  Recently, several classifiers that combine primary tumor data, like gene
expression data, and secondary data sources, such as protein-protein
interaction networks, have been proposed for predicting outcome in breast
cancer. In these approaches, new composite features are typically constructed
by aggregating the expression levels of several genes. The secondary data
sources are employed to guide this aggregation. Although many studies claim
that these approaches improve classification performance over single gene
classifiers, the gain in performance is difficult to assess. This stems mainly
from the fact that different breast cancer data sets and validation procedures
are employed to assess the performance. Here we address these issues by
employing a large cohort of six breast cancer data sets as benchmark set and by
performing an unbiased evaluation of the classification accuracies of the
different approaches. Contrary to previous claims, we find that composite
feature classifiers do not outperform simple single gene classifiers. We
investigate the effect of (1) the number of selected features; (2) the specific
gene set from which features are selected; (3) the size of the training set and
(4) the heterogeneity of the data set on the performance of composite feature
and single gene classifiers. Strikingly, we find that randomization of
secondary data sources, which destroys all biological information in these
sources, does not result in a deterioration in performance of composite feature
classifiers. Finally, we show that when a proper correction for gene set size
is performed, the stability of single gene sets is similar to the stability of
composite feature sets. Based on these results there is currently no reason to
prefer prognostic classifiers based on composite features over single gene
classifiers for predicting outcome in breast cancer.
