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Open Access Highly Accessed Research article

Pooling breast cancer datasets has a synergetic effect on classification performance and improves signature stability

Martin H van Vliet12*, Fabien Reyal35, Hugo M Horlings3, Marc J van de Vijver34, Marcel JT Reinders1 and Lodewyk FA Wessels12

Author Affiliations

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

3 Department of Pathology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

4 Department of Pathology, Academic Medical Center, Meibergdreef 9, 1100 DD, Amsterdam, The Netherlands

5 Department of Surgery, Institut Curie, 6 rue d'Ulm, 75005 Paris, France

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BMC Genomics 2008, 9:375  doi:10.1186/1471-2164-9-375

Published: 6 August 2008

Abstract

Background

Michiels et al. (Lancet 2005; 365: 488–92) employed a resampling strategy to show that the genes identified as predictors of prognosis from resamplings of a single gene expression dataset are highly variable. The genes most frequently identified in the separate resamplings were put forward as a 'gold standard'. On a higher level, breast cancer datasets collected by different institutions can be considered as resamplings from the underlying breast cancer population. The limited overlap between published prognostic signatures confirms the trend of signature instability identified by the resampling strategy. Six breast cancer datasets, totaling 947 samples, all measured on the Affymetrix platform, are currently available. This provides a unique opportunity to employ a substantial dataset to investigate the effects of pooling datasets on classifier accuracy, signature stability and enrichment of functional categories.

Results

We show that the resampling strategy produces a suboptimal ranking of genes, which can not be considered to be a 'gold standard'. When pooling breast cancer datasets, we observed a synergetic effect on the classification performance in 73% of the cases. We also observe a significant positive correlation between the number of datasets that is pooled, the validation performance, the number of genes selected, and the enrichment of specific functional categories. In addition, we have evaluated the support for five explanations that have been postulated for the limited overlap of signatures.

Conclusion

The limited overlap of current signature genes can be attributed to small sample size. Pooling datasets results in more accurate classification and a convergence of signature genes. We therefore advocate the analysis of new data within the context of a compendium, rather than analysis in isolation.