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Integrating informatics tools and portable sequencing technology for rapid detection of resistance to anti-tuberculous drugs

2019-06-24Artigo científico Acesso aberto
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dc.contributor.authorPhelan, Jody E.
dc.contributor.authorO'Sullivan, Denise M.
dc.contributor.authorMachado, Diana
dc.contributor.authorRamos, Jorge
dc.contributor.authorOppong, Yaa E.A.
dc.contributor.authorCampino, Susana
dc.contributor.authorO'Grady, Justin
dc.contributor.authorMcNerney, Ruth
dc.contributor.authorHibberd, Martin L.
dc.contributor.authorViveiros, Miguel
dc.contributor.authorHuggett, Jim F.
dc.contributor.authorClark, Taane G.
dc.contributor.institutionTB, HIV and opportunistic diseases and pathogens (THOP)
dc.contributor.institutionGlobal Health and Tropical Medicine (GHTM)
dc.contributor.institutionInstituto de Higiene e Medicina Tropical (IHMT)
dc.contributor.pblBioMed Central (BMC)
dc.date.accessioned2021-05-02T22:44:21Z
dc.date.available2021-05-02T22:44:21Z
dc.date.issued2019-06-24
dc.description.abstractBackground: Mycobacterium tuberculosis resistance to anti-tuberculosis drugs is a major threat to global public health. Whole genome sequencing (WGS) is rapidly gaining traction as a diagnostic tool for clinical tuberculosis settings. To support this informatically, previous work led to the development of the widely used TBProfiler webtool, which predicts resistance to 14 drugs from WGS data. However, for accurate and rapid high throughput of samples in clinical or epidemiological settings, there is a need for a stand-alone tool and the ability to analyse data across multiple WGS platforms, including Oxford Nanopore MinION. Results: We present a new command line version of the TBProfiler webserver, which includes hetero-resistance calling and will facilitate the batch processing of samples. The TBProfiler database has been expanded to incorporate 178 new markers across 16 anti-tuberculosis drugs. The predictive performance of the mutation library has been assessed using > 17,000 clinical isolates with WGS and laboratory-based drug susceptibility testing (DST) data. An integrated MinION analysis pipeline was assessed by performing WGS on 34 replicates across 3 multi-drug resistant isolates with known resistance mutations. TBProfiler accuracy varied by individual drug. Assuming DST as the gold standard, sensitivities for detecting multi-drug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) were 94% (95%CI 93-95%) and 83% (95%CI 79-87%) with specificities of 98% (95%CI 98-99%) and 96% (95%CI 95-97%) respectively. Using MinION data, only one resistance mutation was missed by TBProfiler, involving an insertion in the tlyA gene coding for capreomycin resistance. When compared to alternative platforms (e.g. Mykrobe predictor TB, the CRyPTIC library), TBProfiler demonstrated superior predictive performance across first- and second-line drugs. Conclusions: The new version of TBProfiler can rapidly and accurately predict anti-TB drug resistance profiles across large numbers of samples with WGS data. The computing architecture allows for the ability to modify the core bioinformatic pipelines and outputs, including the analysis of WGS data sourced from portable technologies. TBProfiler has the potential to be integrated into the point of care and WGS diagnostic environments, including in resource-poor settings.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent7
dc.format.extent408301
dc.identifier.doi10.1186/s13073-019-0650-x
dc.identifier.otherPURE: 14105817
dc.identifier.otherPURE UUID: 4a37b6ba-02bf-468d-9a5b-865a67c22594
dc.identifier.otherScopus: 85068258625
dc.identifier.otherPubMedCentral: PMC6591855
dc.identifier.otherPubMed: 31234910
dc.identifier.otherORCID: /0000-0001-9676-6251/work/63725163
dc.identifier.otherORCID: /0000-0003-2375-2726/work/64041259
dc.identifier.urihttp://hdl.handle.net/10362/116711
dc.identifier.urlhttps://www.scopus.com/pages/publications/85068258625
dc.language.isoeng
dc.peerreviewedyes
dc.subjectDiagnostics
dc.subjectDrug resistance
dc.subjectDrug-susceptibility testing
dc.subjectMDR-TB
dc.subjectTuberculosis
dc.subjectWGS
dc.subjectXDR-TB
dc.subjectMolecular Medicine
dc.subjectMolecular Biology
dc.subjectGenetics
dc.subjectGenetics(clinical)
dc.subjectSDG 3 - Good Health and Well-being
dc.titleIntegrating informatics tools and portable sequencing technology for rapid detection of resistance to anti-tuberculous drugsen
dc.typejournal article
degois.publication.firstPage41
degois.publication.issue1
degois.publication.lastPage48
degois.publication.titleGenome Medicine
degois.publication.volume11
dspace.entity.typePublication
rcaap.rightsopenAccess

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