Application of Machine Learning Classifier to Candida auris Drug Resistance Analysis

Candida auris (C. auris) is an emerging fungus associated with high morbidity. It has a unique transmission ability and is often resistant to multiple drugs. In this study, we evaluated the ability of different machine learning models to classify the drug resistance and predicted and ranked the drug resistance mutations of C. auris. Two C. auris strains were obtained. Combined with other 356 strains collected from the European Bioinformatics Institute (EBI) databases, the whole genome sequencing (WGS) data were analyzed by bioinformatics. Machine learning classifiers were used to build drug resistance models, which were evaluated and compared by various evaluation methods based on AUC value. Briefly, two strains were assigned to Clade III in the phylogenetic tree, which was consistent with previous studies; nevertheless, the phylogenetic tree was not completely consistent with the conclusion of clustering according to the geographical location discovered earlier. The clustering results of C. auris were related to its drug resistance. The resistance genes of C. auris were not under additional strong selection pressure, and the performance of different models varied greatly for different drugs. For drugs such as azoles and echinocandins, the models performed relatively well. In addition, two machine learning algorithms, based on the balanced test and imbalanced test, were designed and evaluated; for most drugs, the evaluation results on the balanced test set were better than on the imbalanced test set. The mutations strongly be associated with drug resistance of C. auris were predicted and ranked by Recursive Feature Elimination with Cross-Validation (RFECV) combined with a machine learning classifier. In addition to known drug resistance mutations, some new resistance mutations were predicted, such as Y501H and I466M mutation in the ERG11 gene and R278H mutation in the ERG10 gene, which may be associated with fluconazole (FCZ), micafungin (MCF), and amphotericin B (AmB) resistance, respectively; these mutations were in the "hot spot" regions of the ergosterol pathway. To sum up, this study suggested that machine learning classifiers are a useful and cost-effective method to identify fungal drug resistance-related mutations, which is of great significance for the research on the resistance mechanism of C. auris.