<?xml version="1.0" encoding="UTF-8"?><xml><records><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Timothy M Walker</style></author><author><style face="normal" font="default" size="100%">Paolo Miotto</style></author><author><style face="normal" font="default" size="100%">Claudio U Köser</style></author><author><style face="normal" font="default" size="100%">Philip W Fowler</style></author><author><style face="normal" font="default" size="100%">Jeff Knaggs</style></author><author><style face="normal" font="default" size="100%">Iqbal, Zamin</style></author><author><style face="normal" font="default" size="100%">Martin Hunt</style></author><author><style face="normal" font="default" size="100%">Leonid Chindelevitch</style></author><author><style face="normal" font="default" size="100%">Maha Farhat</style></author><author><style face="normal" font="default" size="100%">Daniela Maria Cirillo</style></author><author><style face="normal" font="default" size="100%">Iñaki Comas</style></author><author><style face="normal" font="default" size="100%">James Posey</style></author><author><style face="normal" font="default" size="100%">Shaheed V Omar</style></author><author><style face="normal" font="default" size="100%">Timothy EA Peto</style></author><author><style face="normal" font="default" size="100%">Anita Suresh</style></author><author><style face="normal" font="default" size="100%">Swapna Uplekar</style></author><author><style face="normal" font="default" size="100%">Sacha Laurent</style></author><author><style face="normal" font="default" size="100%">Rebecca E Colman</style></author><author><style face="normal" font="default" size="100%">Carl-Michael Nathanson</style></author><author><style face="normal" font="default" size="100%">Matteo Zignol</style></author><author><style face="normal" font="default" size="100%">Ann Sarah Walker</style></author><author><style face="normal" font="default" size="100%">Derrick W Crook</style></author><author><style face="normal" font="default" size="100%">Nazir Ismail</style></author><author><style face="normal" font="default" size="100%">Timothy C Rodwell</style></author><author><style face="normal" font="default" size="100%">Vanessa Mathys</style></author></authors><translated-authors><author><style face="normal" font="default" size="100%">CRyPTIC Consortium</style></author><author><style face="normal" font="default" size="100%">Seq&amp;Treat Consortium</style></author></translated-authors></contributors><titles><title><style face="normal" font="default" size="100%">The 2021 WHO catalogue of  complex mutations associated with drug resistance: A genotypic analysis.</style></title><secondary-title><style face="normal" font="default" size="100%">Lancet Microbe</style></secondary-title></titles><keywords><keyword><style  face="normal" font="default" size="100%">Drug Resistance</style></keyword><keyword><style  face="normal" font="default" size="100%">mutations</style></keyword><keyword><style  face="normal" font="default" size="100%">Tuberculosis</style></keyword></keywords><dates><year><style  face="normal" font="default" size="100%">2022</style></year><pub-dates><date><style  face="normal" font="default" size="100%">2022 Apr</style></date></pub-dates></dates><volume><style face="normal" font="default" size="100%">3</style></volume><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">&lt;p&gt;&lt;b&gt;Background: &lt;/b&gt;Molecular diagnostics are considered the most promising route to achieving rapid, universal drug susceptibility testing for 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.&lt;/p&gt;

&lt;p&gt;&lt;b&gt;Methods: &lt;/b&gt;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 &amp;gt;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 &amp;gt;25%. A series of expert rules were applied for final confidence grading of each mutation.&lt;/p&gt;

&lt;p&gt;&lt;b&gt;Findings: &lt;/b&gt;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 &amp;gt;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.&lt;/p&gt;

&lt;p&gt;&lt;b&gt;Interpretation: &lt;/b&gt;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.&lt;/p&gt;

&lt;p&gt;&lt;b&gt;Funding: &lt;/b&gt;UNITAID, Wellcome, MRC, BMGF.&lt;/p&gt;
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