JSNMF enables effective and accurate integrative analysis of single-cell multiomics data.

The single-cell multiomics technologies provide an unprecedented opportunity to study the cellular heterogeneity from different layers of transcriptional regulation. However, the datasets generated from these technologies tend to have high levels of noise, making data analysis challenging. Here, we propose jointly semi-orthogonal nonnegative matrix factorization (JSNMF), which is a versatile toolkit for the integrative analysis of transcriptomic and epigenomic data profiled from the same cell. JSNMF enables data visualization and clustering of the cells and also facilitates downstream analysis, including the characterization of markers and functional pathway enrichment analysis. The core of JSNMF is an unsupervised method based on JSNMF, where it assumes different latent variables for the two molecular modalities, and integrates the information of transcriptomic and epigenomic data with consensus graph fusion, which better tackles the distinct characteristics and levels of noise across different molecular modalities in single-cell multiomics data. We applied JSNMF to single-cell multiomics datasets from different tissues and different technologies. The results demonstrate the superior performance of JSNMF in clustering and data visualization of the cells. JSNMF also allows joint analysis of multiple single-cell multiomics experiments and single-cell multiomics data with more than two modalities profiled on the same cell. JSNMF also provides rich biological insight on the markers, cell-type-specific region-gene associations and the functions of the identified cell subpopulation.

scAWMV: an adaptively weighted multi-view learning framework for the integrative analysis of parallel scRNA-seq and scATAC-seq data.

MOTIVATION: Technological advances have enabled us to profile single-cell multi-omics data from the same cells, providing us with an unprecedented opportunity to understand the cellular phenotype and links to its genotype. The available protocols and multi-omics datasets [including parallel single-cell RNA sequencing (scRNA-seq) and single-cell ATAC sequencing (scATAC-seq) data profiled from the same cell] are growing increasingly. However, such data are highly sparse and tend to have high level of noise, making data analysis challenging. The methods that integrate the multi-omics data can potentially improve the capacity of revealing the cellular heterogeneity. RESULTS: We propose an adaptively weighted multi-view learning (scAWMV) method for the integrative analysis of parallel scRNA-seq and scATAC-seq data profiled from the same cell. scAWMV considers both the difference in importance across different modalities in multi-omics data and the biological connection of the features in the scRNA-seq and scATAC-seq data. It generates biologically meaningful low-dimensional representations for the transcriptomic and epigenomic profiles via unsupervised learning. Application to four real datasets demonstrates that our framework scAWMV is an efficient method to dissect cellular heterogeneity for single-cell multi-omics data. AVAILABILITY AND IMPLEMENTATION: The software and datasets are available at https://github.com/pengchengzeng/scAWMV. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Coupled co-clustering-based unsupervised transfer learning for the integrative analysis of single-cell genomic data.

Unsupervised methods, such as clustering methods, are essential to the analysis of single-cell genomic data. The most current clustering methods are designed for one data type only, such as single-cell RNA sequencing (scRNA-seq), single-cell ATAC sequencing (scATAC-seq) or sc-methylation data alone, and a few are developed for the integrative analysis of multiple data types. The integrative analysis of multimodal single-cell genomic data sets leverages the power in multiple data sets and can deepen the biological insight. In this paper, we propose a coupled co-clustering-based unsupervised transfer learning algorithm (coupleCoC) for the integrative analysis of multimodal single-cell data. Our proposed coupleCoC builds upon the information theoretic co-clustering framework. In co-clustering, both the cells and the genomic features are simultaneously clustered. Clustering similar genomic features reduces the noise in single-cell data and facilitates transfer of knowledge across single-cell datasets. We applied coupleCoC for the integrative analysis of scATAC-seq and scRNA-seq data, sc-methylation and scRNA-seq data and scRNA-seq data from mouse and human. We demonstrate that coupleCoC improves the overall clustering performance and matches the cell subpopulations across multimodal single-cell genomic datasets. Our method coupleCoC is also computationally efficient and can scale up to large datasets. Availability: The software and datasets are available at https://github.com/cuhklinlab/coupleCoC.

coupleCoC+: An information-theoretic co-clustering-based transfer learning framework for the integrative analysis of single-cell genomic data.

Technological advances have enabled us to profile multiple molecular layers at unprecedented single-cell resolution and the available datasets from multiple samples or domains are growing. These datasets, including scRNA-seq data, scATAC-seq data and sc-methylation data, usually have different powers in identifying the unknown cell types through clustering. So, methods that integrate multiple datasets can potentially lead to a better clustering performance. Here we propose coupleCoC+ for the integrative analysis of single-cell genomic data. coupleCoC+ is a transfer learning method based on the information-theoretic co-clustering framework. In coupleCoC+, we utilize the information in one dataset, the source data, to facilitate the analysis of another dataset, the target data. coupleCoC+ uses the linked features in the two datasets for effective knowledge transfer, and it also uses the information of the features in the target data that are unlinked with the source data. In addition, coupleCoC+ matches similar cell types across the source data and the target data. By applying coupleCoC+ to the integrative clustering of mouse cortex scATAC-seq data and scRNA-seq data, mouse and human scRNA-seq data, mouse cortex sc-methylation and scRNA-seq data, and human blood dendritic cells scRNA-seq data from two batches, we demonstrate that coupleCoC+ improves the overall clustering performance and matches the cell subpopulations across multimodal single-cell genomic datasets. coupleCoC+ has fast convergence and it is computationally efficient. The software is available at https://github.com/cuhklinlab/coupleCoC_plus.

Generation of arbitrary partially coherent Bessel beam array with a LED for confocal imaging.

As the most important class of self-imaging beams, Bessel Beams (BBs) have been extensively studied, and various applications in optical trapping, communication, imaging and quantum studies have been found. In this paper, we propose a new method to generate arbitrary (quasi-) BB arrays by using a single LED light source. The method is simpler, cheaper, and more compatible than other existing methods. The key idea of the proposed method is to form spatially controllable incoherent point sources used to generate BB array imaging. Detailed theoretical deduction, analysis of properties of the generated BB array and comparison with those generated by coherent light sources are depicted. Further application to confocal imaging shows that the BB array is promising for fast, super depth-of-field imaging and multi-particle optical manipulations.

scICML: Information-Theoretic Co-Clustering-Based Multi-View Learning for the Integrative Analysis of Single-Cell Multi-Omics Data.

Modern high-throughput sequencing technologies have enabled us to profile multiple molecular modalities from the same single cell, providing unprecedented opportunities to assay cellular heterogeneity from multiple biological layers. However, the datasets generated from these technologies tend to have high level of noise and are highly sparse, bringing challenges to data analysis. In this paper, we develop a novel information-theoretic co-clustering-based multi-view learning (scICML) method for multi-omics single-cell data integration. scICML utilizes co-clusterings to aggregate similar features for each view of data and uncover the common clustering pattern for cells. In addition, scICML automatically matches the clusters of the linked features across different data types for considering the biological dependency structure across different types of genomic features. Our experiments on four real-world datasets demonstrate that scICML improves the overall clustering performance and provides biological insights into the data analysis of peripheral blood mononuclear cells.

Improved PAA algorithm for breast mass detection in mammograms.

Mammography screening is instrumental in the early detection and diagnosis of breast cancer by identifying masses in mammograms. With the rapid development of deep learning, numerous deep learning-based object detection algorithms have been explored for mass detection studies. However, these methods often yield a high false positive rate per image (FPPI) while achieving a high true positive rate (TPR). To maintain a higher TPR while also ensuring lower FPPI, we improved the Probability Anchor Assignment (PAA) algorithm to enhance the detection capability for mammographic characteristics with our previous work. We considered three dimensions: the backbone network, feature fusion module, and dense detection heads. The final experiment showed the effectiveness of the proposed method, and the TPR/FPPI values of the final improved PAA algorithm were 0.96/0.56 on the INbreast datasets. Compared to other methods, our method stands distinguished with its effectiveness in addressing the imbalance between positive and negative classes in cases of single lesion detection.

Model-based joint curve registration and classification.

In this paper, we consider the problem of classification of misaligned multivariate functional data. We propose to use a model-based approach for the joint registration and classification of such data. The observed functional inputs are modeled as a functional nonlinear mixed effects model containing a nonlinear functional fixed effect constructed upon warping functions to account for curve alignment, and a nonlinear functional random effects component to address the variability among subjects. The warping functions are also modeled to accommodate common effect within groups and the variability between subjects. Then, a functional logistic regression model defined upon the representation of the aligned curves and scalar inputs is used to account for curve classification. EM-based algorithms are developed to perform maximum likelihood inference of the proposed models. The identifiability of the registration model and the asymptotical properties of the proposed method are established. The performance of the proposed procedure is illustrated via simulation studies and an analysis of a hyoid bone movement data application. The statistical developments proposed in this paper were motivated by the hyoid bone movement study, the methodology is designed and presented generality and can be applied to numerous areas of scientific research.

Semi-automatic tracking, smoothing and segmentation of hyoid bone motion from videofluoroscopic swallowing study.

Motion analysis of the hyoid bone via videofluoroscopic study has been used in clinical research, but the classical manual tracking method is generally labor intensive and time consuming. Although some automatic tracking methods have been developed, masked points could not be tracked and smoothing and segmentation, which are necessary for functional motion analysis prior to registration, were not provided by the previous software. We developed software to track the hyoid bone motion semi-automatically. It works even in the situation where the hyoid bone is masked by the mandible and has been validated in dysphagia patients with stroke. In addition, we added the function of semi-automatic smoothing and segmentation. A total of 30 patients' data were used to develop the software, and data collected from 17 patients were used for validation, of which the trajectories of 8 patients were partly masked. Pearson correlation coefficients between the manual and automatic tracking are high and statistically significant (0.942 to 0.991, P-value<0.0001). Relative errors between automatic tracking and manual tracking in terms of the x-axis, y-axis and 2D range of hyoid bone excursion range from 3.3% to 9.2%. We also developed an automatic method to segment each hyoid bone trajectory into four phases (elevation phase, anterior movement phase, descending phase and returning phase). The semi-automatic hyoid bone tracking from VFSS data by our software is valid compared to the conventional manual tracking method. In addition, the ability of automatic indication to switch the automatic mode to manual mode in extreme cases and calibration without attaching the radiopaque object is convenient and useful for users. Semi-automatic smoothing and segmentation provide further information for functional motion analysis which is beneficial to further statistical analysis such as functional classification and prognostication for dysphagia. Therefore, this software could provide the researchers in the field of dysphagia with a convenient, useful, and all-in-one platform for analyzing the hyoid bone motion. Further development of our method to track the other swallowing related structures or objects such as epiglottis and bolus and to carry out the 2D curve registration may be needed for a more comprehensive functional data analysis for dysphagia with big data.