FeatureMAP enables network-guided interpretation of untargeted metabolomics

Untargeted liquid chromatography-mass spectrometry (LC-MS) metabolomics generates thousands of features, but incomplete metabolite annotation and reliance on predefined pathways limit their biological interpretation. Here we present FeatureMAP, an LC-MS feature-centric computational framework that integrates multi-evidence metabolite annotation, network-guided refinement, metabolic module discovery, and structured large language model-based functional interpretation. Across ten public datasets, FeatureMAP improved MS1-based metabolite candidate prioritization while reducing annotation redundancy. In semi-synthetic benchmarks, FeatureMAP recovered coordinated metabolic perturbations, achieving 92% recovery of a simulated perturbation, and distinguished concurrent metabolic processes. Controlled benchmarks further evaluated functional interpretation under competing metabolite-level signals. Based on FeatureMAP, we additionally developed PhenoMAP, a phenotype-aware knowledge graph comprising 12,929 dysregulated metabolic modules from 501 human metabolomics studies spanning 326 phenotypes. Module-level comparisons revealed reproducible metabolic similarities across independent studies and biologically supported relationships among phenotypes. Application to Alzheimer's disease cerebrospinal fluid and cellular datasets identified convergent membrane-lipid alterations and implicated galactose-linked glycosphingolipid remodeling. Together, FeatureMAP and PhenoMAP enable network-grounded interpretation of incompletely annotated LC-MS metabolomics data and systematic investigation of metabolic dysregulation across biological conditions.

Wang, Y., Zhang, F., Peng, G., Qiu, L., Zeng, L., Liu, Y., Kinchagawat, J., Yang, X., Liu, C., Johnson, C., Su, Q., Wang, C., Shen, X.

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