title: Rapid antibiotic-resistance predictions from genome sequence data for Staphylococcus aureus and Mycobacterium tuberculosis.
abstract: The rise of antibiotic-resistant bacteria has led to an urgent need for rapid detection of drug resistance in clinical samples, and improvements in global surveillance. Here we show how de Bruijn graph representation of bacterial diversity can be used to identify species and resistance profiles of clinical isolates. We implement this method for Staphylococcus aureus and Mycobacterium tuberculosis in a software package ('Mykrobe predictor') that takes raw sequence data as input, and generates a clinician-friendly report within 3 minutes on a laptop. For S. aureus, the error rates of our method are comparable to gold-standard phenotypic methods, with sensitivity/specificity of 99.1%/99.6% across 12 antibiotics (using an independent validation set, n=470). For M. tuberculosis, our method predicts resistance with sensitivity/specificity of 82.6%/98.5% (independent validation set, n=1,609); sensitivity is lower here, probably because of limited understanding of the underlying genetic mechanisms. We give evidence that minor alleles improve detection of extremely drug-resistant strains, and demonstrate feasibility of the use of emerging single-molecule nanopore sequencing techniques for these purposes.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Phelim
authors.identifier: http://orcid.org/0000-0003-3967-3037
authors.initials: P
authors.lastname: Bradley
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford OX1 1NF, UK.
authors.forename: N Claire
authors.initials: NC
authors.lastname: Gordon
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford OX1 1NF, UK.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Walker
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford OX1 1NF, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Dunn
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Heys
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Bill
authors.initials: B
authors.lastname: Huang
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford OX1 1NF, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Earle
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford OX1 1NF, UK.
authors.forename: Louise J
authors.initials: LJ
authors.lastname: Pankhurst
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford OX1 1NF, UK.
authors.forename: Luke
authors.initials: L
authors.lastname: Anson
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Mariateresa
authors.initials: M
authors.lastname: de Cesare
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Paolo
authors.initials: P
authors.lastname: Piazza
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford OX1 1NF, UK.
authors.forename: Antonina A
authors.initials: AA
authors.lastname: Votintseva
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford OX1 1NF, UK.
authors.forename: Tanya
authors.initials: T
authors.lastname: Golubchik
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.|Nuffield Department of Medicine, University of Oxford, Oxford OX1 1NF, UK.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wilson
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford OX1 1NF, UK.
authors.forename: David H
authors.initials: DH
authors.lastname: Wyllie
authors.affiliation: Institute for Epidemiology, University Medical Hospital Schleswig-Holstein, Niemannsweg 11, 24105 Kiel, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Diel
authors.affiliation: Molecular and Experimental Mycobacteriology, Research Centre Borstel, Parkallee 1, 23845 Borstel, Germany.|German Centre for Infection Research, Partner Site Borstel, Parkallee 1, 23845 Borstel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Niemann
authors.affiliation: Molecular and Experimental Mycobacteriology, Research Centre Borstel, Parkallee 1, 23845 Borstel, Germany.|German Centre for Infection Research, Partner Site Borstel, Parkallee 1, 23845 Borstel, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Feuerriegel
authors.affiliation: Molecular and Experimental Mycobacteriology, Research Centre Borstel, Parkallee 1, 23845 Borstel, Germany.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Kohl
authors.affiliation: Centre for Tuberculosis, National Institute for Communicable Diseases, Private Bag X4 Sandringham, Johannesburg 2131, South Africa.|Department of Medical Microbiology, University of Pretoria, PO Box 667, Pretoria 0001, South Africa.
authors.forename: Nazir
authors.initials: N
authors.lastname: Ismail
authors.affiliation: Centre for Tuberculosis, National Institute for Communicable Diseases, Private Bag X4 Sandringham, Johannesburg 2131, South Africa.
authors.forename: Shaheed V
authors.initials: SV
authors.lastname: Omar
authors.affiliation: Regional Centre for Mycobacteriology, PHE Public Health Laboratory Birmingham. Heartlands Hospital, Bordesley Green East, Birmingham B9 5SS, UK.
authors.forename: E Grace
authors.initials: EG
authors.lastname: Smith
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: David
authors.initials: D
authors.lastname: Buck
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Gil
authors.initials: G
authors.lastname: McVean
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford OX1 1NF, UK.|Biomedical Research Centre, NIHR (National Institutes of Health Research) Oxford Biomedical Research Centre, Oxford OX3 7LE, UK.
authors.forename: A Sarah
authors.initials: AS
authors.lastname: Walker
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford OX1 1NF, UK.|Biomedical Research Centre, NIHR (National Institutes of Health Research) Oxford Biomedical Research Centre, Oxford OX3 7LE, UK.
authors.forename: Tim E A
authors.initials: TE
authors.lastname: Peto
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford OX1 1NF, UK.|Biomedical Research Centre, NIHR (National Institutes of Health Research) Oxford Biomedical Research Centre, Oxford OX3 7LE, UK.|National Infection Service, Public Health England, Wellington House, 133-155 Waterloo Road, London SE1 8UG, UK.
authors.forename: Derrick W
authors.initials: DW
authors.lastname: Crook
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Zamin
authors.identifier: http://orcid.org/0000-0001-8466-7547
authors.initials: Z
authors.lastname: Iqbal
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial; D016680:Genome, Bacterial; D006801:Humans; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics*; D013203:Staphylococcal Infections / Q000382:microbiology*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000235:genetics*; D014376:Tuberculosis / Q000382:microbiology*
chemical_list: D000900:Anti-Bacterial Agents