DNA Sequencing Predicts 1st-Line Tuberculosis Drug Susceptibility Profiles

BACKGROUND The World Health Organization recommends drug‐susceptibility testing of Mycobacterium tuberculosis complex for all patients with tuberculosis to guide treatment decisions and improve outcomes. Whether DNA sequencing can be used to accurately predict profiles of susceptibility to first‐line antituberculosis drugs has not been clear. METHODS We obtained whole‐genome sequences and associated phenotypes of resistance or susceptibility to the first‐line antituberculosis drugs isoniazid, rifampin, ethambutol, and pyrazinamide for isolates from 16 countries across six continents. For each isolate, mutations associated with drug resistance and drug susceptibility were identified across nine genes, and individual phenotypes were predicted unless mutations of unknown association were also present. To identify how whole‐genome sequencing might direct first‐line drug therapy, complete susceptibility profiles were predicted. These profiles were predicted to be susceptible to all four drugs (i.e., pansusceptible) if they were predicted to be susceptible to isoniazid and to the other drugs or if they contained mutations of unknown association in genes that affect susceptibility to the other drugs. We simulated the way in which the negative predictive value changed with the prevalence of drug resistance. RESULTS A total of 10,209 isolates were analyzed. The largest proportion of phenotypes was predicted for rifampin (9660 [95.4%] of 10,130) and the smallest was predicted for ethambutol (8794 [89.8%] of 9794). Resistance to isoniazid, rifampin, ethambutol, and pyrazinamide was correctly predicted with 97.1%, 97.5%, 94.6%, and 91.3% sensitivity, respectively, and susceptibility to these drugs was correctly predicted with 99.0%, 98.8%, 93.6%, and 96.8% specificity. Of the 7516 isolates with complete phenotypic drug‐susceptibility profiles, 5865 (78.0%) had complete genotypic predictions, among which 5250 profiles (89.5%) were correctly predicted. Among the 4037 phenotypic profiles that were predicted to be pansusceptible, 3952 (97.9%) were correctly predicted. CONCLUSIONS Genotypic predictions of the susceptibility of M. tuberculosis to first‐line drugs were found to be correlated with phenotypic susceptibility to these drugs. (Funded by the Bill and Melinda Gates Foundation and others.)

Phelim Bradley | Zamin Iqbal | Baoli Zhu | Daniel J. Wilson | Jay Shendure | Qian Gao | Marco Schito | Timothy Rodwell | Stefan Niemann | Vitali Sintchenko | Martin Hunt | Matthew W. Snyder | Jennifer Gardy | Tim E A Peto | Tanya Golubchik | Alexander Pym | Matthias Merker | Thomas A Kohl | Philip Supply | A Sarah Walker | Yang Yang | David A Clifton | Guy Thwaites | Daniel J Wilson | Camilla Rodrigues | Ana Gil-Brusola | Enrico Tortoli | Nazir Ismail | Sarah Hoosdally | Xin Shen | Mark Wilcox | Dick van Soolingen | Angela M Starks | Andrea M Cabibbe | Daniela M Cirillo | Louis Grandjean | J. Shendure | M. Caulfield | Y. Teo | Z. Iqbal | D. Clifton | B. Zhu | J. Gardy | P. Beckert | S. Niemann | C. Khor | Yang Yang | T. Walker | A. Walker | T. Peto | D. Crook | V. Sintchenko | Q. Gao | D. van Soolingen | R. Diel | D. Wilson | F. Drobniewski | Martin Hunt | M. Snyder | L. Bi | J. Posey | R. Ong | M. Schito | I. Comas | T. Golubchik | D. Wyllie | M. Wilcox | P. Fowler | Yanlin Zhao | C. Rodrigues | J. Johnston | G. Rossolini | P. Tang | G. Thwaites | S. Lipworth | Tom A Fowler | M. Farhat | M. Merker | A. Pym | A. Chaiprasert | T. Prammananan | L. Grandjean | D. Cirillo | P. Bradley | T. Kohl | P. Supply | T. Rodwell | M. D. De Filippo | E. Tortoli | N. Ismail | S. Tahseen | F. Khanzada | Derrick W Crook | Roland Diel | Iñaki Comas | Mark J Caulfield | Patrick Beckert | D. Gascoyne-Binzi | J. Guthrie | Qingyun Liu | S. Omar | E. G. Smith | Yik-Ying Teo | Lijun Bi | Deborah Gascoyne-Binzi | Megan Murray | Jennifer L Guthrie | Clare Kong | Mabel Rodrigues | Patrick Tang | James Johnston | M. Rodrigues | A. Sloutsky | N. Mistry | Timothy M Walker | E Grace Smith | M. Bonnet | K. Faksri | S. Hoosdally | Maryline Bonnet | Yanlin Zhao | Guangxue He | Xin Shen | Chiea C Khor | Maria R De Filippo | David Wyllie | Philip Fowler | Maha R Farhat | Paolo Miotto | Qingyun Liu | Shaheed V Omar | Vanessa Mathys | Alex Sloutsky | Francis A Drobniewski | Caroline Allix-Béguec | Therdsak Prammananan | Clare Kong | P. Miotto | Matthew Snyder | G. He | A. Gil-Brusola | Joy Fleming | James E Posey | Hongtai Zhang | Angkana Chaiprasert | Irena Arandjelovic | Irving Cancino-Muñoz | Han de Neeling | Kiatichai Faksri | Ana-Luiza Gibertoni-Cruz | Ximena Gonzalo | Faisal M Khanzada | Sam Lipworth | Gugu Maphalala | Elena Martinez | Nerges Mistry | David A J Moore | Rick T-H Ong | Gian M Rossolini | Elisabeth Sánchez Padilla | Karine Soetaert | Prapat Suriyapol | Sabira Tahseen | Thuong N T Thuong | Angela M. Starks | A. Cabibbe | Elisabeth Sánchez Padilla | E. Martínez | V. Mathys | Hongtai Zhang | J. Fleming | Irena Arandjelović | G. Maphalala | K. Soetaert | X. Gonzalo | A. G. Gibertoni Cruz | I. Cancino-Muñoz | H. de Neeling | C. Allix-Béguec | Caroline Irena Lijun Patrick Maryline Phelim Andrea M Irvin Allix-Béguec Arandjelovic Bi Beckert Bon | Megan Murray | Prapat Suriyapol | T. N. T. Thuong | David A. J. Moore | Ana-Luiza Gibertoni-Cruz | Joy Fleming | Megan R. Murray | Patrick Beckert | Marco Schito | A. Walker | Phelim Bradley | Tanya Golubchik | Tom Fowler | P. Tang | Thuong Nguyen Thuy Thuong | Han de Neeling

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