title: Correlation set analysis: detecting active regulators in disease populations using prior causal knowledge.
abstract: 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 literature-derived 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.
authors.affiliation: Bioinformatics Graduate Program, and Department of Biomedical Engineering, Boston University, 44 Cummington Street, Boston, MA 02215, USA.
authors.forename: Chia-Ling
authors.initials: CL
authors.lastname: Huang
authors.forename: John
authors.initials: J
authors.lastname: Lamb
authors.forename: Leonid
authors.initials: L
authors.lastname: Chindelevitch
authors.forename: Jarek
authors.initials: J
authors.lastname: Kostrowicki
authors.forename: Justin
authors.initials: J
authors.lastname: Guinney
authors.forename: Charles
authors.initials: C
authors.lastname: Delisi
authors.forename: Daniel
authors.initials: D
authors.lastname: Ziemek
mesh_terms: D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D005260:Female; D053263:Gene Regulatory Networks; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics; D008659:Metabolic Diseases / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics; D018401:Sample Size; D014158:Transcription, Genetic