title: Transmission of multidrug-resistant Mycobacterium tuberculosis in Shanghai, China: a retrospective observational study using whole-genome sequencing and epidemiological investigation.
abstract: Multidrug-resistance is a substantial threat to global elimination of tuberculosis. Understanding transmission patterns is crucial for control of the disease. We used a genomic and epidemiological approach to assess recent transmission of multidrug-resistant (MDR) tuberculosis and identify potential risk factors for transmission.
  
  
  
  We did a population-based, retrospective study of patients who tested positive for tuberculosis between Jan 1, 2009, and Dec 31, 2012, in Shanghai, China. We did variable-number-of-tandem-repeat genotyping and whole-genome sequencing of isolates. We measured strain diversity within and between genomically clustered isolates. Genomic and epidemiological data were combined to construct transmission networks.
  
  
  
  367 (5%) of 7982 patients with tuberculosis had MDR tuberculosis and 324 (88%) of these had isolates available for genomic analysis. 103 (32%) of the 324 MDR strains were in 38 genomic clusters that differed by 12 or fewer single nucleotide polymorphisms (SNPs), indicating recent transmission of MDR strains. Patients who had delayed diagnosis or were older than 45 years had high risk of recent transmission. 235 (73%) patients with MDR tuberculosis probably had transmission of MDR strains. Transmission network analysis showed that 33 (87%) of the 38 clusters accumulated additional drug-resistance mutations through emergence or fixation of mutations during transmission. 68 (66%) of 103 clustered MDR strains had compensatory mutations of rifampicin resistance.
  
  
  
  Recent transmission of MDR tuberculosis strains, with increasing drug-resistance, drives the MDR tuberculosis epidemic in Shanghai, China. Whole-genome sequencing can measure of the heterogeneity of drug-resistant mutations within and between hosts and help to determine the transmission patterns of MDR tuberculosis.
  
  
  
  National Science and Technology Major Project, National Natural Science Foundation of China, and US National Insitutes of Health.
authors.affiliation: The Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Institutes of Biomedical Sciences, and Institute of Medical Microbiology, School of Basic Medical Science, Fudan University, 131 DongAn Road, Shanghai, China, 200032.|Department of Epidemiology of Microbial Diseases, School of Public Health, Yale University, 60 College Street, New Haven, CT, USA, 06510.
authors.forename: Chongguang
authors.initials: C
authors.lastname: Yang
authors.affiliation: The Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Institutes of Biomedical Sciences, and Institute of Medical Microbiology, School of Basic Medical Science, Fudan University, 131 DongAn Road, Shanghai, China, 200032.|School of Basic Medical Science and the West China Center of Medical Sciences of Sichuan University, Chengdu, Sichuan, China, 610041.
authors.forename: Tao
authors.initials: T
authors.lastname: Luo
authors.affiliation: Department of tuberculosis Control, Shanghai Municipal Center for Disease Control and Prevention, 1380 West Zhong Shan Road, Shanghai, China, 200336.
authors.forename: Xin
authors.initials: X
authors.lastname: Shen
authors.affiliation: Department of tuberculosis Control, Shanghai Municipal Center for Disease Control and Prevention, 1380 West Zhong Shan Road, Shanghai, China, 200336.
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.affiliation: The Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Institutes of Biomedical Sciences, and Institute of Medical Microbiology, School of Basic Medical Science, Fudan University, 131 DongAn Road, Shanghai, China, 200032.
authors.forename: Mingyu
authors.initials: M
authors.lastname: Gan
authors.affiliation: The Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Institutes of Biomedical Sciences, and Institute of Medical Microbiology, School of Basic Medical Science, Fudan University, 131 DongAn Road, Shanghai, China, 200032.
authors.forename: Peng
authors.initials: P
authors.lastname: Xu
authors.affiliation: Department of tuberculosis Control, Shanghai Municipal Center for Disease Control and Prevention, 1380 West Zhong Shan Road, Shanghai, China, 200336.
authors.forename: Zheyuan
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of tuberculosis Control, Shanghai Municipal Center for Disease Control and Prevention, 1380 West Zhong Shan Road, Shanghai, China, 200336.
authors.forename: Senlin
authors.initials: S
authors.lastname: Lin
authors.affiliation: The Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Institutes of Biomedical Sciences, and Institute of Medical Microbiology, School of Basic Medical Science, Fudan University, 131 DongAn Road, Shanghai, China, 200032.
authors.forename: Jiyun
authors.initials: J
authors.lastname: Tian
authors.affiliation: The Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Institutes of Biomedical Sciences, and Institute of Medical Microbiology, School of Basic Medical Science, Fudan University, 131 DongAn Road, Shanghai, China, 200032.
authors.forename: Qingyun
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of tuberculosis Control, Shanghai Municipal Center for Disease Control and Prevention, 1380 West Zhong Shan Road, Shanghai, China, 200336.
authors.forename: ZhengAn
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Department of tuberculosis Control, Shanghai Municipal Center for Disease Control and Prevention, 1380 West Zhong Shan Road, Shanghai, China, 200336.
authors.forename: Jian
authors.initials: J
authors.lastname: Mei
authors.affiliation: School of Medicine, University of California, Davis, One Shields Avenue, Davis, CA, USA, 95616.
authors.forename: Kathryn
authors.initials: K
authors.lastname: DeRiemer
authors.affiliation: The Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Institutes of Biomedical Sciences, and Institute of Medical Microbiology, School of Basic Medical Science, Fudan University, 131 DongAn Road, Shanghai, China, 200032.
authors.forename: Qian
authors.initials: Q
authors.lastname: Gao
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000995:Antitubercular Agents / Q000494:pharmacology; D002681:China; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics; D005260:Female; D016680:Genome, Bacterial; D006801:Humans; D008297:Male; D008875:Middle Aged; D017720:Molecular Epidemiology; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000302:isolation & purification; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D018088:Tuberculosis, Multidrug-Resistant / Q000453:epidemiology / Q000235:genetics / Q000635:transmission*
chemical_list: D000995:Antitubercular Agents