Metabolic Function-based Normalization Improves Transcriptome Data-driven Reduction of Genome-scale Metabolic Models

Genome-scale metabolic models (GEMs) are extensively used to simulate cell metabolism and predict cell phenotypes. GEMs can also be tailored to generate context-specific GEMs, using omics data integration approaches. To date, many integration approaches have been developed, however, each with specific pros and cons; and none of these algorithms systematically outperforms the others. The key to successful implementation of such integration algorithms lies in the optimal selection of parameters, and thresholding is a crucial component in this process. To improve the predictive accuracy of context-specific models, we introduce a new integration framework that improves the ranking of related genes and homogenizes the expression values of those gene sets using single-sample Gene Set Enrichment Analysis (ssGSEA). In this study, we coupled ssGSEA with GIMME and validated the advantages of the proposed framework to predict the ethanol formation of yeast grown in the glucose-limited chemostats, and to simulate metabolic behaviors of yeast growth in four different carbon sources. This framework enhances the predictive accuracy of GIMME which we demonstrate for predicting the yeast physiology in nutrient-limited cultures.