The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: a genotypic analysis
Issued Date
2022-04-01
Resource Type
eISSN
26665247
Scopus ID
2-s2.0-85127127568
Journal Title
The Lancet Microbe
Volume
3
Issue
4
Start Page
e265
End Page
e273
Rights Holder(s)
SCOPUS
Bibliographic Citation
The Lancet Microbe Vol.3 No.4 (2022) , e265-e273
Suggested Citation
Walker T.M., Miotto P., Köser C.U., Fowler P.W., Knaggs J., Iqbal Z., Hunt M., Chindelevitch L., Farhat M.R., Cirillo D.M., Comas I., Posey J., Omar S.V., Peto T.E.A., Suresh A., Uplekar S., Laurent S., Colman R.E., Nathanson C.M., Zignol M., Walker A.S., Crook D.W., Ismail N., Rodwell T.C., Barilar I., Battaglia S., Borroni E., Brandao A.P., Brankin A., Cabibbe A.M., Carter J., Chetty D., Claxton P., Clifton D.A., Cohen T., Coronel J., Dreyer V., Earle S.G., Escuyer V., Ferrazoli L., Gao G.F., Gardy J., Gharbia S., Ghisi K.T., Ghodousi A., Cruz A.L.G., Grazian C., Groenheit R., Guthrie J.L., He W., Hoffmann H., Hoosdally S.J., Jarrett L., Joseph L., Jou R., Kambli P., Khot R., Koch A., Kohl T.A., Kohlerschmidt D., Kouchaki S., Lachapelle A.S., Lalvani A., Grandjean L., Lapierre S.G., Laurenson I.F., Letcher B., Lin W.H., Liu C., Liu D., Malone K.M., Mandal A., Masjö M., Matias D., Meintjes G., Mendes F.F., Merker M., Mihalic M., Millard J., Mistry N., Moore D.A.J., Musser K.A., Ngcamu D., Hoang N.N., Niemann S., Nilgiriwala K.S., Nimmo C., O'Donnell M., Okozi N., Oliveira R.S., Paton N.I., Pinhata J.M.W., Plesnik S., Puyen Z.M., Rabodoarivelo M.S., Rakotosamimanana N., Rancoita P.M.V., Rathod P., Robinson E.R., Rodger G. The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: a genotypic analysis. The Lancet Microbe Vol.3 No.4 (2022) , e265-e273. e273. doi:10.1016/S2666-5247(21)00301-3 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/102459
Title
The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: a genotypic analysis
Author(s)
Walker T.M.
Miotto P.
Köser C.U.
Fowler P.W.
Knaggs J.
Iqbal Z.
Hunt M.
Chindelevitch L.
Farhat M.R.
Cirillo D.M.
Comas I.
Posey J.
Omar S.V.
Peto T.E.A.
Suresh A.
Uplekar S.
Laurent S.
Colman R.E.
Nathanson C.M.
Zignol M.
Walker A.S.
Crook D.W.
Ismail N.
Rodwell T.C.
Barilar I.
Battaglia S.
Borroni E.
Brandao A.P.
Brankin A.
Cabibbe A.M.
Carter J.
Chetty D.
Claxton P.
Clifton D.A.
Cohen T.
Coronel J.
Dreyer V.
Earle S.G.
Escuyer V.
Ferrazoli L.
Gao G.F.
Gardy J.
Gharbia S.
Ghisi K.T.
Ghodousi A.
Cruz A.L.G.
Grazian C.
Groenheit R.
Guthrie J.L.
He W.
Hoffmann H.
Hoosdally S.J.
Jarrett L.
Joseph L.
Jou R.
Kambli P.
Khot R.
Koch A.
Kohl T.A.
Kohlerschmidt D.
Kouchaki S.
Lachapelle A.S.
Lalvani A.
Grandjean L.
Lapierre S.G.
Laurenson I.F.
Letcher B.
Lin W.H.
Liu C.
Liu D.
Malone K.M.
Mandal A.
Masjö M.
Matias D.
Meintjes G.
Mendes F.F.
Merker M.
Mihalic M.
Millard J.
Mistry N.
Moore D.A.J.
Musser K.A.
Ngcamu D.
Hoang N.N.
Niemann S.
Nilgiriwala K.S.
Nimmo C.
O'Donnell M.
Okozi N.
Oliveira R.S.
Paton N.I.
Pinhata J.M.W.
Plesnik S.
Puyen Z.M.
Rabodoarivelo M.S.
Rakotosamimanana N.
Rancoita P.M.V.
Rathod P.
Robinson E.R.
Rodger G.
Miotto P.
Köser C.U.
Fowler P.W.
Knaggs J.
Iqbal Z.
Hunt M.
Chindelevitch L.
Farhat M.R.
Cirillo D.M.
Comas I.
Posey J.
Omar S.V.
Peto T.E.A.
Suresh A.
Uplekar S.
Laurent S.
Colman R.E.
Nathanson C.M.
Zignol M.
Walker A.S.
Crook D.W.
Ismail N.
Rodwell T.C.
Barilar I.
Battaglia S.
Borroni E.
Brandao A.P.
Brankin A.
Cabibbe A.M.
Carter J.
Chetty D.
Claxton P.
Clifton D.A.
Cohen T.
Coronel J.
Dreyer V.
Earle S.G.
Escuyer V.
Ferrazoli L.
Gao G.F.
Gardy J.
Gharbia S.
Ghisi K.T.
Ghodousi A.
Cruz A.L.G.
Grazian C.
Groenheit R.
Guthrie J.L.
He W.
Hoffmann H.
Hoosdally S.J.
Jarrett L.
Joseph L.
Jou R.
Kambli P.
Khot R.
Koch A.
Kohl T.A.
Kohlerschmidt D.
Kouchaki S.
Lachapelle A.S.
Lalvani A.
Grandjean L.
Lapierre S.G.
Laurenson I.F.
Letcher B.
Lin W.H.
Liu C.
Liu D.
Malone K.M.
Mandal A.
Masjö M.
Matias D.
Meintjes G.
Mendes F.F.
Merker M.
Mihalic M.
Millard J.
Mistry N.
Moore D.A.J.
Musser K.A.
Ngcamu D.
Hoang N.N.
Niemann S.
Nilgiriwala K.S.
Nimmo C.
O'Donnell M.
Okozi N.
Oliveira R.S.
Paton N.I.
Pinhata J.M.W.
Plesnik S.
Puyen Z.M.
Rabodoarivelo M.S.
Rakotosamimanana N.
Rancoita P.M.V.
Rathod P.
Robinson E.R.
Rodger G.
Author's Affiliation
UK Health Security Agency
NIHR Oxford Biomedical Research Centre
Africa Health Research Institute
Public Health Agency of Sweden
Oxford University Clinical Research Unit
Public Health Ontario
Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública
Forschungszentrum Borstel - Zentrum für Medizin und Biowissenschaften
Institut Pasteur de Madagascar
National Institute of Health, Lima
Universidad Peruana Cayetano Heredia
The Foundation for Medical Research India
Stanford University School of Medicine
CSIC - Instituto de Biomedicina de Valencia (IBV)
National Institute for Communicable Diseases
Chinese Center for Disease Control and Prevention
London School of Hygiene & Tropical Medicine
University of Cambridge
University of California, San Diego
Columbia University
Instituto Adolfo Lutz
Organisation Mondiale de la Santé
University of Oxford
EMBL’s European Bioinformatics Institute
Fundacao Oswaldo Cruz
The University of Sydney
IRCCS Ospedale San Raffaele
P.D. Hinduja National Hospital and Medical Research Centre
Bill & Melinda Gates Foundation
University College London
Centers for Disease Control and Prevention
University of Surrey
University of Liverpool
National University of Singapore
Imperial College London
Wadsworth Center for Laboratories and Research
The University of British Columbia
Università Vita-Salute San Raffaele
University of Montreal
Nuffield Department of Medicine
Taiwan Centers for Disease Control
Yale University
Harvard Medical School
University of Cape Town
FIND
SYNLAB Gauting
IMLred
German Center for Infection Research (DZIF)
Scottish Mycobacteria Reference Laboratory
NIHR Oxford Biomedical Research Centre
Africa Health Research Institute
Public Health Agency of Sweden
Oxford University Clinical Research Unit
Public Health Ontario
Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública
Forschungszentrum Borstel - Zentrum für Medizin und Biowissenschaften
Institut Pasteur de Madagascar
National Institute of Health, Lima
Universidad Peruana Cayetano Heredia
The Foundation for Medical Research India
Stanford University School of Medicine
CSIC - Instituto de Biomedicina de Valencia (IBV)
National Institute for Communicable Diseases
Chinese Center for Disease Control and Prevention
London School of Hygiene & Tropical Medicine
University of Cambridge
University of California, San Diego
Columbia University
Instituto Adolfo Lutz
Organisation Mondiale de la Santé
University of Oxford
EMBL’s European Bioinformatics Institute
Fundacao Oswaldo Cruz
The University of Sydney
IRCCS Ospedale San Raffaele
P.D. Hinduja National Hospital and Medical Research Centre
Bill & Melinda Gates Foundation
University College London
Centers for Disease Control and Prevention
University of Surrey
University of Liverpool
National University of Singapore
Imperial College London
Wadsworth Center for Laboratories and Research
The University of British Columbia
Università Vita-Salute San Raffaele
University of Montreal
Nuffield Department of Medicine
Taiwan Centers for Disease Control
Yale University
Harvard Medical School
University of Cape Town
FIND
SYNLAB Gauting
IMLred
German Center for Infection Research (DZIF)
Scottish Mycobacteria Reference Laboratory
Corresponding Author(s)
Other Contributor(s)
Abstract
Background: Molecular diagnostics are considered the most promising route to achievement of rapid, universal drug susceptibility testing for Mycobacterium tuberculosis complex (MTBC). We aimed to generate a WHO-endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction. Methods: In this systematic analysis, we used a candidate gene approach to identify mutations associated with resistance or consistent with susceptibility for 13 WHO-endorsed antituberculosis drugs. We collected existing worldwide MTBC whole-genome sequencing data and phenotypic data from academic groups and consortia, reference laboratories, public health organisations, and published literature. We categorised phenotypes as follows: methods and critical concentrations currently endorsed by WHO (category 1); critical concentrations previously endorsed by WHO for those methods (category 2); methods or critical concentrations not currently endorsed by WHO (category 3). For each mutation, we used a contingency table of binary phenotypes and presence or absence of the mutation to compute positive predictive value, and we used Fisher's exact tests to generate odds ratios and Benjamini-Hochberg corrected p values. Mutations were graded as associated with resistance if present in at least five isolates, if the odds ratio was more than 1 with a statistically significant corrected p value, and if the lower bound of the 95% CI on the positive predictive value for phenotypic resistance was greater than 25%. A series of expert rules were applied for final confidence grading of each mutation. Findings: We analysed 41 137 MTBC isolates with phenotypic and whole-genome sequencing data from 45 countries. 38 215 MTBC isolates passed quality control steps and were included in the final analysis. 15 667 associations were computed for 13 211 unique mutations linked to one or more drugs. 1149 (7·3%) of 15 667 mutations were classified as associated with phenotypic resistance and 107 (0·7%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations' pooled sensitivity was more than 80%. Specificity was over 95% for all drugs except ethionamide (91·4%), moxifloxacin (91·6%) and ethambutol (93·3%). Only two resistance mutations were identified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs. Interpretation: We present the first WHO-endorsed catalogue of molecular targets for MTBC drug susceptibility testing, which is intended to provide a global standard for resistance interpretation. The existence of this catalogue should encourage the implementation of molecular diagnostics by national tuberculosis programmes. Funding: Unitaid, Wellcome Trust, UK Medical Research Council, and Bill and Melinda Gates Foundation.