A mixture of attention experts-embedded flow-based generative model to create synthetic cells in single-cell RNA-Seq datasets A mixture of attention experts-embedded flow-based generative model in single-cell RNA-Seq

Abstract

Single-cell RNA-seq (scRNAseq) analyses performed at the cellular level aim to understand the cellular landscape of tissue sections, offer insights into rare cell-types, and identify marker genes for annotating distinct cell types. ScRNAseq analyses are widely applied to cancer research to understand tumor heterogeneity, disease progression, and resistance to therapy. Single-cell data processing is a challenging task due to its high-dimensionality, sparsity, and having imbalanced class(cell-type) distributions. An accurate cell-type identification is highly dependent on preprocessing and quality control steps. To address these issues, generative models have been widely used in recent years. Techniques frequently used include Variational Autoencoders (VAE), Generative Adversarial Networks (GANs), Gaussian-based methods, and, more recently, Flow-based (FB) generative models. We developed a Masked Affine Autoregressive transform-embedded FB (MAF-FB) model. Then, to improve MAF-FB further, we incorporated a mixture of experts (MOE) of attention mechanisms on top of it, resulting in our proposed MOE-FB model. We conducted a comparative analysis of fundamental generative models, aiming to serve as a preliminary guidance for developing novel automated scRNAseq data analysis systems. We performed a large-scale analysis by combiningfour datasets derived from pancreatic tissue sections and for further generalizability assessments, we employed Peripheral Blood Mononuclear Cells (PBMC68K and PBMC3K) and Human Cell Atlas Bone Marrow (HCA-BM10K) datasets. We utilized VAE, GAN, Gaussian Copula, and Automated Cell-Type-informed Introspective Variational Autoencoder (ACTIVA), and compared them against our two novel FB models, MAF-FB and MOE-FB for ScRnaseq synthesis. To evaluate the performances of generative models, we used various discrepancy metrics and performed automated cell-type classification tasks. We also identified differentially expressed genes for each cell type, and inferred cell-cell interactions based on ligand-receptor bindings across distinct cell-type pairs.