Graph Pseudotime Analysis and Neural Stochastic Differential Equations for Analyzing Retinal Degeneration Dynamics and Beyond

Abstract

Understanding disease progression at the molecular pathway level usually requires capturing both structural dependencies between pathways and the temporal dynamics of disease evolution. In this work, we solve the former challenge by developing a biologically informed graph-forming method to efficiently construct pathway graphs for subjects from our newly curated JR5558 mouse transcriptomics dataset. We then develop Graph-level Pseudotime Analysis (GPA) to infer graph-level trajectories that reveal how disease progresses at the population level, rather than in individual subjects. Based on the trajectories estimated by GPA, we identify the most sensitive pathways that drive disease stage transitions. In addition, we measure changes in pathway features using neural stochastic differential equations (SDEs), which enables us to formally define and compute pathway stability and disease bifurcation points (points of no return), two fundamental problems in disease progression research. We further extend our theory to the case when pathways can interact with each other, enabling a more comprehensive and multi-faceted characterization of disease phenotypes. The comprehensive experimental results demonstrate the effectiveness of our framework in reconstructing the dynamics of the pathway, identifying critical transitions, and providing novel insights into the mechanistic understanding of disease evolution.