Abstract
BackgroundCurrent outcome predictors based on "molecular profiling" rely on gene lists selected without consideration for their molecular mechanisms. This study was designed to demonstrate that we could learn about genes related to a specific mechanism and further use this knowledge to predict outcome in patients – a paradigm shift towards accurate "mechanism-anchored profiling". We propose a novel algorithm, PGnet, which predicts a tripartite mechanism-anchored network associated to epigenetic regulation consisting of phenotypes, genes and mechanisms. Genes termed as GEMs in this network meet all of the following criteria: (i) they are co-expressed with genes known to be involved in the biological mechanism of interest, (ii) they are also differentially expressed between distinct phenotypes relevant to the study, and (iii) as a biomodule, genes correlate with both the mechanism and the phenotype.ResultsThis proof-of-concept study, which focuses on epigenetic mechanisms, was conducted in a well-studied set of 132 acute lymphoblastic leukemia (ALL) microarrays annotated with nine distinct phenotypes and three measures of response to therapy. We used established parametric and non parametric statistics to derive the PGnet tripartite network that consisted of 10 phenotypes and 33 significant clusters of GEMs comprising 535 distinct genes. The significance of PGnet was estimated from empirical p-values, and a robust subnetwork derived from ALL outcome data was produced by repeated random sampling. The evaluation of derived robust network to predict outcome (relapse of ALL) was significant (p = 3%), using one hundred three-fold cross-validations and the shrunken centroids classifier.ConclusionTo our knowledge, this is the first method predicting co-expression networks of genes associated with epigenetic mechanisms and to demonstrate its inherent capability to predict therapeutic outcome. This PGnet approach can be applied to any regulatory mechanisms including transcriptional or microRNA regulation in order to derive predictive molecular profiles that are mechanistically anchored. The implementation of PGnet in R is freely available at .
Highlights
Current outcome predictors based on “molecular profiling” rely on gene lists selected without consideration for their molecular mechanisms
BMC Bioinformatics 2009, 10(Suppl 9):S6 http://www.biomedcentral.com/1471-2105/10/S9/S6 therapeutic outcome. This phenotype-genotype-network” method (PGnet) approach can be applied to any regulatory mechanisms including transcriptional or microRNA regulation in order to derive predictive molecular profiles that are mechanistically anchored
This method can be generalized to other molecular mechanisms and other diseases, we focused this study on epigenetic alterations in acute lymphoblastic leukemia (ALL)
Summary
Current outcome predictors based on “molecular profiling” rely on gene lists selected without consideration for their molecular mechanisms. Profiles are accompanied with followon enrichment studies or curated annotations that predict their possible mechanisms; while in other cases, functional clustering has been proposed to understand microarray data profiles [3] In this manuscript, we propose a novel computational strategy based on genes associated to known biological mechanisms to derive mechanism-anchored expression profiles ab initio that can accurately predict disease outcome. To demonstrate the applicability of the proposed phenotype-genotype-network” method (PGnet), a set of known biological mechanism-anchored genes are required as the “seed” (input) This method can be generalized to other molecular mechanisms and other diseases, we focused this study on epigenetic alterations in acute lymphoblastic leukemia (ALL)
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