scTCA: a hybrid Transformer-CNN architecture for imputation and denoising of scDNA-seq data

Single-cell DNA sequencing (scDNA-seq) has been widely used to unmask tumor copy number alterations (CNAs) at single-cell resolution. Despite that arm-level CNAs can be accurately detected from single-cell read counts, it is difficult to precisely identify focal CNAs as the read counts are featured with high dimensionality, high sparsity and low signal-to-noise ratio. This gives rise to a desperate demand for reconstructing high-quality scDNA-seq data. We develop a new method called scTCA for imputation and denoising of single-cell read counts, thus aiding in downstream analysis of both arm-level and focal CNAs. scTCA employs hybrid Transformer-CNN architectures to identify local and non-local correlations between genes for precise recovery of the read counts. Unlike conventional Transformers, the Transformer block in scTCA is a two-stage attention module containing a stepwise self-attention layer and a window Transformer, and can efficiently deal with the high-dimensional read counts data. We showcase the superior performance of scTCA through comparison with the state-of-the-arts on both synthetic and real datasets. The results indicate it is highly effective in imputation and denoising of scDNA-seq data.