Deep learning in spatially resolved transcriptfomics: a comprehensive technical view

Spatially resolved transcriptomics (SRT) is a pioneering method for simultaneously studying morphological contexts and gene expression at single-cell precision. Data emerging from SRT are multifaceted, presenting researchers with intricate gene expression matrices, precise spatial details and comprehensive histology visuals. Such rich and intricate datasets, unfortunately, render many conventional methods like traditional machine learning and statistical models ineffective. The unique challenges posed by the specialized nature of SRT data have led the scientific community to explore more sophisticated analytical avenues. Recent trends indicate an increasing reliance on deep learning algorithms, especially in areas such as spatial clustering, identification of spatially variable genes and data alignment tasks. In this manuscript, we provide a rigorous critique of these advanced deep learning methodologies, probing into their merits, limitations and avenues for further refinement. Our in-depth analysis underscores that while the recent innovations in deep learning tailored for SRT have been promising, there remains a substantial potential for enhancement. A crucial area that demands attention is the development of models that can incorporate intricate biological nuances, such as phylogeny-aware processing or in-depth analysis of minuscule histology image segments. Furthermore, addressing challenges like the elimination of batch effects, perfecting data normalization techniques and countering the overdispersion and zero inflation patterns seen in gene expression is pivotal. To support the broader scientific community in their SRT endeavors, we have meticulously assembled a comprehensive directory of readily accessible SRT databases, hoping to serve as a foundation for future research initiatives.

A Comprehensive Investigation of Genomic Variants in Prostate Cancer Reveals 30 Putative Regulatory Variants.

Prostate cancer (PC) is the most frequently diagnosed non-skin cancer in the world. Previous studies have shown that genomic alterations represent the most common mechanism for molecular alterations responsible for the development and progression of PC. This highlights the importance of identifying functional genomic variants for early detection in high-risk PC individuals. Great efforts have been made to identify common protein-coding genetic variations; however, the impact of non-coding variations, including regulatory genetic variants, is not well understood. Identification of these variants and the underlying target genes will be a key step in improving the detection and treatment of PC. To gain an understanding of the functional impact of genetic variants, and in particular, regulatory variants in PC, we developed an integrative pipeline (AGV) that uses whole genome/exome sequences, GWAS SNPs, chromosome conformation capture data, and ChIP-Seq signals to investigate the potential impact of genomic variants on the underlying target genes in PC. We identified 646 putative regulatory variants, of which 30 significantly altered the expression of at least one protein-coding gene. Our analysis of chromatin interactions data (Hi-C) revealed that the 30 putative regulatory variants could affect 131 coding and non-coding genes. Interestingly, our study identified the 131 protein-coding genes that are involved in disease-related pathways, including Reactome and MSigDB, for most of which targeted treatment options are currently available. Notably, our analysis revealed several non-coding RNAs, including RP11-136K7.2 and RAMP2-AS1, as potential enhancer elements of the protein-coding genes CDH12 and EZH1, respectively. Our results provide a comprehensive map of genomic variants in PC and reveal their potential contribution to prostate cancer progression and development.

Integrative analysis of mutated genes and mutational processes reveals novel mutational biomarkers in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Recent studies have observed causative mutations in susceptible genes related to colorectal cancer in 10 to 15% of the patients. This highlights the importance of identifying mutations for early detection of this cancer for more effective treatments among high risk individuals. Mutation is considered as the key point in cancer research. Many studies have performed cancer subtyping based on the type of frequently mutated genes, or the proportion of mutational processes. However, to the best of our knowledge, combination of these features has never been used together for this task. This highlights the potential to introduce better and more inclusive subtype classification approaches using wider range of related features to enable biomarker discovery and thus inform drug development for CRC. RESULTS: In this study, we develop a new pipeline based on a novel concept called 'gene-motif', which merges mutated gene information with tri-nucleotide motif of mutated sites, for colorectal cancer subtype identification. We apply our pipeline to the International Cancer Genome Consortium (ICGC) CRC samples and identify, for the first time, 3131 gene-motif combinations that are significantly mutated in 536 ICGC colorectal cancer samples. Using these features, we identify seven CRC subtypes with distinguishable phenotypes and biomarkers, including unique cancer related signaling pathways, in which for most of them targeted treatment options are currently available. Interestingly, we also identify several genes that are mutated in multiple subtypes but with unique sequence contexts. CONCLUSION: Our results highlight the importance of considering both the mutation type and mutated genes in identification of cancer subtypes and cancer biomarkers. The new CRC subtypes presented in this study demonstrates distinguished phenotypic properties which can be effectively used to develop new treatments. By knowing the genes and phenotypes associated with the subtypes, a personalized treatment plan can be developed that considers the specific phenotypes associated with their genomic lesion.

Impact of the COVID-19 pandemic on the stage and the type of surgical treatment of laryngeal cancer.

PURPOSE: Changes in the entire health care system during COVID-19 epidemic have affected the management of patients with head and neck cancer and posed several clinical challenges for ENT surgeons. Therefore, the present study aimed to investigate the effect of COVID-19 on the stage and the type of surgical treatments used in laryngeal cancer (including total laryngectomy, supracricoid partial laryngectomy (SCPL) and transoral laser microsurgery (TLM)) and also to compare the results of April 2020 to April 2021 with the previous year. MATERIALS AND METHODS: This cross-sectional study was performed on all patients with a diagnosis of laryngeal cancer who underwent surgery in the tertiary care center from April 2020 to April 2021 and the year before the pandemic in the same time. Demographic, cancer stage, and treatment data of all patients were recorded and analysis in two groups. RESULTS: Patients referred at the time of the virus outbreak; 111 were male and 5 were female, and in the group of patients referred before COVID-19, 90 were male and 12 were female. The type of surgical treatment of laryngeal cancer, mean time elapsed from sampling to surgery, stage of disease and mean tumor volume was statistically significant differences in patients before and during the outbreak. CONCLUSION: Patients who referred for diagnosis and treatment at the time of COVID-19 outbreak had more advanced stages of the disease and also the tumor volume was higher in them than patients who had referred before the outbreak. It is necessary to provide new solutions, education and treatment management for patients with laryngeal cancer in such pandemics.

KARAJ: An Efficient Adaptive Multi-Processor Tool to Streamline Genomic and Transcriptomic Sequence Data Acquisition.

Here we developed KARAJ, a fast and flexible Linux command-line tool to automate the end-to-end process of querying and downloading a wide range of genomic and transcriptomic sequence data types. The input to KARAJ is a list of PMCIDs or publication URLs or various types of accession numbers to automate four tasks as follows; firstly, it provides a summary list of accessible datasets generated by or used in these scientific articles, enabling users to select appropriate datasets; secondly, KARAJ calculates the size of files that users want to download and confirms the availability of adequate space on the local disk; thirdly, it generates a metadata table containing sample information and the experimental design of the corresponding study; and lastly, it enables users to download supplementary data tables attached to publications. Further, KARAJ provides a parallel downloading framework powered by Aspera connect which reduces the downloading time significantly.

Increasing stage and depth of invasion (DOI) in patients with tongue cancer during the COVID-19 pandemic: A time series study.

Background and Aims: The outbreak of the Coronavirus disease 2019 (COVID-19) pandemic had a significant effect on the diagnosis and treatment of head and neck cancers. Therefore, in this study, we decided to discuss the impact of COVID-19 on the stage and histological characteristics of patients with tongue cancer from March 2020 to March 2021 and compared to the previous 3 years. Methods: In this time series study, patients diagnosed with squamous cell carcinoma of the operated tongue cancer were divided into two groups. Patients who operated from March 2020 to March 2021 (n = 36) and patients who operated 3 years ago (n = 70) were included in the study. The results were analyzed using SPSS 21 software. Results: The study found that during the pandemic, the stage of tongue cancer in patients who underwent surgery was higher than before the pandemic (p = 0.01). Moreover, the depth of invasion was significantly higher during the COVID-19 outbreak in the pathology sample of the patients (p = 0.006), while the involvement of lymph nodes and other variables between the groups was not statistically significant. Conclusion: COVID-19 has adverse effects on the diagnosis and treatment of tongue cancer. Also, it leads to advanced stages of the tumor and increases the depth of invasion of the cancer. Hence, it is important to plan correctly and appropriately for the diagnosis and treatment of these patients in conditions such as the COVID-19 pandemic.

A priority queue-based telemonitoring system for automatic diagnosis of heart diseases in integrated fog computing environments.

Various studies have shown the benefits of using distributed fog computing for healthcare systems. The new pattern of fog and edge computing reduces latency for data processing compared to cloud computing. Nevertheless, the proposed fog models still have many limitations in improving system performance and patients' response time.This paper, proposes a new performance model by integrating fog computing, priority queues and certainty theory into the Edge computing devices and validating it by analyzing heart disease patients' conditions in clinical decision support systems (CDSS). In this model, a Certainty Factor (CF) value is assigned to each symptom of heart disease. When one or more symptoms show an abnormal value, the patient's condition will be evaluated using CF values in the fog layer. In the fog layer, requests are categorized in different priority queues before arriving into the system. The results demonstrate that network usage, latency, and response time of patients' requests are respectively improved by 25.55%, 42.92%, and 34.28% compared to the cloud model. Prioritizing patient requests with respect to CF values in the CDSS provides higher system Quality of Service (QoS) and patients' response time.

Four-layer ConvNet to facial emotion recognition with minimal epochs and the significance of data diversity.

Emotion recognition is defined as identifying human emotion and is directly related to different fields such as human-computer interfaces, human emotional processing, irrational analysis, medical diagnostics, data-driven animation, human-robot communication, and many more. This paper proposes a new facial emotional recognition model using a convolutional neural network. Our proposed model, "ConvNet", detects seven specific emotions from image data including anger, disgust, fear, happiness, neutrality, sadness, and surprise. The features extracted by the Local Binary Pattern (LBP), region based Oriented FAST and rotated BRIEF (ORB) and Convolutional Neural network (CNN) from facial expressions images were fused to develop the classification model through training by our proposed CNN model (ConvNet). Our method can converge quickly and achieves good performance which the authors can develop a real-time schema that can easily fit the model and sense emotions. Furthermore, this study focuses on the mental or emotional stuff of a man or woman using the behavioral aspects. To complete the training of the CNN network model, we use the FER2013 databases at first, and then apply the generalization techniques to the JAFFE and CK+ datasets respectively in the testing stage to evaluate the performance of the model. In the generalization approach on the JAFFE dataset, we get a 92.05% accuracy, while on the CK+ dataset, we acquire a 98.13% accuracy which achieve the best performance among existing methods. We also test the system's success by identifying facial expressions in real-time. ConvNet consists of four layers of convolution together with two fully connected layers. The experimental results show that the ConvNet is able to achieve 96% training accuracy which is much better than current existing models. However, when compared to other validation methods, the suggested technique was more accurate. ConvNet also achieved validation accuracy of 91.01% for the FER2013 dataset. We also made all the materials publicly accessible for the research community at: https://github.com/Tanoy004/Emotion-recognition-through-CNN .

PeakCNV: A multi-feature ranking algorithm-based tool for genome-wide copy number variation-association study.

Copy Number Variation (CNV) refers to a type of structural genomic alteration in which a segment of chromosome is duplicated or deleted. To date, many CNVs have been identified as causative genetic elements for several diseases and phenotypes. However, performing a CNV-based genome-wide association study is challenging due to inconsistency in length and occurrence of CNVs across different individuals under investigation. One of the most efficient strategies to address this issue is building CNV regions (genomic regions in which CNVs are overlapping - CNVRs). However, this approach is susceptible to a high false positive rate due to overlapping and co-occurring of confounding CNVRs with true positive CNVRs. Here, we develop PeakCNV that differentiates false-positive CNVRs from true positives by calculating a new metric, independence ranking score, (IR-score) via a feature ranking approach. We compared the performance of PeakCNV with other current existing tools by carrying out two case studies one using the CNV genotype data for individuals with prostate cancer (194 cases and 2,392 healthy individuals) and the second one for individuals with neurodevelopmental disorders (19,642 cases and 6,451 healthy individuals). Crucially, our benchmarking analyses on prostate cancer cohort indicated that PeakCNV identifies a fewer risk candidate CNVRs with shorter lengths compared to other tools. Importantly, these CNVRs cover a greater proportion of case over healthy individuals compared to other tools. The accuracy of PeakCNV in identifying relevant candidate CNVRs was reproducible in the case study on neurodevelopmental disorders. Using data from the FANTOM5 expression atlas and the Clinical Genomic Database, we show that the candidate CNVRs identified by PeakCNV for neurodevelopmental disorders overlap with a greater number of genes with the brain-enriched expression, and a greater number of genes that are associated with neurological conditions compared to candidate CNVRs identified by other tools. Taken together, PeakCNV outperformed current existing CNV association study tools by identifying more biologically meaningful CNVRs relevant to the phenotype of interest. PeakCNV is publicly available for the analysis of CNV-associated diseases and is accessible from https://rdrr.io/github/mahdieh1/PeakCNV.

A Survey on Deep Learning Event Extraction: Approaches and Applications.

Event extraction (EE) is a crucial research task for promptly apprehending event information from massive textual data. With the rapid development of deep learning, EE based on deep learning technology has become a research hotspot. Numerous methods, datasets, and evaluation metrics have been proposed in the literature, raising the need for a comprehensive and updated survey. This article fills the research gap by reviewing the state-of-the-art approaches, especially focusing on the general domain EE based on deep learning models. We introduce a new literature classification of current general domain EE research according to the task definition. Afterward, we summarize the paradigm and models of EE approaches, and then discuss each of them in detail. As an important aspect, we summarize the benchmarks that support tests of predictions and evaluation metrics. A comprehensive comparison among different approaches is also provided in this survey. Finally, we conclude by summarizing future research directions facing the research area.

A Survey on Machine Learning and Internet of Medical Things-Based Approaches for Handling COVID-19: Meta-Analysis.

Early diagnosis, prioritization, screening, clustering, and tracking of patients with COVID-19, and production of drugs and vaccines are some of the applications that have made it necessary to use a new style of technology to involve, manage, and deal with this epidemic. Strategies backed by artificial intelligence (A.I.) and the Internet of Things (IoT) have been undeniably effective to understand how the virus works and prevent it from spreading. Accordingly, the main aim of this survey is to critically review the ML, IoT, and the integration of IoT and ML-based techniques in the applications related to COVID-19, from the diagnosis of the disease to the prediction of its outbreak. According to the main findings, IoT provided a prompt and efficient approach to tracking the disease spread. On the other hand, most of the studies developed by ML-based techniques aimed at the detection and handling of challenges associated with the COVID-19 pandemic. Among different approaches, Convolutional Neural Network (CNN), Support Vector Machine, Genetic CNN, and pre-trained CNN, followed by ResNet have demonstrated the best performances compared to other methods.

Deep reinforcement learning guided graph neural networks for brain network analysis.

Modern neuroimaging techniques enable us to construct human brains as brain networks or connectomes. Capturing brain networks' structural information and hierarchical patterns is essential for understanding brain functions and disease states. Recently, the promising network representation learning capability of graph neural networks (GNNs) has prompted related methods for brain network analysis to be proposed. Specifically, these methods apply feature aggregation and global pooling to convert brain network instances into vector representations encoding brain structure induction for downstream brain network analysis tasks. However, existing GNN-based methods often neglect that brain networks of different subjects may require various aggregation iterations and use GNN with a fixed number of layers to learn all brain networks. Therefore, how to fully release the potential of GNNs to promote brain network analysis is still non-trivial. In our work, a novel brain network representation framework, BN-GNN, is proposed to solve this difficulty, which searches for the optimal GNN architecture for each brain network. Concretely, BN-GNN employs deep reinforcement learning (DRL) to automatically predict the optimal number of feature propagations (reflected in the number of GNN layers) required for a given brain network. Furthermore, BN-GNN improves the upper bound of traditional GNNs' performance in eight brain network disease analysis tasks.

VIRMOTIF: A User-Friendly Tool for Viral Sequence Analysis.

Bioinformatics and computational biology have significantly contributed to the generation of vast and important knowledge that can lead to great improvements and advancements in biology and its related fields. Over the past three decades, a wide range of tools and methods have been developed and proposed to enhance performance, diagnosis, and throughput while maintaining feasibility and convenience for users. Here, we propose a new user-friendly comprehensive tool called VIRMOTIF to analyze DNA sequences. VIRMOTIF brings different tools together as one package so that users can perform their analysis as a whole and in one place. VIRMOTIF is able to complete different tasks, including computing the number or probability of motifs appearing in DNA sequences, visualizing data using the matplotlib and heatmap libraries, and clustering data using four different methods, namely K-means, PCA, Mean Shift, and ClusterMap. VIRMOTIF is the only tool with the ability to analyze genomic motifs based on their frequency and representation (D-ratio) in a virus genome.

Whole-Genome Analysis of De Novo Somatic Point Mutations Reveals Novel Mutational Biomarkers in Pancreatic Cancer.

It is now known that at least 10% of samples with pancreatic cancers (PC) contain a causative mutation in the known susceptibility genes, suggesting the importance of identifying cancer-associated genes that carry the causative mutations in high-risk individuals for early detection of PC. In this study, we develop a statistical pipeline using a new concept, called gene-motif, that utilizes both mutated genes and mutational processes to identify 4211 3-nucleotide PC-associated gene-motifs within 203 significantly mutated genes in PC. Using these gene-motifs as distinguishable features for pancreatic cancer subtyping results in identifying five PC subtypes with distinguishable phenotypes and genotypes. Our comprehensive biological characterization reveals that these PC subtypes are associated with different molecular mechanisms including unique cancer related signaling pathways, in which for most of the subtypes targeted treatment options are currently available. Some of the pathways we identified in all five PC subtypes, including cell cycle and the Axon guidance pathway are frequently seen and mutated in cancer. We also identified Protein kinase C, EGFR (epidermal growth factor receptor) signaling pathway and P53 signaling pathways as potential targets for treatment of the PC subtypes. Altogether, our results uncover the importance of considering both the mutation type and mutated genes in the identification of cancer subtypes and biomarkers.

Proposing a novel community detection approach to identify cointeracting genomic regions.

Modern next generation sequencing technologies produce huge amounts of genome-wide data that allow researchers to have a deeper understanding of genomics of organisms. Despite these huge amounts of data, our understanding of the transcriptional regulatory networks is still incomplete. Conformation dependent chromosome interaction maps technologies (Hi-C) have enabled us to detect elements in the genome which interact with each other and regulate the genes. Summarizing these interactions as a data network leads to investigation of the most important properties of the 3D genome structure such as gene co-expression networks. In this work, a Pareto-Based Multi-Objective Optimization algorithm is proposed to detect the co-expressed genomic regions in Hi-C interactions. The proposed method uses fixed sized genomic regions as the vertices of the graph. Number of read between two interacting genomic regions indicate the weight of each edge. The performance of our proposed algorithm was compared to the Multi-Objective PSO algorithm on five networks derived from cis genomic interactions in three Hi-C datasets (GM12878, CD34+ and ESCs). The experimental results show that our proposed algorithm outperforms Multi-Objective PSO technique in the identification of co-interacting genomic regions.