Deep Learning in Spatially Resolved Transcriptomics: A Comprehensive Technical View

Spatially resolved transcriptomics (SRT) has evolved rapidly through various technologies, enabling scientists to investigate both morphological contexts and gene expression profiling at single-cell resolution in parallel. SRT data are complex and multi-modal, comprising gene expression matrices, spatial information, and often high-resolution histology images. Because of this complexity and multi-modality, sophisticated computational algorithms are required to accurately analyze SRT data. Most efforts in this domain have been made to utilize conventional machine learning and statistical approaches, exhibiting sub-optimal results due to the complicated nature of SRT datasets. To address these shortcomings, researchers have recently employed deep learning algorithms including various state-of-the-art methods mainly in spatial clustering, spatially variable gene identification, and alignment. While great progress has been made in developing deep learning-based models for SRT data analysis, further improvement is still needed to create more biologically aware models that consider aspects such as phylogeny-aware clustering or the analysis of small histology image patches. Additionally, strategies for batch effect removal, normalization, and handling overdispersion and zero inflation patterns of gene expression are still needed in the analysis of SRT data using deep learning methods. In this paper, we provide a comprehensive overview of these deep learning methods, including their strengths and limitations. We also highlight new frontiers, current challenges, limitations, and open questions in this field. Also, we provide a comprehensive list of all available SRT databases that can be used as an extensive resource for future studies.