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

Paolo Miotto; Belay Tessema; Elisa Tagliani; Leonid Chindelevitch; Angela M Starks; Claudia Emerson; Debra Hanna; Peter S Kim; Richard Liwski; Matteo Zignol; Christopher Gilpin; Stefan Niemann; Claudia M Denkinger; Joy Fleming; Robin M Warren; Derrick Crook; James Posey; Sebastien Gagneux; Sven Hoffner; Camilla Rodrigues; Iñaki Comas; David M Engelthaler; Megan Murray; David Alland; Leen Rigouts; Christoph Lange; Keertan Dheda; Rumina Hasan; Uma Devi K Ranganathan; Ruth McNerney; Matthew Ezewudo; Daniela M Cirillo; Marco Schito; Claudio U Köser; Timothy C Rodwell

doi:10.1183/13993003.01354-2017

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

Journal article

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Peer reviewed

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

Paolo Miotto, Belay Tessema, Elisa Tagliani, Leonid Chindelevitch, Angela M Starks, Claudia Emerson, Debra Hanna, Peter S Kim, Richard Liwski, Matteo Zignol, …

The European respiratory journal, Vol.50(6), pp.1701354-1701354

12/2017

DOI: https://doi.org/10.1183/13993003.01354-2017

PMCID: PMC5898944

PMID: 29284687

Abstract

Data Interpretation, Statistical

Humans

Antitubercular Agents - pharmacology

Bacterial Proteins - genetics

Genotype

Mycobacterium tuberculosis - drug effects

Sequence Analysis, DNA

Tuberculosis, Multidrug-Resistant - diagnosis

Microbial Sensitivity Tests

Phenotype

DNA, Bacterial - genetics

Tuberculosis, Multidrug-Resistant - microbiology

Systematic Reviews as Topic

Mutation

Drug Resistance, Multiple, Bacterial - genetics

Mycobacterium tuberculosis - genetics

A clear understanding of the genetic basis of antibiotic resistance in 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 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.

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Title: A standardised method for interpreting the association between mutations and phenotypic drug resistance in Mycobacterium tuberculosis
Creators: Paolo Miotto - Emerging Bacterial Pathogens Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy miotto.paolo@hsr.it
Belay Tessema - Department of Medical Microbiology, University of Gondar, Gondar, Ethiopia
Elisa Tagliani - Emerging Bacterial Pathogens Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
Leonid Chindelevitch - School of Computing Science, Simon Fraser University, Burnaby, BC, Canada
Angela M Starks - Division of Tuberculosis Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
Claudia Emerson - Institute on Ethics & Policy for Innovation, Department of Philosophy, McMaster University, Hamilton, ON, Canada
Debra Hanna - Critical Path Institute, Tucson, AZ, USA
Peter S Kim - Office of AIDS Research, National Institutes of Health, Rockville, MD, USA
Richard Liwski - Critical Path Institute, Tucson, AZ, USA
Matteo Zignol - Global Tuberculosis Programme, World Health Organization, Geneva, Switzerland
Christopher Gilpin - Global Tuberculosis Programme, World Health Organization, Geneva, Switzerland
Stefan Niemann - German Center for Infection Research, Borstel, Germany
Claudia M Denkinger - Foundation for Innovative New Diagnostics, Campus Biotech, Geneva, Switzerland
Joy Fleming - Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
Robin M Warren - DST/NRF Centre of Excellence for Biomedical Tuberculosis Research/SAMRC Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa
Derrick Crook - National Infection Service, Public Health England, London, UK
James Posey - Division of Tuberculosis Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
Sebastien Gagneux - University of Basel, Basel, Switzerland
Sven Hoffner - Public Health Agency of Sweden, Solna, Sweden
Camilla Rodrigues - Hinduja Hospital, Veer Savarkar Marg, Mumbai, India
Iñaki Comas - CIBER (Centros de Investigación Biomédica en Red) in Epidemiology and Public Health, Madrid, Spain
David M Engelthaler - Translational Genomics Research Institute, Flagstaff, AZ, USA
Megan Murray - Harvard School of Public Health, Department of Epidemiology, Boston, MA, USA
David Alland - Center for Emerging Pathogens, Rutgers-New Jersey Medical School, Newark, NJ, USA
Leen Rigouts - Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium
Christoph Lange - Department of Internal Medicine, University of Namibia School of Medicine, Windhoek, Namibia
Keertan Dheda - Lung Infection and Immunity Unit, Department of Medicine, Division of Pulmonology and UCT Lung Institute, University of Cape Town, Groote Schuur Hospital, Cape Town, South Africa
Rumina Hasan - Department of Pathology and Laboratory Medicine, Aga Khan University, Karachi, Pakistan
Uma Devi K Ranganathan - National Institute for Research in Tuberculosis (ICMR), No 1, Chennai, India
Ruth McNerney - Department of Medicine, Division of Pulmonology, University of Cape Town, Groote Schuur Hospital, Cape Town, South Africa
Matthew Ezewudo - Critical Path Institute, Tucson, AZ, USA
Daniela M Cirillo - Emerging Bacterial Pathogens Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
Marco Schito - Critical Path Institute, Tucson, AZ, USA
Claudio U Köser - Department of Genetics, University of Cambridge, Cambridge, UK
Timothy C Rodwell - Department of Medicine, University of California, San Diego, CA, USA
Publication Details: The European respiratory journal, Vol.50(6), pp.1701354-1701354
Date published: 12/2017
Grant note: 638553 / European Research Council 001 / World Health Organization
Academic Unit: Medicine - Infectious Diseases (NJMS)
Language: English
Resource Type: Journal article
Identifiers: 991031654931104646