1. A biochemically-interpretable machine learning classifier for microbial GWAS.
- Author
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Kavvas, Erol S., Yang, Laurence, Monk, Jonathan M., Heckmann, David, and Palsson, Bernhard O.
- Subjects
DRUG resistance in microorganisms ,MYCOBACTERIUM tuberculosis ,MACHINE learning ,ALLELES ,DIGITAL image correlation - Abstract
Current machine learning classifiers have successfully been applied to whole-genome sequencing data to identify genetic determinants of antimicrobial resistance (AMR), but they lack causal interpretation. Here we present a metabolic model-based machine learning classifier, named Metabolic Allele Classifier (MAC), that uses flux balance analysis to estimate the biochemical effects of alleles. We apply the MAC to a dataset of 1595 drug-tested Mycobacterium tuberculosis strains and show that MACs predict AMR phenotypes with accuracy on par with mechanism-agnostic machine learning models (isoniazid AUC = 0.93) while enabling a biochemical interpretation of the genotype-phenotype map. Interpretation of MACs for three antibiotics (pyrazinamide, para-aminosalicylic acid, and isoniazid) recapitulates known AMR mechanisms and suggest a biochemical basis for how the identified alleles cause AMR. Extending flux balance analysis to identify accurate sequence classifiers thus contributes mechanistic insights to GWAS, a field thus far dominated by mechanism-agnostic results. Current machine learning classifiers have been applied to whole-genome sequencing data to identify determinants of antimicrobial resistance, but they lack interpretability. Here the authors present a metabolic machine learning classifier that uses flux balance analysis to estimate the biochemical effects of alleles. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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