La medicina di precisione come opera d'arte collettiva.

Advancing our understanding of complex diseases necessitates an interdisciplinary dialogue beyond artificial intelligence (AI) in the field of medicine. Two decades after the completion of the Human Genome Project, genetic sequencing has facilitated targeted therapies for gene mutation-related ailments. However, this achievement has unveiled the immense gaps in our comprehension of life and disease mechanisms. Complex diseases, including cancer, diabetes, and autoimmune disorders, remain elusive due to their multifactorial nature. Consequently, a more holistic approach integrating AI with diverse scientific disciplines becomes imperative. This paper emphasizes the urgency of fostering collaboration among genetics, molecular biology, computational biology, and clinical research to unravel the intricate complexities underlying these diseases. By synergizing expertise and data from various domains, we can make significant strides towards unraveling the intricate web of complex diseases, leading to improved diagnosis, treatment, and ultimately, patient outcomes.

Network medicine for patients' stratification: From single-layer to multi-omics.

Precision medicine research increasingly relies on the integrated analysis of multiple types of omics. In the era of big data, the large availability of different health-related information represents a great, but at the same time untapped, chance with a potentially fundamental role in the prevention, diagnosis and prognosis of diseases. Computational methods are needed to combine this data to create a comprehensive view of a given disease. Network science can model biomedical data in terms of relationships among molecular players of different nature and has been successfully proposed as a new paradigm for studying human diseases. Patient stratification is an open challenge aimed at identifying subtypes with different disease manifestations, severity, and expected survival time. Several stratification approaches based on high-throughput gene expression measurements have been successfully applied. However, few attempts have been proposed to exploit the integration of various genotypic and phenotypic data to discover novel sub-types or improve the detection of known groupings. This article is categorized under: Cancer > Biomedical Engineering Cancer > Computational Models Cancer > Genetics/Genomics/Epigenetics.

Assessment of community efforts to advance network-based prediction of protein-protein interactions.

Comprehensive understanding of the human protein-protein interaction (PPI) network, aka the human interactome, can provide important insights into the molecular mechanisms of complex biological processes and diseases. Despite the remarkable experimental efforts undertaken to date to determine the structure of the human interactome, many PPIs remain unmapped. Computational approaches, especially network-based methods, can facilitate the identification of previously uncharacterized PPIs. Many such methods have been proposed. Yet, a systematic evaluation of existing network-based methods in predicting PPIs is still lacking. Here, we report community efforts initiated by the International Network Medicine Consortium to benchmark the ability of 26 representative network-based methods to predict PPIs across six different interactomes of four different organisms: A. thaliana, C. elegans, S. cerevisiae, and H. sapiens. Through extensive computational and experimental validations, we found that advanced similarity-based methods, which leverage the underlying network characteristics of PPIs, show superior performance over other general link prediction methods in the interactomes we considered.

Networks as Biomarkers: Uses and Purposes.

Networks-based approaches are often used to analyze gene expression data or protein-protein interactions but are not usually applied to study the relationships between different biomarkers. Given the clinical need for more comprehensive and integrative biomarkers that can help to identify personalized therapies, the integration of biomarkers of different natures is an emerging trend in the literature. Network analysis can be used to analyze the relationships between different features of a disease; nodes can be disease-related phenotypes, gene expression, mutational events, protein quantification, imaging-derived features and more. Since different biomarkers can exert causal effects between them, describing such interrelationships can be used to better understand the underlying mechanisms of complex diseases. Networks as biomarkers are not yet commonly used, despite being proven to lead to interesting results. Here, we discuss in which ways they have been used to provide novel insights into disease susceptibility, disease development and severity.

Network-based validation of the psychometric questionnaire EDI-3 for the assessment of eating disorders.

Assessing the validity of a psychometric test is fundamental to ensure a reliable interpretation of its outcomes. Few attempts have been made recently to complement classical approaches (e.g., factor models) with a novel technique based on network analysis. The objective of the current study is to carry out a network-based validation of the Eating Disorder Inventory 3 (EDI-3), a questionnaire designed for the assessment of eating disorders. Exploiting a reliable, open source sample of 1206 patients diagnosed with an eating disorder, we set up a robust validation process encompassing detection and handling of redundant EDI-3 items, estimation of the cross-sample psychometric network, resampling bootstrap procedure and computation of the median network of the replica samples. We then employed a community detection algorithm to identify the topological clusters, evaluated their coherence with the EDI-3 subscales and replicated the full validation analysis on the subpopulations corresponding to patients diagnosed with either anorexia nervosa or bulimia nervosa. Results of the network-based analysis, and particularly the topological community structures, provided support for almost all the composite scores of the EDI-3 and for 2 single subscales: Bulimia and Maturity Fear. A moderate instability of some dimensions led to the identification of a few multidimensional items that should be better located in the intersection of multiple psychological scales. We also found that, besides symptoms typically attributed to eating disorders, such as drive for thinness, also non-specific symptoms like low self-esteem and interoceptive deficits play a central role in both the cross-sample and the diagnosis-specific networks. Our work adds insights into the complex and multidimensional structure of EDI-3 by providing support to its network-based validity on both mixed and diagnosis-specific samples. Moreover, we replicated previous results that reinforce the transdiagnostic theory of eating disorders.

Network-based methods for psychometric data of eating disorders: A systematic review.

BACKGROUND: Network science represents a powerful and increasingly promising method for studying complex real-world problems. In the last decade, it has been applied to psychometric data in the attempt to explain psychopathologies as complex systems of causally interconnected symptoms. One category of mental disorders, relevant for their severity, incidence and multifaceted structure, is that of eating disorders (EDs), serious disturbances that negatively affect a person's eating behavior. AIMS: We aimed to review the corpus of psychometric network analysis methods by scrutinizing a large sample of network-based studies that exploit psychometric data related to EDs. A particular focus is given to the description of the methodologies for network estimation, network description and network stability analysis providing also a review of the statistical software packages currently used to carry out each phase of the network estimation and analysis workflow. Moreover, we try to highlight aspects with potential clinical impact such as core symptoms, influences of external factors, comorbidities, and related changes in network structure and connectivity across both time and subpopulations. METHODS: A systematic search was conducted (February 2022) on three different literature databases to identify 57 relevant research articles. The exclusion criteria comprehended studies not based on psychometric data, studies not using network analysis, studies with different aims or not focused on ED, and review articles. RESULTS: Almost all the selected 57 papers employed the same analytical procedures implemented in a collection of R packages specifically designed for psychometric network analysis and are mostly based on cross-sectional data retrieved from structured psychometric questionnaires, with just few exemptions of panel data. Most of them used the same techniques for all phases of their analysis. In particular, a pervasive use of the Gaussian Graphical Model with LASSO regularization was registered for in network estimation step. Among the clinically relevant results, we can include the fact that all papers found strong symptom interconnections between specific and nonspecific ED symptoms, suggesting that both types should therefore be addressed by clinical treatment. CONCLUSIONS: We here presented the largest and most comprehensive review to date about psychometric network analysis methods. Although these methods still need solid validation in the clinical setting, they have already been able to show many strengths and important results, as well as great potentials and perspectives, which have been analyzed here to provide suggestions on their use and their possible improvement.

Neural Networks and Connectivity among Brain Regions.

As is widely understood, brain functioning depends on the interaction among several neural populations, which are linked via complex connectivity circuits and work together (in antagonistic or synergistic ways) to exchange information, synchronize their activity, adapt plastically to external stimuli or internal requirements, and more generally to participate in solving multifaceted cognitive tasks [...].

Multi-layer analysis of multi-frequency brain networks as a new tool to study EEG topological organization.

Oscillatory activity rising from the interaction among neurons is widely observed in the brain at different scales and is thought to encode distinctive properties of the neural processing. Classical investigations of neuroelectrical activity and connectivity usually focus on specific frequency bands, considered as separate aspects of brain functioning. However, this might not paint the whole picture, preventing to see the brain activity as a whole, as the result of an integrated process. This study aims to provide a new framework for the analysis of the functional interaction between brain regions across frequencies and different subjects. We ground our work on the latest advances in graph theory, exploiting multi-layer community detection. In our multi-layer network model, layers keep track of single frequencies, including all the information in a unique graph. Community detection is then applied by means of a multilayer formulation of modularity. As a proof-of-concept of our approach, we provide here an application to multi-frequency functional brain networks derived from resting state EEG collected in a group of healthy subjects. Our results indicate that α-band selectively characterizes an inter-individual common organization of EEG brain networks during open eyes resting state. Future applications of this new approach may include the extraction of subject-specific features able to capture selected properties of the brain processes, related to physiological or pathological conditions.

A Novel Method to Assess Motor Cortex Connectivity and Event Related Desynchronization Based on Mass Models.

Knowledge of motor cortex connectivity is of great value in cognitive neuroscience, in order to provide a better understanding of motor organization and its alterations in pathological conditions. Traditional methods provide connectivity estimations which may vary depending on the task. This work aims to propose a new method for motor connectivity assessment based on the hypothesis of a task-independent connectivity network, assuming nonlinear behavior. The model considers six cortical regions of interest (ROIs) involved in hand movement. The dynamics of each region is simulated using a neural mass model, which reproduces the oscillatory activity through the interaction among four neural populations. Parameters of the model have been assigned to simulate both power spectral densities and coherences of a patient with left-hemisphere stroke during resting condition, movement of the affected, and movement of the unaffected hand. The presented model can simulate the three conditions using a single set of connectivity parameters, assuming that only inputs to the ROIs change from one condition to the other. The proposed procedure represents an innovative method to assess a brain circuit, which does not rely on a task-dependent connectivity network and allows brain rhythms and desynchronization to be assessed on a quantitative basis.

MOSES: A New Approach to Integrate Interactome Topology and Functional Features for Disease Gene Prediction.

Disease gene prediction is to date one of the main computational challenges of precision medicine. It is still uncertain if disease genes have unique functional properties that distinguish them from other non-disease genes or, from a network perspective, if they are located randomly in the interactome or show specific patterns in the network topology. In this study, we propose a new method for disease gene prediction based on the use of biological knowledge-bases (gene-disease associations, genes functional annotations, etc.) and interactome network topology. The proposed algorithm called MOSES is based on the definition of two somewhat opposing sets of genes both disease-specific from different perspectives: warm seeds (i.e., disease genes obtained from databases) and cold seeds (genes far from the disease genes on the interactome and not involved in their biological functions). The application of MOSES to a set of 40 diseases showed that the suggested putative disease genes are significantly enriched in their reference disease. Reassuringly, known and predicted disease genes together, tend to form a connected network module on the human interactome, mitigating the scattered distribution of disease genes which is probably due to both the paucity of disease-gene associations and the incompleteness of the interactome.

SEED-G: Simulated EEG Data Generator for Testing Connectivity Algorithms.

EEG signals are widely used to estimate brain circuits associated with specific tasks and cognitive processes. The testing of connectivity estimators is still an open issue because of the lack of a ground-truth in real data. Existing solutions such as the generation of simulated data based on a manually imposed connectivity pattern or mass oscillators can model only a few real cases with limited number of signals and spectral properties that do not reflect those of real brain activity. Furthermore, the generation of time series reproducing non-ideal and non-stationary ground-truth models is still missing. In this work, we present the SEED-G toolbox for the generation of pseudo-EEG data with imposed connectivity patterns, overcoming the existing limitations and enabling control of several parameters for data simulation according to the user's needs. We first described the toolbox including guidelines for its correct use and then we tested its performances showing how, in a wide range of conditions, datasets composed by up to 60 time series were successfully generated in less than 5 s and with spectral features similar to real data. Then, SEED-G is employed for studying the effect of inter-trial variability Partial Directed Coherence (PDC) estimates, confirming its robustness.

SEaCorAl: Identifying and contrasting the regulation-correlation bias in RNA-Seq paired expression data of patient groups.

The Cancer Genome Atlas database offers the possibility of analyzing genome-wide expression RNA-Seq cancer data using paired counts, that is, studies where expression data are collected in pairs of normal and cancer cells, by taking samples from the same individual. Correlation of gene expression profiles is the most common analysis to study co-expression groups, which is used to find biological interpretation of -omics big data. The aim of the paper is threefold: firstly we show for the first time, the presence of a "regulation-correlation bias" in RNA-Seq paired expression data, that is an artifactual link between the expression status (up- or down-regulation) of a gene pair and the sign of the corresponding correlation coefficient. Secondly, we provide a statistical model able to theoretically explain the reasons for the presence of such a bias. Thirdly, we present a bias-removal algorithm, called SEaCorAl, able to effectively reduce bias effects and improve the biological significance of correlation analysis. Validation of the SEaCorAl algorithm is performed by showing a significant increase in the ability to detect biologically meaningful associations of positive correlations and a significant increase of the modularity of the resulting unbiased correlation network.

A Comprehensive Analysis of Multilayer Community Detection Algorithms for Application to EEG-Based Brain Networks.

Modular organization is an emergent property of brain networks, responsible for shaping communication processes and underpinning brain functioning. Moreover, brain networks are intrinsically multilayer since their attributes can vary across time, subjects, frequency, or other domains. Identifying the modular structure in multilayer brain networks represents a gateway toward a deeper understanding of neural processes underlying cognition. Electroencephalographic (EEG) signals, thanks to their high temporal resolution, can give rise to multilayer networks able to follow the dynamics of brain activity. Despite this potential, the community organization has not yet been thoroughly investigated in brain networks estimated from EEG. Furthermore, at the state of the art, there is still no agreement about which algorithm is the most suitable to detect communities in multilayer brain networks, and a way to test and compare them all under a variety of conditions is lacking. In this work, we perform a comprehensive analysis of three algorithms at the state of the art for multilayer community detection (namely, genLouvain, DynMoga, and FacetNet) as compared with an approach based on the application of a single-layer clustering algorithm to each slice of the multilayer network. We test their ability to identify both steady and dynamic modular structures. We statistically evaluate their performances by means of ad hoc benchmark graphs characterized by properties covering a broad range of conditions in terms of graph density, number of clusters, noise level, and number of layers. The results of this simulation study aim to provide guidelines about the choice of the more appropriate algorithm according to the different properties of the brain network under examination. Finally, as a proof of concept, we show an application of the algorithms to real functional brain networks derived from EEG signals collected at rest with closed and open eyes. The test on real data provided results in agreement with the conclusions of the simulation study and confirmed the feasibility of multilayer analysis of EEG-based brain networks in both steady and dynamic conditions.

The modular organization of brain cortical connectivity across the human lifespan.

The network architecture of the human brain contributes in shaping neural activity, influencing cognitive and behavioral processes. The availability of neuroimaging data across the lifespan allows us to monitor how this architecture reorganizes, influenced by processes like learning, adaptation, maturation, and senescence. Changing patterns in brain connectivity can be analyzed with the tools of network science, which can be used to reveal organizational principles such as modular network topology. The identification of network modules is fundamental, as they parse the brain into coherent sub-systems and allow for both functional integration and segregation among different brain areas. In this work we examined the brain's modular organization by developing an ensemble-based multilayer network approach, allowing us to link changes of structural connectivity patterns to development and aging. We show that modular structure exhibits both linear and nonlinear age-related trends. In the early and late lifespan, communities are more modular, and we track the origins of this high modularity to two different substrates in brain connectivity, linked to the number and the weights of the intra-clusters edges. We also demonstrate that aging leads to a progressive and increasing reconfiguration of modules and a redistribution across hemispheres. Finally, we identify those brain regions that most contribute to network reconfiguration and those that remain more stable across the lifespan.

Molecular networks in Network Medicine: Development and applications.

Network Medicine applies network science approaches to investigate disease pathogenesis. Many different analytical methods have been used to infer relevant molecular networks, including protein-protein interaction networks, correlation-based networks, gene regulatory networks, and Bayesian networks. Network Medicine applies these integrated approaches to Omics Big Data (including genetics, epigenetics, transcriptomics, metabolomics, and proteomics) using computational biology tools and, thereby, has the potential to provide improvements in the diagnosis, prognosis, and treatment of complex diseases. We discuss briefly the types of molecular data that are used in molecular network analyses, survey the analytical methods for inferring molecular networks, and review efforts to validate and visualize molecular networks. Successful applications of molecular network analysis have been reported in pulmonary arterial hypertension, coronary heart disease, diabetes mellitus, chronic lung diseases, and drug development. Important knowledge gaps in Network Medicine include incompleteness of the molecular interactome, challenges in identifying key genes within genetic association regions, and limited applications to human diseases. This article is categorized under: Models of Systems Properties and Processes > Mechanistic Models Translational, Genomic, and Systems Medicine > Translational Medicine Analytical and Computational Methods > Analytical Methods Analytical and Computational Methods > Computational Methods.

Connectivity Significance for Disease Gene Prioritization in an Expanding Universe.

A fundamental topic in network medicine is disease genes prioritization. The underlying hypothesis is that disease genes are organized as modules confined within the interactome. Here, we propose a novel algorithm called DiaBLE (DIAMOnD Background Local Expansion) which is a modified version of DIAMOnD, a successful algorithm based on the concept of connectivity significance. Instead of taking the whole interactome as the background model, DiaBLE considers as gene universe the smallest local expansion of the current seeds set at each iteration step. We show that DiaBLE significantly increases the overall DIAMOnD ranking quality of genes prioritization both in terms of cross-validation and biological consistency. Here, we focus on the two algorithms only since a comparative analysis among gene prioritization methods is beyond the scope of this study. Finally, we briefly discuss the improvement of biological insight provided by DiaBLE for two cancers (head and neck squamous cell carcinoma and kidney renal clear cell carcinoma).

An EEG index of sensorimotor interhemispheric coupling after unilateral stroke: clinical and neurophysiological study.

Brain connectivity has been employed to investigate on post-stroke recovery mechanisms and assess the effect of specific rehabilitation interventions. Changes in interhemispheric coupling after stroke have been related to the extent of damage in the corticospinal tract (CST) and thus, to motor impairment. In this study, we aimed at defining an index of interhemispheric connectivity derived from electroencephalography (EEG), correlated with CST integrity and clinical impairment. Thirty sub-acute stroke patients underwent clinical and neurophysiological evaluation: CST integrity was assessed by Transcranial Magnetic Stimulation and high-density EEG was recorded at rest. Connectivity was assessed by means of Partial Directed Coherence and the normalized Inter-Hemispheric Strength (nIHS) was calculated for each patient and frequency band on the whole network and in three sub-networks relative to the frontal, central (sensorimotor) and occipital areas. Interhemipheric coupling as expressed by nIHS on the whole network was significantly higher in patients with preserved CST integrity in beta and gamma bands. The same index estimated for the three sub-networks showed significant differences only in the sensorimotor area in lower beta, with higher values in patients with preserved CST integrity. The sensorimotor lower beta nIHS showed a significant positive correlation with clinical impairment. We propose an EEG-based connectivity index which is a measure of the interhemispheric cross-talking and correlates with functional motor impairment in subacute stroke patients. Such index could be employed to evaluate the effects of training aimed at re-establishing interhemispheric balance and eventually drive the design of future connectivity-driven rehabilitation interventions.

Investigating Cooperative Behavior in Ecological Settings: An EEG Hyperscanning Study.

The coordinated interactions between individuals are fundamental for the success of the activities in some professional categories. We reported on brain-to-brain cooperative interactions between civil pilots during a simulated flight. We demonstrated for the first time how the combination of neuroelectrical hyperscanning and intersubject connectivity could provide indicators sensitive to the humans' degree of synchronization under a highly demanding task performed in an ecological environment. Our results showed how intersubject connectivity was able to i) characterize the degree of cooperation between pilots in different phases of the flight, and ii) to highlight the role of specific brain macro areas in cooperative behavior. During the most cooperative flight phases pilots showed, in fact, dense patterns of interbrain connectivity, mainly linking frontal and parietal brain areas. On the contrary, the amount of interbrain connections went close to zero in the non-cooperative phase. The reliability of the interbrain connectivity patterns was verified by means of a baseline condition represented by formal couples, i.e. pilots paired offline for the connectivity analysis but not simultaneously recorded during the flight. Interbrain density was, in fact, significantly higher in real couples with respect to formal couples in the cooperative flight phases. All the achieved results demonstrated how the description of brain networks at the basis of cooperation could effectively benefit from a hyperscanning approach. Interbrain connectivity was, in fact, more informative in the investigation of cooperative behavior with respect to established EEG signal processing methodologies applied at a single subject level.

EEG Resting-State Brain Topological Reorganization as a Function of Age.

Resting state connectivity has been increasingly studied to investigate the effects of aging on the brain. A reduced organization in the communication between brain areas was demonstrated by combining a variety of different imaging technologies (fMRI, EEG, and MEG) and graph theory. In this paper, we propose a methodology to get new insights into resting state connectivity and its variations with age, by combining advanced techniques of effective connectivity estimation, graph theoretical approach, and classification by SVM method. We analyzed high density EEG signals recorded at rest from 71 healthy subjects (age: 20-63 years). Weighted and directed connectivity was computed by means of Partial Directed Coherence based on a General Linear Kalman filter approach. To keep the information collected by the estimator, weighted and directed graph indices were extracted from the resulting networks. A relation between brain network properties and age of the subject was found, indicating a tendency of the network to randomly organize increasing with age. This result is also confirmed dividing the whole population into two subgroups according to the age (young and middle-aged adults): significant differences exist in terms of network organization measures. Classification of the subjects by means of such indices returns an accuracy greater than 80%.

Brain-computer interface boosts motor imagery practice during stroke recovery.

OBJECTIVE: Motor imagery (MI) is assumed to enhance poststroke motor recovery, yet its benefits are debatable. Brain-computer interfaces (BCIs) can provide instantaneous and quantitative measure of cerebral functions modulated by MI. The efficacy of BCI-monitored MI practice as add-on intervention to usual rehabilitation care was evaluated in a randomized controlled pilot study in subacute stroke patients. METHODS: Twenty-eight hospitalized subacute stroke patients with severe motor deficits were randomized into 2 intervention groups: 1-month BCI-supported MI training (BCI group, n = 14) and 1-month MI training without BCI support (control group; n = 14). Functional and neurophysiological assessments were performed before and after the interventions, including evaluation of the upper limbs by Fugl-Meyer Assessment (FMA; primary outcome measure) and analysis of oscillatory activity and connectivity at rest, based on high-density electroencephalographic (EEG) recordings. RESULTS: Better functional outcome was observed in the BCI group, including a significantly higher probability of achieving a clinically relevant increase in the FMA score (p < 0.03). Post-BCI training changes in EEG sensorimotor power spectra (ie, stronger desynchronization in the alpha and beta bands) occurred with greater involvement of the ipsilesional hemisphere in response to MI of the paralyzed trained hand. Also, FMA improvements (effectiveness of FMA) correlated with the changes (ie, post-training increase) at rest in ipsilesional intrahemispheric connectivity in the same bands (p < 0.05). INTERPRETATION: The introduction of BCI technology in assisting MI practice demonstrates the rehabilitative potential of MI, contributing to significantly better motor functional outcomes in subacute stroke patients with severe motor impairments.