Network medicine applies fundamental principles of complexity science and systems medicine to integrate and analyze complex structured data, including genomics, transcriptomics, proteomics, and metabolomics, to characterize the dynamical states of health and disease within biological networks. In this perspective, we discuss the major successes of the field and how incorporating techniques based on statistical physics and machine learning in network medicine has significantly refined our understanding of disease networks. Despite these achievements, the maturation of network medicine presents challenges that must be addressed. Limitations in defining biological units and interactions, interpreting network models, and accounting for experimental uncertainties hinder the field’s progress. The next phase of network medicine must expand the current framework by incorporating more realistic assumptions about biological units and their interactions across multiple relevant scales. This expansion is crucial for advancing our understanding of complex diseases and improving strategies for their diagnosis, treatment, and prevention.

Digital twins (DTs) in precision medicine are increasingly viable, propelled by extensive data collection and advancements in artificial intelligence (AI), alongside traditional biomedical methodologies. We argue that including mechanistic simulations that produce behavior based on explicitly defined biological hypotheses and multiscale mechanisms is beneficial. It enables the exploration of diverse therapeutic strategies and supports dynamic clinical decision-making through insights from network science, quantitative biology, and digital medicine.

Protein–protein interaction networks have been used to investigate the influence of SARS-CoV-2 viral proteins on the function of human cells, laying out a deeper understanding of COVID–19 and providing ground for applications, such as drug repurposing. Characterizing molecular (dis)similarities between SARS-CoV-2 and other viral agents allows one to exploit existing information about the alteration of key biological processes due to known viruses for predicting the potential effects of this new virus. Here, we compare the novel coronavirus network against 92 known viruses, from the perspective of statistical physics and computational biology. We show that regulatory spreading patterns, physical features and enriched biological pathways in targeted proteins lead, overall, to meaningful clusters of viruses which, across scales, provide complementary perspectives to better characterize SARS-CoV-2 and its effects on humans. Our results indicate that the virus responsible for COVID–19 exhibits expected similarities, such as to Influenza A and Human Respiratory Syncytial viruses, and unexpected ones with different infection types and from distant viral families, like HIV1 and Human Herpes virus. Taken together, our findings indicate that COVID–19 is a systemic disease with potential effects on the function of multiple organs and human body sub-systems.

Introduction: We introduce in this study CovMulNet19, a comprehensive COVID-19 network containing all available known interactions involving SARS-CoV-2 proteins, interacting-human proteins, diseases and symptoms that are related to these human proteins, and compounds that can potentially target them. Materials and Methods: Extensive network analysis methods, based on a bootstrap approach, allow us to prioritize a list of diseases that display a high similarity to COVID-19 and a list of drugs that could potentially be beneficial to treat patients. As a key feature of CovMulNet19, the inclusion of symptoms allows a deeper characterization of the disease pathology, representing a useful proxy for COVID-19-related molecular processes. Results: We recapitulate many of the known symptoms of the disease and we find the most similar diseases to COVID-19 reflect conditions that are risk factors in patients. In particular, the comparison between CovMulNet19 and randomized networks recovers many of the known associated comorbidities that are important risk factors for COVID-19 patients, through identified similarities with intestinal, hepatic, and neurological diseases as well as with respiratory conditions, in line with reported comorbidities. Conclusion: CovMulNet19 can be suitably used for network medicine analysis, as a valuable tool for exploring drug repurposing while accounting for the intervening multidimensional factors, from molecular interactions to symptoms.

Identification of modules in molecular networks is at the core of many current analysis methods in biomedical research. However, how well different approaches identify disease-relevant modules in different types of networks remains poorly understood. We launched the "Disease Module Identification DREAM Challenge", an open competition to comprehensively assess module identification methods across diverse gene, protein and signaling networks. Predicted network modules were tested for association with complex traits and diseases using a unique collection of 180 genome-wide association studies (GWAS). While a number of approaches were successful in terms of discovering complementary trait-associated modules, consensus predictions derived from the challenge submissions performed best. We find that most of these modules correspond to core disease-relevant pathways, which often comprise therapeutic targets and correctly prioritize candidate disease genes. This community challenge establishes benchmarks, tools and guidelines for molecular network analysis to study human disease biology (https://synapse.org/modulechallenge).

Untangling the complex interplay between phenotype and genotype is crucial to the effective characterization and subtyping of diseases. Here we build and analyze the multiplex network of 779 human diseases, which consists of a genotype-based layer and a phenotype-based layer. We show that diseases with common genetic constituents tend to share symptoms, and uncover how phenotype information helps boost genotype information. Moreover, we offer a flexible classification of diseases that considers their molecular underpinnings alongside their clinical manifestations. We detect cohesive groups of diseases that have high intra-group similarity at both the molecular and the phenotypic level. Inspecting these disease classes, we demonstrate the underlying pathways that connect diseases mechanistically. We observe monogenic disorders grouped together with complex diseases for which they increase the risk factor. We propose potentially new disease associations that arise as a unique feature of the information flow within and across the two layers.

Biological systems, from a cell to the human brain, are inherently complex. A powerful representation of such systems, described by an intricate web of relationships across multiple scales, is provided by complex networks. Recently, several studies are highlighting how simple networks – obtained by aggregating or neglecting temporal or categorical description of biological data – are not able to account for the richness of information characterizing biological systems. More complex models, namely multilayer networks, are needed to account for interdependencies, often varying across time, of biological interacting units within a cell, a tissue or parts of an organism. Gosak et al. [1] review the most recent advances in the application of multilayer networks for modeling complex biological systems, from molecular interactions within a cell to neuronal connectivity of the human brain.

A variety of complex systems exhibit different types of relationships simultaneously that can be modeled by multiplex networks. A typical problem is to determine the community structure of such systems that, in general, depend on one or more parameters to be tuned. In this study we propose one measure, grounded on information theory, to find the optimal value of the relax rate characterizing Multiplex Infomap, the generalization of the Infomap algorithm to the realm of multilayer networks. We evaluate our methodology on synthetic networks, to show that the most representative community structure can be reliably identified when the most appropriate relax rate is used. Capitalizing on these results, we use this measure to identify the most reliable meso-scale functional organization in the human protein-protein interaction multiplex network and compare the observed clusters against a collection of independently annotated gene sets from the Molecular Signatures Database (MSigDB). Our analysis reveals that modules obtained with the optimal value of the relax rate are biologically significant and, remarkably, with higher functional content than the ones obtained from the aggregate representation of the human proteome. Our framework allows us to characterize the meso-scale structure of those multilayer systems whose layers are not explicitly interconnected each other -- as in the case of edge-colored models -- the ones describing most biological networks, from proteomes to connectomes.

Many complex systems can be represented as networks composed by distinct layers, interacting and depending on each others. For example, in biology, a good description of the full protein-protein interactome requires, for some organisms, up to seven distinct network layers, with thousands of protein-protein interactions each. A fundamental open question is then how much information is really necessary to accurately represent the structure of a multilayer complex system, and if and when some of the layers can indeed be aggregated. Here we introduce a method, based on information theory, to reduce the number of layers in multilayer networks, while minimizing information loss. We validate our approach on a set of synthetic benchmarks, and prove its applicability to an extended data set of protein-genetic interactions, showing cases where a strong reduction is possible and cases where it is not. Using this method we can describe complex systems with an optimal trade--off between accuracy and complexity.

Multilayer relationships among entities and information about entities must be accompanied by the means to analyse, visualize and obtain insights from such data. We present open-source software (muxViz) that contains a collection of algorithms for the analysis of multilayer networks, which are an important way to represent a large variety of complex systems throughout science and engineering. We demonstrate the ability of muxViz to analyse and interactively visualize multilayer data using empirical genetic, neuronal and transportation networks. Our software is available at https://github.com/manlius/muxViz.