Identification of COVID-19 severity biomarkers based on feature selection on single-cell RNA-Seq data of CD8+ T cells.

The global outbreak of the COVID-19 epidemic has become a major public health problem. COVID-19 virus infection triggers a complex immune response. CD8+ T cells, in particular, play an essential role in controlling the severity of the disease. However, the mechanism of the regulatory role of CD8+ T cells on COVID-19 remains poorly investigated. In this study, single-cell gene expression profiles from three CD8+ T cell subtypes (effector, memory, and naive T cells) were downloaded. Each cell subtype included three disease states, namely, acute COVID-19, convalescent COVID-19, and unexposed individuals. The profiles on each cell subtype were individually analyzed in the same way. Irrelevant features in the profiles were first excluded by the Boruta method. The remaining features for each CD8+ T cells subtype were further analyzed by Max-Relevance and Min-Redundancy, Monte Carlo feature selection, and light gradient boosting machine methods to obtain three feature lists. These lists were then brought into the incremental feature selection method to determine the optimal features for each cell subtype. Their corresponding genes may be latent biomarkers to determine COVID-19 severity. Genes, such as ZFP36, DUSP1, TCR, and IL7R, can be confirmed to play an immune regulatory role in COVID-19 infection and recovery. The results of functional enrichment analysis revealed that these important genes may be associated with immune functions, such as response to cAMP, response to virus, T cell receptor complex, T cell activation, and T cell differentiation. This study further set up different gene expression pattens, represented by classification rules, on three states of COVID-19 and constructed several efficient classifiers to distinguish COVID-19 severity. The findings of this study provided new insights into the biological processes of CD8+ T cells in regulating the immune response.

Identification of Transcriptome Biomarkers for Severe COVID-19 with Machine Learning Methods.

The rapid spread of COVID-19 has become a major concern for people's lives and health all around the world. COVID-19 patients in various phases and severity require individualized treatment given that different patients may develop different symptoms. We employed machine learning methods to discover biomarkers that may accurately classify COVID-19 in various disease states and severities in this study. The blood gene expression profiles from 50 COVID-19 patients without intensive care, 50 COVID-19 patients with intensive care, 10 non-COVID-19 individuals without intensive care, and 16 non-COVID-19 individuals with intensive care were analyzed. Boruta was first used to remove irrelevant gene features in the expression profiles, and then, the minimum redundancy maximum relevance was applied to sort the remaining features. The generated feature-ranked list was fed into the incremental feature selection method to discover the essential genes and build powerful classifiers. The molecular mechanism of some biomarker genes was addressed using recent studies, and biological functions enriched by essential genes were examined. Our findings imply that genes including UBE2C, PCLAF, CDK1, CCNB1, MND1, APOBEC3G, TRAF3IP3, CD48, and GZMA play key roles in defining the different states and severity of COVID-19. Thus, a new point of reference is provided for understanding the disease's etiology and facilitating a precise therapy.

Identification of methylation signatures and rules for predicting the severity of SARS-CoV-2 infection with machine learning methods.

Patients infected with SARS-CoV-2 at various severities have different clinical manifestations and treatments. Mild or moderate patients usually recover with conventional medical treatment, but severe patients require prompt professional treatment. Thus, stratifying infected patients for targeted treatment is meaningful. A computational workflow was designed in this study to identify key blood methylation features and rules that can distinguish the severity of SARS-CoV-2 infection. First, the methylation features in the expression profile were deeply analyzed by a Monte Carlo feature selection method. A feature list was generated. Next, this ranked feature list was fed into the incremental feature selection method to determine the optimal features for different classification algorithms, thereby further building optimal classifiers. These selected key features were analyzed by functional enrichment to detect their biofunctional information. Furthermore, a set of rules were set up by a white-box algorithm, decision tree, to uncover different methylation patterns on various severity of SARS-CoV-2 infection. Some genes (PARP9, MX1, IRF7), corresponding to essential methylation sites, and rules were validated by published academic literature. Overall, this study contributes to revealing potential expression features and provides a reference for patient stratification. The physicians can prioritize and allocate health and medical resources for COVID-19 patients based on their predicted severe clinical outcomes.

Identification of DNA Methylation Signature and Rules for SARS-CoV-2 Associated with Age.

BACKGROUND: COVID-19 displays an increased mortality rate and higher risk of severe symptoms with increasing age, which is thought to be a result of the compromised immunity of elderly patients. However, the underlying mechanisms of aging-associated immunodeficiency against Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains unclear. Epigenetic modifications show considerable changes with age, causing altered gene regulations and cell functions during the aging process. The DNA methylation patterns among patients with coronavirus 2019 disease (COVID-19) who had different ages were compared to explore the effect of aging-associated methylation modifications in SARS-CoV-2 infection. METHODS: Patients with COVID-19 were divided into three groups according to age. Boruta was used on the DNA methylation profiles of the patients to remove irrelevant features and retain essential signature sites to identify substantial aging-associated DNA methylation changes in COVID-19. Next, these features were ranked using the minimum redundancy maximum relevance (mRMR) method, and the feature list generated by mRMR was processed into the incremental feature selection method with decision tree (DT), random forest, k-nearest neighbor, and support vector machine to obtain the key methylation sites, optimal classifier, and decision rules. RESULTS: Several key methylation sites that showed distinct patterns among the patients with COVID-19 who had different ages were identified, and these methylation modifications may play crucial roles in regulating immune cell functions. An optimal classifier was built based on selected methylation signatures, which can be useful to predict the aging-associated disease risk of COVID-19. CONCLUSIONS: Existing works and our predictions suggest that the methylation modifications of genes, such as NHLH2, ZEB2, NWD1, ELOVL2, FGGY, and FHL2, are closely associated with age in patients with COVID-19, and the 39 decision rules extracted with the optimal DT classifier provides quantitative context to the methylation modifications in elderly patients with COVID-19. Our findings contribute to the understanding of the epigenetic regulations of aging-associated COVID-19 symptoms and provide the potential methylation targets for intervention strategies in elderly patients.

Identifying Methylation Signatures and Rules for COVID-19 With Machine Learning Methods.

The occurrence of coronavirus disease 2019 (COVID-19) has become a serious challenge to global public health. Definitive and effective treatments for COVID-19 are still lacking, and targeted antiviral drugs are not available. In addition, viruses can regulate host innate immunity and antiviral processes through the epigenome to promote viral self-replication and disease progression. In this study, we first analyzed the methylation dataset of COVID-19 using the Monte Carlo feature selection method to obtain a feature list. This feature list was subjected to the incremental feature selection method combined with a decision tree algorithm to extract key biomarkers, build effective classification models and classification rules that can remarkably distinguish patients with or without COVID-19. EPSTI1, NACAP1, SHROOM3, C19ORF35, and MX1 as the essential features play important roles in the infection and immune response to novel coronavirus. The six significant rules extracted from the optimal classifier quantitatively explained the expression pattern of COVID-19. Therefore, these findings validated that our method can distinguish COVID-19 at the methylation level and provide guidance for the diagnosis and treatment of COVID-19.

Recognition of Immune Cell Markers of COVID-19 Severity with Machine Learning Methods.

COVID-19 is hypothesized to be linked to the host's excessive inflammatory immunological response to SARS-CoV-2 infection, which is regarded to be a major factor in disease severity and mortality. Numerous immune cells play a key role in immune response regulation, and gene expression analysis in these cells could be a useful method for studying disease states, assessing immunological responses, and detecting biomarkers. Here, we developed a machine learning procedure to find biomarkers that discriminate disease severity in individual immune cells (B cell, CD4+ cell, CD8+ cell, monocyte, and NK cell) using single-cell gene expression profiles of COVID-19. The gene features of each profile were first filtered and ranked using the Boruta feature selection method and mRMR, and the resulting ranked feature lists were then fed into the incremental feature selection method to determine the optimal number of features with decision tree and random forest algorithms. Meanwhile, we extracted the classification rules in each cell type from the optimal decision tree classifiers. The best gene sets discovered in this study were analyzed by GO and KEGG pathway enrichment, and some important biomarkers like TLR2, ITK, CX3CR1, IL1B, and PRDM1 were validated by recent literature. The findings reveal that the optimal gene sets for each cell type can accurately classify COVID-19 disease severity and provide insight into the molecular mechanisms involved in disease progression.

Identification of COVID-19 Infection-Related Human Genes Based on a Random Walk Model in a Virus-Human Protein Interaction Network.

Coronaviruses are specific crown-shaped viruses that were first identified in the 1960s, and three typical examples of the most recent coronavirus disease outbreaks include severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and COVID-19. Particularly, COVID-19 is currently causing a worldwide pandemic, threatening the health of human beings globally. The identification of viral pathogenic mechanisms is important for further developing effective drugs and targeted clinical treatment methods. The delayed revelation of viral infectious mechanisms is currently one of the technical obstacles in the prevention and treatment of infectious diseases. In this study, we proposed a random walk model to identify the potential pathological mechanisms of COVID-19 on a virus-human protein interaction network, and we effectively identified a group of proteins that have already been determined to be potentially important for COVID-19 infection and for similar SARS infections, which help further developing drugs and targeted therapeutic methods against COVID-19. Moreover, we constructed a standard computational workflow for predicting the pathological biomarkers and related pharmacological targets of infectious diseases.