Background: Identification of active causal regulators is a crucial problem in understanding mechanism of diseases
or finding drug targets. Methods that infer causal regulators directly from primary data have been proposed and
successfully validated in some cases. These methods necessarily require very large sample sizes or a mix of
different data types. Recent studies have shown that prior biological knowledge can successfully boost a method’s
ability to find regulators.
Results: We present a simple data-driven method, Correlation Set Analysis (CSA), for comprehensively detecting
active regulators in disease populations by integrating co-expression analysis and a specific type of literaturederived causal relationships. Instead of investigating the co-expression level between regulators and their
regulatees, we focus on coherence of regulatees of a regulator. Using simulated datasets we show that our
method performs very well at recovering even weak regulatory relationships with a low false discovery rate. Using
three separate real biological datasets we were able to recover well known and as yet undescribed, active
regulators for each disease population. The results are represented as a rank-ordered list of regulators, and reveals
both single and higher-order regulatory relationships.
Conclusions: CSA is an intuitive data-driven way of selecting directed perturbation experiments that are relevant
to a disease population of interest and represent a starting point for further investigation. Our findings
demonstrate that combining co-expression analysis on regulatee sets with a literature-derived network can
successfully identify causal regulators and help develop possible hypothesis to explain disease progression.