Motivation: Biological network alignment aims to identify similar regions between networks of different species. Existing methods compute node similarities to rapidly identify from possible alignments the high-scoring alignments with respect to the overall node similarity. But, the accuracy of the alignments is then evaluated with some other measure that is different than the node similarity used to construct the alignments. Typically, one measures the amount of conserved edges. Thus, the existing methods align similar nodes between networks hoping to conserve many edges (after the alignment is constructed!).

Motivation: Network alignment aims to find conserved regions between different networks. Existing methods aim to maximize total similarity over all aligned nodes (i.e. node conservation). Then, they evaluate alignment quality by measuring the amount of conserved edges, but only after the alignment is constructed. Thus, we recently introduced MAGNA (Maximizing Accuracy in Global Network Alignment) to directly maximize edge conservation while producing alignments and showed its superiority over the existing methods. Here, we extend the original MAGNA with several important algorithmic advances into a new MAGNA++ framework. Results: MAGNA++ introduces several novelties: (i) it simultaneously maximizes any one of three different measures of edge conservation (including our recent superior $S3$ measure) and any desired node conservation measure, which further improves alignment quality compared with maximizing only node conservation or only edge conservation; (ii) it speeds up the original MAGNA algorithm by parallelizing it to automatically use all available resources, as well as by reimplementing the edge conservation measures more efficiently; (iii) it provides a friendly graphical user interface for easy use by domain (e.g. biological) scientists; and (iv) at the same time, MAGNA++ offers source code for easy extensibility by computational scientists. Availability and implementation: http://www.nd.edu/∼cone/MAGNA++/ Contact: tmilenko@nd.edu

Summary: Network biology is an interdisciplinary field bridging computational and biological sciences that has proved pivotal in advancing the understanding of cellular functions and diseases across biological systems and scales. Although the field has been around for two decades, it remains nascent. It has witnessed rapid evolution, accompanied by emerging challenges. These stem from various factors, notably the growing complexity and volume of data together with the increased diversity of data types describing different tiers of biological organization. We discuss prevailing research directions in network biology, focusing on molecular/cellular networks but also on other biological network types such as biomedical knowledge graphs, patient similarity networks, brain networks, and social/contact networks relevant to disease spread. In more detail, we highlight areas of inference and comparison of biological networks, multimodal data integration and heterogeneous networks, higher-order network analysis, machine learning on networks, and network-based personalized medicine. Following the overview of recent breakthroughs across these five areas, we offer a perspective on future directions of network biology. Additionally, we discuss scientific communities, educational initiatives, and the importance of fostering diversity within the field. This article establishes a roadmap for an immediate and long-term vision for network biology. Availability and implementation: Not applicable.

Motivation: With increasing availability of temporal real-world networks, how to efficiently study these data? One can model a temporal network as a single aggregate static network, or as a series of time-specific snapshots, each being an aggregate static network over the corresponding time window. Then, one can use established methods for static analysis on the resulting aggregate network(s), but losing in the process valuable temporal information either completely, or at the interface between different snapshots, respectively. Here, we develop a novel approach for studying a temporal network more explicitly, by capturing inter-snapshot relationships. Results: We base our methodology on well-established graphlets (subgraphs), which have been proven in numerous contexts in static network research. We develop new theory to allow for graphlet-based analyses of temporal networks. Our new notion of dynamic graphlets is different from existing dynamic network approaches that are based on temporal motifs (statistically significant subgraphs). The latter have limitations: their results depend on the choice of a null network model that is required to evaluate the significance of a subgraph, and choosing a good null model is non-trivial. Our dynamic graphlets overcome the limitations of the temporal motifs. Also, when we aim to characterize the structure and function of an entire temporal network or of individual nodes, our dynamic graphlets outperform the static graphlets. Clearly, accounting for temporal information helps. We apply dynamic graphlets to temporal age-specific molecular network data to deepen our limited knowledge about human aging. Availability and implementation:http://www.nd.edu/∼cone/DG. Contact:tmilenko@nd.edu Supplementary information: Supplementary data are available at Bioinformatics online.

Motivation: Because susceptibility to diseases increases with age, studying aging gains importance. Analyses of gene expression or sequence data, which have been indispensable for investigating aging, have been limited to studying genes and their protein products in isolation, ignoring their connectivities. However, proteins function by interacting with other proteins, and this is exactly what biological networks (BNs) model. Thus, analyzing the proteins’ BN topologies could contribute to the understanding of aging. Current methods for analyzing systems-level BNs deal with their static representations, even though cells are dynamic. For this reason, and because different data types can give complementary biological insights, we integrate current static BNs with aging-related gene expression data to construct dynamic age-specific BNs. Then, we apply sensitive measures of topology to the dynamic BNs to study cellular changes with age. Results: While global BN topologies do not significantly change with age, local topologies of a number of genes do. We predict such genes to be aging-related. We demonstrate credibility of our predictions by (i) observing significant overlap between our predicted aging-related genes and ‘ground truth’ aging-related genes; (ii) observing significant overlap between functions and diseases that are enriched in our aging-related predictions and those that are enriched in ‘ground truth’ aging-related data; (iii) providing evidence that diseases which are enriched in our aging-related predictions are linked to human aging; and (iv) validating our high-scoring novel predictions in the literature. Availability and implementation: Software executables are available upon request. Contact:tmilenko@nd.edu Supplementary information: Supplementary Data are available at Bioinformatics online.

Motivation: Network alignment (NA) aims to find regions of similarities between species’ molecular networks. There exist two NA categories: local (LNA) and global (GNA). LNA finds small highly conserved network regions and produces a many-to-many node mapping. GNA finds large conserved regions and produces a one-to-one node mapping. Given the different outputs of LNA and GNA, when a new NA method is proposed, it is compared against existing methods from the same category. However, both NA categories have the same goal: to allow for transferring functional knowledge from well- to poorly-studied species between conserved network regions. So, which one to choose, LNA or GNA? To answer this, we introduce the first systematic evaluation of the two NA categories. Results: We introduce new measures of alignment quality that allow for fair comparison of the different LNA and GNA outputs, as such measures do not exist. We provide user-friendly software for efficient alignment evaluation that implements the new and existing measures. We evaluate prominent LNA and GNA methods on synthetic and real-world biological networks. We study the effect on alignment quality of using different interaction types and confidence levels. We find that the superiority of one NA category over the other is context-dependent. Further, when we contrast LNA and GNA in the application of learning novel protein functional knowledge, the two produce very different predictions, indicating their complementarity. Our results and software provide guidelines for future NA method development and evaluation. Availability and implementation: Software: http://www.nd.edu/~cone/LNA_GNA Contact: tmilenko@nd.edu Supplementary information: Supplementary data are available at Bioinformatics online.