Using network analysis to model the effects of the SARS Cov2 pandemic on acute patient care within a healthcare system.

Consolidation of healthcare in the US has resulted in integrated organizations, encompassing large geographic areas, with varying services and complex patient flows. Profound changes in patient volumes and behavior have occurred during the SARS Cov2 pandemic, but understanding these across organizations is challenging. Network analysis provides a novel approach to address this. We retrospectively evaluated hospital-based encounters with an index emergency department visit in a healthcare system comprising 18 hospitals, using patient transfer as a marker of unmet clinical need. We developed quantitative models of transfers using network analysis incorporating the level of care provided (ward, progressive care, intensive care) during pre-pandemic (May 25, 2018 to March 16, 2020) and mid-pandemic (March 17, 2020 to March 8, 2021) time periods. 829,455 encounters were evaluated. The system functioned as a non-small-world, non-scale-free, dissociative network. Our models reflected transfer destination diversification and variations in volume between the two time points - results of intentional efforts during the pandemic. Known hub-spoke architecture correlated with quantitative analysis. Applying network analysis in an integrated US healthcare organization demonstrates changing patterns of care and the emergence of bottlenecks in response to the SARS Cov2 pandemic, consistent with clinical experience, providing a degree of face validity. The modelling of multiple influences can identify susceptibility to stress and opportunities to strengthen the system where patient movement is common and voluminous. The technique provides a mechanism to analyze the effects of intentional and contextual changes on system behavior.

Group contribution method for thermodynamic analysis of complex metabolic networks.

A new, to our knowledge, group contribution method based on the group contribution method of Mavrovouniotis is introduced for estimating the standard Gibbs free energy of formation (Delta(f)G'(o)) and reaction (Delta(r)G'(o)) in biochemical systems. Gibbs free energy contribution values were estimated for 74 distinct molecular substructures and 11 interaction factors using multiple linear regression against a training set of 645 reactions and 224 compounds. The standard error for the fitted values was 1.90 kcal/mol. Cross-validation analysis was utilized to determine the accuracy of the methodology in estimating Delta(r)G'(o) and Delta(f)G'(o) for reactions and compounds not included in the training set, and based on the results of the cross-validation, the standard error involved in these estimations is 2.22 kcal/mol. This group contribution method is demonstrated to be capable of estimating Delta(r)G'(o) and Delta(f)G'(o) for the majority of the biochemical compounds and reactions found in the iJR904 and iAF1260 genome-scale metabolic models of Escherichia coli and in the Kyoto Encyclopedia of Genes and Genomes and University of Minnesota Biocatalysis and Biodegradation Database. A web-based implementation of this new group contribution method is available free at http://sparta.chem-eng.northwestern.edu/cgi-bin/GCM/WebGCM.cgi.

Genome-scale thermodynamic analysis of Escherichia coli metabolism.

Genome-scale metabolic models are an invaluable tool for analyzing metabolic systems as they provide a more complete picture of the processes of metabolism. We have constructed a genome-scale metabolic model of Escherichia coli based on the iJR904 model developed by the Palsson Laboratory at the University of California at San Diego. Group contribution methods were utilized to estimate the standard Gibbs free energy change of every reaction in the constructed model. Reactions in the model were classified based on the activity of the reactions during optimal growth on glucose in aerobic media. The most thermodynamically unfavorable reactions involved in the production of biomass in E. coli were identified as ATP phosphoribosyltransferase, ATP synthase, methylene-tetra-hydrofolate dehydrogenase, and tryptophanase. The effect of a knockout of these reactions on the production of biomass and the production of individual biomass precursors was analyzed. Changes in the distribution of fluxes in the cell after knockout of these unfavorable reactions were also studied. The methodologies and results discussed can be used to facilitate the refinement of the feasible ranges for cellular parameters such as species concentrations and reaction rate constants.

Exploring the diversity of complex metabolic networks.

MOTIVATION: Metabolism, the network of chemical reactions that make life possible, is one of the most complex processes in nature. We describe here the development of a computational approach for the identification of every possible biochemical reaction from a given set of enzyme reaction rules that allows the de novo synthesis of metabolic pathways composed of these reactions, and the evaluation of these novel pathways with respect to their thermodynamic properties. RESULTS: We applied this framework to the analysis of the aromatic amino acid pathways and discovered almost 75,000 novel biochemical routes from chorismate to phenylalanine, more than 350,000 from chorismate to tyrosine, but only 13 from chorismate to tryptophan. Thermodynamic analysis of these pathways suggests that the native pathways are thermodynamically more favorable than the alternative possible pathways. The pathways generated involve compounds that exist in biological databases, as well as compounds that exist in chemical databases and novel compounds, suggesting novel biochemical routes for these compounds and the existence of biochemical compounds that remain to be discovered or synthesized through enzyme and pathway engineering. AVAILABILITY: Framework will be available via web interface at http://systemsbiology.northwestern.edu/BNICE (site under construction). CONTACT: vassily@northwestern.edu or broadbelt@northwestern.edu SUPPLEMENTARY INFORMATION: http://systemsbiology.northwestern.edu/BNICE/publications.