Rank-based integration identifies convergent disease mechanisms across omics

Abstract

The rapid growth of omics studies offers new opportunities to uncover disease mechanisms, yet findings from individual studies or single omics may be influenced by cohort-, platform- and layer-specific variation. Integrating evidence across studies and omics layers can reveal robust biological signals that are reproducible across molecular layers, but differences in assay platforms, sample sizes and feature coverage complicate direct combination of summary statistics. Here we present the Omics Rank-Based Integration Tool (ORBIT), a direction-aware framework for prioritizing concordant signals across omics layers using only within-dataset feature ranks and effect directions. ORBIT tests directional rank consistency across omics layers against a closed-form variance-gamma null distribution while accounting for inter-dataset correlation and incomplete feature overlap. Simulations show that ORBIT maintains well-calibrated false-positive rates under inter-omics correlation, increasing numbers of omics layers and missingness, while detecting concordant signals with increasing power as the number of layers grows. We applied ORBIT to tubulointerstitial transcriptomic data from patients with chronic kidney disease in the C-PROBE cohort and proteomic data from the Kidney Precision Medicine Project, identifying a concordant injury programme marked by inflammatory and fibrotic remodeling together with impaired energy metabolism. We also used ORBIT to integrate ten transcriptomic, four proteomic and one translatomic datasets in dilated cardiomyopathy heart tissue, identifying extracellular matrix remodeling and mitochondrial energy failure as the dominant concordant biological programmes. In both diseases, ORBIT prioritized concordant genes and identified pathways that were not significant in any single omics layer alone. These results show that directional rank integration can be used for integrating heterogeneous omics summary data and prioritizing robust molecular mechanisms.