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A standardised method for interpreting the association between mutations and phenotypic drug resistance in Mycobacterium tuberculosis

Miotto, Paolo and Tessema, Belay and Tagliani, Elisa and Chindelevitch, Leonid and Starks, Angela M. and Emerson, Claudia and Hanna, Debra and Kim, Peter S. and Liwski, Richard and Zignol, Matteo and Gilpin, Christopher and Niemann, Stefan and Denkinger, Claudia M. and Fleming, Joy and Warren, Robin M. and Crook, Derrick and Posey, James and Gagneux, Sebastien and Hoffner, Sven and Rodrigues, Camilla and Comas, Iñaki and Engelthaler, David M. and Murray, Megan and Alland, David and Rigouts, Leen and Lange, Christoph and Dheda, Keertan and Hasan, Rumina and Ranganathan, Uma Devi K. and McNerney, Ruth and Ezewudo, Matthew and Cirillo, Daniela M. and Schito, Marco and Köser, Claudio U. and Rodwell, Timothy C.. (2017) A standardised method for interpreting the association between mutations and phenotypic drug resistance in Mycobacterium tuberculosis. The European respiratory journal, 50 (6). p. 1701354.

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Official URL: http://edoc.unibas.ch/58355/

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Abstract

A clear understanding of the genetic basis of antibiotic resistance in Mycobacterium tuberculosis is required to accelerate the development of rapid drug susceptibility testing methods based on genetic sequence.Raw genotype-phenotype correlation data were extracted as part of a comprehensive systematic review to develop a standardised analytical approach for interpreting resistance associated mutations for rifampicin, isoniazid, ofloxacin/levofloxacin, moxifloxacin, amikacin, kanamycin, capreomycin, streptomycin, ethionamide/prothionamide and pyrazinamide. Mutation frequencies in resistant and susceptible isolates were calculated, together with novel statistical measures to classify mutations as high, moderate, minimal or indeterminate confidence for predicting resistance.We identified 286 confidence-graded mutations associated with resistance. Compared to phenotypic methods, sensitivity (95% CI) for rifampicin was 90.3% (89.6-90.9%), while for isoniazid it was 78.2% (77.4-79.0%) and their specificities were 96.3% (95.7-96.8%) and 94.4% (93.1-95.5%), respectively. For second-line drugs, sensitivity varied from 67.4% (64.1-70.6%) for capreomycin to 88.2% (85.1-90.9%) for moxifloxacin, with specificity ranging from 90.0% (87.1-92.5%) for moxifloxacin to 99.5% (99.0-99.8%) for amikacin.This study provides a standardised and comprehensive approach for the interpretation of mutations as predictors of M. tuberculosis drug-resistant phenotypes. These data have implications for the clinical interpretation of molecular diagnostics and next-generation sequencing as well as efficient individualised therapy for patients with drug-resistant tuberculosis.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Tuberculosis Research (Gagneux)
UniBasel Contributors:Gagneux, Sebastien
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Munksgaard
ISSN:0903-1936
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:02 Feb 2018 10:23
Deposited On:02 Feb 2018 10:23

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