Integration of multiomic and multi-phenotypic data identifies biological pathways associated with physical fitness

Unraveling the complex associations between human phenotypes and molecular pathways can pave the way to improved health and performance, but faces a fundamental challenge: the measurable genes, proteins, and metabolites vastly outnumber the participants in even the largest studies, yielding spurious correlations. To address this, we developed PhenoMol, a bioinformatic framework that integrates comprehensive phenotypic data predictive of outcomes and reduces multi-omic dimensionality using graph theory constrained by prior biological knowledge. This approach generates biologically informed “expression circuits” to identify causal patterns. Applied to a deeply characterized healthy cohort, PhenoMol successfully predicted elite physical performance and outperformed regression models lacking network-based dimensionality reduction. Designed to be versatile and generalizable, PhenoMol enables studies across small and large populations to predict wellness, performance, and disease outcomes. The software is openly available to support future research in health, disease, and performance optimization. PhenoMol integrates graph theory and biological knowledge to reduce multi-omic dimensionality, predict phenotypes, and reveal causal patterns. It outperforms conventional models that lack biological constraints and is openly available for health, performance, and disease research.