MEGA-ODE: Learning Biologically Structured and Navigable Continuous Perturbation Dynamics from Sparse Omics

作者：Yujia Xiang, Yongge Li, Chunyan Tian, Ruichu Gu, Fuchu He, Han Wen, Linhai Xie, Peijie Zhou · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2026 · DOI：10.64898/2026.08.05.742921 · 研究领域：Single-cell and spatial transcriptomics、Gene Regulatory Network Analysis、Bioinformatics and Genomic Networks

Abstract Perturbation-omics experiments usually measure only a subset of molecular feature, intervention and time space, leaving many response trajectories, perturbation effects and disease- or differentiation-associated transitions unobserved. Here we present MEGA-ODE, a graph-constrained continuous-time framework for reconstructing sparse dynamic omics landscapes, predicting unmeasured molecular states and prioritizing virtual perturbations toward defined biological endpoints. MEGA-ODE integrates molecular-network priors, graph neural ordinary differential equations and context-adaptive mixture-of-experts routing. In L1000 transcriptomic perturbations and CPPA proteomic drug-response data, MEGA-ODE improved held-out-feature and unseen-perturbation prediction over baseline methods, and in SARS-CoV-2 infection time-series data it remained competitive for future-time-point forecasting. In a COVID-19 patient cohort, predicted intermediate profiles improved retrospective disease-stage stratification relative to observed profiles alone, while expert programs highlighted immune and inflammatory signals associated with severity. Across the MAPK drug-response and stem-cell differentiation case studies, graph- and expert-level attributions prioritized perturbation-associated MAPK edges, developmental regulators and TF-target relationships supported by independent promoter-proximal ChIP-seq overlap. In hESC-to-definitive-endoderm differentiation, MEGA-ODE prioritized candidate transcr...