ProtoCell4P: an explainable prototype-based neural network for patient classification using single-cell RNA-seq.

MOTIVATION: The rapid advance in single-cell RNA sequencing (scRNA-seq) technology over the past decade has provided a rich resource of gene expression profiles of single cells measured on patients, facilitating the study of many biological questions at the single-cell level. One intriguing research is to study the single cells which play critical roles in the phenotypes of patients, which has the potential to identify those cells and genes driving the disease phenotypes. To this end, deep learning models are expected to well encode the single-cell information and achieve precise prediction of patients' phenotypes using scRNA-seq data. However, we are facing critical challenges in designing deep learning models for classifying patient samples due to (i) the samples collected in the same dataset contain a variable number of cells-some samples might only have hundreds of cells sequenced while others could have thousands of cells, and (ii) the number of samples available is typically small and the expression profile of each cell is noisy and extremely high-dimensional. Moreover, the black-box nature of existing deep learning models makes it difficult for the researchers to interpret the models and extract useful knowledge from them. RESULTS: We propose a prototype-based and cell-informed model for patient phenotype classification, termed ProtoCell4P, that can alleviate problems of the sample scarcity and the diverse number of cells by leveraging the cell knowledge with representatives of cells (called prototypes), and precisely classify the patients by adaptively incorporating information from different cells. Moreover, this classification process can be explicitly interpreted by identifying the key cells for decision making and by further summarizing the knowledge of cell types to unravel the biological nature of the classification. Our approach is explainable at the single-cell resolution which can identify the key cells in each patient's classification. The experimental results demonstrate that our proposed method can effectively deal with patient classifications using single-cell data and outperforms the existing approaches. Furthermore, our approach is able to uncover the association between cell types and biological classes of interest from a data-driven perspective. AVAILABILITY AND IMPLEMENTATION: https://github.com/Teddy-XiongGZ/ProtoCell4P.