Fig. 1.

Process flowchart representing an outline of the steps that were implemented in the analysis presented in the paper. Published mathematical models for metabolism, hypothalamic-pituitary-adrenal (HPA) axis, inflammation, and hypoxia signaling were integrated into a single composite model based on the data reported in literature. Model was recalibrated, and metabolic control analysis (MCA) was performed to obtain metabolite concentration response coefficients (MCRCs) and associated regulatory states with reference to the pattern of statistically different metabolites in subjects with posttraumatic stress disorder (PTSD). Orange arrows represent flow of data from statistics to model analysis and causal inference. Response coefficients were used to generate hypothesis on the potential process that could be affected in PTSD. To validate the hypotheses, correlation analysis followed by causal inference and mediation analysis were performed using estimation of propensity scores and average causal effects, sensitivity analysis, and natural effects models. CBPS, covariate balancing propensity scores; ODEs, ordinary differential equations.