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Transmission electron microscopy imaging provides a unique opportunity to inspect the detailed structure of infected lung cells with SARS-CoV-2. Unlike previous studies, this novel study aims to investigate COVID-19 classification at the lung cellular level in response to SARS-CoV-2. Particularly, differentiating between healthy and infected human alveolar type II (hAT2) cells with SARS-CoV-2. Hence, we explore the feasibility of deep transfer learning (DTL) and introduce a highly accurate approach that works as follows: First, we downloaded and processed 286 images pertaining to healthy and infected hAT2 cells obtained from the electron microscopy public image archive. Second, we provided processed images to two DTL computations to induce ten DTL models. The first DTL computation employs five pre-trained models (including DenseNet201 and ResNet152V2) trained on more than one million images from the ImageNet database to extract features from hAT2 images. Then, it flattens and provides the output feature vectors to a trained, densely connected classifier with the Adam optimizer. The second DTL computation works in a similar manner, with a minor difference in that we freeze the first layers for feature extraction in pre-trained models while unfreezing and jointly training the next layers. The results using five-fold cross-validation demonstrated that TFeDenseNet201 is 12.37× faster and superior, yielding the highest average ACC of 0.993 (F1 of 0.992 and MCC of 0.986) with statistical significance ( P < 2.2 × 10 − 16 from a t-test) compared to an average ACC of 0.937 (F1 of 0.938 and MCC of 0.877) for the counterpart (TFtDenseNet201), showing no significance results ( P = 0.093 from a t-test). [ABSTRACT FROM AUTHOR]

Accurate deep learning (DL) models to predict type 2 diabetes (T2D) are concerned not only with targeting the discrimination task but also with learning useful feature representation. However, existing DL tools are far from perfect and do not provide appropriate interpretation as a guideline to explain and promote superior performance in the target task. Therefore, we provide an interpretable approach for our presented deep transfer learning (DTL) models to overcome such drawbacks, working as follows. We utilize several pre-trained models including SEResNet152, and SEResNeXT101. Then, we transfer knowledge from pre-trained models via keeping the weights in the convolutional base (i.e., feature extraction part) while modifying the classification part with the use of Adam optimizer to deal with classifying healthy controls and T2D based on single-cell gene regulatory network (SCGRN) images. Another DTL models work in a similar manner but just with keeping weights of the bottom layers in the feature extraction unaltered while updating weights of consecutive layers through training from scratch. Experimental results on the whole 224 SCGRN images using five-fold cross-validation show that our model (TFeSEResNeXT101) achieving the highest average balanced accuracy (BAC) of 0.97 and thereby significantly outperforming the baseline that resulted in an average BAC of 0.86. Moreover, the simulation study demonstrated that the superiority is attributed to the distributional conformance of model weight parameters obtained with Adam optimizer when coupled with weights from a pre-trained model. [ABSTRACT FROM AUTHOR]

It is difficult to identify histone modification from datasets that contain high-throughput sequencing data. Although multiple methods have been developed to identify histone modification, most of these methods are not specific to histone modification but are general methods that aim to identify protein binding to the genome. In this study, tensor decomposition (TD) and principal component analysis (PCA)-based unsupervised feature extraction with optimized standard deviation were successfully applied to gene expression and DNA methylation. The proposed method was used to identify histone modification. Histone modification along the genome is binned within the region of length L. Considering principal components (PCs) or singular value vectors (SVVs) that PCA or TD attributes to samples, we can select PCs or SVVs attributed to regions. The selected PCs and SVVs further attribute p-values to regions, and adjusted p-values are used to select regions. The proposed method identified various histone modifications successfully and outperformed various state-of-the-art methods. This method is expected to serve as a de facto standard method to identify histone modification. For reproducibility and to ensure the systematic analysis of our study is applicable to datasets from different gene expression experiments, we have made our tools publicly available for download from gitHub. [ABSTRACT FROM AUTHOR]

The integrated analysis of multiple gene expression profiles previously measured in distinct studies is problematic since missing both sample matches and common labels prevent their integration in fully data-driven, unsupervised training. In this study, we propose a strategy to enable the integration of multiple gene expression profiles among multiple independent studies with neither labeling nor sample matching using tensor decomposition unsupervised feature extraction. We apply this strategy to Alzheimer's disease (AD)-related gene expression profiles that lack precise correspondence among samples, including AD single-cell RNA sequence (scRNA-seq) data. We were able to select biologically reasonable genes using the integrated analysis. Overall, integrated gene expression profiles can function analogously to prior- and/or transfer-learning strategies in other machine-learning applications. For scRNA-seq, the proposed approach significantly reduces the required computational memory. [ABSTRACT FROM AUTHOR]

Tensor decomposition- and principal component analysis-based unsupervised feature extraction were proposed almost 5 and 10 years ago, respectively; although these methods have been successfully applied to a wide range of genome analyses, including drug repositioning, biomarker identification, and disease-causing genes' identification, some fundamental problems have been identified: the number of genes identified was too small to assume that there were no false negatives, and the histogram of P values derived was not fully coincident with the null hypothesis that principal component and singular value vectors follow the Gaussian distribution. Optimizing the standard deviation such that the histogram of P values is as much as possible coincident with the null hypothesis results in an increase in the number and biological reliability of the selected genes. Our contribution was that we improved these methods so as to be able to select biologically more reasonable differentially expressed genes than the state of art methods that must empirically assume negative binomial distributions and dispersion relation, which is required for the selecting more expressed genes than less expressed ones, which can be achieved by the proposed methods that do not have to assume these. [ABSTRACT FROM AUTHOR]

Identifying differentially expressed genes is difficult because of the small number of available samples compared with the large number of genes. Conventional gene selection methods employing statistical tests have the critical problem of heavy dependence of P-values on sample size. Although the recently proposed principal component analysis (PCA) and tensor decomposition (TD)-based unsupervised feature extraction (FE) has often outperformed these statistical test-based methods, the reason why they worked so well is unclear. In this study, we aim to understand this reason in the context of projection pursuit (PP) that was proposed a long time ago to solve the problem of dimensions; we can relate the space spanned by singular value vectors with that spanned by the optimal cluster centroids obtained from K-means. Thus, the success of PCA- and TD-based unsupervised FE can be understood by this equivalence. In addition to this, empirical threshold adjusted P-values of 0.01 assuming the null hypothesis that singular value vectors attributed to genes obey the Gaussian distribution empirically corresponds to threshold-adjusted P-values of 0.1 when the null distribution is generated by gene order shuffling. For this purpose, we newly applied PP to the three data sets to which PCA and TD based unsupervised FE were previously applied; these data sets treated two topics, biomarker identification for kidney cancers (the first two) and the drug discovery for COVID-19 (the thrid one). Then we found the coincidence between PP and PCA or TD based unsupervised FE is pretty well. Shuffling procedures described above are also successfully applied to these three data sets. These findings thus rationalize the success of PCA- and TD-based unsupervised FE for the first time. [ABSTRACT FROM AUTHOR]

Background: Feature selection of multi-omics data analysis remains challenging owing to the size of omics datasets, comprising approximately 10 2 – 10 5 features. In particular, appropriate methods to weight individual omics datasets are unclear, and the approach adopted has substantial consequences for feature selection. In this study, we extended a recently proposed kernel tensor decomposition (KTD)-based unsupervised feature extraction (FE) method to integrate multi-omics datasets obtained from common samples in a weight-free manner. Method: KTD-based unsupervised FE was reformatted as the collection of kernelized tensors sharing common samples, which was applied to synthetic and real datasets. Results: The proposed advanced KTD-based unsupervised FE method showed comparative performance to that of the previously proposed KTD method, as well as tensor decomposition-based unsupervised FE, but required reduced memory and central processing unit time. Moreover, this advanced KTD method, specifically designed for multi-omics analysis, attributes P values to features, which is rare for existing multi-omics–oriented methods. Conclusions: The sample R code is available at https://github.com/tagtag/MultiR/. [ABSTRACT FROM AUTHOR]

The histone group added to a gene sequence must be removed during mitosis to halt transcription during the DNA replication stage of the cell cycle. However, the detailed mechanism of this transcription regulation remains unclear. In particular, it is not realistic to reconstruct all appropriate histone modifications throughout the genome from scratch after mitosis. Thus, it is reasonable to assume that there might be a type of "bookmark" that retains the positions of histone modifications, which can be readily restored after mitosis. We developed a novel computational approach comprising tensor decomposition (TD)-based unsupervised feature extraction (FE) to identify transcription factors (TFs) that bind to genes associated with reactivated histone modifications as candidate histone bookmarks. To the best of our knowledge, this is the first application of TD-based unsupervised FE to the cell division context and phases pertaining to the cell cycle in general. The candidate TFs identified with this approach were functionally related to cell division, suggesting the suitability of this method and the potential of the identified TFs as bookmarks for histone modification during mitosis. [ABSTRACT FROM AUTHOR]

To better understand the genes with altered expression caused by infection with the novel coronavirus strain SARS-CoV-2 causing COVID-19 infectious disease, a tensor decomposition (TD)-based unsupervised feature extraction (FE) approach was applied to a gene expression profile dataset of the mouse liver and spleen with experimental infection of mouse hepatitis virus, which is regarded as a suitable model of human coronavirus infection. TD-based unsupervised FE selected 134 altered genes, which were enriched in protein-protein interactions with orf1ab, polyprotein, and 3C-like protease that are well known to play critical roles in coronavirus infection, suggesting that these 134 genes can represent the coronavirus infectious process. We then selected compounds targeting the expression of the 134 selected genes based on a public domain database. The identified drug compounds were mainly related to known antiviral drugs, several of which were also included in those previously screened with an in silico method to identify candidate drugs for treating COVID-19. [ABSTRACT FROM AUTHOR]

Background: COVID-19 is a critical pandemic that has affected human communities worldwide, and there is an urgent need to develop effective drugs. Although there are a large number of candidate drug compounds that may be useful for treating COVID-19, the evaluation of these drugs is time-consuming and costly. Thus, screening to identify potentially effective drugs prior to experimental validation is necessary. Method: In this study, we applied the recently proposed method tensor decomposition (TD)-based unsupervised feature extraction (FE) to gene expression profiles of multiple lung cancer cell lines infected with severe acute respiratory syndrome coronavirus 2. We identified drug candidate compounds that significantly altered the expression of the 163 genes selected by TD-based unsupervised FE. Results: Numerous drugs were successfully screened, including many known antiviral drug compounds such as C646, chelerythrine chloride, canertinib, BX-795, sorafenib, sorafenib, QL-X-138, radicicol, A-443654, CGP-60474, alvocidib, mitoxantrone, QL-XII-47, geldanamycin, fluticasone, atorvastatin, quercetin, motexafin gadolinium, trovafloxacin, doxycycline, meloxicam, gentamicin, and dibromochloromethane. The screen also identified ivermectin, which was first identified as an anti-parasite drug and recently the drug was included in clinical trials for SARS-CoV-2. Conclusions: The drugs screened using our strategy may be effective candidates for treating patients with COVID-19. [ABSTRACT FROM AUTHOR]

Gene expression profiles of tissues treated with drugs have recently been used to infer clinical outcomes. Although this method is often successful from the application point of view, gene expression altered by drugs is rarely analyzed in detail, because of the extremely large number of genes involved. Here, we applied tensor decomposition (TD)-based unsupervised feature extraction (FE) to the gene expression profiles of 24 mouse tissues treated with 15 drugs. TD-based unsupervised FE enabled identification of the common effects of 15 drugs including an interesting universal feature: these drugs affect genes in a gene-group-wide manner and were dependent on three tissue types (neuronal, muscular, and gastroenterological). For each tissue group, TD-based unsupervised FE enabled identification of a few tens to a few hundreds of genes affected by the drug treatment. These genes are distinctly expressed between drug treatments and controls as well as between tissues in individual tissue groups and other tissues. We also validated the assignment of genes to individual tissue groups using multiple enrichment analyses. We conclude that TD-based unsupervised FE is a promising method for integrated analysis of gene expression profiles from multiple tissues treated with multiple drugs in a completely unsupervised manner. [ABSTRACT FROM AUTHOR]

In contrast to RNA-seq analysis, which has various standard methods, no standard methods for identifying differentially methylated cytosines (DMCs) exist. To identify DMCs, we tested principal component analysis and tensor decomposition-based unsupervised feature extraction with optimized standard deviation, which has been shown to be effective for differentially expressed gene (DEG) identification. The proposed method outperformed certain conventional methods, including those that assume beta-binomial distribution for methylation as the proposed method does not require this, especially when applied to methylation profiles measured using high throughput sequencing. DMCs identified by the proposed method also significantly overlapped with various functional sites, including known differentially methylated regions, enhancers, and DNase I hypersensitive sites. The proposed method was applied to data sets retrieved from The Cancer Genome Atlas to identify DMCs using American Joint Committee on Cancer staging system edition labels. This suggests that the proposed method is a promising standard method for identifying DMCs. [ABSTRACT FROM AUTHOR]

The development of the medical applications for substances or materials that contact cells is important. Hence, it is necessary to elucidate how substances that surround cells affect gene expression during incubation. In the current study, we compared the gene expression profiles of cell lines that were in contact with collagen–glycosaminoglycan mesh and control cells. Principal component analysis-based unsupervised feature extraction was applied to identify genes with altered expression during incubation in the treated cell lines but not in the controls. The identified genes were enriched in various biological terms. Our method also outperformed a conventional methodology, namely, gene selection based on linear regression with time course. [ABSTRACT FROM AUTHOR]

Analysis of single-cell multiomics datasets is a novel topic and is considerably challenging because such datasets contain a large number of features with numerous missing values. In this study, we implemented a recently proposed tensor-decomposition (TD)-based unsupervised feature extraction (FE) technique to address this difficult problem. The technique can successfully integrate single-cell multiomics data composed of gene expression, DNA methylation, and accessibility. Although the last two have large dimensions, as many as ten million, containing only a few percentage of nonzero values, TD-based unsupervised FE can integrate three omics datasets without filling in missing values. Together with UMAP, which is used frequently when embedding single-cell measurements into two-dimensional space, TD-based unsupervised FE can produce two-dimensional embedding coincident with classification when integrating single-cell omics datasets. Genes selected based on TD-based unsupervised FE are also significantly related to reasonable biological roles. [ABSTRACT FROM AUTHOR]

• DDIs to Saccharomyces cerevisiae gene expression profiles is studied. • Integrated analyses was performed towards the collection of gene expression profiles obtained by multiple drugs treatments. • Novel unsupervised tensor-based method for evaluating DDIs is proposed. • Findings demonstrate non-linear kinetics for DDIs at various doses. • The proposed method contributes to a better understanding of DDIs. [Display omitted] The accurate prediction of new interactions between drugs is important for avoiding unknown (mild or severe) adverse reactions to drug combinations. The development of effective in silico methods for evaluating drug interactions based on gene expression data requires an understanding of how various drugs alter gene expression. Current computational methods for the prediction of drug-drug interactions (DDIs) utilize data for known DDIs to predict unknown interactions. However, these methods are limited in the absence of known predictive DDIs. To improve DDIs interpretation, a recent study has demonstrated strong non-linear (i.e., dose-dependent) effects of DDIs. In this study, we present a new unsupervised learning approach involving tensor decomposition (TD)-based unsupervised feature extraction (FE) in 3D. We utilize our approach to reanalyze available gene expression profiles for Saccharomyces cerevisiae. We found that non-linearity is possible, even for single drugs. Thus, non-linear dose-dependence cannot always be attributed to DDIs. Our analysis provides a basis for the design of effective methods for evaluating DDIs. [ABSTRACT FROM AUTHOR]

In this work, we extended the recently developed tensor decomposition (TD) based unsupervised feature extraction (FE) to a kernel-based method through a mathematical formulation. Subsequently, the kernel TD (KTD) based unsupervised FE was applied to two synthetic examples as well as real data sets, and the findings were compared with those obtained previously using the TD-based unsupervised FE approaches. The KTD-based unsupervised FE outperformed or performed comparably with the TD-based unsupervised FE in large p small n situations, which are situations involving a limited number of samples with many variables (observations). Nevertheless, the KTD-based unsupervised FE outperformed the TD-based unsupervised FE in non large p small n situations. In general, although the use of the kernel trick can help the TD-based unsupervised FE gain more variations, a wider range of problems may also be encountered. Considering the outperformance or comparable performance of the KTD-based unsupervised FE compared to the TD-based unsupervised FE when applied to large p small n problems, it is expected that the KTD-based unsupervised FE can be applied in the genomic science domain, which involves many large p small n problems, and, in which, the TD-based unsupervised FE approach has been effectively applied. • Developed kernelized tensor decomposition method for unsupervised feature extraction. • Method can realize efficient tensor computation in high dimensional feature space. • Applied method in various biological applications to demonstrate effectivity. • Proposed method can capture different underlying structures in data sets. [ABSTRACT FROM AUTHOR]

The large p small n problem is a challenge without a de facto standard method available to it. In this study, we propose a tensor-decomposition (TD)-based unsupervised feature extraction (FE) formalism applied to multiomics datasets, in which the number of features is more than 100,000 whereas the number of samples is as small as about 100, hence constituting a typical large p small n problem. The proposed TD-based unsupervised FE outperformed other conventional supervised feature selection methods, random forest, categorical regression (also known as analysis of variance, or ANOVA), penalized linear discriminant analysis, and two unsupervised methods, multiple non-negative matrix factorization and principal component analysis (PCA) based unsupervised FE when applied to synthetic datasets and four methods other than PCA based unsupervised FE when applied to multiomics datasets. The genes selected by TD-based unsupervised FE were enriched in genes known to be related to tissues and transcription factors measured. TD-based unsupervised FE was demonstrated to be not only the superior feature selection method but also the method that can select biologically reliable genes. To our knowledge, this is the first study in which TD-based unsupervised FE has been successfully applied to the integration of this variety of multiomics measurements. [ABSTRACT FROM AUTHOR]