Quantitative measurement of antibiotic resistance in Mycobacterium tuberculosis reveals genetic determinants of resistance and susceptibility in a target gene approach
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Barilar, Ivan | Battaglia, Simone | Borroni, Emanuele | Brandao, Angela Pires | Brankin, Alice | Cabibbe, Andrea Maurizio | Carter, Joshua | Chetty, Darren | Cirillo, Daniela Maria | Claxton, Pauline | Clifton, David | Cohen, Ted | Coronel, Jorge | Crook, Derrick | Dreyer, Viola | Earle, Sarah | Escuyer, Vincent | Ferrazoli, Lucilaine | Fowler, Philip | Gao, George Fu | Gardy, Jennifer | Gharbia, Saheer | Ghisi, Kelen Teixeira | Ghodousi, Arash | Gibertoni Cruz, Ana Luíza | Grandjean, Louis | Grazian, Clara | Groenheit, Ramona | Guthrie, Jennifer | He, Wencong | Hoffmann, Harald | Hoosdally, Sarah | Hunt, Martin | Iqbal, Zamin | Ismail, Nazir Ahmed | Jarrett, Lisa | Joseph, Lavania | Jou, Ruwen | Kambli, Priti | Khot, Rukhsar | Knaggs, Jeff | Koch, Anastasia | Kohlerschmidt, Donna | Kouchaki, Samaneh | Lachapelle, Alexander | Lalvani, Ajit | Lapierre, Simon Grandjean | Laurenson, Ian | Letcher, Brice | Lin, Wan-Hsuan | Liu, Chunfa | Liu, Dongxin | Malone, Kerri | Mandal, Ayan | Mansjö, Mikael | Calisto Matias, Daniela Vicente Lucena | Meintjes, Graeme | de Freitas Mendes, Flávia | Merker, Matthias | Mihalic, Marina | Millard, James | Miotto, Paolo | Mistry, Nerges | Moore, David | Musser, Kimberlee | Ngcamu, Dumisani | Nhung, Hoang Ngoc | Niemann, Stefan | Nilgiriwala, Kayzad Soli | Nimmo, Camus | O’donnell, Max | Okozi, Nana | Oliveira, Rosangela Siqueira | Omar, Shaheed Vally | Paton, Nicholas | Peto, Timothy | Pinhata, Juliana Maira Watanabe | Plesnik, Sara | Puyen, Zully | Rabodoarivelo, Marie Sylvianne | Rakotosamimanana, Niaina | Rancoita, Paola | Rathod, Priti | Robinson, Esther Rhiannon | Rodger, Gillian | Rodrigues, Camilla | Rodwell, Timothy | Roohi, Aysha | Santos-Lazaro, David | Shah, Sanchi | Smith, Grace | Kohl, Thomas Andreas | Solano, Walter | Spitaleri, Andrea | Steyn, Adrie | Supply, Philip | Surve, Utkarsha | Tahseen, Sabira | Thuong, Nguyen Thuy Thuong | Thwaites, Guy | Todt, Katharina | Trovato, Alberto | Utpatel, Christian | van Rie, Annelies | Vijay, Srinivasan | Walker, A. Sarah | Walker, Timothy | Warren, Robin | Werngren, Jim | Wijkander, Maria | Wilkinson, Robert | Wilson, Daniel | Wintringer, Penelope | Xiao, Yu-Xin | Yang, Yang | Yanlin, Zhao | Yao, Shen-Yuan | Zhu, Baoli
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International audience.
The World Health Organization has a goal of universal drug susceptibility testing for patients with tuberculosis. However, molecular diagnostics to date have focused largely on first-line drugs and predicting susceptibilities in a binary manner (classifying strains as either susceptible or resistant). Here, we used a multivariable linear mixed model alongside whole genome sequencing and a quantitative microtiter plate assay to relate genomic mutations to minimum inhibitory concentration (MIC) in 15,211 Mycobacterium tuberculosis clinical isolates from 23 countries across five continents. We identified 492 unique MIC-elevating variants across 13 drugs, as well as 91 mutations likely linked to hypersensitivity. Our results advance genetics-based diagnostics for tuberculosis and serve as a curated training/testing dataset for development of drug resistance prediction algorithms.
