Pathway relevance ranking for tumor samples through network-based data integration

The study of cancer, a highly heterogeneous disease with different causes and clinical outcomes, requires a multi-angle approach and the collection of large multi-omics datasets that, ideally, should be analyzed simultaneously. We present a new pathway relevance ranking method that is able to prioritize pathways according to the information contained in any combination of tumor related omics datasets. Key to the method is the conversion of all available data into a single comprehensive network representation containing not only genes but also individual patient samples. Additionally, all data are linked through a network of previously identified molecular interactions. We demonstrate the performance of the new method by applying it to breast and ovarian cancer datasets from The Cancer Genome Atlas. By integrating gene expression, copy number, mutation and methylation data, the method's potential to identify key pathways involved in breast cancer development shared by different molecular subtypes is illustrated. Interestingly, certain pathways were ranked equally important for different subtypes, even when the underlying (epi)-genetic disturbances were diverse. Next to prioritizing universally high-scoring pathways, the pathway ranking method was able to identify subtype-specific pathways. Often the score of a pathway could not be motivated by a single mutation, copy number or methylation alteration, but rather by a combination of genetic and epi-genetic disturbances, stressing the need for a network-based data integration approach. The analysis of ovarian tumors, as a function of survival-based subtypes, demonstrated the method's ability to correctly identify key pathways, irrespective of tumor subtype. A differential analysis of survival-based subtypes revealed several pathways with higher importance for the bad-outcome patient group than for the good-outcome patient group. Many of the pathways exhibiting higher importance for the bad-outcome patient group could be related to ovarian tumor proliferation and survival

EPSILON: an eQTL prioritization framework using similarity measures derived from local networks

Motivation: When genomic data are associated with gene expression data, the resulting expression quantitative trait loci (eQTL) will likely span multiple genes. eQTL prioritization techniques can be used to select the most likely causal gene affecting the expression of a target gene from a list of candidates. As an input, these techniques use physical interaction networks that often contain highly connected genes and unreliable or irrelevant interactions that can interfere with the prioritization process. We present EPSILON, an extendable framework for eQTL prioritization, which mitigates the effect of highly connected genes and unreliable interactions by constructing a local network before a network-based similarity measure is applied to select the true causal gene. Results: We tested the new method on three eQTL datasets derived from yeast data using three different association techniques. A physical interaction network was constructed, and each eQTL in each dataset was prioritized using the EPSILON approach: first, a local network was constructed using a k-trials shortest path algorithm, followed by the calculation of a network-based similarity measure. Three similarity measures were evaluated: random walks, the Laplacian Exponential Diffusion kernel and the Regularized Commute-Time kernel. The aim was to predict knockout interactions from a yeast knockout compendium. EPSILON outperformed two reference prioritization methods, random assignment and shortest path prioritization. Next, we found that using a local network significantly increased prioritization performance in terms of predicted knockout pairs when compared with using exactly the same network similarity measures on the global network, with an average increase in prioritization performance of 8 percentage points (P < 10(-5))

Efficient Regularized Least-Squares Algorithms for Conditional Ranking on Relational Data

In domains like bioinformatics, information retrieval and social network analysis, one can find learning tasks where the goal consists of inferring a ranking of objects, conditioned on a particular target object. We present a general kernel framework for learning conditional rankings from various types of relational data, where rankings can be conditioned on unseen data objects. We propose efficient algorithms for conditional ranking by optimizing squared regression and ranking loss functions. We show theoretically, that learning with the ranking loss is likely to generalize better than with the regression loss. Further, we prove that symmetry or reciprocity properties of relations can be efficiently enforced in the learned models. Experiments on synthetic and real-world data illustrate that the proposed methods deliver state-of-the-art performance in terms of predictive power and computational efficiency. Moreover, we also show empirically that incorporating symmetry or reciprocity properties can improve the generalization performance