Construction and validation of a predictive model for the efficacy of valproic acid monotherapy in epilepsy based on Lasso-logistic regression

Abstract

Introduction  Valproic acid (VPA) is a broad-spectrum antiepileptic drug; but its therapeutic efficacy varies significantly among individuals. The objective of this study is to identify the specific biomarkers that can predict the efficacy of VPA.

Methods  The GSE143272 dataset from the Gene Expression Omnibus (GEO) was utilized to identify Differentially Expressed Genes (DEGs) between responders and non-responders to VPA. Weighted Gene Co-expression Network Analysis (WGCNA) was employed to identify genes related to the non-responder phenotype. Intersection genes were selected to obtain the core genes affecting VPA tolerance. Lasso regression was applied to determine the core genes that influence the VPA effect. Lasso regression was applied to screen these core genes, using their expression values as independent variables and VPA response as the dependent variable in constructing a univariate logistic regression model. Peripheral blood samples from epileptic patients treated solely with VPA were collected according to nano-discharge standard. The expression levels of target genes were determined by qPCR to validate the accuracy of the model.

Results  86 genes were closely related to the response phenotype through WGCNA. 13 intersection genes were obtained by intersection with 97 DEGs, which mainly involve mRNA splicing function and transport pathway. Ultimately, 3 genes-NELL2, SNORD3A and mir-1974 were included in the final model. The Area Under Curve (AUC) for this predictive model was found to be 0.70 (95 % CI: 0.70). qPCR analysis revealed a significant difference in the relative expression of the SNORD3A gene between the responder and non-responder groups.

Conclusion  Epilepsy patients are at an increased risk of developing drug resistance when undergoing VPA monotherapy. The risk prediction model based on Lasso-Logistic regression demonstrates strong predictive capabilities. The SNORD3A gene may serve as a valuable biomarker for predicting the likelihood of VPA resistance.