title: Differential correlation for sequencing data.
abstract: BACKGROUND
  Several methods have been developed to identify differential correlation (DC) between pairs of molecular features from -omics studies. Most DC methods have only been tested with microarrays and other platforms producing continuous and Gaussian-like data. Sequencing data is in the form of counts, often modeled with a negative binomial distribution making it difficult to apply standard correlation metrics. We have developed an R package for identifying DC called Discordant which uses mixture models for correlations between features and the Expectation Maximization (EM) algorithm for fitting parameters of the mixture model. Several correlation metrics for sequencing data are provided and tested using simulations. Other extensions in the Discordant package include additional modeling for different types of differential correlation, and faster implementation, using a subsampling routine to reduce run-time and address the assumption of independence between molecular feature pairs.
  
  
  RESULTS
  With simulations and breast cancer miRNA-Seq and RNA-Seq data, we find that Spearman's correlation has the best performance among the tested correlation methods for identifying differential correlation. Application of Spearman's correlation in the Discordant method demonstrated the most power in ROC curves and sensitivity/specificity plots, and improved ability to identify experimentally validated breast cancer miRNA. We also considered including additional types of differential correlation, which showed a slight reduction in power due to the additional parameters that need to be estimated, but more versatility in applications. Finally, subsampling within the EM algorithm considerably decreased run-time with negligible effect on performance.
  
  
  CONCLUSIONS
  A new method and R package called Discordant is presented for identifying differential correlation with sequencing data. Based on comparisons with different correlation metrics, this study suggests Spearman's correlation is appropriate for sequencing data, but other correlation metrics are available to the user depending on the application and data type. The Discordant method can also be extended to investigate additional DC types and subsampling with the EM algorithm is now available for reduced run-time. These extensions to the R package make Discordant more robust and versatile for multiple -omics studies.
authors.affiliation: Computational Bioscience Program, Department of Pharmacology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. charlotte.siska@ucdenver.edu.
authors.forename: Charlotte
authors.identifier: http://orcid.org/0000-0002-7595-4322
authors.initials: C
authors.lastname: Siska
authors.affiliation: Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Katerina
authors.initials: K
authors.lastname: Kechris
mesh_terms: D000465:Algorithms; D001943:Breast Neoplasms / Q000235:genetics; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D020869:Gene Expression Profiling / Q000379:methods*; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D035683:MicroRNAs / Q000032:analysis; D015233:Models, Statistical; D009369:Neoplasms / Q000235:genetics; D016011:Normal Distribution; D012372:ROC Curve; D012680:Sensitivity and Specificity; D017423:Sequence Analysis, RNA / Q000379:methods*; D012984:Software; D059467:Transcriptome
chemical_list: D035683:MicroRNAs