scAMAC: self-supervised clustering of scRNA-seq data based on adaptive multi-scale autoencoder.

Cluster assignment is vital to analyzing single-cell RNA sequencing (scRNA-seq) data to understand high-level biological processes. Deep learning-based clustering methods have recently been widely used in scRNA-seq data analysis. However, existing deep models often overlook the interconnections and interactions among network layers, leading to the loss of structural information within the network layers. Herein, we develop a new self-supervised clustering method based on an adaptive multi-scale autoencoder, called scAMAC. The self-supervised clustering network utilizes the Multi-Scale Attention mechanism to fuse the feature information from the encoder, hidden and decoder layers of the multi-scale autoencoder, which enables the exploration of cellular correlations within the same scale and captures deep features across different scales. The self-supervised clustering network calculates the membership matrix using the fused latent features and optimizes the clustering network based on the membership matrix. scAMAC employs an adaptive feedback mechanism to supervise the parameter updates of the multi-scale autoencoder, obtaining a more effective representation of cell features. scAMAC not only enables cell clustering but also performs data reconstruction through the decoding layer. Through extensive experiments, we demonstrate that scAMAC is superior to several advanced clustering and imputation methods in both data clustering and reconstruction. In addition, scAMAC is beneficial for downstream analysis, such as cell trajectory inference. Our scAMAC model codes are freely available at https://github.com/yancy2024/scAMAC.

AFSC: A self-supervised augmentation-free spatial clustering method based on contrastive learning for identifying spatial domains.

Recent research in spatial transcriptomics allows researchers to analyze gene expression without losing spatial information. Spatial information can assist in cell communication, identification of new cell subtypes, which provides important research methods for multiple fields such as microenvironment interactions and pathological processes of diseases. Identifying spatial domains is an important step in spatial transcriptomics analysis, and improving spatial clustering methods can benefit for identifying spatial domains. In addition to eliminating noise in original gene expression, how to use spatial information to assist clustering has also become a new problem. A variety of calculating methods have been applied to spatial clustering, including contrastive learning methods. However, existing spatial clustering methods based on contrastive learning use data augmentation to generate positive and negative pairs, which will inevitably destroy the biological meaning of the data. We propose a new self-supervised spatial clustering method based on contrastive learning, Augmentation-Free Spatial Clustering (AFSC), which integrates spatial information and gene expression to learn latent representations. We construct a contrastive learning module without negative pairs or data augmentation by designing Teacher and Student Encoder. We also design an unsupervised clustering module to make clustering and contrastive learning be trained together. Experiments on multiple spatial transcriptomics datasets at different resolutions demonstrate that our method performs well in self-supervised spatial clustering tasks. Furthermore, the learned representations can be used for various downstream tasks including visualization and trajectory inference.

Differentiable self-supervised clustering with intrinsic interpretability.

Self-supervised clustering has garnered widespread attention due to its ability to discover latent clustering structures without the need for external labels. However, most existing approaches on self-supervised clustering lack of inherent interpretability in the data clustering process. In this paper, we propose a differentiable self-supervised clustering method with intrinsic interpretability (DSC2I), which provides an interpretable data clustering mechanism by reformulating clustering process based on differentiable programming. To be specific, we first design a differentiable mutual information measurement to explicitly train a neural network with analytical gradients, which avoids variational inference and learns a discriminative and compact representation. Then, an interpretable clustering mechanism based on differentiable programming is devised to transform fundamental clustering process (i.e., minimum intra-cluster distance, maximum inter-cluster distance) into neural networks and convert cluster centers to learnable neural parameters, which allows us to obtain a transparent and interpretable clustering layer. Finally, a unified optimization method is designed, in which the differentiable representation learning and interpretable clustering can be optimized simultaneously in a self-supervised manner. Extensive experiments demonstrate the effectiveness of the proposed DSC2I method compared with 16 clustering approaches.