth-Bolard, Caroline, Deshpande, Charu, Ruivenkamp, Claudia AL, Wieczorek, Dagmar, Study, The Deciphering Developmental Disorders, Baralle, Diana, Blair, Edward M, Engels, Hartmut, Lüdecke, Hermann-Josef, Eason, Jacqueline, Santen, Gijs WE, Clayton-Smith, Jill, Chandler, Kate, Tatton-Brown, Katrina, Payne, Katelyn, Helbig, Katherine, Radtke, Kelly, Nugent, Kimberly M, Cremer, Kirsten, Strom, Tim M, Bird, Lynne M, Sinnema, Margje, Bitner-Glindzicz, Maria, van Dooren, Marieke F, Alders, Marielle, Koopmans, Marije, Brick, Lauren, Kozenko, Mariya, Harline, Megan L, Klaassens, Merel, Steinraths, Michelle, Cooper, Nicola S, Edery, Patrick, Yap, Patrick, Terhal, Paulien A, van der Spek, Peter J, Lakeman, Phillis, Taylor, Rachel L, Littlejohn, Rebecca O, Pfundt, Rolph, Mercimek-Andrews, Saadet, Stegmann, Alexander PA, Kant, Sarina G, McLean, Scott, Joss, Shelagh, Swagemakers, Sigrid MA, Douzgou, Sofia, Wall, Steven A, Küry, Sébastien, Calpena, Eduardo, Koelling, Nils, McGowan, Simon J, Twigg, Stephen RF, Mathijssen, Irene MJ, Nellaker, Christoffer, Brunner, Han G, and Wilkie, Andrew OM

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Biotechnology, Brain Disorders, Human Genome, Neurosciences, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Adolescent, Adult, Base Sequence, Cell Line, Child, Child, Preschool, Facies, Female, Genetic Association Studies, Humans, Infant, Inheritance Patterns, Loss of Function Mutation, Male, Neurodevelopmental Disorders, Protein Kinases, RNA, Messenger, Translocation, Genetic, Young Adult, Deciphering Developmental Disorders Study, Tousled-like, facial averaging, haploinsufficiency, intellectual disability, kinase, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2.

Published
2018

22. Participants aux Davidson's Principles and Practice of Medicine, 23eédition

Author

Angus, Brian J., primary, Anstee, Quentin M., additional, Burnett, Leslie, additional, Byers, Mark, additional, Campbell, Harry, additional, Clunie, Gavin P.R., additional, Colvin, Lesley A., additional, Conway, Bryan, additional, Cooper, Nicola, additional, Cracknell, Alison L., additional, Culligan, Dominic J., additional, Dark, Graham G., additional, Davenport, Richard J., additional, Dockrell, David H., additional, El-Omar, Emad, additional, Fallon, Marie, additional, FitzPatrick, David R., additional, Grubb, Neil R., additional, Ibbotson, Sally H., additional, Innes, J. Alastair, additional, Jenks, Sara J., additional, Johnston, Sarah L., additional, Jones, David E.J., additional, Langhorne, Peter, additional, Lawrie, Stephen M., additional, Leach, John Paul, additional, Maartens, Gary, additional, Mackillop, Lucy, additional, MacMahon, Michael J., additional, Mann, Rebecca, additional, Manson, Lynn M., additional, Marshall, Sara E., additional, Mather, Amanda, additional, Maxwell, Simon R., additional, McAllister, David A., additional, McCrimmon, Rory J., additional, McLean, Mairi, additional, Neuberger, Francesca E.M., additional, Newby, David E., additional, Newell-Price, John D.C., additional, Olson, John, additional, Pearson, Ewan R., additional, Phelan, Paul J., additional, Ralston, Stuart H., additional, Reid, Peter T., additional, Sandoe, Jonathan A.T., additional, Scott, Gordon R., additional, Shand, Alan G., additional, Steel, Robby M., additional, Stewart, Grant D., additional, Stewart, Peter, additional, Strachan, Mark W.J., additional, Sullivan, David R., additional, Sundar, Shyam, additional, Tallentire, Victoria R., additional, Tatton-Brown, Katrina, additional, Thomas, Simon H.L., additional, Watson, Henry G., additional, White, Julian, additional, Wilding, John P.H., additional, and Witham, Miles D., additional

Published
2022
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30. New horizons in evidence synthesis for older adults

Author

Cooper, Nicola, primary, Germeni, Evi, additional, Freeman, Suzanne C, additional, Jaiswal, Nishant, additional, Nevill, Clareece R, additional, Sutton, Alex J, additional, Taylor-Rowan, Martin, additional, and Quinn, Terence J, additional

Published
2023
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35. Phosphodiesterase 4 inhibitors for the treatment of inflammation associated with respiratory disease

Author

Cooper, Nicola, Chowdhry, Babur, and Spencer, John

Subjects
500, RC Internal medicine
Abstract

This submission for a PhD, by publication, which is based upon a series of original research studies published between 1998 and 2002 focuses on the selection of novel phosphodiesterase 4 (PDE4) inhibitors for the treatment of inflammation associated with respiratory diseases such as asthma and chronic obstructive pulmonary disease. A number of issues, relevant at the time, have been considered including: a) in vitro methods predictive of in vivo therapeutic index of anti-inflammatory efficacy over emetic side effects, b) in vivo methods for confirming therapeutic index and c) early confirmation of functional activity in a human system. In addition to 10 peer-reviewed articles, a poster presented at the American Thoracic Society (ATS) conference in 1999 and a review article published in Trends in Pharmacological Sciences (publication 1) in 1997 are also included. In the initial work (publication 2) to investigate if it was possible to correlate in vitro activity with in vivo efficacy for PDE4 inhibitors structurally diverse compounds were tested in a series of experimental systems. The compounds tested were SB 207499, LAS 31025, CDP 840, rolipram and RP 73401. The in vitro experiments consisted of PDE4 enzyme activity (guinea pig and human inflammatory cells) and rolipram binding activity, RBA (rat brain). The in vivo model used was the guinea pig skin model of eosinophil recruitment, which involves systemic 111In-eosinophil recruitment to guinea pig skin induced by a range of inflammatory mediators [i.e. PCA, PAF and zymosan activated plasma (ZAP)]. Previous studies with PDE4 inhibitors had not examined the correlation between in vitro and in vivo activities in this way. RP73401 was the most potent PDE4 enzyme inhibitor (guinea pig macrophage) followed by SB 207499>CDP 840> rolipram>LAS 31025. Rolipram binding activity did not follow the same ranking, though RP73401 was again the most potent followed by rolipram>SB 207499>CDP 840>LAS31025. Attenuation of eosinophil recruitment was consistently observed regardless of inflammogen with the following rank order of potency: RP 73401= rolipram>LAS 31025>SB 207499>CDP 840. In this model no correlation was found between the in vitro activities and in vivo efficacy. A cell based in vitro assay, LPS induced TNF release from human PBMCs was also included in this publication. All of the PDE4 inhibitors tested were efficacious in this assay with a potency order of: RP 73401>SB 207499 = rolipram = CDP 840>LAS 31025. In publications 3-7, in vitro and in vivo data are presented on a large number of compounds from a diverse range of chemical classes. In all cases the in vitro focus pertains to the ratio of PDE4 enzyme activity to rolipram binding activity (PDE4:RBA) as a method of selecting compounds with an improved therapeutic index of anti-inflammatory efficacy over emetic side effects. In these publications emesis data were included together with efficacy data in order to determine if in vitro predictions of therapeutic index were of relevance in vivo. The drug classes examined were xanthines, aryl sulphonamides, quinolones, 7-methoxybenzofuran-4-carboxamides, and 7-methoxyfuro[2,3-c]pyridine-4-carboxamides. The lead molecules selected in each publication had improved PDE4:RBA ratios which translated into an improved therapeutic window in vivo. These generated lead molecules (compound numbers from publication); corresponding PDE4:RBA ratios, skin eosinophilia efficacious dose and ferret non-emetic doses are as follows: publication 3, xanthine (3c), 4.1, 5 mg/kg, 10 mg/kg; publication 4, aryl sulphonamide (20), <0.6, 5 mg/kg, 10 mg/kg; publication 5, quinolone (7g), <0.7, 10 mg/kg, 20 mg/kg; publication 6, 7-methoxybenzofuran-4-carboxamides (3a), 0.37, 0.5 mg/kg, 10 mg/kg and publication 7, 7-methoxyfuro[2,3-c]pyridine-4-carboxamides (8a), 0.16, 10 mg/kg (lung eosinophilia), not evaluated in the ferret. The objective of the method for the selection of novel PDE4 inhibitors for the treatment of inflammation associated with respiratory diseases was to nominate compounds into drug development. The molecules had to successfully exhibit all of the criteria set in the screening cascade to be considered safe and efficacious enough to be tested in clinical trials. Publication 8 and the ATS poster refer to the first development compound nominated for clinical development, D 4418. This compound demonstrated efficacy in the guinea pig lung model of airway function, eosinophil infiltration and bronchial hyperreactivity at 10 mg/kg, p.o. and did not evoke emesis in the ferret at 100 mg/kg. In a Phase I clinical trial when dosed between 5 and 200 mg, D 4418 had a good pharmacokinetic profile and only mild side effects of headache, dizziness and nausea but no vomiting. No further clinical development was carried out with this molecule. Publications 9, 10 and 11 refer to the discovery, synthesis and pharmacology of a second development candidate, SCH 351591. This compound was more potent than D 4418 both in vitro and in vivo and had a wider therapeutic index for efficacy over side effects. SCH 351591 demonstrated efficacy in the guinea pig lung model of airway function, eosinophil infiltration and bronchial hyperreactivity at 0.3 mg/kg, p.o. and did not evoke emesis in the ferret at 5 mg/kg showing it to have a promising preclinical profile for the treatment of respiratory inflammation. Due to the final submitted publication being dated as 2002 two sections are included at the end of this thesis to cover further work carried out on SCH 351591 and in the PDE4 area from 2002 to date.

Published
2010

36. CERT1 mutations perturb human development by disrupting sphingolipid homeostasis

Author

Gehin, Charlotte, primary, Lone, Museer A., additional, Lee, Winston, additional, Capolupo, Laura, additional, Ho, Sylvia, additional, Adeyemi, Adekemi M., additional, Gerkes, Erica H., additional, Stegmann, Alexander P.A., additional, López-Martín, Estrella, additional, Bermejo-Sánchez, Eva, additional, Martínez-Delgado, Beatriz, additional, Zweier, Christiane, additional, Kraus, Cornelia, additional, Popp, Bernt, additional, Strehlow, Vincent, additional, Gräfe, Daniel, additional, Knerr, Ina, additional, Jones, Eppie R., additional, Zamuner, Stefano, additional, Abriata, Luciano A., additional, Kunnathully, Vidya, additional, Moeller, Brandon E., additional, Vocat, Anthony, additional, Rommelaere, Samuel, additional, Bocquete, Jean-Philippe, additional, Ruchti, Evelyne, additional, Limoni, Greta, additional, Van Campenhoudt, Marine, additional, Bourgeat, Samuel, additional, Henklein, Petra, additional, Gilissen, Christian, additional, van Bon, Bregje W., additional, Pfundt, Rolph, additional, Willemsen, Marjolein H., additional, Schieving, Jolanda H., additional, Leonardi, Emanuela, additional, Soli, Fiorenza, additional, Murgia, Alessandra, additional, Guo, Hui, additional, Zhang, Qiumeng, additional, Xia, Kun, additional, Fagerberg, Christina R., additional, Beier, Christoph P., additional, Larsen, Martin J., additional, Valenzuela, Irene, additional, Fernández-Álvarez, Paula, additional, Xiong, Shiyi, additional, Śmigiel, Robert, additional, López-González, Vanesa, additional, Armengol, Lluís, additional, Morleo, Manuela, additional, Selicorni, Angelo, additional, Torella, Annalaura, additional, Blyth, Moira, additional, Cooper, Nicola S., additional, Wilson, Valerie, additional, Oegema, Renske, additional, Herenger, Yvan, additional, Garde, Aurore, additional, Bruel, Ange-Line, additional, Tran Mau-Them, Frederic, additional, Maddocks, Alexis B.R., additional, Bain, Jennifer M., additional, Bhat, Musadiq A., additional, Costain, Gregory, additional, Kannu, Peter, additional, Marwaha, Ashish, additional, Champaigne, Neena L., additional, Friez, Michael J., additional, Richardson, Ellen B., additional, Gowda, Vykuntaraju K., additional, Srinivasan, Varunvenkat M., additional, Gupta, Yask, additional, Lim, Tze Y., additional, Sanna-Cherchi, Simone, additional, Lemaitre, Bruno, additional, Yamaji, Toshiyuki, additional, Hanada, Kentaro, additional, Burke, John E., additional, Jakšić, Ana Marjia, additional, McCabe, Brian D., additional, De Los Rios, Paolo, additional, Hornemann, Thorsten, additional, D’Angelo, Giovanni, additional, and Gennarino, Vincenzo A., additional

Published
2023
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45. HUWE1 variants cause dominant X-linked intellectual disability: a clinical study of 21 patients

Author

Moortgat, Stéphanie, Berland, Siren, Aukrust, Ingvild, Maystadt, Isabelle, Baker, Laura, Benoit, Valerie, Caro-Llopis, Alfonso, Cooper, Nicola S., Debray, François-Guillaume, Faivre, Laurence, Gardeitchik, Thatjana, Haukanes, Bjørn I., Houge, Gunnar, Kivuva, Emma, Martinez, Francisco, Mehta, Sarju G., Nassogne, Marie-Cécile, Powell-Hamilton, Nina, Pfundt, Rolph, Rosello, Monica, Prescott, Trine, Vasudevan, Pradeep, van Loon, Barbara, Verellen-Dumoulin, Christine, Verloes, Alain, Lippe, Charlotte von der, Wakeling, Emma, Wilkie, Andrew O. M., Wilson, Louise, Yuen, Amy, Study, DDD, Low, Karen J., and Newbury-Ecob, Ruth A.

Published
2018
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46. French colonial discourses : the case of French Indochina 1900-1939

Author

Cooper, Nicola J.

Subjects
900, DC France, DS Asia
Abstract

This thesis focuses upon French colonial discourses at the height of the French imperial encounter with Indochina: 1900-1939. It examines the way in which imperial France viewed her role in Indochina, and the representations and perceptions of Indochina which were produced and disseminated in a variety of cultural media emanating from the metropole. Framed by political, ideological and historical developments and debates, each chapter develops a socio-cultural account of France's own understanding of her role in Indochina, and her relationship with the colony during this crucial period. The thesis asserts that although consistent, French discourses of Empire do not present a coherent view of the nation's imperial identity or role, and that this lack of coherence is epitomised by the Franco-indochinese relationship. The thesis seeks to demonstrate that French perceptions of Indochina were marked above all by a striking ambivalence, and that the metropole's view of the status of Indochina within the Empire was often contradictory, and at times paradoxical. Indeed, the thesis argues that Indochina was imagined through a series of antitheses which reflect the incoherent nature of French colonial discourse during this period. This thesis uses as its primary material a variety of key cultural media which informed the popular perception of Indochina during this period: metropolitan and Franco-indochinese school manuals; the writings and designs of French colonial urbanists; the works of influential colonial apologists; 'official' texts relating to the organisation and impact of the Exposition coloniale of 1931; travel journalism; and metropolitan fiction relating to Indochina. The discursive approach that this thesis takes, focusing clearly upon the socio-cultural dimension, should provide an important re-evaluation of French Indochina and its legacy, and should make a contribution to the understanding of France's relations with her colonial territories during the first half of the twentieth century.

Published
1997

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