title: Sexually-dimorphic targeting of functionally-related genes in COPD.
abstract: BACKGROUND
  There is growing evidence that many diseases develop, progress, and respond to therapy differently in men and women. This variability may manifest as a result of sex-specific structures in gene regulatory networks that influence how those networks operate. However, there are few methods to identify and characterize differences in network structure, slowing progress in understanding mechanisms driving sexual dimorphism.
  
  
  RESULTS
  Here we apply an integrative network inference method, PANDA (Passing Attributes between Networks for Data Assimilation), to model sex-specific networks in blood and sputum samples from subjects with Chronic Obstructive Pulmonary Disease (COPD). We used a jack-knifing approach to build an ensemble of likely networks for each sex. By adapting statistical methods to compare these network ensembles, we were able to identify strong differential-targeting patterns associated with functionally-related sets of genes, including those involved in mitochondrial function and energy metabolism. Network analysis also identified several potential sex- and disease-specific transcriptional regulators of these pathways.
  
  
  CONCLUSIONS
  Network analysis yielded insight into potential mechanisms driving sexual dimorphism in COPD that were not evident from gene expression analysis alone. We believe our ensemble approach to network analysis provides a principled way to capture sex-specific regulatory relationships and could be applied to identify differences in gene regulatory patterns in a wide variety of diseases and contexts.
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA. rekrg@channing.harvard.edu.|Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA. rekrg@channing.harvard.edu.|Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. rekrg@channing.harvard.edu.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Glass
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA. johnq@jimmy.harvard.edu.|Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA. johnq@jimmy.harvard.edu.|Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. johnq@jimmy.harvard.edu.
authors.forename: John
authors.initials: J
authors.lastname: Quackenbush
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. reeks@channing.harvard.edu.|Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA. reeks@channing.harvard.edu.
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA. bcelli@partners.org.
authors.forename: Bartolome
authors.initials: B
authors.lastname: Celli
authors.affiliation: Division of Pulmonary, Critical Care, Sleep and Allergy, University of Nebraska Medical Center, Omaha, NE, USA. srennard@unmc.edu.
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Rennard
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA. gcyuan@jimmy.harvard.edu.|Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA. gcyuan@jimmy.harvard.edu.
authors.forename: Guo-Cheng
authors.initials: GC
authors.lastname: Yuan
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. redld@channing.harvard.edu.|Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA. redld@channing.harvard.edu.
authors.forename: Dawn L
authors.initials: DL
authors.lastname: DeMeo
mesh_terms: D005260:Female; D053263:Gene Regulatory Networks / Q000235:genetics*; D006801:Humans; D008297:Male; D008954:Models, Biological; D025341:Principal Component Analysis; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood / Q000235:genetics*; D050436:Regulatory Elements, Transcriptional / Q000235:genetics; D012727:Sex Characteristics; D012984:Software; D013183:Sputum / Q000378:metabolism