A comprehensive survey of regulatory network inference methods using single cell RNA sequencing data

Abstract Gene regulatory network is a complicated set of interactions between genetic materials, which dictates how cells develop in living organisms and react to their surrounding environment. Robust comprehension of these interactions would help explain how cells function as well as predict their reactions to external factors. This knowledge can benefit both developmental biology and clinical research such as drug development or epidemiology research. Recently, the rapid advance of single-cell sequencing technologies, which pushed the limit of transcriptomic profiling to the individual cell level, opens up an entirely new area for regulatory network research. To exploit this new abundant source of data and take advantage of data in single-cell resolution, a number of computational methods have been proposed to uncover the interactions hidden by the averaging process in standard bulk sequencing. In this article, we review 15 such network inference methods developed for single-cell data. We discuss their underlying assumptions, inference techniques, usability, and pros and cons. In an extensive analysis using simulation, we also assess the methods’ performance, sensitivity to dropout and time complexity. The main objective of this survey is to assist not only life scientists in selecting suitable methods for their data and analysis purposes but also computational scientists in developing new methods by highlighting outstanding challenges in the field that remain to be addressed in the future development.

Download Full-text

Single-cell regulatory network inference and clustering from high-dimensional sequencing data

2019 IEEE International Conference on Big Data (Big Data) ◽

10.1109/bigdata47090.2019.9006016 ◽

2019 ◽

Author(s):

Aristidis G. Vrahatis ◽

Georgios N. Dimitrakopoulos ◽

Sotiris K. Tasoulis ◽

Spiros V. Georgakopoulos ◽

Vassilis P. Plagianakos

Keyword(s):

Single Cell ◽

Regulatory Network ◽

Network Inference ◽

High Dimensional ◽

Sequencing Data

Download Full-text

Identifying strengths and weaknesses of methods for computational network inference from single cell RNA-seq data

10.1101/2021.06.01.446671 ◽

2021 ◽

Author(s):

Matthew Stone ◽

Sunnie Grace McCalla ◽

Alireza Fotuhi Siahpirani ◽

Viswesh Periyasamy ◽

Junha Shin ◽

...

Keyword(s):

Single Cell ◽

Rna Sequencing ◽

Gene Regulatory Network ◽

Regulatory Network ◽

Network Inference ◽

Cost Effective ◽

Gene Regulatory Network Inference ◽

Single Cell Rna Sequencing ◽

Gene Regulatory ◽

Inference Methods

Single-cell RNA-sequencing (scRNA-seq) offers unparalleled insight into the transcriptional pro- grams of different cellular states by measuring the transcriptome of thousands individual cells. An emerging problem in the analysis of scRNA-seq is the inference of transcriptional gene regulatory net- works and a number of methods with different learning frameworks have been developed. Here we present a expanded benchmarking study of eleven recent network inference methods on six published single-cell RNA-sequencing datasets in human, mouse, and yeast considering different types of gold standard networks and evaluation metrics. We evaluate methods based on their computing requirements as well as on their ability to recover the network structure. We find that while no method is a universal winner and most methods have a modest recovery of experimentally derived interactions based on global metrics such as AUPR, methods are able to capture targets of regulators that are relevant to the system under study. Based on overall performance we grouped the methods into three main categories and found a combination of information-theoretic and regression-based methods to have a generally high perfor- mance. We also evaluate the utility of imputation for gene regulatory network inference and find that a small number of methods benefit from imputation, which further depends upon the dataset. Finally, comparisons to inferred networks for comparable bulk conditions showed that networks inferred from scRNA-seq datasets are often better or at par to those from bulk suggesting that scRNA-seq datasets can be a cost-effective way for gene regulatory network inference. Our analysis should be beneficial in selecting algorithms for performing network inference but also argues for improved methods and better gold standards for accurate assessment of regulatory network inference methods for mammalian systems.

Download Full-text

Faculty Opinions recommendation of SCENIC: single-cell regulatory network inference and clustering.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.731968869.793540434 ◽

2017 ◽

Author(s):

Chao Cheng

Keyword(s):

Single Cell ◽

Regulatory Network ◽

Network Inference

Download Full-text

Evaluating the reproducibility of single-cell gene regulatory network inference algorithms

10.1101/2020.11.10.375923 ◽

2020 ◽

Author(s):

Yoonjee Kang ◽

Denis Thieffry ◽

Laura Cantini

Keyword(s):

Single Cell ◽

Network Inference ◽

Simulated Data ◽

Ground Truth ◽

Real Data ◽

Gene Regulatory Network Inference ◽

Sequencing Platform ◽

Cell Network ◽

Inference Algorithms ◽

Inference Methods

AbstractNetworks are powerful tools to represent and investigate biological systems. The development of algorithms inferring regulatory interactions from functional genomics data has been an active area of research. With the advent of single-cell RNA-seq data (scRNA-seq), numerous methods specifically designed to take advantage of single-cell datasets have been proposed. However, published benchmarks on single-cell network inference are mostly based on simulated data. Once applied to real data, these benchmarks take into account only a small set of genes and only compare the inferred networks with an imposed ground-truth.Here, we benchmark four single-cell network inference methods based on their reproducibility, i.e. their ability to infer similar networks when applied to two independent datasets for the same biological condition. We tested each of these methods on real data from three biological conditions: human retina, T-cells in colorectal cancer, and human hematopoiesis.GENIE3 results to be the most reproducible algorithm, independently from the single-cell sequencing platform, the cell type annotation system, the number of cells constituting the dataset, or the thresholding applied to the links of the inferred networks. In order to ensure the reproducibility and ease extensions of this benchmark study, we implemented all the analyses in scNET, a Jupyter notebook available at https://github.com/ComputationalSystemsBiology/scNET.

Download Full-text

BRANE Cut: Biologically-Related A priori Network Enhancement with Graph cuts for Gene Regulatory Network Inference

10.1101/032383 ◽

2015 ◽

Author(s):

Aurélie Pirayre ◽

Camille Couprie ◽

Frédérique Bidard ◽

Laurent Duval ◽

Jean-Christophe Pesquet

Keyword(s):

Gene Regulatory Network ◽

Regulatory Network ◽

Gene Networks ◽

Network Inference ◽

State Of The Art ◽

A Priori ◽

Graph Cuts ◽

Gene Regulatory Network Inference ◽

Gene Regulatory ◽

Inference Methods

Background: Inferring gene networks from high-throughput data constitutes an important step in the discovery of relevant regulatory relationships in organism cells. Despite the large number of available Gene Regulatory Network inference methods, the problem remains challenging: the underdetermination in the space of possible solutions requires additional constraints that incorporate a priori information on gene interactions. Methods: Weighting all possible pairwise gene relationships by a probability of edge presence, we formulate the regulatory network inference as a discrete variational problem on graphs. We enforce biologically plausible coupling between groups and types of genes by minimizing an edge labeling functional coding for a priori structures. The optimization is carried out with Graph cuts, an approach popular in image processing and computer vision. We compare the inferred regulatory networks to results achieved by the mutual-information-based Context Likelihood of Relatedness (CLR) method and by the state-of-the-art GENIE3, winner of the DREAM4 multifactorial challenge. Results: Our BRANE Cut approach infers more accurately the five DREAM4 in silico networks (with improvements from 6% to 11%). On a real Escherichia coli compendium, an improvement of 11.8% compared to CLR and 3% compared to GENIE3 is obtained in terms of Area Under Precision-Recall curve. Up to 48 additional verified interactions are obtained over GENIE3 for a given precision. On this dataset involving 4345 genes, our method achieves a performance similar to that of GENIE3, while being more than seven times faster. The BRANE Cut code is available at: http://www-syscom.univ-mlv.fr/~pirayre/Codes-GRN-BRANE-cut.html Conclusions: BRANE Cut is a weighted graph thresholding method. Using biologically sound penalties and data-driven parameters, it improves three state-of-the-art GRN inference methods. It is applicable as a generic network inference post-processing, due its computational efficiency.

Download Full-text

SimiC: A Single Cell Gene Regulatory Network Inference method with Similarity Constraints

10.1101/2020.04.03.023002 ◽

2020 ◽

Author(s):

Jianhao Peng ◽

Ullas V. Chembazhi ◽

Sushant Bangru ◽

Ian M. Traniello ◽

Auinash Kalsotra ◽

...

Keyword(s):

Single Cell ◽

Network Inference ◽

Regional Analysis ◽

Supplementary Information ◽

Inference Method ◽

Gene Regulatory Network Inference ◽

Inference Problem ◽

Cell State ◽

Gene Regulatory ◽

Inference Methods

AbstractMotivationWith the use of single-cell RNA sequencing (scRNA-Seq) technologies, it is now possible to acquire gene expression data for each individual cell in samples containing up to millions of cells. These cells can be further grouped into different states along an inferred cell differentiation path, which are potentially characterized by similar, but distinct enough, gene regulatory networks (GRNs). Hence, it would be desirable for scRNA-Seq GRN inference methods to capture the GRN dynamics across cell states. However, current GRN inference methods produce a unique GRN per input dataset (or independent GRNs per cell state), failing to capture these regulatory dynamics.ResultsWe propose a novel single-cell GRN inference method, named SimiC, that jointly infers the GRNs corresponding to each state. SimiC models the GRN inference problem as a LASSO optimization problem with an added similarity constraint, on the GRNs associated to contiguous cell states, that captures the inter-cell-state homogeneity. We show on a mouse hepatocyte single-cell data generated after partial hepatectomy that, contrary to previous GRN methods for scRNA-Seq data, SimiC is able to capture the transcription factor (TF) dynamics across liver regeneration, as well as the cell-level behavior for the regulatory program of each TF across cell states. In addition, on a honey bee scRNA-Seq experiment, SimiC is able to capture the increased heterogeneity of cells on whole-brain tissue with respect to a regional analysis tissue, and the TFs associated specifically to each sequenced tissue.AvailabilitySimiC is written in Python and includes an R API. It can be downloaded from https://github.com/jianhao2016/[email protected], [email protected] informationSupplementary data are available at the code repository.

Download Full-text

Identifying tumor clones in sparse single-cell mutation data

Bioinformatics ◽

10.1093/bioinformatics/btaa449 ◽

2020 ◽

Vol 36 (Supplement_1) ◽

pp. i186-i193

Author(s):

Matthew A Myers ◽

Simone Zaccaria ◽

Benjamin J Raphael

Keyword(s):

Single Cell ◽

Genome Sequencing ◽

Whole Genome ◽

Sequencing Data ◽

Single Nucleotide ◽

Sequencing Coverage ◽

Sequencing Technologies ◽

Low Coverage ◽

Clonal Composition ◽

Cancer Studies

Abstract Motivation Recent single-cell DNA sequencing technologies enable whole-genome sequencing of hundreds to thousands of individual cells. However, these technologies have ultra-low sequencing coverage (<0.5× per cell) which has limited their use to the analysis of large copy-number aberrations (CNAs) in individual cells. While CNAs are useful markers in cancer studies, single-nucleotide mutations are equally important, both in cancer studies and in other applications. However, ultra-low coverage sequencing yields single-nucleotide mutation data that are too sparse for current single-cell analysis methods. Results We introduce SBMClone, a method to infer clusters of cells, or clones, that share groups of somatic single-nucleotide mutations. SBMClone uses a stochastic block model to overcome sparsity in ultra-low coverage single-cell sequencing data, and we show that SBMClone accurately infers the true clonal composition on simulated datasets with coverage at low as 0.2×. We applied SBMClone to single-cell whole-genome sequencing data from two breast cancer patients obtained using two different sequencing technologies. On the first patient, sequenced using the 10X Genomics CNV solution with sequencing coverage ≈0.03×, SBMClone recovers the major clonal composition when incorporating a small amount of additional information. On the second patient, where pre- and post-treatment tumor samples were sequenced using DOP-PCR with sequencing coverage ≈0.5×, SBMClone shows that tumor cells are present in the post-treatment sample, contrary to published analysis of this dataset. Availability and implementation SBMClone is available on the GitHub repository https://github.com/raphael-group/SBMClone. Supplementary information Supplementary data are available at Bioinformatics online.

Download Full-text

Splatter: simulation of single-cell RNA sequencing data

10.1101/133173 ◽

2017 ◽

Cited By ~ 8

Author(s):

Luke Zappia ◽

Belinda Phipson ◽

Alicia Oshlack

Keyword(s):

Single Cell ◽

Rna Sequencing ◽

Real Data ◽

Cell Types ◽

Rna Seq ◽

Sequencing Data ◽

Sequencing Technologies ◽

Simulation Based ◽

Single Cell Rna Sequencing ◽

Multiple Cell

AbstractAs single-cell RNA sequencing technologies have rapidly developed, so have analysis methods. Many methods have been tested, developed and validated using simulated datasets. Unfortunately, current simulations are often poorly documented, their similarity to real data is not demonstrated, or reproducible code is not available.Here we present the Splatter Bioconductor package for simple, reproducible and well-documented simulation of single-cell RNA-seq data. Splatter provides an interface to multiple simulation methods including Splat, our own simulation, based on a gamma-Poisson distribution. Splat can simulate single populations of cells, populations with multiple cell types or differentiation paths.

Download Full-text

EnImpute: imputing dropout events in single-cell RNA-sequencing data via ensemble learning

Bioinformatics ◽

10.1093/bioinformatics/btz435 ◽

2019 ◽

Vol 35 (22) ◽

pp. 4827-4829 ◽

Cited By ~ 6

Author(s):

Xiao-Fei Zhang ◽

Le Ou-Yang ◽

Shuo Yang ◽

Xing-Ming Zhao ◽

Xiaohua Hu ◽

...

Keyword(s):

Single Cell ◽

Rna Sequencing ◽

Ensemble Learning ◽

R Package ◽

Supplementary Information ◽

Sequencing Data ◽

Single Cell Rna Sequencing ◽

The Individual ◽

Downstream Analysis ◽

Shiny Application

Abstract Summary Imputation of dropout events that may mislead downstream analyses is a key step in analyzing single-cell RNA-sequencing (scRNA-seq) data. We develop EnImpute, an R package that introduces an ensemble learning method for imputing dropout events in scRNA-seq data. EnImpute combines the results obtained from multiple imputation methods to generate a more accurate result. A Shiny application is developed to provide easier implementation and visualization. Experiment results show that EnImpute outperforms the individual state-of-the-art methods in almost all situations. EnImpute is useful for correcting the noisy scRNA-seq data before performing downstream analysis. Availability and implementation The R package and Shiny application are available through Github at https://github.com/Zhangxf-ccnu/EnImpute. Supplementary information Supplementary data are available at Bioinformatics online.

Download Full-text