Accurate Single-Cell Clustering through Ensemble Similarity Learning

Single-cell sequencing provides novel means to interpret the transcriptomic profiles of individual cells. To obtain in-depth analysis of single-cell sequencing, it requires effective computational methods to accurately predict single-cell clusters because single-cell sequencing techniques only provide the transcriptomic profiles of each cell. Although an accurate estimation of the cell-to-cell similarity is an essential first step to derive reliable single-cell clustering results, it is challenging to obtain the accurate similarity measurement because it highly depends on a selection of genes for similarity evaluations and the optimal set of genes for the accurate similarity estimation is typically unknown. Moreover, due to technical limitations, single-cell sequencing includes a larger number of artificial zeros, and the technical noise makes it difficult to develop effective single-cell clustering algorithms. Here, we describe a novel single-cell clustering algorithm that can accurately predict single-cell clusters in large-scale single-cell sequencing by effectively reducing the zero-inflated noise and accurately estimating the cell-to-cell similarities. First, we construct an ensemble similarity network based on different similarity estimates, and reduce the artificial noise using a random walk with restart framework. Finally, starting from a larger number small size but highly consistent clusters, we iteratively merge a pair of clusters with the maximum similarities until it reaches the predicted number of clusters. Extensive performance evaluation shows that the proposed single-cell clustering algorithm can yield the accurate single-cell clustering results and it can help deciphering the key messages underlying complex biological mechanisms.