Algebraic shortcuts for leave-one-out cross-validation in supervised network inference

Supervised machine learning techniques have traditionally been very successful at reconstructing biological networks, such as protein-ligand interaction, protein-protein interaction and gene regulatory networks. Many supervised techniques for network prediction use linear models on a possibly nonlinear pairwise feature representation of edges. Recently, much emphasis has been placed on the correct evaluation of such supervised models. It is vital to distinguish between using a model to either predict new interactions in a given network or to predict interactions for a new vertex not present in the original network. This distinction matters because (i) the performance might dramatically differ between the prediction settings and (ii) tuning the model hyperparameters to obtain the best possible model depends on the setting of interest. Specific cross-validation schemes need to be used to assess the performance in such different prediction settings. In this work we discuss a state-of-the-art kernel-based network inference technique called two-step kernel ridge regression. We show that this regression model can be trained efficiently, with a time complexity scaling with the number of vertices rather than the number of edges. Furthermore, this framework leads to a series of cross-validation shortcuts that allow one to rapidly estimate the model performance for any relevant network prediction setting. This allows computational biologists to fully assess the capabilities of their models

Classifying pairs with trees for supervised biological network inference

Networks are ubiquitous in biology and computational approaches have been largely investigated for their inference. In particular, supervised machine learning methods can be used to complete a partially known network by integrating various measurements. Two main supervised frameworks have been proposed: the local approach, which trains a separate model for each network node, and the global approach, which trains a single model over pairs of nodes. Here, we systematically investigate, theoretically and empirically, the exploitation of tree-based ensemble methods in the context of these two approaches for biological network inference. We first formalize the problem of network inference as classification of pairs, unifying in the process homogeneous and bipartite graphs and discussing two main sampling schemes. We then present the global and the local approaches, extending the later for the prediction of interactions between two unseen network nodes, and discuss their specializations to tree-based ensemble methods, highlighting their interpretability and drawing links with clustering techniques. Extensive computational experiments are carried out with these methods on various biological networks that clearly highlight that these methods are competitive with existing methods.Comment: 22 page

Data-driven network alignment

Biological network alignment (NA) aims to find a node mapping between species' molecular networks that uncovers similar network regions, thus allowing for transfer of functional knowledge between the aligned nodes. However, current NA methods do not end up aligning functionally related nodes. A likely reason is that they assume it is topologically similar nodes that are functionally related. However, we show that this assumption does not hold well. So, a paradigm shift is needed with how the NA problem is approached. We redefine NA as a data-driven framework, TARA (daTA-dRiven network Alignment), which attempts to learn the relationship between topological relatedness and functional relatedness without assuming that topological relatedness corresponds to topological similarity, like traditional NA methods do. TARA trains a classifier to predict whether two nodes from different networks are functionally related based on their network topological patterns. We find that TARA is able to make accurate predictions. TARA then takes each pair of nodes that are predicted as related to be part of an alignment. Like traditional NA methods, TARA uses this alignment for the across-species transfer of functional knowledge. Clearly, TARA as currently implemented uses topological but not protein sequence information for this task. We find that TARA outperforms existing state-of-the-art NA methods that also use topological information, WAVE and SANA, and even outperforms or complements a state-of-the-art NA method that uses both topological and sequence information, PrimAlign. Hence, adding sequence information to TARA, which is our future work, is likely to further improve its performance

Machine Learning and Integrative Analysis of Biomedical Big Data.

Recent developments in high-throughput technologies have accelerated the accumulation of massive amounts of omics data from multiple sources: genome, epigenome, transcriptome, proteome, metabolome, etc. Traditionally, data from each source (e.g., genome) is analyzed in isolation using statistical and machine learning (ML) methods. Integrative analysis of multi-omics and clinical data is key to new biomedical discoveries and advancements in precision medicine. However, data integration poses new computational challenges as well as exacerbates the ones associated with single-omics studies. Specialized computational approaches are required to effectively and efficiently perform integrative analysis of biomedical data acquired from diverse modalities. In this review, we discuss state-of-the-art ML-based approaches for tackling five specific computational challenges associated with integrative analysis: curse of dimensionality, data heterogeneity, missing data, class imbalance and scalability issues