The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: A genotypic analysis.
Authors
Walker, Timothy M
Miotto, Paolo
Köser, Claudio U
Fowler, Philip W
Knaggs, Jeff
Hunt, Martin
Chindelevitch, Leonid
Farhat, Maha
Cirillo, Daniela Maria
Comas, Iñaki
Posey, James
Omar, Shaheed V
Peto, Timothy Ea
Suresh, Anita
Uplekar, Swapna
Laurent, Sacha
Colman, Rebecca E
Nathanson, Carl-Michael
Zignol, Matteo
Walker, Ann Sarah
CRyPTIC Consortium
Seq&Treat Consortium
Crook, Derrick W
Ismail, Nazir
Rodwell, Timothy C
Publication Date
2022-04Journal Title
Lancet Microbe
ISSN
2666-5247
Publisher
Elsevier BV
Volume
3
Issue
4
Pages
e265-e273
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Walker, T. M., Miotto, P., Köser, C. U., Fowler, P. W., Knaggs, J., Iqbal, Z., Hunt, M., et al. (2022). The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: A genotypic analysis.. Lancet Microbe, 3 (4), e265-e273. https://doi.org/10.1016/S2666-5247(21)00301-3
Abstract
BACKGROUND: Molecular diagnostics are considered the most promising route to achieving rapid, universal drug susceptibility testing for Mycobacterium tuberculosiscomplex (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: A candidate gene approach was used to identify mutations as associated with resistance, or consistent with susceptibility, for 13 WHO endorsed anti-tuberculosis drugs. 38,215 MTBC isolates with paired whole-genome sequencing and phenotypic drug susceptibility testing data were amassed from 45 countries. For each mutation, a contingency table of binary phenotypes and presence or absence of the mutation computed positive predictive value, and Fisher's exact tests generated odds ratios and Benjamini-Hochberg corrected p-values. Mutations were graded as Associated with Resistance if present in at least 5 isolates, if the odds ratio was >1 with a statistically significant corrected p-value, and if the lower bound of the 95% confidence interval on the positive predictive value for phenotypic resistance was >25%. A series of expert rules were applied for final confidence grading of each mutation. FINDINGS: 15,667 associations were computed for 13,211 unique mutations linked to one or more drugs. 1,149/15,667 (7·3%) mutations were classified as associated with phenotypic resistance and 107/15,667 (0·7%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations' pooled sensitivity was >80%. Specificity was over 95% for all drugs except ethionamide (91·4%), moxifloxacin (91·6%) and ethambutol (93·3%). Only two resistance mutations were classified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs. INTERPRETATION: This first WHO endorsed catalogue of molecular targets for MTBC drug susceptibility testing provides a global standard for resistance interpretation. Its existence should encourage the implementation of molecular diagnostics by National Tuberculosis Programmes. FUNDING: UNITAID, Wellcome, MRC, BMGF.
Keywords
Mycobacterium tuberculosis, Ethambutol, Antitubercular Agents, Microbial Sensitivity Tests, Drug Resistance, Mutation, World Health Organization
Sponsorship
Wellcome Trust (101237/Z/13/B, 203583/Z/16/Z, 098316, 203135/Z/16/Z, 203141/Z/16/Z, 214321/Z/18/Z, 214560, 201470/Z/16/Z, 206724/Z/17/Z, 200205/Z/15/Z, 203919/Z/16/Z, 200205, 214560/Z/18/Z)
NIAID NIH HHS (R01 AI131939)
World Health Organization (001)
European Research Council (101001038)
Medical Research Council (MC_PC_16027)
Swiss National Science Foundation (153442, 320030)
Identifiers
35373160, PMC7612554
External DOI: https://doi.org/10.1016/S2666-5247(21)00301-3
This record's URL: https://www.repository.cam.ac.uk/handle/1810/336869
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