Robust detection of point mutations involved in multidrug-resistant Mycobacterium tuberculosis in the presence of co-occurrent resistance markers

PLoS Comput Biol. 2020 Dec 21;16(12):e1008518. doi: 10.1371/journal.pcbi.1008518. eCollection 2020 Dec.

Abstract

Tuberculosis disease is a major global public health concern and the growing prevalence of drug-resistant Mycobacterium tuberculosis is making disease control more difficult. However, the increasing application of whole-genome sequencing as a diagnostic tool is leading to the profiling of drug resistance to inform clinical practice and treatment decision making. Computational approaches for identifying established and novel resistance-conferring mutations in genomic data include genome-wide association study (GWAS) methodologies, tests for convergent evolution and machine learning techniques. These methods may be confounded by extensive co-occurrent resistance, where statistical models for a drug include unrelated mutations known to be causing resistance to other drugs. Here, we introduce a novel 'cannibalistic' elimination algorithm ("Hungry, Hungry SNPos") that attempts to remove these co-occurrent resistant variants. Using an M. tuberculosis genomic dataset for the virulent Beijing strain-type (n = 3,574) with phenotypic resistance data across five drugs (isoniazid, rifampicin, ethambutol, pyrazinamide, and streptomycin), we demonstrate that this new approach is considerably more robust than traditional methods and detects resistance-associated variants too rare to be likely picked up by correlation-based techniques like GWAS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Antitubercular Agents / pharmacology
  • Drug Resistance, Multiple, Bacterial / genetics*
  • Genes, Bacterial
  • Genetic Markers
  • Genome-Wide Association Study
  • Machine Learning
  • Microbial Sensitivity Tests
  • Models, Biological
  • Mycobacterium tuberculosis / drug effects
  • Mycobacterium tuberculosis / genetics*
  • Phylogeny
  • Point Mutation*
  • Polymorphism, Single Nucleotide
  • Tuberculosis, Multidrug-Resistant / microbiology*

Substances

  • Antitubercular Agents
  • Genetic Markers