Integration of gene signatures using biological knowledge

OBJECTIVE Gene expression patterns that distinguish clinically significant disease subclasses may not only play a prominent role in diagnosis, but also lead to the therapeutic strategies tailoring the treatment to the particular biology of each disease. Nevertheless, gene expression signatures derived through statistical feature-extraction procedures on population datasets have received rightful criticism, since they share few genes in common, even when derived from the same dataset. We focus on knowledge complementarities conveyed by two or more gene-expression signatures by means of embedded biological processes and pathways, which alternatively form a meta-knowledge platform of analysis towards a more global, robust and powerful solution. METHODS The main contribution of this work is the introduction and study of an approach for integrating different gene signatures based on the underlying biological knowledge, in an attempt to derive a unified global solution. It is further recognized that one group's signature does not perform well on another group's data, due to incompatibilities of microarray technologies and the experimental design. We assess this cross-platform aspect, showing that a unified solution derived on the basis of both statistical and biological validation may also help in overcoming such inconsistencies. RESULTS Based on the proposed approach we derived a unified 69-gene signature, which outperforms significantly the performance of the initial signatures succeeding a 0.73 accuracy metric on 234 new patients with 81% sensitivity and 64% specificity. The same signature manages to reveal the two prognostic groups on an additional dataset of 286 new patients obtained through a different experimental protocol and microarray platform. Furthermore, it manages to derive two clusters in a dataset from a different platform, showing remarkable difference on both gene-expression and survival-prediction levels.