Many studies and applications in the post-genomic era have been devoted to analyze complex biological systems by computational inference methods. We propose to apply manifold learning methods to protein-protein interaction networks (PPIN). Despite their popularity in data-intensive applications, these methods have received limited attention in the context of biological networks. We show that there is both utility and unexplored potential in adopting manifold learning for network inference purposes. In particular, the following advantages are highlighted: (a) fusion with diagnostic statistical tools designed to assign significance to protein interactions based on pre-selected topological features; (b) dissection into components of the interactome in order to elucidate global and local connectivity organization; (c) relevance of embedding the interactome in reduced dimensions for biological validation purposes. We have compared the performances of three well-known techniques-kernel-PCA, RADICAL ICA, and ISOMAP-relatively to their power of mapping the interactome onto new coordinate dimensions where important associations among proteins can be detected, and then back projected such that the corresponding sub-interactomes are reconstructed. This recovery has been done selectively, by using significant information according to a robust statistical procedure, and then standard biological annotation has been provided to validate the results. We expect that a byproduct of using subspace analysis by the proposed techniques is a possible calibration of interactome modularity studies.
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