Optimizing network propagation for multi-omics data integration

Network propagation refers to a class of algorithms that integrate information from input data across connected nodes in a given network. These algorithms have wide applications in systems biology, protein function prediction, inferring condition-specifically altered sub-networks, and prioritizing disease genes. Despite the popularity of network propagation, there is a lack of comparative analyses of different algorithms on real data and little guidance on how to select and parameterize the various algorithms. Here, we address this problem by analyzing different combinations of network normalization and propagation methods and by demonstrating schemes for the identification of optimal parameter settings on real proteome and transcriptome data. Our work highlights the risk of a ‘topology bias’ caused by the incorrect use of network normalization approaches. Capitalizing on the fact that network propagation is a regularization approach, we show that minimizing the bias-variance tradeoff can be utilized for selecting optimal parameters. The application to real multi-omics data demonstrated that optimal parameters could also be obtained by either maximizing the agreement between different omics layers (e.g. proteome and transcriptome) or by maximizing the consistency between biological replicates. Furthermore, we exemplified the utility and robustness of network propagation on multi-omics datasets for identifying ageing-associated genes in brain and liver tissues of rats and for elucidating molecular mechanisms underlying prostate cancer progression. Overall, this work compares different network propagation approaches and it presents strategies for how to use network propagation algorithms to optimally address a specific research question at hand.Author summary: Modern technologies enable the simultaneous measurement of tens of thousands of molecules in biological samples. Algorithms called network propagation or network smoothing are frequently used to integrate such data with already known molecular interaction data, such as protein and gene interaction networks. These methods distribute the information on molecular perturbations within the network and help identifying network regions that are enriched for many perturbed (affected) molecules. Despite the popularity of these methods, there is a lack of guidance on how to optimally use them. Here, we highlight possible pitfalls when using incorrect network normalization methods. Further, we present different ways for optimizing the smoothing parameters used during network smoothing: the first approach maximizes the consistency between replicate measurements within a dataset; the second one maximizes the consistency between different types of ‘omics’ measurements, such as proteomics and transcriptomics. Using two multi-omics datasets, one from a cohort of prostate cancer patients, the other one from an ageing study on rat brain and liver tissues, we exemplify the effects of these strategies on real data.