Discretization Provides a Conceptually Simple Tool to Build Expression Networks

Biomarker identification, using network methods, depends on finding regular co-expression patterns; the overall connectivity is of greater importance than any single relationship. A second requirement is a simple algorithm for ranking patients on how relevant a gene-set is. For both of these requirements discretized data helps to first identify gene cliques, and then to stratify patients. We explore a biologically intuitive discretization technique which codes genes as up- or down-regulated, with values close to the mean set as unchanged; this allows a richer description of relationships between genes than can be achieved by positive and negative correlation. We find a close agreement between our results and the template gene-interactions used to build synthetic microarray-like data by SynTReN, which synthesizes “microarray” data using known relationships which are successfully identified by our method. We are able to split positive co-regulation into up-together and down-together and negative co-regulation is considered as directed up-down relationships. In some cases these exist in only one direction, with real data, but not with the synthetic data. We illustrate our approach using two studies on white blood cells and derived immortalized cell lines and compare the approach with standard correlation-based computations. No attempt is made to distinguish possible causal links as the search for biomarkers would be crippled by losing highly significant co-expression relationships. This contrasts with approaches like ARACNE and IRIS. The method is illustrated with an analysis of gene-expression for energy metabolism pathways. For each discovered relationship we are able to identify the samples on which this is based in the discretized sample-gene matrix, along with a simplified view of the patterns of gene expression; this helps to dissect the gene-sample relevant to a research topic - identifying sets of co-regulated and anti-regulated genes and the samples or patients in which this relationship occurs.