Quasi-dynamic reconstruction of directed physiological networks from cross-sectional data using idopNetwork and path homology.
TL;DR
By decoupling directed regulatory flows from systemic confounding, this macroscopic algebraic approach challenges universal treatment protocols, highlighting the necessity for sex-specific precision interventions in managing obesity-driven cardiometabolic risk.
Abstract
Background
Excessive adiposity drives cardiometabolic morbidity through macroscopic systemic mechanisms rather than isolated metabolic defects. While conventional statistical models effectively estimate marginal biomarker associations, they cannot resolve the directed and cyclic regulatory dependencies underlying this pathogenesis. Network physiology offers a robust mathematical framework to delineate these complex, feedback-driven interactions.
Methods
Applying the idopNetwork framework to cross-sectional data from a primary clinical cohort (N=7,343) and an external validation cohort (N=6,881), we reconstructed directed, weighted hematometabolic networks across four body mass index (BMI) strata. This analytical pipeline mapped static clinical snapshots onto a continuous coordinate space to extract quasi-dynamic autoregressive trajectories. GLMY path homology was subsequently integrated to quantify macroscopic network rigidity via higher-order topological features.
Results
Progressive adiposity manifested a graded topological reorganization along the allostatic load gradient, characterized by the functional polarity inversion of core physiological hubs. Uric acid initially centralized as a primary conduit of metabolic load, preceding the transition of hemoglobin from a homeostatic anchor into a predictive promoter of systemic inflammation. GLMY path homology defined advanced obesity as a rigid systemic gridlock, quantified by the abnormal accumulation of persistent one-dimensional cyclic loops (β1) and two-dimensional voids (β2). This terminal architecture exhibited profound sexual dimorphism. Male adiposity degraded into hyper-reactive inflammatory β1 cyclic tangling, whereas the female network experienced a near-complete depletion of preexisting β2 voids upon entering advanced obesity, culminating in extensive topological barrenness and the attenuation of compensatory feedback.
Conclusions
The internal physiological ecosystem structurally deteriorates from robust homeostatic buffering into an advanced, sexually dimorphic allostatic deadlock. By decoupling directed regulatory flows from systemic confounding, this macroscopic algebraic approach challenges universal treatment protocols, highlighting the necessity for sex-specific precision interventions in managing obesity-driven cardiometabolic risk.