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Computational deconvolution to estimate cell type-specific gene expression from bulk data.

ABSTRACT: Computational deconvolution is a time and cost-efficient approach to obtain cell type-specific information from bulk gene expression of heterogeneous tissues like blood. Deconvolution can aim to either estimate cell type proportions or abundances in samples, or estimate how strongly each present cell type expresses different genes, or both tasks simultaneously. Among the two separate goals, the estimation of cell type proportions/abundances is widely studied, but less attention has been paid on defining the cell type-specific expression profiles. Here, we address this gap by introducing a novel method Rodeo and empirically evaluating it and the other available tools from multiple perspectives utilizing diverse datasets.

SUBMITTER: Jaakkola MK

PROVIDER: S-EPMC7803005 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Computational deconvolution to estimate cell type-specific gene expression from bulk data.

Jaakkola Maria K MK Elo Laura L LL

NAR genomics and bioinformatics 20210112 1

Computational deconvolution is a time and cost-efficient approach to obtain cell type-specific information from bulk gene expression of heterogeneous tissues like blood. Deconvolution can aim to either estimate cell type proportions or abundances in samples, or estimate how strongly each present cell type expresses different genes, or both tasks simultaneously. Among the two separate goals, the estimation of cell type proportions/abundances is widely studied, but less attention has been paid on ...[more]

PMID: 33575652

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Project description:BackgroundBiological tissues consist of heterogenous populations of cells. Because gene expression patterns from bulk tissue samples reflect the contributions from all cells in the tissue, understanding the contribution of individual cell types to the overall gene expression in the tissue is fundamentally important. We recently developed a computational method, CDSeq, that can simultaneously estimate both sample-specific cell-type proportions and cell-type-specific gene expression profiles using only bulk RNA-Seq counts from multiple samples. Here we present an R implementation of CDSeq (CDSeqR) with significant performance improvement over the original implementation in MATLAB and an added new function to aid cell type annotation. The R package would be of interest for the broader R community.ResultWe developed a novel strategy to substantially improve computational efficiency in both speed and memory usage. In addition, we designed and implemented a new function for annotating the CDSeq estimated cell types using single-cell RNA sequencing (scRNA-seq) data. This function allows users to readily interpret and visualize the CDSeq estimated cell types. In addition, this new function further allows the users to annotate CDSeq-estimated cell types using marker genes. We carried out additional validations of the CDSeqR software using synthetic, real cell mixtures, and real bulk RNA-seq data from the Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) project.ConclusionsThe existing bulk RNA-seq repositories, such as TCGA and GTEx, provide enormous resources for better understanding changes in transcriptomics and human diseases. They are also potentially useful for studying cell-cell interactions in the tissue microenvironment. Bulk level analyses neglect tissue heterogeneity, however, and hinder investigation of a cell-type-specific expression. The CDSeqR package may aid in silico dissection of bulk expression data, enabling researchers to recover cell-type-specific information.

Project description:While single-cell experiments provide deep cellular resolution within a single sample, some single-cell experiments are inherently more challenging than bulk experiments due to dissociation difficulties, cost, or limited tissue availability. This creates a situation where we have deep cellular profiles of one sample or condition, and bulk profiles across multiple samples and conditions. To bridge this gap, we propose BuDDI (BUlk Deconvolution with Domain Invariance). BuDDI utilizes domain adaptation techniques to effectively integrate available corpora of case-control bulk and reference scRNA-seq observations to infer cell-type-specific perturbation effects. BuDDI achieves this by learning independent latent spaces within a single variational autoencoder (VAE) encompassing at least four sources of variability: 1) cell-type proportion, 2) perturbation effect, 3) structured experimental variability, and 4) remaining variability. Since each latent space is encouraged to be independent, we simulate perturbation responses by independently composing each latent space to simulate cell-type-specific perturbation responses. We evaluated BuDDI's performance on simulated and real data with experimental designs of increasing complexity. We first validated that BuDDI could learn domain invariant latent spaces on data with matched samples across each source of variability. Then we validated that BuDDI could accurately predict cell-type-specific perturbation response when no single-cell perturbed profiles were used during training; instead, only bulk samples had both perturbed and non-perturbed observations. Finally, we validated BuDDI on predicting sex-specific differences, an experimental design where it is not possible to have matched samples. In each experiment, BuDDI outperformed all other comparative methods and baselines. As more reference atlases are completed, BuDDI provides a path to combine these resources with bulk-profiled treatment or disease signatures to study perturbations, sex differences, or other factors at single-cell resolution.

Dataset Information

Computational deconvolution to estimate cell type-specific gene expression from bulk data.

Publications

Computational deconvolution to estimate cell type-specific gene expression from bulk data.

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