Nephrotoxicity Development of a Clinical Decision Support System Based on Tree-Based Machine Learning Methods to Detect Diagnostic Biomarkers from Genomic Data in Methotrexate-Induced Rats

Abstract

Background: The purpose of this study was to carry out the bioinformatic analysis of lncRNA data obtained from the genomic analysis of kidney tissue samples taken from rats with nephrotoxicity induced by methotrexate (MTX) and from rats without pathology and modeling with the tree-based machine learning method. Another aim of the study was to identify potential biomarkers for the diagnosis of nephrotoxicity and to provide a better understanding of the nephrotoxicity formation process by providing the interpretability of the model with explainable artificial intelligence methods as a result of the modeling. Methods: To identify potential indicators of drug-induced nephrotoxicity, 20 female Wistar albino rats were separated into two groups: MTX-treated and the control. Kidney tissue samples were collected from the rats, and genomic, histological, and immunohistochemical analyses were performed. The dataset obtained as a result of genomic analysis was modeled with random forest (RF), a tree-based method. Modeling results were evaluated with sensitivity (Se), specificity (Sp), balanced accuracy (B-Acc), negative predictive value (Npv), accuracy (Acc), positive predictive value (Ppv), and F1-score performance metrics. The local interpretable model-agnostic annotations (LIME) method was used to determine the lncRNAs that could be biomarkers for nephrotoxicity by providing the interpretability of the RF model. Results: The outcomes of the histological and immunohistochemical analyses conducted in the study support the conclusion that MTX use caused kidney injury. According to the results of the bioinformatics analysis, 52 lncRNAs showed different expressions in the groups. As a result of modeling with RF for lncRNAs selected with Boruta variable selection, the B-Acc, Acc, Sp, Se, Npv, Ppv, and F1-score were 88.9%, 90%, 90.9%, 88.9%, 90.9%, 88.9%, and 88.9%, respectively. lncRNAs with id rnaXR_591534.3 rnaXR_005503408.1, rnaXR_005495645.1, rnaXR_001839007.2, rnaXR_005492056.1, and rna_XR_005492522.1. The lncRNAs with the highest variable importance values produced from RF modeling can be used as nephrotoxicity biomarker candidates. Furthermore, according to the LIME results, the high level of lncRNAs with id rnaXR_591534.3 and rnaXR_005503408.1 particularly increased the possibility of nephrotoxicity. Conclusions: With the possible biomarkers resulting from the analyses in this study, it can be ensured that the procedures for the diagnosis of drug-induced nephrotoxicity can be carried out easily, quickly, and effectively.

Keywords

• nephrotoxicity
• methotrexate
• genomics
• machine learning
• explainable artificial intelligence
• biomarker