A toolbox of machine learning software to support microbiome analysis.

The human microbiome has become an area of intense research due to its potential impact on human health. However, the analysis and interpretation of this data have proven to be challenging due to its complexity and high dimensionality. Machine learning (ML) algorithms can process vast amounts of data to uncover informative patterns and relationships within the data, even with limited prior knowledge. Therefore, there has been a rapid growth in the development of software specifically designed for the analysis and interpretation of microbiome data using ML techniques. These software incorporate a wide range of ML algorithms for clustering, classification, regression, or feature selection, to identify microbial patterns and relationships within the data and generate predictive models. This rapid development with a constant need for new developments and integration of new features require efforts into compile, catalog and classify these tools to create infrastructures and services with easy, transparent, and trustable standards. Here we review the state-of-the-art for ML tools applied in human microbiome studies, performed as part of the COST Action ML4Microbiome activities. This scoping review focuses on ML based software and framework resources currently available for the analysis of microbiome data in humans. The aim is to support microbiologists and biomedical scientists to go deeper into specialized resources that integrate ML techniques and facilitate future benchmarking to create standards for the analysis of microbiome data. The software resources are organized based on the type of analysis they were developed for and the ML techniques they implement. A description of each software with examples of usage is provided including comments about pitfalls and lacks in the usage of software based on ML methods in relation to microbiome data that need to be considered by developers and users. This review represents an extensive compilation to date, offering valuable insights and guidance for researchers interested in leveraging ML approaches for microbiome analysis.

microBiomeGSM: the identification of taxonomic biomarkers from metagenomic data using grouping, scoring and modeling (G-S-M) approach.

Numerous biological environments have been characterized with the advent of metagenomic sequencing using next generation sequencing which lays out the relative abundance values of microbial taxa. Modeling the human microbiome using machine learning models has the potential to identify microbial biomarkers and aid in the diagnosis of a variety of diseases such as inflammatory bowel disease, diabetes, colorectal cancer, and many others. The goal of this study is to develop an effective classification model for the analysis of metagenomic datasets associated with different diseases. In this way, we aim to identify taxonomic biomarkers associated with these diseases and facilitate disease diagnosis. The microBiomeGSM tool presented in this work incorporates the pre-existing taxonomy information into a machine learning approach and challenges to solve the classification problem in metagenomics disease-associated datasets. Based on the G-S-M (Grouping-Scoring-Modeling) approach, species level information is used as features and classified by relating their taxonomic features at different levels, including genus, family, and order. Using four different disease associated metagenomics datasets, the performance of microBiomeGSM is comparatively evaluated with other feature selection methods such as Fast Correlation Based Filter (FCBF), Select K Best (SKB), Extreme Gradient Boosting (XGB), Conditional Mutual Information Maximization (CMIM), Maximum Likelihood and Minimum Redundancy (MRMR) and Information Gain (IG), also with other classifiers such as AdaBoost, Decision Tree, LogitBoost and Random Forest. microBiomeGSM achieved the highest results with an Area under the curve (AUC) value of 0.98% at the order taxonomic level for IBDMD dataset. Another significant output of microBiomeGSM is the list of taxonomic groups that are identified as important for the disease under study and the names of the species within these groups. The association between the detected species and the disease under investigation is confirmed by previous studies in the literature. The microBiomeGSM tool and other supplementary files are publicly available at: https://github.com/malikyousef/microBiomeGSM.

miRGediNET: A comprehensive examination of common genes in miRNA-Target interactions and disease associations: Insights from a grouping-scoring-modeling approach.

In the broad and complex field of biological data analysis, researchers frequently gather information from a single source or database. Despite being a widespread practice, this has disadvantages. Relying exclusively on a single source can limit our comprehension as it may omit various perspectives that could be obtained by combining multiple knowledge bases. Acknowledging this shortcoming, we report on miRGediNET, a novel approach combining information from three biological databases. Our investigation focuses on microRNAs (miRNAs), small non-coding RNA molecules that regulate gene expression post-transcriptionally. We delve deeply into the knowledge of these miRNA's interactions with genes and the possible effects these interactions may have on different diseases. The scientific community has long recognized a direct correlation between the progression of specific diseases and miRNAs, as well as the genes they target. By using miRGediNET, we go beyond simply acknowledging this relationship. Rather, we actively look for the critical genes that could act as links between the actions of miRNAs and the mechanisms underlying disease. Our methodology, which carefully identifies and investigates these important genes, is supported by a strategic framework that may open up new possibilities for comprehending diseases and creating treatments. We have developed a tool on the Knime platform as a concrete application of our research. This tool serves as both a validation of our study and an invitation to the larger community to interact with, investigate, and build upon our findings. miRGediNET is publicly accessible on GitHub at https://github.com/malikyousef/miRGediNET, providing a collaborative environment for additional research and innovation for enthusiasts and fellow researchers.

TextNetTopics Pro, a topic model-based text classification for short text by integration of semantic and document-topic distribution information.

With the exponential growth in the daily publication of scientific articles, automatic classification and categorization can assist in assigning articles to a predefined category. Article titles are concise descriptions of the articles' content with valuable information that can be useful in document classification and categorization. However, shortness, data sparseness, limited word occurrences, and the inadequate contextual information of scientific document titles hinder the direct application of conventional text mining and machine learning algorithms on these short texts, making their classification a challenging task. This study firstly explores the performance of our earlier study, TextNetTopics on the short text. Secondly, here we propose an advanced version called TextNetTopics Pro, which is a novel short-text classification framework that utilizes a promising combination of lexical features organized in topics of words and topic distribution extracted by a topic model to alleviate the data-sparseness problem when classifying short texts. We evaluate our proposed approach using nine state-of-the-art short-text topic models on two publicly available datasets of scientific article titles as short-text documents. The first dataset is related to the Biomedical field, and the other one is related to Computer Science publications. Additionally, we comparatively evaluate the predictive performance of the models generated with and without using the abstracts. Finally, we demonstrate the robustness and effectiveness of the proposed approach in handling the imbalanced data, particularly in the classification of Drug-Induced Liver Injury articles as part of the CAMDA challenge. Taking advantage of the semantic information detected by topic models proved to be a reliable way to improve the overall performance of ML classifiers.

GeNetOntology: identifying affected gene ontology terms via grouping, scoring, and modeling of gene expression data utilizing biological knowledge-based machine learning.

Introduction: Identifying significant sets of genes that are up/downregulated under specific conditions is vital to understand disease development mechanisms at the molecular level. Along this line, in order to analyze transcriptomic data, several computational feature selection (i.e., gene selection) methods have been proposed. On the other hand, uncovering the core functions of the selected genes provides a deep understanding of diseases. In order to address this problem, biological domain knowledge-based feature selection methods have been proposed. Unlike computational gene selection approaches, these domain knowledge-based methods take the underlying biology into account and integrate knowledge from external biological resources. Gene Ontology (GO) is one such biological resource that provides ontology terms for defining the molecular function, cellular component, and biological process of the gene product. Methods: In this study, we developed a tool named GeNetOntology which performs GO-based feature selection for gene expression data analysis. In the proposed approach, the process of Grouping, Scoring, and Modeling (G-S-M) is used to identify significant GO terms. GO information has been used as the grouping information, which has been embedded into a machine learning (ML) algorithm to select informative ontology terms. The genes annotated with the selected ontology terms have been used in the training part to carry out the classification task of the ML model. The output is an important set of ontologies for the two-class classification task applied to gene expression data for a given phenotype. Results: Our approach has been tested on 11 different gene expression datasets, and the results showed that GeNetOntology successfully identified important disease-related ontology terms to be used in the classification model. Discussion: GeNetOntology will assist geneticists and scientists to identify a range of disease-related genes and ontologies in transcriptomic data analysis, and it will also help doctors design diagnosis platforms and improve patient treatment plans.

Review of feature selection approaches based on grouping of features.

With the rapid development in technology, large amounts of high-dimensional data have been generated. This high dimensionality including redundancy and irrelevancy poses a great challenge in data analysis and decision making. Feature selection (FS) is an effective way to reduce dimensionality by eliminating redundant and irrelevant data. Most traditional FS approaches score and rank each feature individually; and then perform FS either by eliminating lower ranked features or by retaining highly-ranked features. In this review, we discuss an emerging approach to FS that is based on initially grouping features, then scoring groups of features rather than scoring individual features. Despite the presence of reviews on clustering and FS algorithms, to the best of our knowledge, this is the first review focusing on FS techniques based on grouping. The typical idea behind FS through grouping is to generate groups of similar features with dissimilarity between groups, then select representative features from each cluster. Approaches under supervised, unsupervised, semi supervised and integrative frameworks are explored. The comparison of experimental results indicates the effectiveness of sequential, optimization-based (i.e., fuzzy or evolutionary), hybrid and multi-method approaches. When it comes to biological data, the involvement of external biological sources can improve analysis results. We hope this work's findings can guide effective design of new FS approaches using feature grouping.

Invention of 3Mint for feature grouping and scoring in multi-omics.

Advanced genomic and molecular profiling technologies accelerated the enlightenment of the regulatory mechanisms behind cancer development and progression, and the targeted therapies in patients. Along this line, intense studies with immense amounts of biological information have boosted the discovery of molecular biomarkers. Cancer is one of the leading causes of death around the world in recent years. Elucidation of genomic and epigenetic factors in Breast Cancer (BRCA) can provide a roadmap to uncover the disease mechanisms. Accordingly, unraveling the possible systematic connections between-omics data types and their contribution to BRCA tumor progression is crucial. In this study, we have developed a novel machine learning (ML) based integrative approach for multi-omics data analysis. This integrative approach combines information from gene expression (mRNA), microRNA (miRNA) and methylation data. Due to the complexity of cancer, this integrated data is expected to improve the prediction, diagnosis and treatment of disease through patterns only available from the 3-way interactions between these 3-omics datasets. In addition, the proposed method bridges the interpretation gap between the disease mechanisms that drive onset and progression. Our fundamental contribution is the 3 Multi-omics integrative tool (3Mint). This tool aims to perform grouping and scoring of groups using biological knowledge. Another major goal is improved gene selection via detection of novel groups of cross-omics biomarkers. Performance of 3Mint is assessed using different metrics. Our computational performance evaluations showed that the 3Mint classifies the BRCA molecular subtypes with lower number of genes when compared to the miRcorrNet tool which uses miRNA and mRNA gene expression profiles in terms of similar performance metrics (95% Accuracy). The incorporation of methylation data in 3Mint yields a much more focused analysis. The 3Mint tool and all other supplementary files are available at https://github.com/malikyousef/3Mint/.

Predictive factors for degenerative lumbar spinal stenosis: a model obtained from a machine learning algorithm technique.

BACKGROUND: Degenerative lumbar spinal stenosis (DLSS) is the most common spine disease in the elderly population. It is usually associated with lumbar spine joints/or ligaments degeneration. Machine learning technique is an exclusive method for handling big data analysis; however, the development of this method for spine pathology is rare. This study aims to detect the essential variables that predict the development of symptomatic DLSS using the random forest of machine learning (ML) algorithms technique. METHODS: A retrospective study with two groups of individuals. The first included 165 with symptomatic DLSS (sex ratio 80 M/85F), and the second included 180 individuals from the general population (sex ratio: 90 M/90F) without lumbar spinal stenosis symptoms. Lumbar spine measurements such as vertebral or spinal canal diameters from L1 to S1 were conducted on computerized tomography (CT) images. Demographic and health data of all the participants (e.g., body mass index and diabetes mellitus) were also recorded. RESULTS: The decision tree model of ML demonstrate that the anteroposterior diameter of the bony canal at L5 (males) and L4 (females) levels have the greatest stimulus for symptomatic DLSS (scores of 1 and 0.938). In addition, combination of these variables with other lumbar spine features is mandatory for developing the DLSS. CONCLUSIONS: Our results indicate that combination of lumbar spine characteristics such as bony canal and vertebral body dimensions rather than the presence of a sole variable is highly associated with symptomatic DLSS onset.

PriPath: identifying dysregulated pathways from differential gene expression via grouping, scoring, and modeling with an embedded feature selection approach.

BACKGROUND: Cell homeostasis relies on the concerted actions of genes, and dysregulated genes can lead to diseases. In living organisms, genes or their products do not act alone but within networks. Subsets of these networks can be viewed as modules that provide specific functionality to an organism. The Kyoto encyclopedia of genes and genomes (KEGG) systematically analyzes gene functions, proteins, and molecules and combines them into pathways. Measurements of gene expression (e.g., RNA-seq data) can be mapped to KEGG pathways to determine which modules are affected or dysregulated in the disease. However, genes acting in multiple pathways and other inherent issues complicate such analyses. Many current approaches may only employ gene expression data and need to pay more attention to some of the existing knowledge stored in KEGG pathways for detecting dysregulated pathways. New methods that consider more precompiled information are required for a more holistic association between gene expression and diseases. RESULTS: PriPath is a novel approach that transfers the generic process of grouping and scoring, followed by modeling to analyze gene expression with KEGG pathways. In PriPath, KEGG pathways are utilized as the grouping function as part of a machine learning algorithm for selecting the most significant KEGG pathways. A machine learning model is trained to differentiate between diseases and controls using those groups. We have tested PriPath on 13 gene expression datasets of various cancers and other diseases. Our proposed approach successfully assigned biologically and clinically relevant KEGG terms to the samples based on the differentially expressed genes. We have comparatively evaluated the performance of PriPath against other tools, which are similar in their merit. For each dataset, we manually confirmed the top results of PriPath in the literature and found that most predictions can be supported by previous experimental research. CONCLUSIONS: PriPath can thus aid in determining dysregulated pathways, which applies to medical diagnostics. In the future, we aim to advance this approach so that it can perform patient stratification based on gene expression and identify druggable targets. Thereby, we cover two aspects of precision medicine.

Deep learning in bioinformatics.

Deep learning is a powerful machine learning technique that can learn from large amounts of data using multiple layers of artificial neural networks. This paper reviews some applications of deep learning in bioinformatics, a field that deals with analyzing and interpreting biological data. We first introduce the basic concepts of deep learning and then survey the recent advances and challenges of applying deep learning to various bioinformatics problems, such as genome sequencing, gene expression analysis, protein structure prediction, drug discovery, and disease diagnosis. We also discuss future directions and opportunities for deep learning in bioinformatics. We aim to provide an overview of deep learning so that bioinformaticians applying deep learning models can consider all critical technical and ethical aspects. Thus, our target audience is biomedical informatics researchers who use deep learning models for inference. This review will inspire more bioinformatics researchers to adopt deep-learning methods for their research questions while considering fairness, potential biases, explainability, and accountability.

GediNET for discovering gene associations across diseases using knowledge based machine learning approach.

The most common approaches to discovering genes associated with specific diseases are based on machine learning and use a variety of feature selection techniques to identify significant genes that can serve as biomarkers for a given disease. More recently, the integration in this process of prior knowledge-based approaches has shown significant promise in the discovery of new biomarkers with potential translational applications. In this study, we developed a novel approach, GediNET, that integrates prior biological knowledge to gene Groups that are shown to be associated with a specific disease such as a cancer. The novelty of GediNET is that it then also allows the discovery of significant associations between that specific disease and other diseases. The initial step in this process involves the identification of gene Groups. The Groups are then subjected to a Scoring component to identify the top performing classification Groups. The top-ranked gene Groups are then used to train a Machine Learning Model. The process of Grouping, Scoring and Modelling (G-S-M) is used by GediNET to identify other diseases that are similarly associated with this signature. GediNET identifies these relationships through Disease-Disease Association (DDA) based machine learning. DDA explores novel associations between diseases and identifies relationships which could be used to further improve approaches to diagnosis, prognosis, and treatment. The GediNET KNIME workflow can be downloaded from: https://github.com/malikyousef/GediNET.git or https://kni.me/w/3kH1SQV_mMUsMTS .

TextNetTopics: Text Classification Based Word Grouping as Topics and Topics' Scoring.

Medical document classification is one of the active research problems and the most challenging within the text classification domain. Medical datasets often contain massive feature sets where many features are considered irrelevant, redundant, and add noise, thus, reducing the classification performance. Therefore, to obtain a better accuracy of a classification model, it is crucial to choose a set of features (terms) that best discriminate between the classes of medical documents. This study proposes TextNetTopics, a novel approach that applies feature selection by considering Bag-of-topics (BOT) rather than the traditional approach, Bag-of-words (BOW). Thus our approach performs topic selections rather than words selection. TextNetTopics is based on the generic approach entitled G-S-M (Grouping, Scoring, and Modeling), developed by Yousef and his colleagues and used mainly in biological data. The proposed approach suggests scoring topics to select the top topics for training the classifier. This study applied TextNetTopics to textual data to respond to the CAMDA challenge. TextNetTopics outperforms various feature selection approaches while highly performing when applying the model to the validation data provided by the CAMDA. Additionally, we have applied our algorithm to different textual datasets.

miRModuleNet: Detecting miRNA-mRNA Regulatory Modules.

Increasing evidence that microRNAs (miRNAs) play a key role in carcinogenesis has revealed the need for elucidating the mechanisms of miRNA regulation and the roles of miRNAs in gene-regulatory networks. A better understanding of the interactions between miRNAs and their mRNA targets will provide a better understanding of the complex biological processes that occur during carcinogenesis. Increased efforts to reveal these interactions have led to the development of a variety of tools to detect and understand these interactions. We have recently described a machine learning approach miRcorrNet, based on grouping and scoring (ranking) groups of genes, where each group is associated with a miRNA and the group members are genes with expression patterns that are correlated with this specific miRNA. The miRcorrNet tool requires two types of -omics data, miRNA and mRNA expression profiles, as an input file. In this study we describe miRModuleNet, which groups mRNA (genes) that are correlated with each miRNA to form a star shape, which we identify as a miRNA-mRNA regulatory module. A scoring procedure is then applied to each module to further assess their contribution in terms of classification. An important output of miRModuleNet is that it provides a hierarchical list of significant miRNA-mRNA regulatory modules. miRModuleNet was further validated on external datasets for their disease associations, and functional enrichment analysis was also performed. The application of miRModuleNet aids the identification of functional relationships between significant biomarkers and reveals essential pathways involved in cancer pathogenesis. The miRModuleNet tool and all other supplementary files are available at https://github.com/malikyousef/miRModuleNet/.

Inflammatory bowel disease biomarkers of human gut microbiota selected via different feature selection methods.

The tremendous boost in next generation sequencing and in the "omics" technologies makes it possible to characterize the human gut microbiome-the collective genomes of the microbial community that reside in our gastrointestinal tract. Although some of these microorganisms are considered to be essential regulators of our immune system, the alteration of the complexity and eubiotic state of microbiota might promote autoimmune and inflammatory disorders such as diabetes, rheumatoid arthritis, Inflammatory bowel diseases (IBD), obesity, and carcinogenesis. IBD, comprising Crohn's disease and ulcerative colitis, is a gut-related, multifactorial disease with an unknown etiology. IBD presents defects in the detection and control of the gut microbiota, associated with unbalanced immune reactions, genetic mutations that confer susceptibility to the disease, and complex environmental conditions such as westernized lifestyle. Although some existing studies attempt to unveil the composition and functional capacity of the gut microbiome in relation to IBD diseases, a comprehensive picture of the gut microbiome in IBD patients is far from being complete. Due to the complexity of metagenomic studies, the applications of the state-of-the-art machine learning techniques became popular to address a wide range of questions in the field of metagenomic data analysis. In this regard, using IBD associated metagenomics dataset, this study utilizes both supervised and unsupervised machine learning algorithms, (i) to generate a classification model that aids IBD diagnosis, (ii) to discover IBD-associated biomarkers, (iii) to discover subgroups of IBD patients using k-means and hierarchical clustering approaches. To deal with the high dimensionality of features, we applied robust feature selection algorithms such as Conditional Mutual Information Maximization (CMIM), Fast Correlation Based Filter (FCBF), min redundancy max relevance (mRMR), Select K Best (SKB), Information Gain (IG) and Extreme Gradient Boosting (XGBoost). In our experiments with 100-fold Monte Carlo cross-validation (MCCV), XGBoost, IG, and SKB methods showed a considerable effect in terms of minimizing the microbiota used for the diagnosis of IBD and thus reducing the cost and time. We observed that compared to Decision Tree, Support Vector Machine, Logitboost, Adaboost, and stacking ensemble classifiers, our Random Forest classifier resulted in better performance measures for the classification of IBD. Our findings revealed potential microbiome-mediated mechanisms of IBD and these findings might be useful for the development of microbiome-based diagnostics.

Correlates of Hookah Smoking among Arab Adults in Israel Identified by a Machine Learning Algorithm.

BACKGROUND: Hookah smoking is a common activity around the world and has recently become a trend among youth. Studies have indicated a relationship between hookah smoking and a high prevalence of chronic diseases, cancer, cardiovascular, and infectious diseases. In Israel, there has been a sharp increase in hookah smoking among the Arabs. Most studies have focused mainly on hookah smoking among young people. OBJECTIVES: To examine the association between hookah smoking and socioeconomic characteristics, health status and behaviors, and knowledge in the adult Arab population and to build a prediction model using machine learning methods. METHODS: This quantitative study based is on data from the Health and Environment Survey conducted by the Galilee Society in 2015-2016. The data were collected through face-to-face interviews with 2046 adults aged 18 years and older. RESULTS: Using machine learning, a prediction model was built based on eight features. Of the total study population, 13.0% smoked hookah. In the 18-34 age group, 19.5% smoked. Men, people with lower level of health knowledge, heavy consumers of energy drinks and alcohol, and unemployed people were more likely to smoke hookah. Younger and more educated people were more likely to smoke hookah. CONCLUSIONS: Hookah smoking is a widespread behavior among adult Arabs in Israel. The model generated by our study is intended to help health organizations reach people at risk for smoking hookah and to suggest different approaches to eliminate this phenomenon.

Computational Methods for Predicting Mature microRNAs.

Tiny single-stranded noncoding RNAs with size 19-27 nucleotides serve as microRNAs (miRNAs), which have emerged as key gene regulators in the last two decades. miRNAs serve as one of the hallmarks in regulatory pathways with critical roles in human diseases. Ever since the discovery of miRNAs, researchers have focused on how mature miRNAs are produced from precursor mRNAs. Experimental methods are faced with notorious challenges in terms of experimental design, since it is time consuming and not cost-effective. Hence, different computational methods have been employed for the identification of miRNA sequences where most of them labeled as miRNA predictors are in fact pre-miRNA predictors and provide no information about the putative miRNA location within the pre-miRNA. This chapter provides an update and the current state of the art in this area covering various methods and 15 software suites used for prediction of mature miRNA.

Ensemble Classifiers for Multiclass MicroRNA Classification.

Gene regulation is of utmost importance to cell homeostasis; thus, any dysregulation in it often leads to disease. MicroRNAs (miRNAs) are involved in posttranscriptional gene regulation and consequently, their dysregulation has been associated with many diseases.MiRBase version 21 contains microRNAs from about 200 species organized into about 70 clades. It has been shown that not all miRNAs collected in the database are likely to be real and, therefore, novel routes to delineate between correct and false miRNAs should be explored. We introduce a novel approach based on k-mer frequencies and machine learning that assigns an unknown/unlabeled miRNA to its most likely clade/species of origin. A simple way to filter new data would be to ensure that the novel miRNA categorizes closely to the species it is said to originate from. For that, an ensemble classifier of multiple two-class random forest classifiers was designed, where each random forest was trained on one species-clade pair. The approach was tested with different sampling methods on a dataset that was taken from miRBase version 21 and it was evaluated using a hierarchical F-measure. The approach predicted 81% to 94% of the test data correctly, depending on the sampling method. This is the first classifier that can classify miRNAs to their species of origin. This method will aid in the evaluation of miRNA database integrity and analysis of noisy miRNA samples.

44 Current Challenges in miRNomics.

Mature microRNAs (miRNAs) are short RNA sequences about 18-24 nucleotide long, which provide the recognition key within RISC for the posttranscriptional regulation of target RNAs. Considering the canonical pathway, mature miRNAs are produced via a multistep process. Their transcription (pri-miRNAs) and first processing step via the microprocessor complex (pre-miRNAs) occur in the nucleus. Then they are exported into the cytosol, processed again by Dicer (dsRNA) and finally a single strand (mature miRNA) is incorporated into RISC (miRISC). The sequence of the incorporated miRNA provides the function of RNA target recognition via hybridization. Following binding of the target, the mRNA is either degraded or translation is inhibited, which ultimately leads to less protein production. Conversely, it has been shown that binding within the 5' UTR of the mRNA can lead to an increase in protein product. Regulation of homeostasis is very important for a cell; therefore, all steps in the miRNA-based regulation pathway, from transcription to the incorporation of the mature miRNA into RISC, are under tight control. While much research effort has been exerted in this area, the knowledgebase is not sufficient for accurately modelling miRNA regulation computationally. The computational prediction of miRNAs is, however, necessary because it is not feasible to investigate all possible pairs of a miRNA and its target, let alone miRNAs and their targets. We here point out open challenges important for computational modelling or for our general understanding of miRNA-based regulation and show how their investigation is beneficial. It is our hope that this collection of challenges will lead to their resolution in the near future.

miRdisNET: Discovering microRNA biomarkers that are associated with diseases utilizing biological knowledge-based machine learning.

During recent years, biological experiments and increasing evidence have shown that microRNAs play an important role in the diagnosis and treatment of human complex diseases. Therefore, to diagnose and treat human complex diseases, it is necessary to reveal the associations between a specific disease and related miRNAs. Although current computational models based on machine learning attempt to determine miRNA-disease associations, the accuracy of these models need to be improved, and candidate miRNA-disease relations need to be evaluated from a biological perspective. In this paper, we propose a computational model named miRdisNET to predict potential miRNA-disease associations. Specifically, miRdisNET requires two types of data, i.e., miRNA expression profiles and known disease-miRNA associations as input files. First, we generate subsets of specific diseases by applying the grouping component. These subsets contain miRNA expressions with class labels associated with each specific disease. Then, we assign an importance score to each group by using a machine learning method for classification. Finally, we apply a modeling component and obtain outputs. One of the most important outputs of miRdisNET is the performance of miRNA-disease prediction. Compared with the existing methods, miRdisNET obtained the highest AUC value of .9998. Another output of miRdisNET is a list of significant miRNAs for disease under study. The miRNAs identified by miRdisNET are validated via referring to the gold-standard databases which hold information on experimentally verified microRNA-disease associations. miRdisNET has been developed to predict candidate miRNAs for new diseases, where miRNA-disease relation is not yet known. In addition, miRdisNET presents candidate disease-disease associations based on shared miRNA knowledge. The miRdisNET tool and other supplementary files are publicly available at: https://github.com/malikyousef/miRdisNET.

COVIDium: a COVID-19 resource compendium.

The severe acute respiratory syndrome coronavirus 2 that causes coronavirus disease 2019 (COVID-19) disrupted the normal functioning throughout the world since early 2020 and it continues to do so. Nonetheless, the global pandemic was taken up as a challenge by researchers across the globe to discover an effective cure, either in the form of a drug or vaccine. This resulted in an unprecedented surge of experimental and computational data and publications, which often translated their findings in the form of databases (DBs) and tools. Over 160 such DBs and more than 80 software tools were developed, which are uncharacterized, unannotated, deployed at different universal resource locators and are challenging to reach out through a normal web search. Besides, most of the DBs/tools are present on preprints and are either underutilized or unrecognized because of their inability to make it to top Google search hits. Henceforth, there was a need to crawl and characterize these DBs and create a compendium for easy referencing. The current article is one such concerted effort in this direction to create a COVID-19 resource compendium (COVIDium) that would facilitate the researchers to find suitable DBs and tools for their research studies. COVIDium tries to classify the DBs and tools into 11 broad categories for quick navigation. It also provides end-users some generic hit terms to filter the DB entries for quick access to the resources. Additionally, the DB provides Tracker Dashboard, Neuro Resources, references to COVID-19 datasets and protein-protein interactions. This compendium will be periodically updated to accommodate new resources. Database URL: The COVIDium is accessible through http://kraza.in/covidium/.