Higher-Order Inter-chromosomal Hubs Shape 3D Genome Organization in the Nucleus.

Eukaryotic genomes are packaged into a 3-dimensional structure in the nucleus. Current methods for studying genome-wide structure are based on proximity ligation. However, this approach can fail to detect known structures, such as interactions with nuclear bodies, because these DNA regions can be too far apart to directly ligate. Accordingly, our overall understanding of genome organization remains incomplete. Here, we develop split-pool recognition of interactions by tag extension (SPRITE), a method that enables genome-wide detection of higher-order interactions within the nucleus. Using SPRITE, we recapitulate known structures identified by proximity ligation and identify additional interactions occurring across larger distances, including two hubs of inter-chromosomal interactions that are arranged around the nucleolus and nuclear speckles. We show that a substantial fraction of the genome exhibits preferential organization relative to these nuclear bodies. Our results generate a global model whereby nuclear bodies act as inter-chromosomal hubs that shape the overall packaging of DNA in the nucleus.

Enhancer-promoter interactions are reconfigured through the formation of long-range multiway hubs as mouse ES cells exit pluripotency.

Enhancers bind transcription factors, chromatin regulators, and non-coding transcripts to modulate the expression of target genes. Here, we report 3D genome structures of single mouse ES cells as they are induced to exit pluripotency and transition through a formative stage prior to undergoing neuroectodermal differentiation. We find that there is a remarkable reorganization of 3D genome structure where inter-chromosomal intermingling increases dramatically in the formative state. This intermingling is associated with the formation of a large number of multiway hubs that bring together enhancers and promoters with similar chromatin states from typically 5-8 distant chromosomal sites that are often separated by many Mb from each other. In the formative state, genes important for pluripotency exit establish contacts with emerging enhancers within these multiway hubs, suggesting that the structural changes we have observed may play an important role in modulating transcription and establishing new cell identities.

High-Resolution Mapping of Multiway Enhancer-Promoter Interactions Regulating Pathogen Detection.

Eukaryotic gene expression regulation involves thousands of distal regulatory elements. Understanding the quantitative contribution of individual enhancers to gene expression is critical for assessing the role of disease-associated genetic risk variants. Yet, we lack the ability to accurately link genes with their distal regulatory elements. To address this, we used 3D enhancer-promoter (E-P) associations identified using split-pool recognition of interactions by tag extension (SPRITE) to build a predictive model of gene expression. Our model dramatically outperforms models using genomic proximity and can be used to determine the quantitative impact of enhancer loss on gene expression in different genetic backgrounds. We show that genes that form stable E-P hubs have less cell-to-cell variability in gene expression. Finally, we identified transcription factors that regulate stimulation-dependent E-P interactions. Together, our results provide a framework for understanding quantitative contributions of E-P interactions and associated genetic variants to gene expression.

Statistical modeling and significance estimation of multi-way chromatin contacts with HyperloopFinder.

Recent advances in chromatin conformation capture technologies, such as SPRITE and Pore-C, have enabled the detection of simultaneous contacts among multiple chromatin loci. This has made it possible to investigate the cooperative transcriptional regulation involving multiple genes and regulatory elements at the resolution of a single molecule. However, these technologies are unavoidably subject to the random polymer looping effect and technical biases, making it challenging to distinguish genuine regulatory relationships directly from random polymer interactions. Here, we present HyperloopFinder, a method for identifying regulatory multi-way chromatin contacts (hyperloops) by jointly modeling the random polymer looping effect and technical biases to estimate the statistical significance of multi-way contacts. The results show that our model can accurately estimate the expected interaction frequency of multi-way contacts based on the distance distribution of pairwise contacts, revealing that most multi-way contacts can be formed by randomly linking the pairwise contacts adjacent to each other. Moreover, we observed the spatial colocalization of the interaction sites of hyperloops from image-based data. Our results also revealed that hyperloops can function as scaffolds for the cooperation among multiple genes and regulatory elements. In summary, our work contributes novel insights into higher-order chromatin structures and functions and has the potential to enhance our understanding of transcriptional regulation and other cellular processes.

Analyzing postprandial metabolomics data using multiway models: a simulation study.

BACKGROUND: Analysis of time-resolved postprandial metabolomics data can improve the understanding of metabolic mechanisms, potentially revealing biomarkers for early diagnosis of metabolic diseases and advancing precision nutrition and medicine. Postprandial metabolomics measurements at several time points from multiple subjects can be arranged as a subjects by metabolites by time points array. Traditional analysis methods are limited in terms of revealing subject groups, related metabolites, and temporal patterns simultaneously from such three-way data. RESULTS: We introduce an unsupervised multiway analysis approach based on the CANDECOMP/PARAFAC (CP) model for improved analysis of postprandial metabolomics data guided by a simulation study. Because of the lack of ground truth in real data, we generate simulated data using a comprehensive human metabolic model. This allows us to assess the performance of CP models in terms of revealing subject groups and underlying metabolic processes. We study three analysis approaches: analysis of fasting-state data using principal component analysis, T0-corrected data (i.e., data corrected by subtracting fasting-state data) using a CP model and full-dynamic (i.e., full postprandial) data using CP. Through extensive simulations, we demonstrate that CP models capture meaningful and stable patterns from simulated meal challenge data, revealing underlying mechanisms and differences between diseased versus healthy groups. CONCLUSIONS: Our experiments show that it is crucial to analyze both fasting-state and T0-corrected data for understanding metabolic differences among subject groups. Depending on the nature of the subject group structure, the best group separation may be achieved by CP models of T0-corrected or full-dynamic data. This study introduces an improved analysis approach for postprandial metabolomics data while also shedding light on the debate about correcting baseline values in longitudinal data analysis.

MCIBox: a toolkit for single-molecule multi-way chromatin interaction visualization and micro-domains identification.

The emerging ligation-free three-dimensional (3D) genome mapping technologies can identify multiplex chromatin interactions with single-molecule precision. These technologies not only offer new insight into high-dimensional chromatin organization and gene regulation, but also introduce new challenges in data visualization and analysis. To overcome these challenges, we developed MCIBox, a toolkit for multi-way chromatin interaction (MCI) analysis, including a visualization tool and a platform for identifying micro-domains with clustered single-molecule chromatin complexes. MCIBox is based on various clustering algorithms integrated with dimensionality reduction methods that can display multiplex chromatin interactions at single-molecule level, allowing users to explore chromatin extrusion patterns and super-enhancers regulation modes in transcription, and to identify single-molecule chromatin complexes that are clustered into micro-domains. Furthermore, MCIBox incorporates a two-dimensional kernel density estimation algorithm to identify micro-domains boundaries automatically. These micro-domains were stratified with distinctive signatures of transcription activity and contained different cell-cycle-associated genes. Taken together, MCIBox represents an invaluable tool for the study of multiple chromatin interactions and inaugurates a previously unappreciated view of 3D genome structure.

Tensor-tensor algebra for optimal representation and compression of multiway data.

With the advent of machine learning and its overarching pervasiveness it is imperative to devise ways to represent large datasets efficiently while distilling intrinsic features necessary for subsequent analysis. The primary workhorse used in data dimensionality reduction and feature extraction has been the matrix singular value decomposition (SVD), which presupposes that data have been arranged in matrix format. A primary goal in this study is to show that high-dimensional datasets are more compressible when treated as tensors (i.e., multiway arrays) and compressed via tensor-SVDs under the tensor-tensor product constructs and its generalizations. We begin by proving Eckart-Young optimality results for families of tensor-SVDs under two different truncation strategies. Since such optimality properties can be proven in both matrix and tensor-based algebras, a fundamental question arises: Does the tensor construct subsume the matrix construct in terms of representation efficiency? The answer is positive, as proven by showing that a tensor-tensor representation of an equal dimensional spanning space can be superior to its matrix counterpart. We then use these optimality results to investigate how the compressed representation provided by the truncated tensor SVD is related both theoretically and empirically to its two closest tensor-based analogs, the truncated high-order SVD and the truncated tensor-train SVD.

Sparse multiway canonical correlation analysis for multimodal stroke recovery data.

Conventional canonical correlation analysis (CCA) measures the association between two datasets and identifies relevant contributors. However, it encounters issues with execution and interpretation when the sample size is smaller than the number of variables or there are more than two datasets. Our motivating example is a stroke-related clinical study on pigs. The data are multimodal and consist of measurements taken at multiple time points and have many more variables than observations. This study aims to uncover important biomarkers and stroke recovery patterns based on physiological changes. To address the issues in the data, we develop two sparse CCA methods for multiple datasets. Various simulated examples are used to illustrate and contrast the performance of the proposed methods with that of the existing methods. In analyzing the pig stroke data, we apply the proposed sparse CCA methods along with dimension reduction techniques, interpret the recovery patterns, and identify influential variables in recovery.

Feasibility of excitation-emission fluorescence spectroscopy in tandem with chemometrics for quantitation of trans-resveratrol in vine-shoot ethanolic extracts.

BACKGROUND: trans-Resveratrol (TR) is a well-known phytochemical compound with important biological properties. It can be recovered from agri-food by-products or wastes, such as vine shoots. Once recovered, its concentration should be measured, possibly in a green, non-destructive, and efficient manner. With these premises, this work aimed to explore the feasibility of excitation-emission fluorescence spectroscopy combined with chemometrics for the analysis of TR in raw extracts obtained from vine shoots. A total of 75 extracts were produced and analyzed by ultra-performance liquid chromatography method with diode array detection (UPLC-DAD) and spectrofluorimetry. Then, the feasibility of two calibration strategies for TR quantitation was assessed - a parallel factor analysis (PARAFAC)-based calibration and the N-way partial least squares (NPLS) regression. RESULTS: The extracts showed variable TR content, the excitation/emission maxima of which were at around 305/390 nm, respectively. The best PARAFAC-based calibration allowed a root mean square error of prediction (RMSEP) of 22.57 mg L-1 , and a relative prediction deviation (RPD) of 2.91 to be obtained but a large number of PARAFAC components should be considered to improve the predictions. The results of the NPLS regression were slightly better, with a RMSEP of 19.47 mg L-1 , and an RPD of 3.33 in the best case. CONCLUSION: Fluorescence could be an alternative analytical technique to measure TR in complex samples. Chemometric tools allowed the identification of the TR signal in the fluorescence landscapes, which could be further used for its non-destructive quantitation. The need for a more accurate criterion for optimal PARAFAC complexity emerged. © 2024 Society of Chemical Industry.

Tucker3-PCovR: The Tucker3 principal covariates regression model.

In behavioral research, it is very common to have manage multiple datasets containing information about the same set of individuals, in such a way that one dataset attempts to explain the others. To address this need, in this paper the Tucker3-PCovR model is proposed. This model is a particular case of PCovR models which focuses on the analysis of a three-way data array and a two-way data matrix where the latter plays the explanatory role. The Tucker3-PCovR model reduces the predictors to a few components and predicts the criterion by using these components and, at the same time, the three-way data is fitted by the Tucker3 model. Both the reduction of the predictors and the prediction of the criterion are done simultaneously. An alternating least squares algorithm is proposed to estimate the Tucker3-PCovR model. A biplot representation is presented to facilitate the interpretation of the results. Some applications are made to empirical datasets from the field of psychology.

Probabilistic PARAFAC2.

The Parallel Factor Analysis 2 (PARAFAC2) is a multimodal factor analysis model suitable for analyzing multi-way data when one of the modes has incomparable observation units, for example, because of differences in signal sampling or batch sizes. A fully probabilistic treatment of the PARAFAC2 is desirable to improve robustness to noise and provide a principled approach for determining the number of factors, but challenging because direct model fitting requires that factor loadings be decomposed into a shared matrix specifying how the components are consistently co-expressed across samples and sample-specific orthogonality-constrained component profiles. We develop two probabilistic formulations of the PARAFAC2 model along with variational Bayesian procedures for inference: In the first approach, the mean values of the factor loadings are orthogonal leading to closed form variational updates, and in the second, the factor loadings themselves are orthogonal using a matrix Von Mises-Fisher distribution. We contrast our probabilistic formulations to the conventional direct fitting algorithm based on maximum likelihood on synthetic data and real fluorescence spectroscopy and gas chromatography-mass spectrometry data showing that the probabilistic formulations are more robust to noise and model order misspecification. The probabilistic PARAFAC2, thus, forms a promising framework for modeling multi-way data accounting for uncertainty.

Likelihood Ratio Test and the Evidential Approach for 2 × 2 Tables.

Categorical data analysis of 2 × 2 contingency tables is extremely common, not least because they provide risk difference, risk ratio, odds ratio, and log odds statistics in medical research. A χ2 test analysis is most often used, although some researchers use likelihood ratio test (LRT) analysis. Does it matter which test is used? A review of the literature, examination of the theoretical foundations, and analyses of simulations and empirical data are used by this paper to argue that only the LRT should be used when we are interested in testing whether the binomial proportions are equal. This so-called test of independence is by far the most popular, meaning the χ2 test is widely misused. By contrast, the χ2 test should be reserved for where the data appear to match too closely a particular hypothesis (e.g., the null hypothesis), where the variance is of interest, and is less than expected. Low variance can be of interest in various scenarios, particularly in investigations of data integrity. Finally, it is argued that the evidential approach provides a consistent and coherent method that avoids the difficulties posed by significance testing. The approach facilitates the calculation of appropriate log likelihood ratios to suit our research aims, whether this is to test the proportions or to test the variance. The conclusions from this paper apply to larger contingency tables, including multi-way tables.

Multiway generalized canonical correlation analysis.

Regularized generalized canonical correlation analysis (RGCCA) is a general multiblock data analysis framework that encompasses several important multivariate analysis methods such as principal component analysis, partial least squares regression, and several versions of generalized canonical correlation analysis. In this article, we extend RGCCA to the case where at least one block has a tensor structure. This method is called multiway generalized canonical correlation analysis (MGCCA). Convergence properties of the MGCCA algorithm are studied, and computation of higher-level components are discussed. The usefulness of MGCCA is shown on simulation and on the analysis of a cognitive study in human infants using electroencephalography (EEG).

Bayesian predictive modeling of multi-source multi-way data.

A Bayesian approach to predict a continuous or binary outcome from data that are collected from multiple sources with a multi-way (i.e., multidimensional tensor) structure is described. As a motivating example, molecular data from multiple 'omics sources, each measured over multiple developmental time points, as predictors of early-life iron deficiency (ID) in a rhesus monkey model are considered. The method uses a linear model with a low-rank structure on the coefficients to capture multi-way dependence and model the variance of the coefficients separately across each source to infer their relative contributions. Conjugate priors facilitate an efficient Gibbs sampling algorithm for posterior inference, assuming a continuous outcome with normal errors or a binary outcome with a probit link. Simulations demonstrate that the model performs as expected in terms of misclassification rates and correlation of estimated coefficients with true coefficients, with large gains in performance by incorporating multi-way structure and modest gains when accounting for differing signal sizes across the different sources. Moreover, it provides robust classification of ID monkeys for the motivating application.

Intelligent Fault Diagnosis of Hydraulic Multi-Way Valve Using the Improved SECNN-GRU Method with mRMR Feature Selection.

Hydraulic multi-way valves as core components are widely applied in engineering machinery, mining machinery, and metallurgical industries. Due to the harsh working environment, faults in hydraulic multi-way valves are prone to occur, and the faults that occur are hidden. Moreover, hydraulic multi-way valves are expensive, and multiple experiments are difficult to replicate to obtain true fault data. Therefore, it is not easy to achieve fault diagnosis of hydraulic multi-way valves. To address this problem, an effective intelligent fault diagnosis method is proposed using an improved Squeeze-Excitation Convolution Neural Network and Gated Recurrent Unit (SECNN-GRU). The effectiveness of the method is verified by designing a simulation model for a hydraulic multi-way valve to generate fault data, as well as the actual data obtained by establishing an experimental platform for a directional valve. In this method, shallow statistical features are first extracted from data containing fault information, and then fault features with high correlation with fault types are selected using the Maximum Relevance Minimum Redundancy algorithm (mRMR). Next, spatial dimension features are extracted through CNN. By adding the Squeeze-Excitation Block, different weights are assigned to features to obtain weighted feature vectors. Finally, the time-dimension features of the weighted feature vectors are extracted and fused through GRU, and the fused features are classified using a classifier. The fault data obtained from the simulation model verifies that the average diagnostic accuracy of this method can reach 98.94%. The average accuracy of this method can reach 92.10% (A1 sensor as an example) through experimental data validation of the directional valve. Compared with other intelligent diagnostic algorithms, the proposed method has better stationarity and higher diagnostic accuracy, providing a feasible solution for fault diagnosis of the hydraulic multi-way valve.

Toward spatially polarized human pressure? A dynamic factor analysis of ecological stability and the role of territorial gradients in Czech Republic.

In light of global change, research on ecosystem dynamics and the related environmental policies are increasingly required to face with the inherent polarization in areas with low and high human pressure. Differential levels of human pressure are hypothesized to reflect development paths toward ecological stability of local systems vis à vis socioeconomic resilience. To delineate the latent nexus between socioeconomic development paths and ecological stability of local systems, we proposed a multidimensional, diachronic analysis of 28 indicators of territorial disparities, and ecological stability in 206 homogeneous administrative units of Czech Republic over almost 30 years (1990-2018). Mixing time-invariant factors with time-varying socio-environmental attributes, a dynamic factor analysis investigated the latent relationship between ecosystem functions, environmental pressures, and the background socioeconomic characteristics of the selected spatial units. We identified four geographical gradients in Czech Republic (namely elevation, economic agglomeration, demographic structure, and soil imperviousness) at the base of territorial divides associated with the increased polarization in areas with low and high human pressure. The role of urbanization, agriculture, and loss of natural habitats reflective of rising human pressure was illustrated along the selected gradients. Finally, policy implications of the (changing) geography of ecological disturbances and local development paths in Czech Republic were briefly discussed.

Multiway clustering with time-varying parameters.

This paper proposes a clustering approach for multivariate time series with time-varying parameters in a multiway framework. Although clustering techniques based on time series distribution characteristics have been extensively studied, methods based on time-varying parameters have only recently been explored and are missing for multivariate time series. This paper fills the gap by proposing a multiway approach for distribution-based clustering of multivariate time series. To show the validity of the proposed clustering procedure, we provide both a simulation study and an application to real air quality time series data.

Real-Time Multiobject Tracking Based on Multiway Concurrency.

This paper explored a pragmatic approach to research the real-time performance of a multiway concurrent multiobject tracking (MOT) system. At present, most research has focused on the tracking of single-image sequences, but in practical applications, multiway video streams need to be processed in parallel by MOT systems. There have been few studies on the real-time performance of multiway concurrent MOT systems. In this paper, we proposed a new MOT framework to solve multiway concurrency scenario based on a tracking-by-detection (TBD) model. The new framework mainly focuses on concurrency and real-time based on limited computing and storage resources, while considering the algorithm performance. For the former, three aspects were studied: (1) Expanded width and depth of tracking-by-detection model. In terms of width, the MOT system can support the process of multiway video sequence at the same time; in terms of depth, image collectors and bounding box collectors were introduced to support batch processing. (2) Considering the real-time performance and multiway concurrency ability, we proposed one kind of real-time MOT algorithm based on directly driven detection. (3) Optimization of system level-we also utilized the inference optimization features of NVIDIA TensorRT to accelerate the deep neural network (DNN) in the tracking algorithm. To trade off the performance of the algorithm, a negative sample (false detection sample) filter was designed to ensure tracking accuracy. Meanwhile, the factors that affect the system real-time performance and concurrency were studied. The experiment results showed that our method has a good performance in processing multiple concurrent real-time video streams.

Chromatographic Applications in the Multi-Way Calibration Field.

In this review, recent advances and applications using multi-way calibration protocols based on the processing of multi-dimensional chromatographic data are discussed. We first describe the various modes in which multi-way chromatographic data sets can be generated, including some important characteristics that should be taken into account for the selection of an adequate data processing model. We then discuss the different manners in which the collected instrumental data can be arranged, and the most usually applied models and algorithms for the decomposition of the data arrays. The latter activity leads to the estimation of surrogate variables (scores), useful for analyte quantitation in the presence of uncalibrated interferences, achieving the second-order advantage. Recent experimental reports based on multi-way liquid and gas chromatographic data are then reviewed. Finally, analytical figures of merit that should always accompany quantitative calibration reports are described.

Multiway PCA for Early Leak Detection in a Pipeline System of a Steam Boiler-Selected Case Studies.

In the paper the usability of the Multiway PCA (MPCA) method for early detection of leakages in the pipeline system of a steam boiler in a thermal-electrical power plant is presented. A long segment of measurements of selected process variables was divided into a series of "batches" (representing daily recordings of normal behavior of the plant) and used to create the MPCA model of a "healthy" system in a reduced space of three principal components (PC). The periodically updated MPCA model was used to establish the confidence ellipsoid for the "healthy" system in the PC coordinates. [d=replaced]The staff's decision of the probable leak detection is supported by comparison of the current location of the operating point (on the "fault trajectory") with the boundaries of the confidence ellipsoid.The location of the process operating point created the "fault trajectory," which (if located outside the confidence ellipsoid) supported the decision of probable leak detection. It must be emphasized that due to daily and seasonal changes of heat/electricity demands, the process variables have substantially greater variability than in the examples of batch processes studied in literature. Despite those real challenges for the MPCA method, numerical examples confirmed that the presented approach was able to foresee the leaks earlier than the operator, typically 3-5 days before the boiler shutdown. The presented methodology may be useful in implementation of an on-line system, developed to improve safety and maintenance of boilers in a thermal-electrical power plant.