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The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: a genotypic analysis.

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Title: The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: a genotypic analysis.
Authors: Walker, TM
Miotto, P
Köser, CU
Fowler, PW
Knaggs, J
Iqbal, Z
Hunt, M
Chindelevitch, L
Farhat, M
Cirillo, DM
Comas, I
Posey, J
Omar, SV
Peto, TE
Suresh, A
Uplekar, S
Laurent, S
Colman, RE
Nathanson, C-M
Zignol, M
Walker, AS
CRyPTIC Consortium
Seq&Treat Consortium
Crook, DW
Ismail, N
Rodwell, TC
Item Type: Journal Article
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.
Issue Date: Apr-2022
Date of Acceptance: 1-Mar-2022
URI: http://hdl.handle.net/10044/1/96635
DOI: 10.1016/S2666-5247(21)00301-3
ISSN: 2666-5247
Publisher: Elsevier
Start Page: e265
End Page: e273
Journal / Book Title: The Lancet Microbe
Volume: 3
Issue: 4
Copyright Statement: © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
Sponsor/Funder: Wellcome Trust
National Institute for Health Research
Funder's Grant Number: WDAI_P83556
NIHR200927
Keywords: CRyPTIC Consortium
Seq&Treat Consortium
Publication Status: Published
Conference Place: England
Open Access location: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7612554/
Online Publication Date: 2022-03-08
Appears in Collections:Department of Infectious Diseases
National Heart and Lung Institute
School of Public Health



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