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Improved cell composition deconvolution method of bulk gene expression profiles to quantify subsets of immune cells.

ABSTRACT: BACKGROUND:To facilitate the investigation of the pathogenic roles played by various immune cells in complex tissues such as tumors, a few computational methods for deconvoluting bulk gene expression profiles to predict cell composition have been created. However, available methods were usually developed along with a set of reference gene expression profiles consisting of imbalanced replicates across different cell types. Therefore, the objective of this study was to create a new deconvolution method equipped with a new set of reference gene expression profiles that incorporate more microarray replicates of the immune cells that have been frequently implicated in the poor prognosis of cancers, such as T helper cells, regulatory T cells and macrophage M1/M2 cells. METHODS:Our deconvolution method was developed by choosing ?-support vector regression (?-SVR) as the core algorithm assigned with a loss function subject to the L1-norm penalty. To construct the reference gene expression signature matrix for regression, a subset of differentially expressed genes were chosen from 148 microarray-based gene expression profiles for 9 types of immune cells by using ANOVA and minimizing condition number. Agreement analyses including mean absolute percentage errors and Bland-Altman plots were carried out to compare the performances of our method and CIBERSORT. RESULTS:In silico cell mixtures, simulated bulk tissues, and real human samples with known immune-cell fractions were used as the test datasets for benchmarking. Our method outperformed CIBERSORT in the benchmarks using in silico breast tissue-immune cell mixtures in the proportions of 30:70 and 50:50, and in the benchmark using 164 human PBMC samples. Our results suggest that the performance of our method was at least comparable to that of a state-of-the-art tool, CIBERSORT. CONCLUSIONS:We developed a new cell composition deconvolution method and the implementation was entirely based on the publicly available R and Python packages. In addition, we compiled a new set of reference gene expression profiles, which might allow for a more robust prediction of the immune cell fractions from the expression profiles of cell mixtures. The source code of our method could be downloaded from https://github.com/holiday01/deconvolution-to-estimate-immune-cell-subsets.

SUBMITTER: Chiu YJ

PROVIDER: S-EPMC6923925 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Improved cell composition deconvolution method of bulk gene expression profiles to quantify subsets of immune cells.

Chiu Yen-Jung YJ Hsieh Yi-Hsuan YH Huang Yen-Hua YH

BMC medical genomics 20191220 Suppl 8

<h4>Background</h4>To facilitate the investigation of the pathogenic roles played by various immune cells in complex tissues such as tumors, a few computational methods for deconvoluting bulk gene expression profiles to predict cell composition have been created. However, available methods were usually developed along with a set of reference gene expression profiles consisting of imbalanced replicates across different cell types. Therefore, the objective of this study was to create a new deconvo ...[more]

PMID: 31856824

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Project description:Acute myeloid leukemia (AML) is one of the malignant hematologic cancers with rapid progress and poor prognosis. Most AML prognostic stratifications focused on genetic abnormalities. However, none of them was established based on the cell type compositions (CTCs) of peripheral blood or bone marrow aspirates from patients at diagnosis. Here we sought to develop a novel prognostic model for AML in adults based on the CTCs. First, we applied the CIBERSORT algorithm to estimate the CTCs for patients from two public datasets (GSE6891 and TCGA-LAML) using a custom gene expression signature reference constructed by an AML single-cell RNA sequencing dataset (GSE116256). Then, a CTC-based prognostic model was established using least absolute shrinkage and selection operator Cox regression, termed CTC score. The constructed prognostic model CTC score comprised 3 cell types, GMP-like, HSC-like, and T. Compared with the low-CTC-score group, the high-CTC-score group showed a 1.57-fold [95% confidence interval (CI), 1.23 to 2.00; p = 0.0002] and a 2.32-fold (95% CI, 1.53 to 3.51; p < 0.0001) higher overall mortality risk in the training set (GSE6891) and validation set (TCGA-LAML), respectively. When adjusting for age at diagnosis, cytogenetic risk, and karyotype, the CTC score remained statistically significant in both the training set [hazard ratio (HR) = 2.25; 95% CI, 1.20 to 4.24; p = 0.0119] and the validation set (HR = 7.97; 95% CI, 2.95 to 21.56; p < 0.0001]. We further compared the performance of the CTC score with two gene expression-based prognostic scores: the 17-gene leukemic stem cell score (LSC17 score) and the AML prognostic score (APS). It turned out that the CTC score achieved comparable performance at 1-, 2-, 3-, and 5-years timepoints and provided independent and additional prognostic information different from the LSC17 score and APS. In conclusion, the CTC score could serve as a powerful prognostic marker for AML and has great potential to assist clinicians to formulate individualized treatment plans.

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.

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Improved cell composition deconvolution method of bulk gene expression profiles to quantify subsets of immune cells.

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Improved cell composition deconvolution method of bulk gene expression profiles to quantify subsets of immune cells.

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