Whole-genome sequencing for surveillance of tuberculosis drug resistance and determination of resistance level in China.
Dongxin Liu, Fei Huang, Guoliang Zhang, Wencong He, Xichao Ou, Ping He, Bing Zhao, Baoli Zhu, Fei Liu, Zhiyuan Li, Chunfa Liu, Hui Xia, Shengfen Wang, Yang Zhou, Timothy M Walker, Lei Liu, Derrick W Crook, Yanlin Zhao
Author Information
Dongxin Liu: Chinese Centre for Disease Control and Prevention, Beijing, China; National Clinical Research Centre for Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, Guangdong Province, China.
Fei Huang: Chinese Centre for Disease Control and Prevention, Beijing, China.
Guoliang Zhang: National Clinical Research Centre for Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, Guangdong Province, China.
Wencong He: Chinese Centre for Disease Control and Prevention, Beijing, China.
Xichao Ou: Chinese Centre for Disease Control and Prevention, Beijing, China.
Ping He: Chinese Centre for Disease Control and Prevention, Beijing, China.
Bing Zhao: Chinese Centre for Disease Control and Prevention, Beijing, China.
Baoli Zhu: Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
Fei Liu: Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
Zhiyuan Li: Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
Chunfa Liu: Chinese Centre for Disease Control and Prevention, Beijing, China.
Hui Xia: Chinese Centre for Disease Control and Prevention, Beijing, China.
Shengfen Wang: Chinese Centre for Disease Control and Prevention, Beijing, China.
Yang Zhou: Chinese Centre for Disease Control and Prevention, Beijing, China.
Timothy M Walker: Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.
Lei Liu: National Clinical Research Centre for Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, Guangdong Province, China.
Derrick W Crook: Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.
Yanlin Zhao: Chinese Centre for Disease Control and Prevention, Beijing, China. Electronic address: zhaoyl@chinacdc.cn.
OBJECTIVES: Phenotypic drug susceptibility testing for prediction of tuberculosis (TB) drug resistance is slow and unreliable, limiting individualized therapy and monitoring of national TB data. Our study evaluated whole-genome sequencing (WGS) for its predictive accuracy, use in TB drug-resistance surveillance and ability to quantify the effects of resistance-associated mutations on MICs of anti-TB drugs. METHODS: We used WGS to measure the susceptibility of 4880 isolates to ten anti-TB drugs; for pyrazinamide, we used BACTEC MGIT 960. We determined the accuracy of WGS by comparing the prevalence of drug resistance, measured by WGS, with the true prevalence, determined by phenotypic susceptibility testing. We used the Student-Newman-Keuls test to confirm MIC differences of mutations. RESULTS: Resistance to isoniazid, rifampin and ethambutol was highly accurately predicted with at least 92.92% (95% confidence interval [CI], 88.19-97.65) sensitivity, resistance to pyrazinamide with 50.52% (95% CI, 40.57-60.47) sensitivity, and resistance to six second-line drugs with 85.05% (95% CI, 80.27-89.83) to 96.01% (95% CI, 93.89-98.13) sensitivity. The rpoB S450L, katG S315T and gyrA D94G mutations always confer high-level resistance, while rpoB L430P, rpoB L452P, fabG1 C-15T and embB G406S often confer low-level resistance or sub-epidemiological cutoff (ECOFF) MIC elevation. CONCLUSION: WGS can predict phenotypic susceptibility with high accuracy and could be a valuable tool for drug-resistance surveillance and allow the detection of drug-resistance level; It can be an important approach in TB drug-resistance surveillance and for determining therapeutic schemes.
