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Record W4390790879 · doi:10.1038/s41467-023-44325-5

Quantitative measurement of antibiotic resistance in Mycobacterium tuberculosis reveals genetic determinants of resistance and susceptibility in a target gene approach

2024· article· en· W4390790879 on OpenAlexaff
Ivan Barilar, Simone Battaglia, Emanuele Borroni, Angela Pires Brandão, Alice Brankin, Andrea Maurizio Cabibbe, Joshua Carter, Darren Chetty, Daniela María Cirillo, Pauline Claxton, David A. Clifton, Ted Cohen, Jorge Coronel, Derrick W. Crook, Viola Dreyer, Sarah G. Earle, Vincent Escuyer, Lucilaine Ferrazoli, Philip W. Fowler, George F. Gao, Jennifer L. Gardy, Saheer E. Gharbia, Kelen Teixeira Ghisi, Arash Ghodousi, Ana Lúıza Gibertoni Cruz, Louis Grandjean, Clara Grazian, Ramona Groenheit, Jennifer L. Guthrie, Wencong He, Harald Hoffmann, Sarah Hoosdally, Martin Hunt, Zamin Iqbal, Nazir Ismail, Lisa Jarrett, Lavania Joseph, Ruwen Jou, Priti Kambli, Rukhsar Khot, Jeff Knaggs, Anastasia Koch, Donna Kohlerschmidt, Samaneh Kouchaki, Alexander S. Lachapelle, Ajit Lalvani, Simon Grandjean Lapierre, Ian F. Laurenson, Brice Letcher, Wan-Hsuan Lin, Chunfa Liu, Dongxin Liu, Kerri M. Malone, Ayan Mandal, Mikael Mansjö, Daniela Matias, Graeme Meintjes, Flávia de Freitas Mendes, Matthias Merker, Marina Mihalic, James Millard, Paolo Miotto, Nerges Mistry, David Moore, Kimberlee A. Musser, Dumisani Ngcamu, Hoang Ngoc Nhung, Stefan Niemann, Kayzad Nilgiriwala, Camus Nimmo, Max R. O’Donnell, Nana Okozi, Rosângela Siqueira de Oliveira, Shaheed Vally Omar, Nicholas I. Paton, Tim Peto, Juliana Maíra Watanabe Pinhata, Sara Plesnik, Zully M. Puyén, Marie Sylvianne Rabodoarivelo, Niaina Rakotosamimanana, Paola M. V. Rancoita, Priti Rathod, Esther Robinson, Gillian Rodger, Camilla Rodrigues, Timothy C. Rodwell, Aysha Roohi, David Santos-Lázaro, Sanchi Shah, Grace Smith, Thomas A. Kohl, Walter Solano, Andrea Spitaleri, Adrie J. C. Steyn, Philip Supply, Utkarsha Surve, Sabira Tahseen, Nguyễn Thụy Thương Thương, Guy Thwaites, Katharina Todt, Alberto Trovato, Christian Utpatel, Annelies Van Rie, Srinivasan Vijay, A Sarah Walker, Robin M. Warren, Jim Werngren, Maria Wijkander, Robert J. Wilkinson, Daniel J. Wilson, Penelope Wintringer, Yu-Xin Xiao, Yang Yang, Shen-Yuan Yao, Baoli Zhu

Bibliographic record

VenueNature Communications · 2024
Typearticle
Languageen
FieldMedicine
TopicTuberculosis Research and Epidemiology
Canadian institutionsUniversité de MontréalPublic Health OntarioUniversity of British Columbia
FundersNational Institute of Allergy and Infectious DiseasesNIHR Oxford Biomedical Research CentreMedical Research CouncilCenters for Disease Control and PreventionNational Institutes of HealthNational Institute for Health Research Health Protection Research UnitUniversity of OxfordVlaamse regeringFolkhälsomyndighetenNational Natural Science Foundation of ChinaDeutsches Zentrum für InfektionsforschungUniversity of PennsylvaniaPublic Health AgencySouth African Medical Research CouncilEuropean CommissionImperial College LondonWellcome TrustCancer Research UKGreat Ormond Street Hospital CharityNational Institute for Health and Care ResearchUK Research and InnovationNational Research FoundationRobertson FoundationFundação de Amparo à Pesquisa do Estado de São PauloNational Institute of General Medical SciencesNational Science and Technology Major ProjectFrancis Crick InstituteFonds Wetenschappelijk OnderzoekBill and Melinda Gates FoundationUnited States Agency for International Development
KeywordsMycobacterium tuberculosisTuberculosisDrug resistanceBiologyGeneticsAntibioticsAntibiotic resistanceGeneWhole genome sequencingGenomeComputational biologyMycobacterium tuberculosis complexMutationGenomicsMicrobiologyMedicine

Abstract

fetched live from OpenAlex

The World Health Organization has a goal of universal drug susceptibility testing for patients with tuberculosis. However, molecular diagnostics to date have focused largely on first-line drugs and predicting susceptibilities in a binary manner (classifying strains as either susceptible or resistant). Here, we used a multivariable linear mixed model alongside whole genome sequencing and a quantitative microtiter plate assay to relate genomic mutations to minimum inhibitory concentration (MIC) in 15,211 Mycobacterium tuberculosis clinical isolates from 23 countries across five continents. We identified 492 unique MIC-elevating variants across 13 drugs, as well as 91 mutations likely linked to hypersensitivity. Our results advance genetics-based diagnostics for tuberculosis and serve as a curated training/testing dataset for development of drug resistance prediction algorithms.

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.

How this classification was reachedexpand

Full frame distilled prediction

Teacher imitation

Not calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.

metaresearch head score (Codex)0.002
metaresearch head score (Gemma)0.002
Version: codex-gemma-dda1882f352aValidation status: machine_predicted_unvalidated
Candidate categoriesnone
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Observational · Consensus signal: Observational
GenreCandidate signal: Empirical · Consensus signal: Empirical
Teacher disagreement score0.117
Threshold uncertainty score0.821

Codex and Gemma teacher scores by category

CategoryCodexGemma
Metaresearch0.0020.002
Meta-epidemiology (narrow)0.0000.000
Meta-epidemiology (broad)0.0010.000
Bibliometrics0.0000.001
Science and technology studies0.0000.000
Scholarly communication0.0000.000
Open science0.0000.000
Research integrity0.0000.001
Insufficient payload (model declined to judge)0.0000.000

Machine scores (provisional)

The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.

Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.

Opus teacher head0.054
GPT teacher head0.365
Teacher spread0.311 · how far apart the two teachers sit on this one work
Validation statusscore_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it

Classification

machine, unvalidated

Machine predicted; a candidate call from one teacher head, not a consensus.

The models applied no category: nothing in the taxonomy fit this work.
Study designObservational
Domainnot available
GenreEmpirical

How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".

Quick stats

Citations45
Published2024
Admission routes1
Has abstractyes

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