1. The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: a genotypic analysis
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Timothy M Walker, DPhil, Paolo Miotto, PhD, Claudio U Köser, PhD, Philip W Fowler, PhD, Jeff Knaggs, BSc, Zamin Iqbal, DPhil, Martin Hunt, PhD, Leonid Chindelevitch, PhD, Maha R Farhat, MD, Daniela Maria Cirillo, PhD, Iñaki Comas, PhD, James Posey, PhD, Shaheed V Omar, PhD, Timothy EA Peto, ProfFRCP, Anita Suresh, MSc, Swapna Uplekar, PhD, Sacha Laurent, PhD, Rebecca E Colman, PhD, Carl-Michael Nathanson, PhD, Matteo Zignol, MD, Ann Sarah Walker, ProfPhD, Derrick W Crook, ProfFRCPath, Nazir Ismail, FRCPath [SA], Timothy C Rodwell, ProfMD, A Sarah Walker, Adrie J C Steyn, Ajit Lalvani, Alain Baulard, Alan Christoffels, Alberto Mendoza-Ticona, Alberto Trovato, Alena Skrahina, Alexander S Lachapelle, Alice Brankin, Amy Piatek, Ana Gibertoni Cruz, Anastasia Koch, Andrea Maurizio Cabibbe, Andrea Spitaleri, Angela P Brandao, Angkana Chaiprasert, Anita Suresh, Anna Barbova, Annelies Van Rie, Arash Ghodousi, Arnold Bainomugisa, Ayan Mandal, Aysha Roohi, Babak Javid, Baoli Zhu, Brice Letcher, Camilla Rodrigues, Camus Nimmo, Carl-Michael NATHANSON, Carla Duncan, Christopher Coulter, Christian Utpatel, Chunfa Liu, Clara Grazian, Clare Kong, Claudio U Köser, Daniel J Wilson, Daniela Maria Cirillo, Daniela Matias, Danielle Jorgensen, Danila Zimenkov, Darren Chetty, David AJ Moore, David A Clifton, Derrick W Crook, Dick van Soolingen, Dongxin Liu, Donna Kohlerschmidt, Draurio Barreira, Dumisani Ngcamu, Elias David Santos Lazaro, Ellis Kelly, Emanuele Borroni, Emma Roycroft, Emmanuel Andre, Erik C Böttger, Esther Robinson, Fabrizio Menardo, Flavia F Mendes, Frances B Jamieson, Francesc Coll, George Fu Gao, George W Kasule, Gian Maria Rossolini, Gillian Rodger, E Grace Smith, Graeme Meintjes, Guy Thwaites, Harald Hoffmann, Heidi Albert, Helen Cox, Ian F Laurenson, Iñaki Comas, Irena Arandjelovic, Ivan Barilar, Jaime Robledo, James Millard, James Johnston, Jamie Posey, Jason R Andrews, Jeff Knaggs, Jennifer Gardy, Jennifer Guthrie, Jill Taylor, Jim Werngren, John Metcalfe, Jorge Coronel, Joseph Shea, Joshua Carter, Juliana MW Pinhata, Julianne V Kus, Katharina Todt, Kathryn Holt, Kayzad S Nilgiriwala, Kelen T Ghisi, Kerri M Malone, Kiatichai Faksri, Kimberlee A Musser, Lavania Joseph, Leen Rigouts, Leonid Chindelevitch, Lisa Jarrett, Louis Grandjean, Lucilaine Ferrazoli, Mabel Rodrigues, Maha Farhat, Marco Schito, Margaret M Fitzgibbon, Marguerite Massinga Loembé, Maria Wijkander, Marie Ballif, Marie-Sylvianne Rabodoarivelo, Marina Mihalic, Mark WILCOX, Martin Hunt, Matteo ZIGNOL, Matthias Merker, Matthias Egger, Max O'Donnell, Maxine Caws, Mei-Hua Wu, Michael G Whitfield, Michael Inouye, Mikael Mansjö, Minh Ha Dang Thi, Moses Joloba, SM Mostofa Kamal, Nana Okozi, Nazir ISMAIL, Nerges Mistry, Nhung N Hoang, Niaina Rakotosamimanana, Nicholas I Paton, Paola M V Rancoita, Paolo Miotto, Pascal Lapierre, Patricia J Hall, Patrick Tang, Pauline Claxton, Penelope Wintringer, Peter M Keller, Phan Vuong Khac Thai, Philip W Fowler, Philip Supply, Prapaporn Srilohasin, Prapat Suriyaphol, Priti Rathod, Priti Kambli, Ramona Groenheit, Rebecca E Colman, Rick Twee-Hee Ong, Robin M Warren, Robert J Wilkinson, Roland Diel, Rosangela S Oliveira, Rukhsar Khot, Ruwen Jou, Sabira Tahseen, Sacha Laurent, Saheer Gharbia, Samaneh Kouchaki, Sanchi Shah, Sara Plesnik, Sarah G Earle, Sarah Dunstan, Sarah J Hoosdally, Satoshi Mitarai, Sebastien Gagneux, Shaheed V Omar, Shen-Yuan Yao, Simon Grandjean Lapierre, Simone Battaglia, Stefan Niemann, Sushil Pandey, Swapna Uplekar, Tanya A Halse, Ted Cohen, Teresa Cortes, Therdsak Prammananan, Thomas A Kohl, Nguyen T T Thuong, Tik Ying Teo, Timothy E A Peto, Timothy C Rodwell, Timothy William, Timothy M Walker, Thomas R Rogers, Utkarsha Surve, Vanessa Mathys, Victoria Furió, Victoria Cook, Srinivasan Vijay, Vincent Escuyer, Viola Dreyer, Vitali Sintchenko, Vonthanak Saphonn, Walter Solano, Wan-Hsuan Lin, Wayne van Gemert, Wencong He, Yang Yang, Yanlin Zhao, Youwen Qin, Yu-Xin Xiao, Zahra Hasan, Zamin Iqbal, and Zully M Puyen
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Medicine (General) ,R5-920 ,Microbiology ,QR1-502 - Abstract
Summary: Background: Molecular diagnostics are considered the most promising route to achievement of rapid, universal drug susceptibility testing for Mycobacterium tuberculosis complex (MTBC). We aimed to generate a WHO-endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction. Methods: In this systematic analysis, we used a candidate gene approach to identify mutations associated with resistance or consistent with susceptibility for 13 WHO-endorsed antituberculosis drugs. We collected existing worldwide MTBC whole-genome sequencing data and phenotypic data from academic groups and consortia, reference laboratories, public health organisations, and published literature. We categorised phenotypes as follows: methods and critical concentrations currently endorsed by WHO (category 1); critical concentrations previously endorsed by WHO for those methods (category 2); methods or critical concentrations not currently endorsed by WHO (category 3). For each mutation, we used a contingency table of binary phenotypes and presence or absence of the mutation to compute positive predictive value, and we used Fisher's exact tests to generate odds ratios and Benjamini-Hochberg corrected p values. Mutations were graded as associated with resistance if present in at least five isolates, if the odds ratio was more than 1 with a statistically significant corrected p value, and if the lower bound of the 95% CI on the positive predictive value for phenotypic resistance was greater than 25%. A series of expert rules were applied for final confidence grading of each mutation. Findings: We analysed 41 137 MTBC isolates with phenotypic and whole-genome sequencing data from 45 countries. 38 215 MTBC isolates passed quality control steps and were included in the final analysis. 15 667 associations were computed for 13 211 unique mutations linked to one or more drugs. 1149 (7·3%) of 15 667 mutations were classified as associated with phenotypic resistance and 107 (0·7%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations' pooled sensitivity was more than 80%. Specificity was over 95% for all drugs except ethionamide (91·4%), moxifloxacin (91·6%) and ethambutol (93·3%). Only two resistance mutations were identified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs. Interpretation: We present the first WHO-endorsed catalogue of molecular targets for MTBC drug susceptibility testing, which is intended to provide a global standard for resistance interpretation. The existence of this catalogue should encourage the implementation of molecular diagnostics by national tuberculosis programmes. Funding: Unitaid, Wellcome Trust, UK Medical Research Council, and Bill and Melinda Gates Foundation.
- Published
- 2022
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