The challenges and opportunities of scRNA-seq in COVID-19 research and clinical translation.

The application of single-cell RNA sequencing in COVID-19 research has greatly improved our understanding of COVID-19 pathogenesis and immunological characteristics. In this commentary, we discuss the current challenges, limitations, and perspectives in harnessing the power of single-cell RNA sequencing to accelerate both basic research and therapeutic development for COVID-19 and other emerging infectious diseases.

Detecting COVID-19 infection status from chest X-ray and CT scan via single transfer learning-driven approach.

COVID-19 has caused over 528 million infected cases and over 6.25 million deaths since its outbreak in 2019. The uncontrolled transmission of the SARS-CoV-2 virus has caused human suffering and the death of uncountable people. Despite the continuous effort by the researchers and laboratories, it has been difficult to develop reliable efficient and stable vaccines to fight against the rapidly evolving virus strains. Therefore, effectively preventing the transmission in the community and globally has remained an urgent task since its outbreak. To avoid the rapid spread of infection, we first need to identify the infected individuals and isolate them. Therefore, screening computed tomography (CT scan) and X-ray can better separate the COVID-19 infected patients from others. However, one of the main challenges is to accurately identify infection from a medical image. Even experienced radiologists often have failed to do it accurately. On the other hand, deep learning algorithms can tackle this task much easier, faster, and more accurately. In this research, we adopt the transfer learning method to identify the COVID-19 patients from normal individuals when there is an inadequacy of medical image data to save time by generating reliable results promptly. Furthermore, our model can perform both X-rays and CT scan. The experimental results found that the introduced model can achieve 99.59% accuracy for X-rays and 99.95% for CT scan images. In summary, the proposed method can effectively identify COVID-19 infected patients, could be a great way which will help to classify COVID-19 patients quickly and prevent the viral transmission in the community.

Evaluation and Optimization of Biomedical Image-Based Deep Convolutional Neural Network Model for COVID-19 Status Classification

Accurate detection of an individual's coronavirus disease 2019 (COVID-19) status has become critical as the COVID-19 pandemic has led to over 615 million cases and over 6.454 million deaths since its outbreak in 2019. Our proposed research work aims to present a deep convolutional neural network-based framework for the detection of COVID-19 status from chest X-ray and CT scan imaging data acquired from three benchmark imagery datasets. VGG-19, ResNet-50 and Inception-V3 models are employed in this research study to perform image classification. A variety of evaluation metrics including kappa statistic, Root-Mean-Square Error (RMSE), accuracy, True Positive Rate (TPR), False Positive Rate (FPR), Recall, precision, and F-measure are used to ensure adequate performance of the proposed framework. Our findings indicate that the Inception-V3 model has the best performance in terms of COVID-19 status detection.

Detecting COVID-19 infection status from chest X-ray and CT scan via single transfer learning-driven approach

COVID-19 has caused over 528 million infected cases and over 6.25 million deaths since its outbreak in 2019. The uncontrolled transmission of the SARS-CoV-2 virus has caused human suffering and the death of uncountable people. Despite the continuous effort by the researchers and laboratories, it has been difficult to develop reliable efficient and stable vaccines to fight against the rapidly evolving virus strains. Therefore, effectively preventing the transmission in the community and globally has remained an urgent task since its outbreak. To avoid the rapid spread of infection, we first need to identify the infected individuals and isolate them. Therefore, screening computed tomography (CT scan) and X-ray can better separate the COVID-19 infected patients from others. However, one of the main challenges is to accurately identify infection from a medical image. Even experienced radiologists often have failed to do it accurately. On the other hand, deep learning algorithms can tackle this task much easier, faster, and more accurately. In this research, we adopt the transfer learning method to identify the COVID-19 patients from normal individuals when there is an inadequacy of medical image data to save time by generating reliable results promptly. Furthermore, our model can perform both X-rays and CT scan. The experimental results found that the introduced model can achieve 99.59% accuracy for X-rays and 99.95% for CT scan images. In summary, the proposed method can effectively identify COVID-19 infected patients, could be a great way which will help to classify COVID-19 patients quickly and prevent the viral transmission in the community.

Designing optimal convolutional neural network architecture using differential evolution algorithm.

Convolutional neural networks (CNNs) are deep learning models used widely for solving various tasks like computer vision and speech recognition. CNNs are developed manually based on problem-specific domain knowledge and tricky settings, which are laborious, time consuming, and challenging. To solve these, our study develops an improved differential evolution of convolutional neural network (IDECNN) algorithm to design CNN layer architectures for image classification. Variable-length encoding is utilized to represent the flexible layer architecture of a CNN model in IDECNN. An efficient heuristic mechanism is proposed in IDECNN to evolve CNN architecture through mutation and crossover to prevent premature convergence during the evolutionary process. Eight well-known imaging datasets were utilized. The results showed that IDECNN could design suitable architecture compared with 20 existing CNN models. Finally, CNN architectures are applied to pneumonia and coronavirus disease 2019 (COVID-19) X-ray biomedical image data. The results demonstrated the usefulness of the proposed approach to generate a suitable CNN model.

Delineating COVID-19 immunological features using single-cell RNA sequencing.

Understanding the molecular mechanisms of coronavirus disease 2019 (COVID-19) pathogenesis and immune response is vital for developing therapies. Single-cell RNA sequencing has been applied to delineate the cellular heterogeneity of the host response toward COVID-19 in multiple tissues and organs. Here, we review the applications and findings from over 80 original COVID-19 single-cell RNA sequencing studies as well as many secondary analysis studies. We describe that single-cell RNA sequencing reveals multiple features of COVID-19 patients with different severity, including cell populations with proportional alteration, COVID-19-induced genes and pathways, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in single cells, and adaptation of immune repertoire. We also collect published single-cell RNA sequencing datasets from original studies. Finally, we discuss the limitations in current studies and perspectives for future advance.

Drug-Target Network Study Reveals the Core Target-Protein Interactions of Various COVID-19 Treatments.

The coronavirus disease 2019 (COVID-19) pandemic has caused a dramatic loss of human life and devastated the worldwide economy. Numerous efforts have been made to mitigate COVID-19 symptoms and reduce the death rate. We conducted literature mining of more than 250 thousand published works and curated the 174 most widely used COVID-19 medications. Overlaid with the human protein-protein interaction (PPI) network, we used Steiner tree analysis to extract a core subnetwork that grew from the pharmacological targets of ten credible drugs ascertained by the CTD database. The resultant core subnetwork consisted of 34 interconnected genes, which were associated with 36 drugs. Immune cell membrane receptors, the downstream cellular signaling cascade, and severe COVID-19 symptom risk were significantly enriched for the core subnetwork genes. The lung mast cell was most enriched for the target genes among 1355 human tissue-cell types. Human bronchoalveolar lavage fluid COVID-19 single-cell RNA-Seq data highlighted the fact that T cells and macrophages have the most overlapping genes from the core subnetwork. Overall, we constructed an actionable human target-protein module that mainly involved anti-inflammatory/antiviral entry functions and highly overlapped with COVID-19-severity-related genes. Our findings could serve as a knowledge base for guiding drug discovery or drug repurposing to confront the fast-evolving SARS-CoV-2 virus and other severe infectious diseases.

Cell-Type-Specific Profibrotic Scores across Multi-Organ Systems Predict Cancer Prognosis.

Fibrosis is a major cause of mortality. Key profibrotic mechanisms are common pathways involved in tumorigenesis. Characterizing the profibrotic phenotype will help reveal the underlying mechanisms of early development and progression of a variety of human diseases, such as fibrosis and cancer. Fibroblasts have been center stage in response to various stimuli, such as viral infections. However, a comprehensive catalog of cell types involved in this process is currently lacking. Here, we deployed single-cell transcriptomic data across multi-organ systems (i.e., heart, kidney, liver, and lung) to identify novel profibrotic cell populations based on ECM pathway activity at single-cell resolution. In addition to fibroblasts, we also reported that epithelial, endothelial, myeloid, natural killer T, and secretory cells, as well as proximal convoluted tubule cells of the nephron, were significantly actively involved. Cell-type-specific gene signatures were enriched in viral infection pathways, enhanced glycolysis, and carcinogenesis, among others; they were validated using independent datasets in this study. By projecting the signatures into bulk TCGA tumor samples, we could predict prognosis in the patients using profibrotic scores. Our profibrotic cellular phenotype is useful for identifying new mechanisms and potential drug targets at the cell-type level for a wide range of diseases involved in ECM pathway activation.

Drug repurposing for COVID-19 using graph neural network and harmonizing multiple evidence.

Since the 2019 novel coronavirus disease (COVID-19) outbreak in 2019 and the pandemic continues for more than one year, a vast amount of drug research has been conducted and few of them got FDA approval. Our objective is to prioritize repurposable drugs using a pipeline that systematically integrates the interaction between COVID-19 and drugs, deep graph neural networks, and in vitro/population-based validations. We first collected all available drugs (n = 3635) related to COVID-19 patient treatment through CTDbase. We built a COVID-19 knowledge graph based on the interactions among virus baits, host genes, pathways, drugs, and phenotypes. A deep graph neural network approach was used to derive the candidate drug's representation based on the biological interactions. We prioritized the candidate drugs using clinical trial history, and then validated them with their genetic profiles, in vitro experimental efficacy, and population-based treatment effect. We highlight the top 22 drugs including Azithromycin, Atorvastatin, Aspirin, Acetaminophen, and Albuterol. We further pinpointed drug combinations that may synergistically target COVID-19. In summary, we demonstrated that the integration of extensive interactions, deep neural networks, and multiple evidence can facilitate the rapid identification of candidate drugs for COVID-19 treatment.

Association of CXCR6 with COVID-19 severity: delineating the host genetic factors in transcriptomic regulation.

The coronavirus disease 2019 (COVID-19) is an infectious disease that mainly affects the host respiratory system with ~ 80% asymptomatic or mild cases and ~ 5% severe cases. Recent genome-wide association studies (GWAS) have identified several genetic loci associated with the severe COVID-19 symptoms. Delineating the genetic variants and genes is important for better understanding its biological mechanisms. We implemented integrative approaches, including transcriptome-wide association studies (TWAS), colocalization analysis, and functional element prediction analysis, to interpret the genetic risks using two independent GWAS datasets in lung and immune cells. To understand the context-specific molecular alteration, we further performed deep learning-based single-cell transcriptomic analyses on a bronchoalveolar lavage fluid (BALF) dataset from moderate and severe COVID-19 patients. We discovered and replicated the genetically regulated expression of CXCR6 and CCR9 genes. These two genes have a protective effect on lung, and a risk effect on whole blood, respectively. The colocalization analysis of GWAS and cis-expression quantitative trait loci highlighted the regulatory effect on CXCR6 expression in lung and immune cells. In the lung-resident memory CD8+ T (TRM) cells, we found a 2.24-fold decrease of cell proportion among CD8+ T cells and lower expression of CXCR6 in the severe patients than moderate patients. Pro-inflammatory transcriptional programs were highlighted in the TRM cellular trajectory from moderate to severe patients. CXCR6 from the 3p21.31 locus is associated with severe COVID-19. CXCR6 tends to have a lower expression in lung TRM cells of severe patients, which aligns with the protective effect of CXCR6 from TWAS analysis.

Investigating Cellular Trajectories in the Severity of COVID-19 and Their Transcriptional Programs Using Machine Learning Approaches.

Single-cell RNA sequencing of the bronchoalveolar lavage fluid (BALF) samples from COVID-19 patients has enabled us to examine gene expression changes of human tissue in response to the SARS-CoV-2 virus infection. However, the underlying mechanisms of COVID-19 pathogenesis at single-cell resolution, its transcriptional drivers, and dynamics require further investigation. In this study, we applied machine learning algorithms to infer the trajectories of cellular changes and identify their transcriptional programs. Our study generated cellular trajectories that show the COVID-19 pathogenesis of healthy-to-moderate and healthy-to-severe on macrophages and T cells, and we observed more diverse trajectories in macrophages compared to T cells. Furthermore, our deep-learning algorithm DrivAER identified several pathways (e.g., xenobiotic pathway and complement pathway) and transcription factors (e.g., MITF and GATA3) that could be potential drivers of the transcriptomic changes for COVID-19 pathogenesis and the markers of the COVID-19 severity. Moreover, macrophages-related functions corresponded more to the disease severity compared to T cells-related functions. Our findings more proficiently dissected the transcriptomic changes leading to the severity of a COVID-19 infection.

Accelerating bioinformatics research with International Conference on Intelligent Biology and Medicine 2020.

The International Association for Intelligent Biology and Medicine (IAIBM) is a nonprofit organization that promotes intelligent biology and medical science. It hosts an annual International Conference on Intelligent Biology and Medicine (ICIBM), which was initially established in 2012. Due to the coronavirus (COVID-19) pandemic, the ICIBM 2020 was held for the first time as a virtual online conference on August 9 to 10. The virtual conference had ~ 300 registered participants and featured 41 online real-time presentations. ICIBM 2020 received a total of 75 manuscript submissions, and 12 were selected to be published in this special issue of BMC Bioinformatics. These 12 manuscripts cover a wide range of bioinformatics topics including network analysis, imaging analysis, machine learning, gene expression analysis, and sequence analysis.

Differential Expression of Viral Transcripts From Single-Cell RNA Sequencing of Moderate and Severe COVID-19 Patients and Its Implications for Case Severity.

With steady increase of new COVID-19 cases around the world, especially in the United States, health care resources in areas with the disease outbreak are quickly exhausted by overwhelming numbers of COVID-19 patients. Therefore, strategies that can effectively and quickly predict the disease progression and stratify patients for appropriate health care arrangements are urgently needed. We explored the features and evolutionary difference of viral gene expression in the SARS-CoV-2 infected cells from the bronchoalveolar lavage fluids of patients with moderate and severe COVID-19 using both single cell and bulk tissue transcriptome data. We found SARS-CoV-2 sequences were detectable in 8 types of immune related cells, including macrophages, T cells, and NK cells. We first reported that the SARS-CoV-2 ORF10 gene was differentially expressed in the severe vs. moderate samples. Specifically, ORF10 was abundantly expressed in infected cells of severe cases, while it was barely detectable in the infected cells of moderate cases. Consequently, the expression ratio of ORF10 to nucleocapsid (N) was significantly higher in severe than moderate cases (p = 0.0062). Moreover, we found transcription regulatory sequences (TRSs) of the viral leader sequence-independent fusions with a 5' joint point at position 1073 of SARS-CoV-2 genome were detected mainly in the patients with death outcome, suggesting its potential indication of clinical outcome. Finally, we identified the motifs in TRS of the viral leader sequence-dependent fusion events of SARS-CoV-2 and compared with that in SARS-CoV, suggesting its evolutionary trajectory. These results implicated potential roles and predictive features of viral transcripts in the pathogenesis of COVID-19 moderate and severe patients. Such features and evolutionary patterns require more data to validate in future.

Drug Repurposing for COVID-19 using Graph Neural Network with Genetic, Mechanistic, and Epidemiological Validation.

Amid the pandemic of 2019 novel coronavirus disease (COVID-19) infected by SARS-CoV-2, a vast amount of drug research for prevention and treatment has been quickly conducted, but these efforts have been unsuccessful thus far. Our objective is to prioritize repurposable drugs using a drug repurposing pipeline that systematically integrates multiple SARS-CoV-2 and drug interactions, deep graph neural networks, and in-vitro/population-based validations. We first collected all the available drugs (n= 3,635) involved in COVID-19 patient treatment through CTDbase. We built a SARS-CoV-2 knowledge graph based on the interactions among virus baits, host genes, pathways, drugs, and phenotypes. A deep graph neural network approach was used to derive the candidate representation based on the biological interactions. We prioritized the candidate drugs using clinical trial history, and then validated them with their genetic profiles, in vitro experimental efficacy, and electronic health records. We highlight the top 22 drugs including Azithromycin, Atorvastatin, Aspirin, Acetaminophen, and Albuterol. We further pinpointed drug combinations that may synergistically target COVID-19. In summary, we demonstrated that the integration of extensive interactions, deep neural networks, and rigorous validation can facilitate the rapid identification of candidate drugs for COVID-19 treatment.