Lingling An

Sequencing-based microbial count data analysis is a challenging task due to the presence of numerous non-biological zeros, which can impede downstream analysis. To tackle this issue, we introduce two novel approaches, PhyImpute and UniFracImpute, which leverage similar microbial samples to identify and impute non-biological zeros in microbial count data. Our proposed methods utilize the probability of non-biological zeros and phylogenetic trees to estimate sample-to-sample similarity, thus addressing this challenge. To evaluate the performance of our proposed methods, we conduct experiments using both simulated and real microbial data. The results demonstrate that PhyImpute and UniFracImpute outperform existing methods in recovering the zeros and empowering downstream analyses such as differential abundance analysis, and disease status classification.

Metagenomic time-course studies provide valuable insights into the dynamics of microbial systems and have become increasingly popular alongside the reduction in costs of next-generation sequencing technologies. Normalization is a common but critical preprocessing step before proceeding with downstream analysis. To the best of our knowledge, currently there is no reported method to appropriately normalize microbial time-series data. We propose TimeNorm, a novel normalization method that considers the compositional property and time dependency in time-course microbiome data. It is the first method designed for normalizing time-series data within the same time point (intra-time normalization) and across time points (bridge normalization), separately. Intra-time normalization normalizes microbial samples under the same condition based on common dominant features. Bridge normalization detects and utilizes a group of most stable features across two adjacent time points for normalization. Through comprehensive simulation studies and application to a real study, we demonstrate that TimeNorm outperforms existing normalization methods and boosts the power of downstream differential abundance analysis.

Positronium lifetime imaging (PLI) is a newly demonstrated technique possible with time-of-flight (TOF) positron emission tomography (PET), capable of producing an image reflecting the lifetime of the positron, more precisely ortho-positronium (o-Ps), before annihilation, in addition to the traditional uptake image of the PET tracer. Due to the limited time resolution of TOF-PET systems and the added complexities in physics and statistics, lifetime image reconstruction presents a challenge. Recently, we described a maximum-likelihood approach for PLI by considering only o-Ps. In real-world scenarios, other populations of positrons that exhibit different lifetimes also exist. This paper introduces a novel two-component model aimed at enhancing the accuracy of o-Ps lifetime images. Through simulation studies, we compare this new model with the existing single-component model and demonstrate its superior performance in accurately capturing complex lifetime distributions.

Understanding gene expression in different cell types within their spatial context is a key goal in genomics research. SPADE (SPAtial DEconvolution), our proposed method, addresses this by integrating spatial patterns into the analysis of cell type composition. This approach uses a combination of single-cell RNA sequencing, spatial transcriptomics, and histological data to accurately estimate the proportions of cell types in various locations. Our analyses of synthetic data have demonstrated SPADE’s capability to discern cell type-specific spatial patterns effectively. When applied to real-life datasets, SPADE provides insights into cellular dynamics and the composition of tumor tissues. This enhances our comprehension of complex biological systems and aids in exploring cellular diversity. SPADE represents a significant advancement in deciphering spatial gene expression patterns, offering a powerful tool for the detailed investigation of cell types in spatial transcriptomics.

Positron Emission Tomography (PET) is a crucial tool in medical imaging, particularly for diagnosing diseases like cancer and Alzheimer's. The advent of Positronium Lifetime Imaging (PLI) has opened new avenues for assessing the tissue micro-environment, which is vital for early-stage disease detection. In this study, we introduce a two-component reconstruction model for PLI in Time-of-Flight (TOF) PET, incorporating both ortho-positronium and para-positronium decays. Our model enhances the accuracy of positronium imaging by providing a more detailed representation of the tissue environment. We conducted simulation studies to evaluate the performance of our model and compared it with existing single-component models. The results demonstrate the superiority of the two-component model in capturing the intricacies of the tissue micro-environment, thus paving the way for more precise and informative PET diagnostics.

The positronium lifetime imaging (PLI) reconstruction is a technique used in time-of-flight (TOF) positron emission tomography (PET) imaging that involves measuring the lifespan of positronium, which is a metastable electron-positron pair that arises when a PET molecule releases a positron, prior to its annihilation. We have previously developed a maximum likelihood (ML) algorithm for PLI reconstruction and demonstrated that it can generate quantitatively accurate lifetime images for a 570 ps (pico-seconds) TOF PET system. In this study, we conducted further investigations into the statistical properties of the algorithm, including the variability of the reconstruction results, the sensitivity of the algorithm to the number of acquired PLI events and its robustness to hyperparameter choices. Our findings indicate that the proposed ML method produces sufficiently stable lifetime images to enable reliable distinction of regions of interest. Moreover, the number of PLI events required to produce quantitatively accurate lifetime images is computationally plausible. These results demonstrate the potential of our ML algorithm for advancing the capabilities of TOF PET imaging.

Bulk RNA-seq experiments, commonly used to discern gene expression changes across conditions, often neglect critical cell type-specific information due to their focus on average transcript abundance. Recognizing cell type contribution is crucial to understanding phenotype and disease variations. The advent of single-cell RNA sequencing has allowed detailed examination of cellular heterogeneity; however, the cost and analytic caveat prohibits such sequencing for a large number of samples. We introduce a novel deconvolution approach, SECRET, that employs cell type-specific gene expression profiles from single-cell RNA-seq to accurately estimate cell type proportions from bulk RNA-seq data. Notably, SECRET can adapt to scenarios where the cell type present in the bulk data is unrepresented in the reference, thereby offering increased flexibility in reference selection. SECRET has demonstrated superior accuracy compared to existing methods using synthetic data and has identified unknown tissue-specific cell types in real human metastatic cancers. Its versatility makes it broadly applicable across various human cancer studies.

The advent of spatial transcriptomics technology has allowed for the acquisition of gene expression profiles with multi-cellular resolution in a spatially resolved manner, presenting a new milestone in the field of genomics. However, the aggregate gene expression from heterogeneous cell types obtained by these technologies poses a significant challenge for a comprehensive delineation of cell type-specific spatial patterns. Here, we propose SPADE (SPAtial DEconvolution), an in-silico method designed to address this challenge by incorporating spatial patterns during cell type decomposition. SPADE utilizes a combination of single-cell RNA sequencing data, spatial location information, and histological information to computationally estimate the proportion of cell types present at each spatial location. In our study, we showcased the effectiveness of SPADE by conducting analyses on synthetic data. Our results indicated that SPADE was able to successfully identify cell type-specific spatial patterns that were not previously identified by existing deconvolution methods. Furthermore, we applied SPADE to a real-world dataset analyzing the developmental chicken heart, where we observed that SPADE was able to accurately capture the intricate processes of cellular differentiation and morphogenesis within the heart. Specifically, we were able to reliably estimate changes in cell type compositions over time, which is a critical aspect of understanding the underlying mechanisms of complex biological systems. These findings underscore the potential of SPADE as a valuable tool for analyzing complex biological systems and shedding light on their underlying mechanisms. Taken together, our results suggest that SPADE represents a significant advancement in the field of spatial transcriptomics, providing a powerful tool for characterizing complex spatial gene expression patterns in heterogeneous tissues.

Single-cell data analysis has been at forefront of development in biology and medicine since sequencing data have been made available. An important challenge in single-cell data analysis is the identification of cell types. Several methods have been proposed for cell-type identification. However, these methods do not capture the higher-order topological relationship between different samples. In this work, we propose an attention-based graph neural network that captures the higher-order topological relationship between different samples and performs transductive learning for predicting cell types. The evaluation of our method on both simulation and publicly available datasets demonstrates the superiority of our method, scAGN, in terms of prediction accuracy. In addition, our method works best for highly sparse datasets in terms of F1 score, precision score, recall score, and Matthew’s correlation coefficients as well. Further, our method’s runtime complexity is consistently faster compared to other methods.

Longitudinal metagenomics has been widely studied in the recent decade to provide valuable insight for understanding microbial dynamics. The correlation within each subject can be observed across repeated measurements. However, previous methods that assume independent correlation may suffer from incorrect inferences. In addition, methods that do account for intra-sample correlation may not be applicable for count data. We proposed a distribution-free approach, namely CorrZIDF, which extends the current method to model correlated zero-inflated metagenomic count data, offering a powerful and accurate solution for detecting significance features. This method can handle different working correlation structures without specifying each margin distribution of the count data. Through simulation studies, we have shown the robustness of CorrZIDF when selecting a working correlation structure for repeated measures studies to enhance the efficiency of estimation. We also compared four methods using two real datasets, and the new proposed method identified more unique features that were reported previously on the relevant research.