The functional or structural spatial regions within tissues, referred to as spatial niches, are elements for illustrating the spatial contexts of multicellular organisms. A key challenge is querying shared niches across diverse tissues, which is crucial for achieving a comprehensive understanding of the organization and phenotypes of cell populations. However, current data analysis methods predominantly focus on creating spatial-aware embeddings for cells, neglecting the development of niche-level representations for effective querying. To address this gap, we introduce QueST, a novel niche representation learning model designed for querying spatial niches across multiple samples. QueST utilizes a novel subgraph contrastive learning approach to explicitly capture niche-level characteristics and incorporates adversarial training to mitigate batch effects. We evaluate QueST on established benchmarks using human and mouse datasets, demonstrating its superiority over state-of-the-art graph representation learning methods in accurate niche queries. Overall, QueST offers a specialized model for spatial niche queries, paving the way for deeper insights into the patterns and mechanisms of cell spatial organization across tissues. Source code can be found at https://github.com/cmhimself/QueST.

Causal discovery based on observational data is important for deciphering the causal mechanism behind complex systems. However, the effectiveness of existing causal discovery methods is limited due to inferior prior knowledge, domain inconsistencies, and the challenges of high-dimensional datasets with small sample sizes. To address this gap, we propose a novel weakly-supervised fuzzy knowledge and data co-driven causal discovery method named KEEL. KEEL adopts a fuzzy causal knowledge schema to encapsulate diverse types of fuzzy knowledge, and forms corresponding weakened constraints. This schema not only lessens the dependency on expertise but also allows various types of limited and error-prone fuzzy knowledge to guide causal discovery. It can enhance the generalization and robustness of causal discovery, especially in high-dimensional and small-sample scenarios. In addition, we integrate the extended linear causal model (ELCM) into KEEL for dealing with the multi-distribution and incomplete data. Extensive experiments with different datasets demonstrate the superiority of KEEL over several state-of-the-art methods in accuracy, robustness and computational efficiency. For causal discovery in real protein signal transduction processes, KEEL outperforms the benchmark method with limited data. In summary, KEEL is effective to tackle the causal discovery tasks with higher accuracy while alleviating the requirement for extensive domain expertise.

Node Importance Estimation (NIE) is a task of inferring importance scores of the nodes in a graph. Due to the availability of richer data and knowledge, recent research interests of NIE have been dedicating to knowledge graphs for predicting future or missing node importance scores. Existing state-of-the-art NIE methods train the model by available labels, and they consider every interested node equally before training. However, the nodes with higher importance often require or receive more attention in real-world scenarios, e.g., people may care more about the movies or webpages with higher importance. To this end, we introduce Label Informed ContrAstive Pretraining (LICAP) to the NIE problem for being better aware of the nodes with high importance scores. Specifically, LICAP is a novel type of contrastive learning framework that aims to fully utilize the continuous labels to generate contrastive samples for pretraining embeddings. Considering the NIE problem, LICAP adopts a novel sampling strategy called top nodes preferred hierarchical sampling to first group all interested nodes into a top bin and a non-top bin based on node importance scores, and then divide the nodes within top bin into several finer bins also based on the scores. The contrastive samples are generated from those bins, and are then used to pretrain node embeddings of knowledge graphs via a newly proposed Predicate-aware Graph Attention Networks (PreGAT), so as to better separate the top nodes from non-top nodes, and distinguish the top nodes within top bin by keeping the relative order among finer bins. Extensive experiments demonstrate that the LICAP pretrained embeddings can further boost the performance of existing NIE methods and achieve the new state-of-the-art performance regarding both regression and ranking metrics. The source code for reproducibility is available at https://github.com/zhangtia16/LICAP

Single-cell RNA sequencing (scRNA-seq) data are important for studying the biology of development or diseases at single-cell level. To better understand the properties of the data, to build controlled benchmark data for testing downstream methods, and to augment data when collecting sufficient real data is challenging, generative models have been proposed to computationally generate synthetic scRNA-seq data. However, the data generated with current models are not very realistic yet, especially when we need to generate data with controlled conditions. In the meantime, the Diffusion models have shown their power in generating data in computer vision at high fidelity, providing a new opportunity for scRNA-seq generation. In this study, we developed scDiffusion, a diffusion-based model to generate high-quality scRNA-seq data with controlled conditions. We designed multiple classifiers to guide the diffusion process simultaneously, enabling scDiffusion to generate data under multiple condition combinations. We also proposed a new control strategy called Gradient Interpolation. This strategy allows the model to generate continuous trajectories of cell development from a given cell state. Experiments showed that scDiffusion can generate single-cell gene expression data closely resembling real scRNA-seq data, surpassing state-of-the-art models in multiple metrics. Also, scDiffusion can conditionally produce data on specific cell types including rare cell types. Furthermore, we could use the multiple-condition generation of scDiffusion to generate cell type that was out of the training data. Leveraging the Gradient Interpolation strategy, we generated a continuous developmental trajectory of mouse embryonic cells. These experiments demonstrate that scDiffusion is a powerful tool for augmenting the real scRNA-seq data and can provide insights into cell fate research.

Advances in high-throughput sequencing technology have led to significant progress in measuring gene expressions at the single-cell level. The amount of publicly available single-cell RNA-seq (scRNA-seq) data is already surpassing 50M records for humans with each record measuring 20,000 genes. This highlights the need for unsupervised representation learning to fully ingest these data, yet classical transformer architectures are prohibitive to train on such data in terms of both computation and memory. To address this challenge, we propose a novel asymmetric encoder-decoder transformer for scRNA-seq data, called xTrimoGene$^\alpha$ (or xTrimoGene for short), which leverages the sparse characteristic of the data to scale up the pre-training. This scalable design of xTrimoGene reduces FLOPs by one to two orders of magnitude compared to classical transformers while maintaining high accuracy, enabling us to train the largest transformer models over the largest scRNA-seq dataset today. Our experiments also show that the performance of xTrimoGene improves as we scale up the model sizes, and it also leads to SOTA performance over various downstream tasks, such as cell type annotation, perturb-seq effect prediction, and drug combination prediction. xTrimoGene model is now available for use as a service via the following link: https://api.biomap.com/xTrimoGene/apply.

The automatic detection of atrial fibrillation based on electrocardiograph (ECG) signals has received wide attention both clinically and practically. It is challenging to process ECG signals with cyclical pattern, varying length and unstable quality due to noise and distortion. Besides, there has been insufficient research on separating persistent atrial fibrillation from paroxysmal atrial fibrillation, and little discussion on locating the onsets and end points of AF episodes. It is even more arduous to perform well on these two distinct but interrelated tasks, while avoiding the mistakes inherent from stage-by-stage approaches. This paper proposes the Multi-level Multi-task Attention-based Recurrent Neural Network for three-class discrimination on patients and localization of the exact timing of AF episodes. Our model captures three-level sequential features based on a hierarchical architecture utilizing Bidirectional Long and Short-Term Memory Network (Bi-LSTM) and attention layers, and accomplishes the two tasks simultaneously with a multi-head classifier. The model is designed as an end-to-end framework to enhance information interaction and reduce error accumulation. Finally, we conduct experiments on CPSC 2021 dataset and the result demonstrates the superior performance of our method, indicating the potential application of MMA-RNN to wearable mobile devices for routine AF monitoring and early diagnosis.