| 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, MR; Cirillo, DM; Comas, I; Posey, J; Omar, SV; Peto, TEA; Suresh, A; Uplekar, S; Laurent, S; Colman, RE; Nathanson, CM; Zignol, M; Walker, AS; Crook, DW; Ismail, N; Rodwell, TC; Barilar, I; Battaglia, S; Borroni, E; Brandao, AP; Brankin, A; Cabibbe, AM; Carter, J; Chetty, D; Claxton, P; Clifton, DA; Cohen, T; Coronel, J; Dreyer, V; Earle, SG; Escuyer, V; Ferrazoli, L; Gao, GF; Gardy, J; Gharbia, S; Ghisi, KT; Ghodousi, A; Cruz, ALG; Grazian, C; Groenheit, R; Guthrie, JL; He, W; Hoffmann, H; Hoosdally, SJ; Jarrett, L; Joseph, L; Jou, R; Kambli, P; Khot, R; Koch, A; Kohl, TA; Kohlerschmidt, D; Kouchaki, S; Lachapelle, AS; Lalvani, A; Grandjean, L; Lapierre, SG; Laurenson, IF; Letcher, B; Lin, WH; Liu, C; Liu, D; Malone, KM; Mandal, A; Masjö, M; Matias, D; Meintjes, G; Mendes, FF; Merker, M; Mihalic, M; Millard, J; Mistry, N; Moore, DAJ; Musser, KA; Ngcamu, D; Hoang, NN; Niemann, S; Nilgiriwala, KS; Nimmo, C; O'Donnell, M; Okozi, N; Oliveira, RS; Paton, NI; Pinhata, JMW; Plesnik, S; Puyen, ZM; Rabodoarivelo, MS; Rakotosamimanana, N; Rancoita, PMV; Rathod, P; Robinson, ER; Rodger, G |
| Publisher Information: |
ELSEVIER |
| Publication Year: |
2022 |
| Collection: |
The University of Melbourne: Digital Repository |
| Description: |
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 ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| ISSN: |
2666-5247 |
| Relation: |
NHMRC/1056689; https://hdl.handle.net/11343/309255 |
| Availability: |
https://hdl.handle.net/11343/309255 |
| Rights: |
https://creativecommons.org/licenses/by/4.0 ; CC BY |
| Accession Number: |
edsbas.D6AD4FC2 |
| Database: |
BASE |