Searching COVID-19 clinical research using graphical abstracts (preprint)

Objective. Graphical abstracts are small graphs of concepts that visually summarize the main findings of scientific articles. While graphical abstracts are customarily used in scientific publications to anticipate and summarize their main results, we propose them as a means for expressing graph searches over existing literature. Materials and methods. We consider the COVID-19 Open Research Dataset (CORD-19), a corpus of more than one million abstracts; each of them is described as a graph of co-occurring ontological terms, selected from the Unified Medical Language System (UMLS) and the Ontology of Coronavirus Infectious Disease (CIDO). Graphical abstracts are also expressed as graphs of ontological terms, possibly augmented by utility terms describing their interactions (e.g., "associated with", "increases", "induces"). We build a co-occurrence network of concepts mentioned in the corpus; we then identify the best matches of graphical abstracts on the network. We exploit graph database technology and shortest-path queries. Results. We build a large co-occurrence network, consisting of 128,249 entities and 47,198,965 relationships. A well-designed interface allows users to explore the network by formulating or adapting queries in the form of an abstract; it produces a bibliography of publications, globally ranked; each publication is further associated with the specific parts of the abstract that it explains, thereby allowing the user to understand each aspect of the matching. Discussion and Conclusion. Our approach supports the process of scientific hypothesis formulation and evidence search; it can be reapplied to any scientific domain, although our mastering of UMLS makes it most suited to clinical domains.

Exploring the evolution of research topics during the COVID-19 pandemic (preprint)

The COVID-19 pandemic has changed the research agendas of most scientific communities, resulting in an overwhelming production of research articles in a variety of domains, including medicine, virology, epidemiology, economy, psychology, and so on. Several open-access corpora and literature hubs were established; among them, the COVID-19 Open Research Dataset (CORD-19) has systematically gathered scientific contributions for 2.5 years, by collecting and indexing over one million articles. Here, we present the CORD-19 Topic Visualizer (CORToViz), a method and associated visualization tool for inspecting the CORD-19 textual corpus of scientific abstracts. Our method is based upon a careful selection of up-to-date technologies (including large language models), resulting in an architecture for clustering articles along orthogonal dimensions and extraction techniques for temporal topic mining. Topic inspection is supported by an interactive dashboard, providing fast, one-click visualization of topic contents as word clouds and topic trends as time series, equipped with easy-to-drive statistical testing for analyzing the significance of topic emergence along arbitrarily selected time windows. The processes of data preparation and results visualization are completely general and virtually applicable to any corpus of textual documents - thus suited for effective adaptation to other contexts.

PG-Triggers: Triggers for Property Graphs (preprint)

Graph databases are emerging as the leading data management technology for storing large knowledge graphs; significant efforts are ongoing to produce new standards (such as the Graph Query Language, GQL), as well as enrich them with properties, types, schemas, and keys. In this article, we introduce PG-Triggers, a complete proposal for adding triggers to Property Graphs, along the direction marked by the SQL3 Standard. We define the syntax and semantics of PG-Triggers and then illustrate how they can be implemented on top of Neo4j, one of the most popular graph databases. In particular, we introduce a syntax-directed translation from PG-Triggers into Neo4j, which makes use of the so-called {\it APOC triggers}; APOC is a community-contributed library for augmenting the Cypher query language supported by Neo4j. We also cover Memgraph, and show that our approach applies to this system in a similar way. We illustrate the use of PG-Triggers through a life science application inspired by the COVID-19 pandemic. The main objective of this article is to introduce an active database standard for graph databases as a first-class citizen at a time when reactive graph management is in its infancy, so as to minimize the conversion efforts towards a full-fledged standard proposal.

Data-driven recombination detection in viral genomes (preprint)

Recombination is a key molecular mechanism for the evolution and adaptation of viruses. The first recombinant SARS-CoV-2 genomes were recognized in 2021; as of today, more than seventy SARS-CoV-2 lineages are designated as recombinant. In the wake of the COVID-19 pandemic, several methods for detecting recombination in SARS-CoV-2 have been proposed; however, none could faithfully reproduce manual analyses by experts in the field. We hereby present RecombinHunt, a novel, automated method for the identification of recombinant genomes purely based on a data-driven approach. RecombinHunt compares favorably with other state-of-the-art methods and recognizes recombinant SARS-CoV-2 genomes (or lineages) with one or two breakpoints with high accuracy, within reduced turn-around times and small discrepancies with respect to the expert manually-curated standard nomenclature. Strikingly, applied to the complete collection of viral sequences from the recent monkeypox epidemic, RecombinHunt identifies recombinant viral genomes in high concordance with manually curated analyses by experts, suggesting that our approach is robust and can be applied to any epidemic/pandemic virus. Although RecombinHunt does not substitute manual expert curation based on phylogenetic analysis, we believe that our method represents a breakthrough for the detection of recombinant viral lineages in pandemic/epidemic scenarios.

Analysis of amino acid change dynamics reveals SARS-CoV-2 variant emergence (preprint)

Since its emergence in late 2019, the diffusion of SARS-CoV-2 is associated with the evolution of its viral genome. The co-occurrence of specific amino acid changes, collectively named 'virus variant', requires scrutiny (as variants may hugely impact the agent's transmission, pathogenesis, or antigenicity); variant evolution is studied using phylogenetics. Yet, never has this problem been tackled by digging into data with ad hoc analysis techniques. Here we show that the emergence of variants can in fact be traced through data-driven methods, further capitalizing on the value of large collections of SARS-CoV-2 sequences. For all countries with sufficient data, we compute weekly counts of amino acid changes, unveil time-varying clusters of changes with similar - rapidly growing - dynamics, and then follow their evolution. Our method succeeds in timely associating clusters to variants of interest/concern, provided their change composition is well characterized. This allows us to detect variants' emergence, rise, peak, and eventual decline under competitive pressure of another variant. Our early warning system, exclusively relying on deposited sequences, shows the power of big data in this context, and concurs to calling for the wide spreading of public SARS-CoV-2 genome sequencing for improved surveillance and control of the COVID-19 pandemic.

Post-Mendelian genetic model in COVID-19 (preprint)

Host genetics is an emerging theme in COVID-19 and few common polymorphisms and some rare variants have been identified, either by GWAS or candidate gene approach, respectively. However, an organic model is still missing. Here, we propose a new model that takes into account common and rare germline variants applied in a cohort of 1,300 Italian SARS-CoV-2 positive individuals. Ordered logistic regression of clinical WHO grading on sex and age was used to obtain a binary phenotypic classification. Genetic variability from WES was synthesized in several boolean representations differentiated according to allele frequencies and genotype effect. LASSO logistic regression was used for extracting relevant genes. We defined about 100 common driver polymorphisms corresponding to classical "threshold model". Extracted genes were demonstrated to be gender specific. Stochastic rare more penetrant events on about additional 100 extracted genes, when occurred in a medium or severe background (common within the family), simulate Mendelian inheritance in 14% of subjects (having only 1 mutation) or oligogenic inheritance (in 10% having 2 mutations, in 11% having 3 mutations, etc). The combined effect of common and rare results can be described as an integrated polygenic score computed as: (nseverity - nmildness) + F (mseverity - mmildness) where n is the number of common driver genes, m is the number of driver rare variants and F is a factor for appropriately weighing the more powerful rare variants. We called the model "post-Mendelian". The model well describes the cohort, and patients are clustered in severe or mild by the integrated polygenic scores, the F factor being calibrated around 2, with a prediction capacity of 65% in males and 70% in females. In conclusion, this is the first comprehensive model interpreting host genetics in a holistic post-Mendelian manner. Further validations are needed in order to consolidate and refine the model which however holds true in thousands of SARS-CoV-2 Italian subjects.

ViruSurf: an integrated database to investigate viral sequences (preprint)

ABSTRACT ViruSurf, available at http://gmql.eu/virusurf/ , is a large public database of viral sequences and integrated and curated metadata from heterogeneous sources (GenBank, COG-UK and NMDC); it also exposes computed nucleotide and amino acid variants, called from original sequences. A GISAID-specific ViruSurf database, available at http://gmql.eu/virusurf_gisaid/ , offers a subset of these functionalities. Given the current pandemic outbreak, SARS-CoV-2 data are collected from the four sources; but ViruSurf contains other virus species harmful to humans, including SARS-CoV, MERS-CoV, Ebola, and Dengue. The database is centered on sequences, described from their biological, technological, and organizational dimensions. In addition, the analytical dimension characterizes the sequence in terms of its annotations and variants. The web interface enables expressing complex search queries in a simple way; arbitrary search queries can freely combine conditions on attributes from the four dimensions, extracting the resulting sequences. Several example queries on the database confirm and possibly improve results from recent research papers; results can be recomputed over time and upon selected populations. Effective search over large and curated sequence data may enable faster responses to future threats that could arise from new viruses.

A Review on Viral Data Sources and Integration Methods for COVID-19 Mitigation (preprint)

With the outbreak of the COVID-19 disease, the research community is producing unprecedented efforts dedicated to better understand and mitigate the affects of the pandemic. In this context, we review the data integration efforts required for accessing and searching genome sequences and metadata of SARS-CoV2, the virus responsible for the COVID-19 disease, which have been deposited into the most important repositories of viral sequences. Organizations that were already present in the virus domain are now dedicating special interest to the emergence of COVID-19 pandemics, by emphasizing specific SARS-CoV2 data and services. At the same time, novel organizations and resources were born in this critical period to serve specifically the purposes of COVID-19 mitigation, while setting the research ground for contrasting possible future pandemics. Accessibility and integration of viral sequence data, possibly in conjunction with the human host genotype and clinical data, are paramount to better understand the COVID-19 disease and mitigate its effects.

Employing a Systematic Approach to Biobanking and Analyzing Genetic and Clinical Data for Advancing COVID-19 Research (preprint)

Within the GEN-COVID Multicenter Study, biospecimens from more than 1,000 SARS-CoV-2-positive individuals have thus far been collected in the GEN-COVID Biobank (GCB). Sample types include whole blood, plasma, serum, leukocytes, and DNA. The GCB links samples to detailed clinical data available in the GEN-COVID Patient Registry (GCPR). It includes hospitalized patients (74.25%), broken down into intubated, treated by CPAP-biPAP, treated with O2 supplementation, and without respiratory support (9.5%, 18.4%, 31.55% and 14.8, respectively); and non-hospitalized subjects (25.75%), either pauci- or asymptomatic. More than 150 clinical patient-level data fields have been collected and binarized for further statistics according to the organs/systems primarily affected by COVID-19: heart, liver, pancreas, kidney, chemosensors, innate or adaptive immunity, and clotting system. Hierarchical Clustering analysis identified five main clinical categories: i) severe multisystemic failure with either thromboembolic or pancreatic variant; ii) cytokine storm type, either severe with liver involvement or moderate; iii) moderate heart type, either with or without liver damage; iv) moderate multisystemic involvement, either with or without liver damage; v) mild, either with or without hyposmia. GCB and GCPR are further linked to the GEN-COVID Genetic Data Repository (GCGDR), which includes data from Whole Exome Sequencing and high-density SNP genotyping. The data are available for sharing through the Network for Italian Genomes, found within the COVID-19 dedicated section. The study objective is to systematize this comprehensive data collection and begin identifying multi-organ involvement in COVID-19, defining genetic parameters for infection susceptibility within the population and mapping genetically COVID-19 severity and clinical complexity among patients.

Empowering Virus Sequences Research through Conceptual Modeling (preprint)

The pandemic outbreak of the coronavirus disease has attracted attention towards the genetic mechanisms of viruses. We hereby present the Viral Conceptual Model (VCM), centered on the virus sequence and described from four perspectives: biological (virus type and hosts/sample), analytical (annotations and variants), organizational (sequencing project) and technical (experimental technology). VCM is inspired by GCM, our previously developed Genomic Conceptual Model, but it introduces many novel concepts, as viral sequences significantly differ from human genomes. When applied to SARS-CoV2 virus, complex conceptual queries upon VCM are able to replicate the search results of recent articles, hence demonstrating huge potential in supporting virology research. In addition to VCM, we also illustrate the data dictionary for patients phenotype used by the COVID-19 Host Genetic Initiative. Our effort is part of a broad vision: availability of conceptual models for both human genomics and viruses will provide important opportunities for research, especially if interconnected by the same human being, playing the role of virus host as well as provider of genomic and phenotype information.