123 research outputs found
TROM: A Testing-based Method for Finding Transcriptomic Similarity of Biological Samples
Comparative transcriptomics has gained increasing popularity in genomic
research thanks to the development of high-throughput technologies including
microarray and next-generation RNA sequencing that have generated numerous
transcriptomic data. An important question is to understand the conservation
and differentiation of biological processes in different species. We propose a
testing-based method TROM (Transcriptome Overlap Measure) for comparing
transcriptomes within or between different species, and provide a different
perspective to interpret transcriptomic similarity in contrast to traditional
correlation analyses. Specifically, the TROM method focuses on identifying
associated genes that capture molecular characteristics of biological samples,
and subsequently comparing the biological samples by testing the overlap of
their associated genes. We use simulation and real data studies to demonstrate
that TROM is more powerful in identifying similar transcriptomes and more
robust to stochastic gene expression noise than Pearson and Spearman
correlations. We apply TROM to compare the developmental stages of six
Drosophila species, C. elegans, S. purpuratus, D. rerio and mouse liver, and
find interesting correspondence patterns that imply conserved gene expression
programs in the development of these species. The TROM method is available as
an R package on CRAN (http://cran.r-project.org/) with manuals and source codes
available at http://www.stat.ucla.edu/ jingyi.li/software-and-data/trom.html
A Bootstrap Lasso + Partial Ridge Method to Construct Confidence Intervals for Parameters in High-dimensional Sparse Linear Models
Constructing confidence intervals for the coefficients of high-dimensional
sparse linear models remains a challenge, mainly because of the complicated
limiting distributions of the widely used estimators, such as the lasso.
Several methods have been developed for constructing such intervals. Bootstrap
lasso+ols is notable for its technical simplicity, good interpretability, and
performance that is comparable with that of other more complicated methods.
However, bootstrap lasso+ols depends on the beta-min assumption, a theoretic
criterion that is often violated in practice. Thus, we introduce a new method,
called bootstrap lasso+partial ridge, to relax this assumption. Lasso+partial
ridge is a two-stage estimator. First, the lasso is used to select features.
Then, the partial ridge is used to refit the coefficients. Simulation results
show that bootstrap lasso+partial ridge outperforms bootstrap lasso+ols when
there exist small, but nonzero coefficients, a common situation that violates
the beta-min assumption. For such coefficients, the confidence intervals
constructed using bootstrap lasso+partial ridge have, on average, larger
coverage probabilities than those of bootstrap lasso+ols. Bootstrap
lasso+partial ridge also has, on average, shorter confidence interval
lengths than those of the de-sparsified lasso methods, regardless of whether
the linear models are misspecified. Additionally, we provide theoretical
guarantees for bootstrap lasso+partial ridge under appropriate conditions, and
implement it in the R package "HDCI.
MSIQ: Joint Modeling of Multiple RNA-seq Samples for Accurate Isoform Quantification
Next-generation RNA sequencing (RNA-seq) technology has been widely used to
assess full-length RNA isoform abundance in a high-throughput manner. RNA-seq
data offer insight into gene expression levels and transcriptome structures,
enabling us to better understand the regulation of gene expression and
fundamental biological processes. Accurate isoform quantification from RNA-seq
data is challenging due to the information loss in sequencing experiments. A
recent accumulation of multiple RNA-seq data sets from the same tissue or cell
type provides new opportunities to improve the accuracy of isoform
quantification. However, existing statistical or computational methods for
multiple RNA-seq samples either pool the samples into one sample or assign
equal weights to the samples when estimating isoform abundance. These methods
ignore the possible heterogeneity in the quality of different samples and could
result in biased and unrobust estimates. In this article, we develop a method,
which we call "joint modeling of multiple RNA-seq samples for accurate isoform
quantification" (MSIQ), for more accurate and robust isoform quantification by
integrating multiple RNA-seq samples under a Bayesian framework. Our method
aims to (1) identify a consistent group of samples with homogeneous quality and
(2) improve isoform quantification accuracy by jointly modeling multiple
RNA-seq samples by allowing for higher weights on the consistent group. We show
that MSIQ provides a consistent estimator of isoform abundance, and we
demonstrate the accuracy and effectiveness of MSIQ compared with alternative
methods through simulation studies on D. melanogaster genes. We justify MSIQ's
advantages over existing approaches via application studies on real RNA-seq
data from human embryonic stem cells, brain tissues, and the HepG2 immortalized
cell line
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Quantitative principles of cis-translational control by general mRNA sequence features in eukaryotes.
BackgroundGeneral translational cis-elements are present in the mRNAs of all genes and affect the recruitment, assembly, and progress of preinitiation complexes and the ribosome under many physiological states. These elements include mRNA folding, upstream open reading frames, specific nucleotides flanking the initiating AUG codon, protein coding sequence length, and codon usage. The quantitative contributions of these sequence features and how and why they coordinate to control translation rates are not well understood.ResultsHere, we show that these sequence features specify 42-81% of the variance in translation rates in Saccharomyces cerevisiae, Schizosaccharomyces pombe, Arabidopsis thaliana, Mus musculus, and Homo sapiens. We establish that control by RNA secondary structure is chiefly mediated by highly folded 25-60 nucleotide segments within mRNA 5' regions, that changes in tri-nucleotide frequencies between highly and poorly translated 5' regions are correlated between all species, and that control by distinct biochemical processes is extensively correlated as is regulation by a single process acting in different parts of the same mRNA.ConclusionsOur work shows that general features control a much larger fraction of the variance in translation rates than previously realized. We provide a more detailed and accurate understanding of the aspects of RNA structure that directs translation in diverse eukaryotes. In addition, we note that the strongly correlated regulation between and within cis-control features will cause more even densities of translational complexes along each mRNA and therefore more efficient use of the translation machinery by the cell
Correspondence of D. melanogaster and C. elegans developmental stages revealed by alternative splicing characteristics of conserved exons
Illustration of RNA-seq datasets. Illustration of RNA-seq datasets of fly and worm from modEncode. (PDF 1020 kb
Issues arising from benchmarking single-cell RNA sequencing imputation methods
On June 25th, 2018, Huang et al. published a computational method SAVER on
Nature Methods for imputing dropout gene expression levels in single cell RNA
sequencing (scRNA-seq) data. Huang et al. performed a set of comprehensive
benchmarking analyses, including comparison with the data from RNA fluorescence
in situ hybridization, to demonstrate that SAVER outperformed two existing
scRNA-seq imputation methods, scImpute and MAGIC. However, their computational
analyses were based on semi-synthetic data that the authors had generated
following the Poisson-Gamma model used in the SAVER method. We have therefore
re-examined Huang et al.'s study. We find that the semi-synthetic data have
very different properties from those of real scRNA-seq data and that the cell
clusters used for benchmarking are inconsistent with the cell types labeled by
biologists. We show that a reanalysis based on real scRNA-seq data and grounded
on biological knowledge of cell types leads to different results and
conclusions from those of Huang et al.Comment: 5 page
Modeling and analysis of RNA-seq data: a review from a statistical perspective
Background: Since the invention of next-generation RNA sequencing (RNA-seq)
technologies, they have become a powerful tool to study the presence and
quantity of RNA molecules in biological samples and have revolutionized
transcriptomic studies. The analysis of RNA-seq data at four different levels
(samples, genes, transcripts, and exons) involve multiple statistical and
computational questions, some of which remain challenging up to date.
Results: We review RNA-seq analysis tools at the sample, gene, transcript,
and exon levels from a statistical perspective. We also highlight the
biological and statistical questions of most practical considerations.
Conclusion: The development of statistical and computational methods for
analyzing RNA- seq data has made significant advances in the past decade.
However, methods developed to answer the same biological question often rely on
diverse statical models and exhibit different performance under different
scenarios. This review discusses and compares multiple commonly used
statistical models regarding their assumptions, in the hope of helping users
select appropriate methods as needed, as well as assisting developers for
future method development
Statistical hypothesis testing versus machine-learning binary classification: distinctions and guidelines
Making binary decisions is a common data analytical task in scientific
research and industrial applications. In data sciences, there are two related
but distinct strategies: hypothesis testing and binary classification. In
practice, how to choose between these two strategies can be unclear and rather
confusing. Here we summarize key distinctions between these two strategies in
three aspects and list five practical guidelines for data analysts to choose
the appropriate strategy for specific analysis needs. We demonstrate the use of
those guidelines in a cancer driver gene prediction example
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