@article{34a21b80f1394b26acce5ba0a1eb8153,
title = "Integrating standardized whole genome sequence analysis with a global Mycobacterium tuberculosis antibiotic resistance knowledgebase",
abstract = "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.",
author = "Matthew Ezewudo and Amanda Borens and {\'A}lvaro Chiner-Oms and Paolo Miotto and Leonid Chindelevitch and Starks, {Angela M.} and Debra Hanna and Richard Liwski and Matteo Zignol and Christopher Gilpin and Stefan Niemann and Kohl, {Thomas Andreas} and Warren, {Robin M.} and Derrick Crook and Sebastien Gagneux and Sven Hoffner and Camilla Rodrigues and I{\~n}aki Comas and Engelthaler, {David M.} and David Alland and Leen Rigouts and Christoph Lange and Keertan Dheda and Rumina Hasan and Ruth McNerney and Cirillo, {Daniela M.} and Marco Schito and Rodwell, {Timothy C.} and James Posey",
note = "Funding Information: Competing Interests: M. Schito, R. Liwski, A. Borens and M. Ezewudo reports grants from Bill & Melinda Gates Foundation, during the conduct of the study. Dr. D. Hanna reports grants from Bill & Melinda Gates Foundation, outside the submitted work. C. Lange reports personal fees from Chiesi, personal fees from Gilead, personal fees from Becton Dickinson, personal fees from Janssen, personal fees from Astra Zeneca, personal fees from Thermo Fisher Scientific, outside the submitted work. I. Comas reports personal fees from FIND Foundation for Innovative Diagnostics, within the scope of relevance to submitted work. D. Alland reports grants from Cepheid, other from Rutgers University Patent Pool, during the conduct of the study; In addition, D. Alland has a patent for primers and probes to detect drug resistance mutations issued. L. Rigouts reports other from FIND, during the conduct of the study. K. Dheda reports grants from FIND, grants and personal fees from ALERE, grants and personal fees from Oxford Immunotec, grants and personal fees from Cellestis (now Qiagen), grants from eNose Company, grants from Statens Serum Institut, grants and personal fees from bioMeriux, grants and personal fees from Cepheid, grants from Antrum Biotec, grants from Hain Lifescience, outside the submitted work; In addition, Dr. Dheda has a patent Characterization of novel TB-specific urinary biomarkers pending, a patent A smart mask for monitoring cough-related infectious diseases pending, and a patent device for diagnosing extrapulmonary tuberculosis (EPTB) issued. S. Niemann reports grants from German Center for Infection Research, during the conduct of the study and worked as consultant for FIND. T.C. Rodwell reports funding from NIH (NIAID) and FIND during the conduct of the study. {\'A}. Chiner-Oms, P. Miotto, A.M. Starks, J. Posey, D. Crook, R.M. Warren, R. Hasan, M. Zignol, C. Gilpin, L. Chindelevitch, R. McNerney, D. Engelthaler, C. Rodrigues, S. Gagneux, D.M. Cirillo, S. Hoffner and T. A. Kohl have nothing to disclose. Funding Information: This study was supported by the Bill & Melinda Gates Foundation under grant agreement OPP1115887 to C-Path for developing the ReSeqTB drug resistance data sharing platform and under grant agreement FIND OPP1115209 to address how to score mutations in the ReSeqTB data sharing platform initiative. The South African MRC and the EDCTP support K. Dheda. I. Comas is supported by the Ministerio de Econom{\'i}a y Competitividad (Spanish Government) research grant SAF2016-77346-R and the European Research Council (ERC) (638553-TB-ACCELERATE). L. Chindelevitch acknowledges support by NSERC, Genome Canada, and the Sloan Foundation. Use of trade names is for identification only and does not constitute endorsement by the US Department of Health and Human Services, the US Public Health Service, or the Centers for Disease Control and Prevention. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the funding agency. Publisher Copyright: {\textcopyright} 2018, The Author(s).",
year = "2018",
month = dec,
day = "1",
doi = "10.1038/s41598-018-33731-1",
language = "English",
volume = "8",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",
}
