Network- and enrichment-based inference of phenotypes and targets from large-scale disease maps.

Complex diseases are inherently multifaceted, and the associated data are often heterogeneous, making linking interactions across genes, metabolites, RNA, proteins, cellular functions, and clinically relevant phenotypes a high-priority challenge. Disease maps have emerged as knowledge bases that capture molecular interactions, disease-related processes, and disease phenotypes with standardized representations in large-scale molecular interaction maps. Various tools are available for disease map analysis, but an intuitive solution to perform in silico experiments on the maps in a wide range of contexts and analyze high-dimensional data is currently missing. To this end, we introduce a two-dimensional enrichment analysis (2DEA) approach to infer downstream and upstream elements through the statistical association of network topology parameters and fold changes from molecular perturbations. We implemented our approach in a plugin suite for the MINERVA platform, providing an environment where experimental data can be mapped onto a disease map and predict potential regulatory interactions through an intuitive graphical user interface. We show several workflows using this approach and analyze two RNA-seq datasets in the Atlas of Inflammation Resolution (AIR) to identify enriched downstream processes and upstream transcription factors. Our work improves the usability of disease maps and increases their functionality by facilitating multi-omics data integration and exploration.