Integrating standardized whole genome sequence analysis with a global Mycobacterium tuberculosis antibiotic resistance knowledgebase

Matthew Ezewudo; Amanda Borens; Álvaro Chiner-Oms; Paolo Miotto; Leonid Chindelevitch; Angela M Starks; Debra Hanna; Richard Liwski; Matteo Zignol; Christopher Gilpin; Stefan Niemann; Thomas Andreas Kohl; Robin M Warren; Derrick Crook; Sebastien Gagneux; Sven Hoffner; Camilla Rodrigues; Iñaki Comas; David M Engelthaler; David Alland; Leen Rigouts; Christoph Lange; Keertan Dheda; Rumina Hasan; Ruth McNerney; Daniela M Cirillo; Marco Schito; Timothy C Rodwell; James Posey

doi:10.1038/s41598-018-33731-1

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Integrating standardized whole genome sequence analysis with a global Mycobacterium tuberculosis antibiotic resistance knowledgebase

Journal article

Open access

Peer reviewed

Integrating standardized whole genome sequence analysis with a global Mycobacterium tuberculosis antibiotic resistance knowledgebase

Matthew Ezewudo, Amanda Borens, Álvaro Chiner-Oms, Paolo Miotto, Leonid Chindelevitch, Angela M Starks, Debra Hanna, Richard Liwski, Matteo Zignol, Christopher Gilpin, …

Scientific reports, Vol.8(1), pp.15382-15382

10/18/2018

DOI: https://doi.org/10.1038/s41598-018-33731-1

PMCID: PMC6194142

PMID: 30337678

Abstract

Genome, Bacterial

Knowledge Bases

Mycobacterium tuberculosis - classification

Humans

Antitubercular Agents - pharmacology

Bacterial Proteins - genetics

Genotype

Tuberculosis, Multidrug-Resistant - genetics

Whole Genome Sequencing - methods

Mycobacterium tuberculosis - drug effects

Mycobacterium tuberculosis - isolation & purification

Tuberculosis, Multidrug-Resistant - microbiology

Polymorphism, Single Nucleotide

Mutation

Drug Resistance, Multiple, Bacterial - genetics

Sequence Analysis, DNA - methods

Mycobacterium tuberculosis - genetics

Tuberculosis, Multidrug-Resistant - drug therapy

Drug-resistant tuberculosis poses a persistent public health threat. The ReSeqTB platform is a collaborative, curated knowledgebase, designed to standardize and aggregate global Mycobacterium tuberculosis complex (MTBC) variant data from whole genome sequencing (WGS) with phenotypic drug susceptibility testing (DST) and clinical data. We developed a unified analysis variant pipeline (UVP) ( https://github.com/CPTR-ReSeqTB/UVP ) to identify variants and assign lineage from MTBC sequence data. Stringent thresholds and quality control measures were incorporated in this open source tool. The pipeline was validated using a well-characterized dataset of 90 diverse MTBC isolates with conventional DST and DNA Sanger sequencing data. The UVP exhibited 98.9% agreement with the variants identified using Sanger sequencing and was 100% concordant with conventional methods of assigning lineage. We analyzed 4636 publicly available MTBC isolates in the ReSeqTB platform representing all seven major MTBC lineages. The variants detected have an above 94% accuracy of predicting drug based on the accompanying DST results in the platform. The aggregation of variants over time in the platform will establish confidence-graded mutations statistically associated with phenotypic drug resistance. These tools serve as critical reference standards for future molecular diagnostic assay developers, researchers, public health agencies and clinicians working towards the control of drug-resistant tuberculosis.

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Title: Integrating standardized whole genome sequence analysis with a global Mycobacterium tuberculosis antibiotic resistance knowledgebase
Creators: Matthew Ezewudo - Critical Path Institute, 1730 E River Rd., Tucson, AZ, 85718, USA
Amanda Borens - Critical Path Institute, 1730 E River Rd., Tucson, AZ, 85718, USA
Álvaro Chiner-Oms - Joint unit Infection and Public Health FISABIO-CSISP/University of Valencia, Institute of integrative Systems Biology, Valencia, Spain
Paolo Miotto - Emerging Bacterial Pathogens Unit, IRCCS San Raffaele Scientific Institute, via Olgettina 58, 20132, Milano, Italy
Leonid Chindelevitch - School of Computing Science, Simon Fraser University, 8888 University Ave, Burnaby, BC, V5A 1S6, Canada
Angela M Starks - Division of Tuberculosis Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, 1600 Clifton Road MS F08, Atlanta, GA, 30329, USA
Debra Hanna - Critical Path Institute, 1730 E River Rd., Tucson, AZ, 85718, USA
Richard Liwski - Critical Path Institute, 1730 E River Rd., Tucson, AZ, 85718, USA
Matteo Zignol - Global Tuberculosis Program, World Health Organization, Geneva, Switzerland
Christopher Gilpin - Global Tuberculosis Program, World Health Organization, Geneva, Switzerland
Stefan Niemann - German Center for Infection Research, Partner Site Borstel, Borstel, Germany
Thomas Andreas Kohl - Molecular and Experimental Mycobacteriology, Priority area Infections, Research Center Borstel, Borstel, Germany
Robin M Warren - DST/NRF Centre of Excellence for Biomedical Tuberculosis Research/SAMRC Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa
Derrick Crook - Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, United Kingdom
Sebastien Gagneux - Swiss Tropical and Public Health Institute, Basel, Switzerland
Sven Hoffner - Department of Public Health Sciences, Karolinska institute, Stockholm, Sweden
Camilla Rodrigues - Hinduja Hospital, Veer Savarkar Marg, Mahim, Mumbai, India
Iñaki Comas - Tuberculosis Genomics Unit, Biomedicine Institute of Valencia (IBV-CSIC), Street Jaime Roig 11. P.O., 4010, Valencia, Spain
David M Engelthaler - Translational Genomics Research Institute, 3051 W. Shamrell Blvd. Ste 106, Flagstaff, AZ, 86005, USA
David Alland - Center for Emerging Pathogens, Rutgers-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ, 07103, USA
Leen Rigouts - Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium
Christoph Lange - Division of Clinical Infectious Diseases and German Center for Infection Research Tuberculosis Unit, Research Center Borstel, Borstel, Germany
Keertan Dheda - Lung Infection and Immunity Unit, Department of Medicine, Division of Pulmonology and UCT Lung Institute, University of Cape Town, Old Main Building, Groote Schuur Hospital, Observatory, Cape Town, South Africa
Rumina Hasan - Department of Pathology and Laboratory Medicine, Aga Khan University, Stadium Road, Karachi, Pakistan
Ruth McNerney - Department of Medicine, Division of Pulmonology, University of Cape Town, Groote Schuur Hospital, Cape Town, South Africa
Daniela M Cirillo - Emerging Bacterial Pathogens Unit, IRCCS San Raffaele Scientific Institute, via Olgettina 58, 20132, Milano, Italy
Marco Schito - Critical Path Institute, 1730 E River Rd., Tucson, AZ, 85718, USA
Timothy C Rodwell - The Foundation for Innovative New Diagnostics, Geneva, Switzerland
James Posey - Division of Tuberculosis Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, 1600 Clifton Road MS F08, Atlanta, GA, 30329, USA. hzp9@cdc.gov
Publication Details: Scientific reports, Vol.8(1), pp.15382-15382
Date published: 10/18/2018
Grant note: 638553 / European Research Council 001 / World Health Organization
Academic Unit: Medicine - Infectious Diseases (NJMS)
Language: English
Resource Type: Journal article
Identifiers: 991031654598104646