Identification of ADME genes polymorphic variants linked to trastuzumab-induced cardiotoxicity in breast cancer patients: Case series of mono-institutional experience.

BACKGROUND: Long-term survival induced by anticancer treatments discloses emerging frailty among breast cancer (BC) survivors. Trastuzumab-induced cardiotoxicity (TIC) is reported in at least 5% of HER2+BC patients. However, TIC mechanism remains unclear and predictive genetic biomarkers are still lacking. Interaction between systemic inflammation, cytokine release and ADME genes in cancer patients might contribute to explain mechanisms underlying individual susceptibility to TIC and drug response variability. We present a single institution case series to investigate the potential role of genetic variants in ADME genes in HER2+BC patients TIC experienced. METHODS: We selected data related to 40 HER2+ BC patients undergone to DMET genotyping of ADME constitutive variant profiling, with the aim to prospectively explore their potential role in developing TIC. Only 3 patients ("case series"), who experienced TIC, were compared to 37 "control group" matched patients cardiotoxicity-sparing. All patients underwent to left ventricular ejection fraction (LVEF) evaluation at diagnosis and during anti-HER2 therapy. Each single probe was clustered to detect SNPs related to cardiotoxicity. RESULTS: In this retrospective analysis, our 3 cases were homogeneous in terms of clinical-pathological characteristics, trastuzumab-based treatment and LVEF decline. We identified 9 polymorphic variants in 8 ADME genes (UGT1A1, UGT1A6, UGT1A7, UGT2B15, SLC22A1, CYP3A5, ABCC4, CYP2D6) potentially associated with TIC. CONCLUSION: Real-world TIC incidence is higher compared to randomized clinical trials and biomarkers with potential predictive value aren't available. Our preliminary data, as proof of concept, could suggest a predictive role of pharmacogenomic approach in the identification of cardiotoxicity risk biomarkers for anti-HER2 treatment.

Genetic Biomarkers of Sorafenib Response in Patients with Hepatocellular Carcinoma.

The identification of biomarkers for predicting inter-individual sorafenib response variability could allow hepatocellular carcinoma (HCC) patient stratification. SNPs in angiogenesis- and drug absorption, distribution, metabolism, and excretion (ADME)-related genes were evaluated to identify new potential predictive biomarkers of sorafenib response in HCC patients. Five known SNPs in angiogenesis-related genes, including VEGF-A, VEGF-C, HIF-1a, ANGPT2, and NOS3, were investigated in 34 HCC patients (9 sorafenib responders and 25 non-responders). A subgroup of 23 patients was genotyped for SNPs in ADME genes. A machine learning classifier method was used to discover classification rules for our dataset. We found that only the VEGF-A (rs2010963) C allele and CC genotype were significantly associated with sorafenib response. ADME-related gene analysis identified 10 polymorphic variants in ADH1A (rs6811453), ADH6 (rs10008281), SULT1A2/CCDC101 (rs11401), CYP26A1 (rs7905939), DPYD (rs2297595 and rs1801265), FMO2 (rs2020863), and SLC22A14 (rs149738, rs171248, and rs183574) significantly associated with sorafenib response. We have identified a genetic signature of predictive response that could permit non-responder/responder patient stratification. Angiogenesis- and ADME-related genes correlation was confirmed by cumulative genetic risk score and network and pathway enrichment analysis. Our findings provide a proof of concept that needs further validation in follow-up studies for HCC patient stratification for sorafenib prescription.

Multilayer network alignment based on topological assessment via embeddings.

BACKGROUND: Network graphs allow modelling the real world objects in terms of interactions. In a multilayer network, the interactions are distributed over layers (i.e., intralayer and interlayer edges). Network alignment (NA) is a methodology that allows mapping nodes between two or multiple given networks, by preserving topologically similar regions. For instance, NA can be applied to transfer knowledge from one biological species to another. In this paper, we present DANTEml, a software tool for the Pairwise Global NA (PGNA) of multilayer networks, based on topological assessment. It builds its own similarity matrix by processing the node embeddings computed from two multilayer networks of interest, to evaluate their topological similarities. The proposed solution can be used via a user-friendly command line interface, also having a built-in guided mode (step-by-step) for defining input parameters. RESULTS: We investigated the performance of DANTEml based on (i) performance evaluation on synthetic multilayer networks, (ii) statistical assessment of the resulting alignments, and (iii) alignment of real multilayer networks. DANTEml over performed a method that does not consider the distribution of nodes and edges over multiple layers by 1193.62%, and a method for temporal NA by 25.88%; we also performed the statistical assessment, which corroborates the significance of its own node mappings. In addition, we tested the proposed solution by using a real multilayer network in presence of several levels of noise, in accordance with the same outcome pursued for the NA on our dataset of synthetic networks. In this case, the improvement is even more evident: +4008.75% and +111.72%, compared to a method that does not consider the distribution of nodes and edges over multiple layers and a method for temporal NA, respectively. CONCLUSIONS: DANTEml is a software tool for the PGNA of multilayer networks based on topological assessment, that is able to provide effective alignments both on synthetic and real multi layer networks, of which node mappings can be validated statistically. Our experimentation reported a high degree of reliability and effectiveness for the proposed solution.

Advances and challenges in Bioinformatics and Biomedical Engineering: IWBBIO 2020.

This Supplement issue, presents five research articles which are distributed, mainly due to the subject they address, from the 8th International Work-Conference on Bioinformatics and Biomedical Engineering (IWBBIO 2020), which was held on line, during September, 30th-2nd October, 2020. These contributions have been chosen because of their quality and the importance of their findings. Those contributions were then invited to participate in this supplement for the following journals of BMC: BMC Bioinformatics and BMC Genomics. In the present Editorial in BMC journal, we summarize the contributions that provide a clear overview of the thematic areas covered by the IWBBIO conference, ranging from theoretical/review aspects to real-world applications of bioinformatic and biomedical engineering.

An Exploratory Application of Multilayer Networks and Pathway Analysis in Pharmacogenomics.

Over the years, network analysis has become a promising strategy for analysing complex system, i.e., systems composed of a large number of interacting elements. In particular, multilayer networks have emerged as a powerful framework for modelling and analysing complex systems with multiple types of interactions. Network analysis can be applied to pharmacogenomics to gain insights into the interactions between genes, drugs, and diseases. By integrating network analysis techniques with pharmacogenomic data, the goal consists of uncovering complex relationships and identifying key genes to use in pathway enrichment analysis to figure out biological pathways involved in drug response and adverse reactions. In this study, we modelled omics, disease, and drug data together through multilayer network representation. Then, we mined the multilayer network with a community detection algorithm to obtain the top communities. After that, we used the identified list of genes from the communities to perform pathway enrichment analysis (PEA) to figure out the biological function affected by the selected genes. The results show that the genes forming the top community have multiple roles through different pathways.

Aligning Cross-Species Interactomes for Studying Complex and Chronic Diseases.

Neurodegenerative diseases (NDs) are a group of complex disorders characterized by the progressive degeneration and dysfunction of neurons in the central nervous system. NDs encompass many conditions, including Alzheimer's disease and Parkinson's disease. Alzheimer's disease (AD) is a complex disease affecting almost forty million people worldwide. AD is characterized by a progressive decline of cognitive functions related to the loss of connections between nerve cells caused by the prevalence of extracellular Aß plaques and intracellular neurofibrillary tangles plaques. Parkinson's disease (PD) is a neurodegenerative disorder that primarily affects the movement of an individual. The exact cause of Parkinson's disease is not fully understood, but it is believed to involve a combination of genetic and environmental factors. Some cases of PD are linked to mutations in the LRRK2, PARKIN and other genes, which are associated with familial forms of the disease. Different research studies have applied the Protein Protein Interaction (PPI) networks to understand different aspects of disease progression. For instance, Caenorhabditis elegans is widely used as a model organism for the study of AD due to roughly 38% of its genes having a human ortholog. This study's goal consists of comparing PPI network of C. elegans and human by applying computational techniques, widely used for the analysis of PPI networks between species, such as Local Network Alignment (LNA). For this aim, we used L-HetNetAligner algorithm to build a local alignment among two PPI networks, i.e., C. elegans and human PPI networks associated with AD and PD built-in silicon. The results show that L-HetNetAligner can find local alignments representing functionally related subregions. In conclusion, since local alignment enables the extraction of functionally related modules, the method can be used to study complex disease progression.

Identifying Candidate Gene-Disease Associations via Graph Neural Networks.

Real-world objects are usually defined in terms of their own relationships or connections. A graph (or network) naturally expresses this model though nodes and edges. In biology, depending on what the nodes and edges represent, we may classify several types of networks, gene-disease associations (GDAs) included. In this paper, we presented a solution based on a graph neural network (GNN) for the identification of candidate GDAs. We trained our model with an initial set of well-known and curated inter- and intra-relationships between genes and diseases. It was based on graph convolutions, making use of multiple convolutional layers and a point-wise non-linearity function following each layer. The embeddings were computed for the input network built on a set of GDAs to map each node into a vector of real numbers in a multidimensional space. Results showed an AUC of 95% for training, validation, and testing, that in the real case translated into a positive response for 93% of the Top-15 (highest dot product) candidate GDAs identified by our solution. The experimentation was conducted on the DisGeNET dataset, while the DiseaseGene Association Miner (DG-AssocMiner) dataset by Stanford's BioSNAP was also processed for performance evaluation only.

A Method Based on Temporal Embedding for the Pairwise Alignment of Dynamic Networks.

In network analysis, real-world systems may be represented via graph models, where nodes and edges represent the set of biological objects (e.g., genes, proteins, molecules) and their interactions, respectively. This representative knowledge-graph model may also consider the dynamics involved in the evolution of the network (i.e., dynamic networks), in addition to a classic static representation (i.e., static networks). Bioinformatics solutions for network analysis allow knowledge extraction from the features related to a single network of interest or by comparing networks of different species. For instance, we may align a network related to a well known species to a more complex one in order to find a match able to support new hypotheses or studies. Therefore, the network alignment is crucial for transferring the knowledge between species, usually from simplest (e.g., rat) to more complex (e.g., human). Methods: In this paper, we present Dynamic Network Alignment based on Temporal Embedding (DANTE), a novel method for pairwise alignment of dynamic networks that applies the temporal embedding to investigate the topological similarities between the two input dynamic networks. The main idea of DANTE is to consider the evolution of interactions and the changes in network topology. Briefly, the proposed solution builds a similarity matrix by integrating the tensors computed via the embedding process and, subsequently, it aligns the pairs of nodes by performing its own iterative maximization function. Results: The performed experiments have reported promising results in terms of precision and accuracy, as well as good robustness as the number of nodes and time points increases. The proposed solution showed an optimal trade-off between sensitivity and specificity on the alignments produced on several noisy versions of the dynamic yeast network, by improving by ∼18.8% (with a maximum of 20.6%) the Area Under the Receiver Operating Characteristic (ROC) Curve (i.e., AUC or AUROC), compared to two well known methods: DYNAMAGNA++ and DYNAWAVE. From the point of view of quality, DANTE outperformed these by ∼91% as nodes increase and by ∼75% as the number of time points increases. Furthermore, a ∼23.73% improvement in terms of node correctness was reported with our solution on real dynamic networks.

Scoliosis Management through Apps and Software Tools.

Background: Scoliosis is curvature of the spine, often found in adolescents, which can impact on quality of life. Generally, scoliosis is diagnosed by measuring the Cobb angle, which represents the gold standard for scoliosis grade quantification. Commonly, scoliosis evaluation is conducted in person by medical professionals using traditional methods (i.e., involving a scoliometer and/or X-ray radiographs). In recent years, as has happened in various medicine disciplines, it is possible also in orthopedics to observe the spread of Information and Communications Technology (ICT) solutions (i.e., software-based approaches). As an example, smartphone applications (apps) and web-based applications may help the doctors in screening and monitoring scoliosis, thereby reducing the number of in-person visits. Objectives: This paper aims to provide an overview of the main features of the most popular scoliosis ICT tools, i.e., apps and web-based applications for scoliosis diagnosis, screening, and monitoring. Several apps are assessed and compared with the aim of providing a valid starting point for doctors and patients in their choice of software-based tools. Benefits for the patients may be: reducing the number of visits to the doctor, self-monitoring of scoliosis. Benefits for the doctors may be: monitoring the scoliosis progression over time, managing several patients in a remote way, mining the data of several patients for evaluating different therapeutic or exercise prescriptions. Materials and Methods: We first propose a methodology for the evaluation of scoliosis apps in which five macro-categories are considered: (i) technological aspects (e.g., available sensors, how angles are measured); (ii) the type of measurements (e.g., Cobb angle, angle of trunk rotation, axial vertebral rotation); (iii) availability (e.g., app store and eventual fee to pay); (iv) the functions offered to the user (e.g., posture monitoring, exercise prescription); (v) overall evaluation (e.g., pros and cons, usability). Then, six apps and one web-based application are described and evaluated using this methodology. Results: The results for assessment of scoliosis apps are shown in a tabular format for ease of understanding and intuitive comparison, which can help the doctors, specialists, and families in their choice of scoliosis apps. Conclusions: The use of ICT solutions for spinal curvature assessment and monitoring brings several advantages to both patients and orthopedics specialists. Six scoliosis apps and one web-based application are evaluated, and a guideline for their selection is provided.

An overview of bioinformatics courses delivered at the academic level in Italy: Reflections and recommendations from BITS.

In Italian universities, bioinformatics courses are increasingly being incorporated into different study paths. However, the content of bioinformatics courses is usually selected by the professor teaching the course, in the absence of national guidelines that identify the minimum indispensable knowledge in bioinformatics that undergraduate students from different scientific fields should achieve. The Training&Teaching group of the Bioinformatics Italian Society (BITS) proposed to university professors a survey aimed at portraying the current situation of bioinformatics courses within undergraduate curricula in Italy (i.e., bioinformatics courses activated within both bachelor's and master's degrees). Furthermore, the Training&Teaching group took a cue from the survey outcomes to develop recommendations for the design and the inclusion of bioinformatics courses in academic curricula. Here, we present the outcomes of the survey, as well as the BITS recommendations, with the hope that they may support BITS members in identifying learning outcomes and selecting content for their bioinformatics courses. As we share our effort with the broader international community involved in teaching bioinformatics at academic level, we seek feedback and thoughts on our proposal and hope to start a fruitful debate on the topic, including how to better fulfill the real bioinformatics knowledge needs of the research and the labor market at both the national and international level.

Temporal networks in biology and medicine: a survey on models, algorithms, and tools.

The use of static graphs for modelling and analysis of biological and biomedical data plays a key role in biomedical research. However, many real-world scenarios present dynamic behaviours resulting in both node and edges modification as well as feature evolution. Consequently, ad-hoc models for capturing these evolutions along the time have been introduced, also referred to as dynamic, temporal, time-varying graphs. Here, we focus on temporal graphs, i.e., graphs whose evolution is represented by a sequence of time-ordered snapshots. Each snapshot represents a graph active in a particular timestamp. We survey temporal graph models and related algorithms, presenting fundamentals aspects and the recent advances. We formally define temporal graphs, focusing on the problem setting and we present their main applications in biology and medicine. We also present temporal graph embedding and the application to recent problems such as epidemic modelling. Finally, we further state some promising research directions in the area. Main results of this study include a systematic review of fundamental temporal network problems and their algorithmic solutions considered in the literature, in particular those having application in computational biology and medicine. We also include the main software developed in this context.

"What Are the Applications for Remote Rehabilitation Management in Cystic Fibrosis?": A Scoping Review Protocol.

BACKGROUND: Telemedicine is an effective, widely used strategy in the field of cystic fibrosis management. The objective of this scoping review is to summarize and analyze the scientific literature with the special focus on the tools and the strategies used in patients with a chronic disease, such as cystic fibrosis. METHODS: This scoping review will be performed in accordance with the Joanna Briggs Institute methodology. In this context, the planned scoping review is a research synthesis that will map the literature on the applications of telemedicine and telemonitoring to the management of cystic fibrosis, with the aim to identify key concepts in the research and work to be conducted that may impact clinical practice. Studies will be included if they meet the following population, concept, and context criteria: all patients with cystic fibrosis receiving treatment with the tools of telemedicine and telemonitoring. No study design, publication type, or data restrictions will be applied. MEDLINE, Scopus, CINHAL, Pedro, Embase, Web of Science, ACM Digital Library, Health Technology Assessment Database (HTA), and Cochrane Central will be searched up to September 2022. DISCUSSION: To the best of our knowledge, this will be the first scoping review to provide a comprehensive overview of the topic. The results could add meaningful information for future research and, especially, for clinical practice, when implementing telerehabilitation in cystic fibrosis treatment. Furthermore, we expect that our work may identify possible knowledge gaps on the topic. The results of this research will be published in a peer-reviewed journal and will be presented at relevant international scientific events, such as in congress or meetings.

Bioinformatics and High-Performance Computing Methods for Deciphering and Fighting COVID-19-Editorial.

The COVID-19 disease (Coronavirus Disease 19), caused by the SARS-CoV-2 virus (Severe Acute Respiratory Syndrome Coronavirus 2), has posed many challenges worldwide at various levels, with special focus to the biological, medical, and epidemiological ones [...].

A Python Clustering Analysis Protocol of Genes Expression Data Sets.

Gene expression and SNPs data hold great potential for a new understanding of disease prognosis, drug sensitivity, and toxicity evaluations. Cluster analysis is used to analyze data that do not contain any specific subgroups. The goal is to use the data itself to recognize meaningful and informative subgroups. In addition, cluster investigation helps data reduction purposes, exposes hidden patterns, and generates hypotheses regarding the relationship between genes and phenotypes. Cluster analysis could also be used to identify bio-markers and yield computational predictive models. The methods used to analyze microarrays data can profoundly influence the interpretation of the results. Therefore, a basic understanding of these computational tools is necessary for optimal experimental design and meaningful data analysis. This manuscript provides an analysis protocol to effectively analyze gene expression data sets through the K-means and DBSCAN algorithms. The general protocol enables analyzing omics data to identify subsets of features with low redundancy and high robustness, speeding up the identification of new bio-markers through pathway enrichment analysis. In addition, to demonstrate the effectiveness of our clustering analysis protocol, we analyze a real data set from the GEO database. Finally, the manuscript provides some best practice and tips to overcome some issues in the analysis of omics data sets through unsupervised learning.

A statistical network pre-processing method to improve relevance and significance of gene lists in microarray gene expression studies.

BACKGROUND: Microarrays can perform large scale studies of differential expressed gene (DEGs) and even single nucleotide polymorphisms (SNPs), thereby screening thousands of genes for single experiment simultaneously. However, DEGs and SNPs are still just as enigmatic as the first sequence of the genome. Because they are independent from the affected biological context. Pathway enrichment analysis (PEA) can overcome this obstacle by linking both DEGs and SNPs to the affected biological pathways and consequently to the underlying biological functions and processes. RESULTS: To improve the enrichment analysis results, we present a new statistical network pre-processing method by mapping DEGs and SNPs on a biological network that can improve the relevance and significance of the DEGs or SNPs of interest to incorporate pathway topology information into the PEA. The proposed methodology improves the statistical significance of the PEA analysis in terms of computed p value for each enriched pathways and limit the number of enriched pathways. This helps reduce the number of relevant biological pathways with respect to a non-specific list of genes. CONCLUSION: The proposed method provides two-fold enhancements. Network analysis reveals fewer DEGs, by selecting only relevant DEGs and the detected DEGs improve the enriched pathways' statistical significance, rather than simply using a general list of genes.

Design and Implementation of a New Local Alignment Algorithm for Multilayer Networks.

Network alignment (NA) is a popular research field that aims to develop algorithms for comparing networks. Applications of network alignment span many fields, from biology to social network analysis. NA comes in two forms: global network alignment (GNA), which aims to find a global similarity, and LNA, which aims to find local regions of similarity. Recently, there has been an increasing interest in introducing complex network models such as multilayer networks. Multilayer networks are common in many application scenarios, such as modelling of relations among people in a social network or representing the interplay of different molecules in a cell or different cells in the brain. Consequently, the need to introduce algorithms for the comparison of such multilayer networks, i.e., local network alignment, arises. Existing algorithms for LNA do not perform well on multilayer networks since they cannot consider inter-layer edges. Thus, we propose local alignment of multilayer networks (MultiLoAl), a novel algorithm for the local alignment of multilayer networks. We define the local alignment of multilayer networks and propose a heuristic for solving it. We present an extensive assessment indicating the strength of the algorithm. Furthermore, we implemented a synthetic multilayer network generator to build the data for the algorithm's evaluation.

Investigating Topic Modeling Techniques to Extract Meaningful Insights in Italian Long COVID Narration.

Through an adequate survey of the history of the disease, Narrative Medicine (NM) aims to allow the definition and implementation of an effective, appropriate, and shared treatment path. In the present study different topic modeling techniques are compared, as Latent Dirichlet Allocation (LDA) and topic modeling based on BERT transformer, to extract meaningful insights in the Italian narration of COVID-19 pandemic. In particular, the main focus was the characterization of Post-acute Sequelae of COVID-19, (i.e., PASC) writings as opposed to writings by health professionals and general reflections on COVID-19, (i.e., non-PASC) writings, modeled as a semi-supervised task. The results show that the BERTopic-based approach outperforms the LDA-base approach by grouping in the same cluster the 97.26% of analyzed documents, and reaching an overall accuracy of 91.97%.

Application of CCTV Methodology to Analyze COVID-19 Evolution in Italy.

Italy was one of the European countries most afflicted by the COVID-19 pandemic. From 2020 to 2022, Italy adopted strong containment measures against the COVID-19 epidemic and then started an important vaccination campaign. Here, we extended previous work by applying the COVID-19 Community Temporal Visualizer (CCTV) methodology to Italian COVID-19 data related to 2020, 2021, and five months of 2022. The aim of this work was to evaluate how Italy reacted to the pandemic in the first two waves of COVID-19, in which only containment measures such as the lockdown had been adopted, in the months following the start of the vaccination campaign, the months with the mildest weather, and the months affected by the new COVID-19 variants. This assessment was conducted by observing the behavior of single regions. CCTV methodology allows us to map the similarities in the behavior of Italian regions on a graph and use a community detection algorithm to visualize and analyze the spatio-temporal evolution of data. The results depict that the communities formed by Italian regions change with respect to the ten data measures and time.

Challenges and Limitations of Biological Network Analysis.

High-Throughput technologies are producing an increasing volume of data that needs large amounts of data storage, effective data models and efficient, possibly parallel analysis algorithms. Pathway and interactomics data are represented as graphs and add a new dimension of analysis, allowing, among other features, graph-based comparison of organisms' properties. For instance, in biological pathway representation, the nodes can represent proteins, RNA and fat molecules, while the edges represent the interaction between molecules. Otherwise, biological networks such as Protein-Protein Interaction (PPI) Networks, represent the biochemical interactions among proteins by using nodes that model the proteins from a given organism, and edges that model the protein-protein interactions, whereas pathway networks enable the representation of biochemical-reaction cascades that happen within the cells or tissues. In this paper, we discuss the main models for standard representation of pathways and PPI networks, the data models for the representation and exchange of pathway and protein interaction data, the main databases in which they are stored and the alignment algorithms for the comparison of pathways and PPI networks of different organisms. Finally, we discuss the challenges and the limitations of pathways and PPI network representation and analysis. We have identified that network alignment presents a lot of open problems worthy of further investigation, especially concerning pathway alignment.