title: SABRE: a method for assessing the stability of gene modules in complex tissues and subject populations.
abstract: BACKGROUND
  Gene network inference (GNI) algorithms can be used to identify sets of coordinately expressed genes, termed network modules from whole transcriptome gene expression data. The identification of such modules has become a popular approach to systems biology, with important applications in translational research. Although diverse computational and statistical approaches have been devised to identify such modules, their performance behavior is still not fully understood, particularly in complex human tissues. Given human heterogeneity, one important question is how the outputs of these computational methods are sensitive to the input sample set, or stability. A related question is how this sensitivity depends on the size of the sample set. We describe here the SABRE (Similarity Across Bootstrap RE-sampling) procedure for assessing the stability of gene network modules using a re-sampling strategy, introduce a novel criterion for identifying stable modules, and demonstrate the utility of this approach in a clinically-relevant cohort, using two different gene network module discovery algorithms.
  
  
  RESULTS
  The stability of modules increased as sample size increased and stable modules were more likely to be replicated in larger sets of samples. Random modules derived from permutated gene expression data were consistently unstable, as assessed by SABRE, and provide a useful baseline value for our proposed stability criterion. Gene module sets identified by different algorithms varied with respect to their stability, as assessed by SABRE. Finally, stable modules were more readily annotated in various curated gene set databases.
  
  
  CONCLUSIONS
  The SABRE procedure and proposed stability criterion may provide guidance when designing systems biology studies in complex human disease and tissues.
authors.affiliation: PROOF Centre of Excellence, Vancouver, BC, Canada. casey.shannon@hli.ubc.ca.|UBC James Hogg Research Centre and Institute of HEART + LUNG Health, Vancouver, BC, Canada. casey.shannon@hli.ubc.ca.
authors.forename: Casey P
authors.initials: CP
authors.lastname: Shannon
authors.affiliation: PROOF Centre of Excellence, Vancouver, BC, Canada.|UBC James Hogg Research Centre and Institute of HEART + LUNG Health, Vancouver, BC, Canada.
authors.forename: Virginia
authors.initials: V
authors.lastname: Chen
authors.affiliation: Department of Computer Science, UBC, Vancouver, BC, Canada.
authors.forename: Mandeep
authors.initials: M
authors.lastname: Takhar
authors.affiliation: PROOF Centre of Excellence, Vancouver, BC, Canada.|UBC James Hogg Research Centre and Institute of HEART + LUNG Health, Vancouver, BC, Canada.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Hollander
authors.affiliation: PROOF Centre of Excellence, Vancouver, BC, Canada.|BC Centre for Disease Control, Vancouver, BC, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Balshaw
authors.affiliation: PROOF Centre of Excellence, Vancouver, BC, Canada.|Department of Pathology and Laboratory Medicine, UBC, Vancouver, BC, Canada.|UBC James Hogg Research Centre and Institute of HEART + LUNG Health, Vancouver, BC, Canada.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: McManus
authors.affiliation: PROOF Centre of Excellence, Vancouver, BC, Canada.|Department of Medicine, Division of Respiratory Medicine, UBC, Vancouver, BC, Canada.|UBC James Hogg Research Centre and Institute of HEART + LUNG Health, Vancouver, BC, Canada.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Tebbutt
authors.affiliation: Department of Medicine, Division of Respiratory Medicine, UBC, Vancouver, BC, Canada.|UBC James Hogg Research Centre and Institute of HEART + LUNG Health, Vancouver, BC, Canada.
authors.forename: Don D
authors.initials: DD
authors.lastname: Sin
authors.affiliation: PROOF Centre of Excellence, Vancouver, BC, Canada.|Department of Computer Science, UBC, Vancouver, BC, Canada.|UBC James Hogg Research Centre and Institute of HEART + LUNG Health, Vancouver, BC, Canada.
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Ng
mesh_terms: D000465:Algorithms; D019295:Computational Biology / Q000379:methods*; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006801:Humans; D012984:Software; D049490:Systems Biology; D059467:Transcriptome
keywords: Bootstrap; Gene modules; Reproducibility; Systems biology; WGCNA