QuantTB – a method to classify mixed Mycobacterium tuberculosis infections within whole genome sequencing data
Abstract Background Mixed infections of Mycobacterium tuberculosis and antibiotic heteroresistance continue to complicate tuberculosis (TB) diagnosis and treatment. Detection of mixed infections has been limited to molecular genotyping techniques, which lack the sensitivity and resolution to accurat...
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doaj-9d60d92478e145f19b9181138a0094452021-01-31T16:11:53ZengBMCBMC Genomics1471-21642020-01-0121111610.1186/s12864-020-6486-3QuantTB – a method to classify mixed Mycobacterium tuberculosis infections within whole genome sequencing dataChristine Anyansi0Arlin Keo1Bruce J. Walker2Timothy J. Straub3Abigail L. Manson4Ashlee M. Earl5Thomas Abeel6Delft Bioinformatics Lab, Delft University of TechnologyDelft Bioinformatics Lab, Delft University of TechnologyInfectious Disease and Microbiome Program, Broad Institute of MIT and HarvardInfectious Disease and Microbiome Program, Broad Institute of MIT and HarvardInfectious Disease and Microbiome Program, Broad Institute of MIT and HarvardInfectious Disease and Microbiome Program, Broad Institute of MIT and HarvardDelft Bioinformatics Lab, Delft University of TechnologyAbstract Background Mixed infections of Mycobacterium tuberculosis and antibiotic heteroresistance continue to complicate tuberculosis (TB) diagnosis and treatment. Detection of mixed infections has been limited to molecular genotyping techniques, which lack the sensitivity and resolution to accurately estimate the multiplicity of TB infections. In contrast, whole genome sequencing offers sensitive views of the genetic differences between strains of M. tuberculosis within a sample. Although metagenomic tools exist to classify strains in a metagenomic sample, most tools have been developed for more divergent species, and therefore cannot provide the sensitivity required to disentangle strains within closely related bacterial species such as M. tuberculosis. Here we present QuantTB, a method to identify and quantify individual M. tuberculosis strains in whole genome sequencing data. QuantTB uses SNP markers to determine the combination of strains that best explain the allelic variation observed in a sample. QuantTB outputs a list of identified strains, their corresponding relative abundances, and a list of drugs for which resistance-conferring mutations (or heteroresistance) have been predicted within the sample. Results We show that QuantTB has a high degree of resolution and is capable of differentiating communities differing by less than 25 SNPs and identifying strains down to 1× coverage. Using simulated data, we found QuantTB outperformed other metagenomic strain identification tools at detecting strains and quantifying strain multiplicity. In a real-world scenario, using a dataset of 50 paired clinical isolates from a study of patients with either reinfections or relapses, we found that QuantTB could detect mixed infections and reinfections at rates concordant with a manually curated approach. Conclusion QuantTB can determine infection multiplicity, identify hetero-resistance patterns, enable differentiation between relapse and re-infection, and clarify transmission events across seemingly unrelated patients – even in low-coverage (1×) samples. QuantTB outperforms existing tools and promises to serve as a valuable resource for both clinicians and researchers working with clinical TB samples.https://doi.org/10.1186/s12864-020-6486-3TuberculosisMycobacterium tuberculosisMixed infectionMetagenomicsStrain level classificationStrain identification |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Christine Anyansi Arlin Keo Bruce J. Walker Timothy J. Straub Abigail L. Manson Ashlee M. Earl Thomas Abeel |
spellingShingle |
Christine Anyansi Arlin Keo Bruce J. Walker Timothy J. Straub Abigail L. Manson Ashlee M. Earl Thomas Abeel QuantTB – a method to classify mixed Mycobacterium tuberculosis infections within whole genome sequencing data BMC Genomics Tuberculosis Mycobacterium tuberculosis Mixed infection Metagenomics Strain level classification Strain identification |
author_facet |
Christine Anyansi Arlin Keo Bruce J. Walker Timothy J. Straub Abigail L. Manson Ashlee M. Earl Thomas Abeel |
author_sort |
Christine Anyansi |
title |
QuantTB – a method to classify mixed Mycobacterium tuberculosis infections within whole genome sequencing data |
title_short |
QuantTB – a method to classify mixed Mycobacterium tuberculosis infections within whole genome sequencing data |
title_full |
QuantTB – a method to classify mixed Mycobacterium tuberculosis infections within whole genome sequencing data |
title_fullStr |
QuantTB – a method to classify mixed Mycobacterium tuberculosis infections within whole genome sequencing data |
title_full_unstemmed |
QuantTB – a method to classify mixed Mycobacterium tuberculosis infections within whole genome sequencing data |
title_sort |
quanttb – a method to classify mixed mycobacterium tuberculosis infections within whole genome sequencing data |
publisher |
BMC |
series |
BMC Genomics |
issn |
1471-2164 |
publishDate |
2020-01-01 |
description |
Abstract Background Mixed infections of Mycobacterium tuberculosis and antibiotic heteroresistance continue to complicate tuberculosis (TB) diagnosis and treatment. Detection of mixed infections has been limited to molecular genotyping techniques, which lack the sensitivity and resolution to accurately estimate the multiplicity of TB infections. In contrast, whole genome sequencing offers sensitive views of the genetic differences between strains of M. tuberculosis within a sample. Although metagenomic tools exist to classify strains in a metagenomic sample, most tools have been developed for more divergent species, and therefore cannot provide the sensitivity required to disentangle strains within closely related bacterial species such as M. tuberculosis. Here we present QuantTB, a method to identify and quantify individual M. tuberculosis strains in whole genome sequencing data. QuantTB uses SNP markers to determine the combination of strains that best explain the allelic variation observed in a sample. QuantTB outputs a list of identified strains, their corresponding relative abundances, and a list of drugs for which resistance-conferring mutations (or heteroresistance) have been predicted within the sample. Results We show that QuantTB has a high degree of resolution and is capable of differentiating communities differing by less than 25 SNPs and identifying strains down to 1× coverage. Using simulated data, we found QuantTB outperformed other metagenomic strain identification tools at detecting strains and quantifying strain multiplicity. In a real-world scenario, using a dataset of 50 paired clinical isolates from a study of patients with either reinfections or relapses, we found that QuantTB could detect mixed infections and reinfections at rates concordant with a manually curated approach. Conclusion QuantTB can determine infection multiplicity, identify hetero-resistance patterns, enable differentiation between relapse and re-infection, and clarify transmission events across seemingly unrelated patients – even in low-coverage (1×) samples. QuantTB outperforms existing tools and promises to serve as a valuable resource for both clinicians and researchers working with clinical TB samples. |
topic |
Tuberculosis Mycobacterium tuberculosis Mixed infection Metagenomics Strain level classification Strain identification |
url |
https://doi.org/10.1186/s12864-020-6486-3 |
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