Mathematical Model of Liver Cirrhosis Formation During Morphological and Molecular-Genetic Preclinical Studies

Abstract

Background. Currently, researchers describe challenges in developing new treatments for fibrosis and cirrhosis: poor quality of preclinical experimental models, insufficient trial duration, and lack of markers of therapeutic response. A separate task is to standardize the process of formation of liver cirrhosis in preclinical trials, which is necessary to obtain accurate quantitative estimates in a short time. The goal is to develop a mathematical model of the formation of liver cirrhosis during preclinical trials. Methods. Liver fibrosis and cirrhosis in male Wistar rats were induced with freshly prepared thioacetamide solution for 17 weeks. The area of connective tissue was determined as a percentage of the image area. The area of interlobular veins was measured in µm2. The numbers of cells expressing the FAP marker and the α-SMA marker were counted. The level of mRNA expression of the Vegfa and Yap1 genes was assessed by real-time polymerase chain reaction. The construction of a mathematical model for classifying observations into stages was carried out using multiple logistic regression with stepwise selection of predictors, followed by calculation of sensitivity, specificity and area under the curve (AUC) with a 95% confidence interval based on ROC analysis. Results. As a result of the analysis, a mathematical model of the formation of liver cirrhosis was developed. The model is based on the values of two indicators: FAP+ cells and Yap1 mRNA and is characterized by good quality. The resulting value of the area under the ROC curve of 0.883 suggests good results for classifying cases. Conclusion. The mathematical model makes it possible to differentiate the stage of liver cirrhosis from the stage of fibrosis during preclinical studies, which will serve as the basis for studying the pathogenesis of liver fibrosis and cirrhosis, identifying new potential molecular targets for antifibrotic therapy, and reducing the number of expensive, labor-intensive laboratory tests. Key words: experimental fibrosis and cirrhosis of the liver, mathematical model, histological and molecular genetic studies