Omics techniques generate comprehensive profiles of biomolecules in cells and tissues. However, a holistic understanding of the data requires joint multi-omics analyses that are challenging. Here we present DPM, a data fusion method for combining multiple omics datasets using directionality and significance estimates of genes, transcripts, or proteins. DPM allows users to define how the input datasets are expected to interact directionally, reflecting the initial experimental design or regulatory relationships between the datasets. DPM statistically prioritises genes and pathways that change consistently across the datasets, while penalising those violating the constraints. Joint analyses of transcriptomic, proteomic, DNA methylation, and clinical datasets of cancer samples demonstrate how directional integration identifies genes and pathways modulated across omics datasets, highlights those with inconsistent evidence, and reveals candidate biomarkers with prognostic signals in multiple datasets. DPM is implemented in the ActivePathways method and provides a general framework for testing detailed hypotheses in multi-omics data.

Directional integration and pathway enrichment analysis for multi-omics data