Reconstructing brain functional networks through identifiability and deep learning.

We propose a novel approach for the reconstruction of functional networks representing brain dynamics based on the idea that the coparticipation of two brain regions in a common cognitive task should result in a drop in their identifiability, or in the uniqueness of their dynamics. This identifiability is estimated through the score obtained by deep learning models in supervised classification tasks and therefore requires no a priori assumptions about the nature of such coparticipation. The method is tested on EEG recordings obtained from Alzheimer's and Parkinson's disease patients, and matched healthy volunteers, for eyes-open and eyes-closed resting-state conditions, and the resulting functional networks are analysed through standard topological metrics. Both groups of patients are characterised by a reduction in the identifiability of the corresponding EEG signals, and by differences in the patterns that support such identifiability. Resulting functional networks are similar, but not identical to those reconstructed by using a correlation metric. Differences between control subjects and patients can be observed in network metrics like the clustering coefficient and the assortativity in different frequency bands. Differences are also observed between eyes open and closed conditions, especially for Parkinson's disease patients.

How representative are air transport functional complex networks? A quantitative validation.

Functional networks have emerged as powerful instruments to characterize the propagation of information in complex systems, with applications ranging from neuroscience to climate and air transport. In spite of their success, reliable methods for validating the resulting structures are still missing, forcing the community to resort to expert knowledge or simplified models of the system's dynamics. We here propose the use of a real-world problem, involving the reconstruction of the structure of flights in the US air transport system from the activity of individual airports, as a way to explore the limits of such an approach. While the true connectivity is known and is, therefore, possible to provide a quantitative benchmark, this problem presents challenges commonly found in other fields, including the presence of non-stationarities and observational noise, and the limitedness of available time series. We explore the impact of elements like the specific functional metric employed, the way of detrending the time series, or the size of the reconstructed system and discuss how the conclusions here drawn could have implications for similar analyses in neuroscience.

Randomized phase II clinical trial of ruxolitinib plus simvastatin in COVID19 clinical outcome and cytokine evolution.

Background: Managing the inflammatory response to SARS-Cov-2 could prevent respiratory insufficiency. Cytokine profiles could identify cases at risk of severe disease. Methods: We designed a randomized phase II clinical trial to determine whether the combination of ruxolitinib (5 mg twice a day for 7 days followed by 10 mg BID for 7 days) plus simvastatin (40 mg once a day for 14 days), could reduce the incidence of respiratory insufficiency in COVID-19. 48 cytokines were correlated with clinical outcome. Participants: Patients admitted due to COVID-19 infection with mild disease. Results: Up to 92 were included. Mean age was 64 ± 17, and 28 (30%) were female. 11 (22%) patients in the control arm and 6 (12%) in the experimental arm reached an OSCI grade of 5 or higher (p = 0.29). Unsupervised analysis of cytokines detected two clusters (CL-1 and CL-2). CL-1 presented a higher risk of clinical deterioration vs CL-2 (13 [33%] vs 2 [6%] cases, p = 0.009) and death (5 [11%] vs 0 cases, p = 0.059). Supervised Machine Learning (ML) analysis led to a model that predicted patient deterioration 48h before occurrence with a 85% accuracy. Conclusions: Ruxolitinib plus simvastatin did not impact the outcome of COVID-19. Cytokine profiling identified patients at risk of severe COVID-19 and predicted clinical deterioration. Trial registration: https://clinicaltrials.gov/, identifier NCT04348695.

On the complementarity of ordinal patterns-based entropy and time asymmetry metrics.

Entropy and time asymmetry are two intertwined aspects of a system's dynamics, with the production of entropy marking a clear direction in the temporal dimension. In the last few years, metrics to quantify both properties in time series have been designed around the same concept, i.e., the use of ordinal patterns. In spite of this, the relationship between these two families of metrics is yet not well understood. In this contribution, we study this problem by constructing an entropy-time asymmetry plane and evaluating it on a large set of synthetic and real-world time series. We show how the two metrics can at times behave independently, the main reason being the presence of patterns with turning points; due to this, they yield complementary information about the underlying systems, and they have different discriminating performance.

Continuous ordinal patterns: Creating a bridge between ordinal analysis and deep learning.

We introduce a generalization of the celebrated ordinal pattern approach for the analysis of time series, in which these are evaluated in terms of their distance to ordinal patterns defined in a continuous way. This allows us to naturally incorporate information about the local amplitude of the data and to optimize the ordinal pattern(s) to the problem under study. This last element represents a novel bridge between standard ordinal analysis and deep learning, allowing the achievement of results comparable to the latter in real-world classification problems while also retaining the conceptual simplicity, computational efficiency, and easy interpretability of the former. We test this through the use of synthetic time series, generated by standard chaotic maps and dynamical models, data sets representing brain activity in health and schizophrenia, and the dynamics of delays in the European air transport system. We further show how the continuous ordinal patterns can be used to assess other aspects of the dynamics, like time irreversibility.

Understanding small-scale COVID-19 transmission dynamics with the Granger causality test.

Mobility patterns have been broadly studied and deeply altered due to the coronavirus disease (COVID-19). In this paper, we study small-scale COVID-19 transmission dynamics in the city of Valencia and the potential role of subway stations and healthcare facilities in this transmission. A total of 2,398 adult patients were included in the analysis. We study the temporal evolution of the pandemic during the first six months at a small-area level. Two Voronoi segmentations of the city (based on the location of subway stations and healthcare facilities) have been considered, and we have applied the Granger causality test at the Voronoi cell level, considering both divisions of the study area. Considering the output of this approach, the so-called 'donor stations' are subway stations that have sent more connections than they have received and are mainly located in interchanger stations. The transmission in primary healthcare facilities showed a heterogeneous pattern. Given that subway interchange stations receive many cases from other regions of the city, implementing isolation measures in these areas might be beneficial for the reduction of transmission.

Gait analysis under the lens of statistical physics.

Human gait is a fundamental activity, essential for the survival of the individual, and an emergent property of the interactions between complex physical and cognitive processes. Gait is altered in many situations, due both to external constraints, as e.g. paced walk, and to physical and neurological pathologies. Its study is therefore important as a way of improving the quality of life of patients, but also as a door to understanding the inner working of the human nervous system. In this review we explore how four statistical physics concepts have been used to characterise normal and pathological gait: entropy, maximum Lyapunov exponent, multi-fractal analysis and irreversibility. Beyond some basic definitions, we present the main results that have been obtained in this field, as well as a discussion of the main limitations researchers have dealt and will have to deal with. We finally conclude with some biomedical considerations and avenues for further development.

Telling functional networks apart using ranked network features stability.

Over the past few years, it has become standard to describe brain anatomical and functional organisation in terms of complex networks, wherein single brain regions or modules and their connections are respectively identified with network nodes and the links connecting them. Often, the goal of a given study is not that of modelling brain activity but, more basically, to discriminate between experimental conditions or populations, thus to find a way to compute differences between them. This in turn involves two important aspects: defining discriminative features and quantifying differences between them. Here we show that the ranked dynamical stability of network features, from links or nodes to higher-level network properties, discriminates well between healthy brain activity and various pathological conditions. These easily computable properties, which constitute local but topographically aspecific aspects of brain activity, greatly simplify inter-network comparisons and spare the need for network pruning. Our results are discussed in terms of microstate stability. Some implications for functional brain activity are discussed.

A Fast Transform for Brain Connectivity Difference Evaluation.

Anatomical and dynamical connectivity are essential to healthy brain function. However, quantifying variations in connectivity across conditions or between patient populations and appraising their functional significance are highly non-trivial tasks. Here we show that link ranking differences induce specific geometries in a convenient auxiliary space that are often easily recognisable at mere eye inspection. Link ranking can also provide fast and reliable criteria for network reconstruction parameters for which no theoretical guideline has been proposed.

Algorithmic Approaches for Assessing Irreversibility in Time Series: Review and Comparison.

The assessment of time irreversibility, i.e., of the lack of invariance of the statistical properties of a system under the operation of time reversal, is a topic steadily gaining attention within the research community. Irreversible dynamics have been found in many real-world systems, with alterations being connected to, for instance, pathologies in the human brain, heart and gait, or to inefficiencies in financial markets. Assessing irreversibility in time series is not an easy task, due to its many aetiologies and to the different ways it manifests in data. It is thus not surprising that several numerical methods have been proposed in the last decades, based on different principles and with different applications in mind. In this contribution we review the most important algorithmic solutions that have been proposed to test the irreversibility of time series, their underlying hypotheses, computational and practical limitations, and their comparative performance. We further provide an open-source software library that includes all tests here considered. As a final point, we show that "one size does not fit all", as tests yield complementary, and sometimes conflicting views to the problem; and discuss some future research avenues.

Classifying diseases by using biological features to identify potential nosological models.

Established nosological models have provided physicians an adequate enough classification of diseases so far. Such systems are important to correctly identify diseases and treat them successfully. However, these taxonomies tend to be based on phenotypical observations, lacking a molecular or biological foundation. Therefore, there is an urgent need to modernize them in order to include the heterogeneous information that is produced in the present, as could be genomic, proteomic, transcriptomic and metabolic data, leading this way to more comprehensive and robust structures. For that purpose, we have developed an extensive methodology to analyse the possibilities when it comes to generate new nosological models from biological features. Different datasets of diseases have been considered, and distinct features related to diseases, namely genes, proteins, metabolic pathways and genetical variants, have been represented as binary and numerical vectors. From those vectors, diseases distances have been computed on the basis of several metrics. Clustering algorithms have been implemented to group diseases, generating different models, each of them corresponding to the distinct combinations of the previous parameters. They have been evaluated by means of intrinsic metrics, proving that some of them are highly suitable to cover new nosologies. One of the clustering configurations has been deeply analysed, demonstrating its quality and validity in the research context, and further biological interpretations have been made. Such model was particularly generated by OPTICS clustering algorithm, by studying the distance between diseases based on gene sharedness and following cosine index metric. 729 clusters were formed in this model, which obtained a Silhouette coefficient of 0.43.

Assessing time series irreversibility through micro-scale trends.

Time irreversibility, defined as the lack of invariance of the statistical properties of a system or time series under the operation of time reversal, has received increasing attention during the last few decades, thanks to the information it provides about the mechanisms underlying the observed dynamics. Following the need of analyzing real-world time series, many irreversibility metrics and tests have been proposed, each one associated with different requirements in terms of, e.g., minimum time series length or computational cost. We here build upon previously proposed tests based on the concept of permutation patterns but deviating from them through the inclusion of information about the amplitude of the signal and how this evolves over time. We show, by means of synthetic time series, that the results yielded by this method are complementary to the ones obtained by using permutation patterns alone, thus suggesting that "one irreversibility metric does not fit all." We further apply the proposed metric to the analysis of two real-world data sets.

Simplifying functional network representation and interpretation through causality clustering.

Functional networks, i.e. networks representing the interactions between the elements of a complex system and reconstructed from the observed elements' dynamics, are becoming a fundamental tool to unravel the structures created by the movement of information in systems like the human brain. They also present drawbacks, one of the most important being the inherent difficulty in representing and interpreting the resulting structures for large number of nodes and links. I here propose a causality clustering approach, based on grouping nodes into clusters according to their similarity in the overall information dynamics, the latter one being measured by a causality metric. The whole system can then arbitrarily be simplified, with nodes being grouped in e.g. sources, brokers and sinks of information. The advantages and limitations of the proposed approach are discussed using a set of synthetic and real-world data sets, the latter ones representing two neuroscience and technological problems.

Statistical and Machine Learning Link Selection Methods for Brain Functional Networks: Review and Comparison.

Network-based representations have introduced a revolution in neuroscience, expanding the understanding of the brain from the activity of individual regions to the interactions between them. This augmented network view comes at the cost of high dimensionality, which hinders both our capacity of deciphering the main mechanisms behind pathologies, and the significance of any statistical and/or machine learning task used in processing this data. A link selection method, allowing to remove irrelevant connections in a given scenario, is an obvious solution that provides improved utilization of these network representations. In this contribution we review a large set of statistical and machine learning link selection methods and evaluate them on real brain functional networks. Results indicate that most methods perform in a qualitatively similar way, with NBS (Network Based Statistics) winning in terms of quantity of retained information, AnovaNet in terms of stability and ExT (Extra Trees) in terms of lower computational cost. While machine learning methods are conceptually more complex than statistical ones, they do not yield a clear advantage. At the same time, the high heterogeneity in the set of links retained by each method suggests that they are offering complementary views to the data. The implications of these results in neuroscience tasks are finally discussed.

Trends in Incidence and Transmission Patterns of COVID-19 in Valencia, Spain.

Importance: Limited information on the transmission and dynamics of SARS-CoV-2 at the city scale is available. Objective: To describe the local spread of SARS-CoV-2 in Valencia, Spain. Design, Setting, and Participants: This single-center epidemiological cohort study of patients with SARS-CoV-2 was performed at University General Hospital in Valencia (population in the hospital catchment area, 364 000), a tertiary hospital. The study included all consecutive patients with COVID-19 isolated at home from the start of the COVID-19 pandemic on February 19 until August 31, 2020. Exposures: Cases of SARS-CoV-2 infection confirmed by the presence of IgM antibodies or a positive polymerase chain reaction test result on a nasopharyngeal swab were included. Cases in which patients with negative laboratory results met diagnostic and clinical criteria were also included. Main Outcomes and Measures: The primary outcome was the characterization of dissemination patterns and connections among the 20 neighborhoods of Valencia during the outbreak. To recreate the transmission network, the inbound and outbound connections were studied for each region, and the relative risk of infection was estimated. Results: In total, 2646 patients were included in the analysis. The mean (SD) age was 45.3 (22.5) years; 1203 (46%) were male and 1442 (54%) were female (data were missing for 1); and the overall mortality was 3.7%. The incidence of SARS-CoV-2 cases was higher in neighborhoods with higher household income (ß2 [for mean income per household] = 0.197; 95% CI, 0.057-0.351) and greater population density (ß1 [inhabitants per km2] = 0.228; 95% CI, 0.085-0.387). Correlations with meteorological variables were not statistically significant. Neighborhood 3, where the hospital and testing facility were located, had the most outbound connections (14). A large residential complex close to the city (neighborhood 20) had the fewest connections (0 outbound and 2 inbound). Five geographically unconnected neighborhoods were of strategic importance in disrupting the transmission network. Conclusions and Relevance: This study of local dissemination of SARS-COV-2 revealed nonevident transmission patterns between geographically unconnected areas. The results suggest that tailor-made containment measures could reduce transmission and that hospitals, including testing facilities, play a crucial role in disease transmission. Consequently, the local dynamics of SARS-CoV-2 spread might inform the strategic lockdown of specific neighborhoods to stop the contagion and avoid a citywide lockdown.

DisMaNET: A network-based tool to cross map disease vocabularies.

BACKGROUND AND OBJECTIVES: The growing integration of healthcare sources is improving our understanding of diseases. Cross-mapping resources such as UMLS play a very important role in this area, but their coverage is still incomplete. With the aim to facilitate the integration and interoperability of biological, clinical and literary sources in studies of diseases, we built DisMaNET, a system to cross-map terms from disease vocabularies by leveraging the power and interpretability of network analysis. METHODS: First, we collected and normalized data from 8 disease vocabularies and mapping sources to generate our datasets. Next, we built DisMaNET by integrating the generated datasets into a Neo4j graph database. Then we exploited the query mechanisms of Neo4j to cross-map disease terms of different vocabularies with a relevance score metric and contrasted the results with some state-of-the-art solutions. Finally, we made our system publicly available for its exploitation and evaluation both through a graphical user interface and REST APIs. RESULTS: DisMaNET contains almost half a million nodes and near nine hundred thousand edges, including hierarchical and mapping relationships. Its query capabilities enabled the detection of connections between disease vocabularies that are not present in major mapping sources such as UMLS and the Disease Ontology, even for rare diseases. Furthermore, DisMaNET was capable of obtaining more than 80% of the mappings with UMLS reported in MonDO and DisGeNET, and it was successfully exploited to resolve the missing mappings in the DISNET project. CONCLUSIONS: DisMaNET is a powerful, intuitive and publicly available system to cross-map terms from different disease vocabularies. Our study proves that it is a competitive alternative to existing mapping systems, incorporating the potential of network analysis and the interpretability of the results through a visual interface as its main advantages. Expansion with new sources, versioning and the improvement of the search and scoring algorithms are envisioned as future lines of work.

Leveraging network analysis to evaluate biomedical named entity recognition tools.

The ever-growing availability of biomedical text sources has resulted in a boost in clinical studies based on their exploitation. Biomedical named-entity recognition (bio-NER) techniques have evolved remarkably in recent years and their application in research is increasingly successful. Still, the disparity of tools and the limited available validation resources are barriers preventing a wider diffusion, especially within clinical practice. We here propose the use of omics data and network analysis as an alternative for the assessment of bio-NER tools. Specifically, our method introduces quality criteria based on edge overlap and community detection. The application of these criteria to four bio-NER solutions yielded comparable results to strategies based on annotated corpora, without suffering from their limitations. Our approach can constitute a guide both for the selection of the best bio-NER tool given a specific task, and for the creation and validation of novel approaches.

Principles and open questions in functional brain network reconstruction.

Graph theory is now becoming a standard tool in system-level neuroscience. However, endowing observed brain anatomy and dynamics with a complex network representation involves often covert theoretical assumptions and methodological choices which affect the way networks are reconstructed from experimental data, and ultimately the resulting network properties and their interpretation. Here, we review some fundamental conceptual underpinnings and technical issues associated with brain network reconstruction, and discuss how their mutual influence concurs in clarifying the organization of brain function.

An Early Stage Researcher's Primer on Systems Medicine Terminology.

Background: Systems Medicine is a novel approach to medicine, that is, an interdisciplinary field that considers the human body as a system, composed of multiple parts and of complex relationships at multiple levels, and further integrated into an environment. Exploring Systems Medicine implies understanding and combining concepts coming from diametral different fields, including medicine, biology, statistics, modeling and simulation, and data science. Such heterogeneity leads to semantic issues, which may slow down implementation and fruitful interaction between these highly diverse fields. Methods: In this review, we collect and explain more than100 terms related to Systems Medicine. These include both modeling and data science terms and basic systems medicine terms, along with some synthetic definitions, examples of applications, and lists of relevant references. Results: This glossary aims at being a first aid kit for the Systems Medicine researcher facing an unfamiliar term, where he/she can get a first understanding of them, and, more importantly, examples and references for digging into the topic.