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    Modeling Based on Ensemble Learning Methods for Detection of Diagnostic Biomarkers from LncRNA Data in Rats Treated with Cis-Platinum-Induced Hepatotoxicity
    (Mdpi, 2023) Kucukakcali, Zeynep; Colak, Cemil; Bag, Harika Gozde Gozukara; Cicek, Ipek Balikci; Ozhan, Onural; Yildiz, Azibe; Danis, Nefsun
    Background: The first aim of this study is to perform bioinformatic analysis of lncRNAs obtained from liver tissue samples from rats treated with cisplatin hepatotoxicity and without pathology. Another aim is to identify possible biomarkers for the diagnosis/early diagnosis of hepatotoxicity by modeling the data obtained from bioinformatics analysis with ensemble learning methods. Methods: In the study, 20 female Sprague-Dawley rats were divided into a control group and a hepatotoxicity group. Liver samples were taken from rats, and transcriptomic and histopathological analyses were performed. The dataset achieved from the transcriptomic analysis was modeled with ensemble learning methods (stacking, bagging, and boosting). Modeling results were evaluated with accuracy (Acc), balanced accuracy (B-Acc), sensitivity (Se), specificity (Sp), positive predictive value (Ppv), negative predictive value (Npv), and F1 score performance metrics. As a result of the modeling, lncRNAs that could be biomarkers were evaluated with variable importance values. Results: According to histopathological and immunohistochemical analyses, a significant increase was observed in the sinusoidal dilatation and Hsp60 immunoreactivity values in the hepatotoxicity group compared to the control group (p < 0.0001). According to the results of the bioinformatics analysis, 589 lncRNAs showed different expressions in the groups. The stacking model had the best classification performance among the applied ensemble learning models. The Acc, B-Acc, Se, Sp, Ppv, Npv, and F1-score values obtained from this model were 90%, 90%, 80%, 100%, 100%, 83.3%, and 88.9%, respectively. lncRNAs with id rna-XR_005492522.1, rna-XR_005492536.1, and rna-XR_005505831.1 with the highest three values according to the variable importance obtained as a result of stacking modeling can be used as predictive biomarker candidates for hepatotoxicity. Conclusions: Among the ensemble algorithms, the stacking technique yielded higher performance results as compared to the bagging and boosting methods on the transcriptomic data. More comprehensive studies can support the possible biomarkers determined due to the research and the decisive results for the diagnosis of drug-induced hepatotoxicity.
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    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
    (Mdpi, 2023) Cicek, Ipek Balikci; Colak, Cemil; Yologlu, Saim; Kucukakcali, Zeynep; Ozhan, Onural; Taslidere, Elif; Danis, Nefsun
    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.