This article is part of the supplement: Selected papers from the Seventh Asia-Pacific Bioinformatics Conference (APBC 2009)
Knowledge driven decomposition of tumor expression profiles
1 Information and Communication Theory Group, Faculty of Electrical Engineering, Mathematics and Computer Science, Delft University of Technology, Mekelweg 4, 2628 CD Delft, The Netherlands
2 Bioinformatics and Statistics group, Department of Molecular Biology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
BMC Bioinformatics 2009, 10(Suppl 1):S20 doi:10.1186/1471-2105-10-S1-S20Published: 30 January 2009
Tumors have been hypothesized to be the result of a mixture of oncogenic events, some of which will be reflected in the gene expression of the tumor. Based on this hypothesis a variety of data-driven methods have been employed to decompose tumor expression profiles into component profiles, hypothetically linked to these events. Interpretation of the resulting data-driven components is often done by post-hoc comparison to, for instance, functional groupings of genes into gene sets. None of the data-driven methods allow the incorporation of that type of knowledge directly into the decomposition.
We present a linear model which uses knowledge driven, pre-defined components to perform the decomposition. We solve this decomposition model in a constrained linear least squares fashion. From a variety of options, a lasso-based solution to the model performs best in linking single gene perturbation data to mouse data. Moreover, we show the decomposition of expression profiles from human breast cancer samples into single gene perturbation profiles and gene sets that are linked to the hallmarks of cancer. For these breast cancer samples we were able to discern several links between clinical parameters, and the decomposition weights, providing new insights into the biology of these tumors. Lastly, we show that the order in which the Lasso regularization shrinks the weights, unveils consensus patterns within clinical subgroups of the breast cancer samples.
The proposed lasso-based constrained least squares decomposition provides a stable and relevant relation between samples and knowledge-based components, and is thus a viable alternative to data-driven methods. In addition, the consensus order of component importance within clinical subgroups provides a better molecular characterization of the subtypes.