Quantifying alternative splicing from paired-end RNA-sequencing data
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Publication:2453673
Abstract: RNA-sequencing has revolutionized biomedical research and, in particular, our ability to study gene alternative splicing. The problem has important implications for human health, as alternative splicing may be involved in malfunctions at the cellular level and multiple diseases. However, the high-dimensional nature of the data and the existence of experimental biases pose serious data analysis challenges. We find that the standard data summaries used to study alternative splicing are severely limited, as they ignore a substantial amount of valuable information. Current data analysis methods are based on such summaries and are hence suboptimal. Further, they have limited flexibility in accounting for technical biases. We propose novel data summaries and a Bayesian modeling framework that overcome these limitations and determine biases in a nonparametric, highly flexible manner. These summaries adapt naturally to the rapid improvements in sequencing technology. We provide efficient point estimates and uncertainty assessments. The approach allows to study alternative splicing patterns for individual samples and can also be the basis for downstream analyses. We found a severalfold improvement in estimation mean square error compared popular approaches in simulations, and substantially higher consistency between replicates in experimental data. Our findings indicate the need for adjusting the routine summarization and analysis of alternative splicing RNA-seq studies. We provide a software implementation in the R package casper.
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Cites work
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- Nonparametric Estimation from Incomplete Observations
- Quantifying alternative splicing from paired-end RNA-sequencing data
- Statistical modeling of RNA-Seq data
Cited in
(13)- New Tools for Expression Alternative Splicing Validation
- Identification and Exploitation of Linkage by Means of Alternative Splicing
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- A Markov random field-based approach for joint estimation of differentially expressed genes in mouse transcriptome data
- Transcriptomics: quantifying non-uniform read distribution using MapReduce
- Exact transcript quantification over splice graphs
- MSIQ: joint modeling of multiple RNA-seq samples for accurate isoform quantification
- ExactDAS: an exact test procedure for the detection of differential alternative splicing in microarray experiments
- Corrigendum: Quantifying alternative splicing from paired-end RNA-sequencing data
- Bayesian estimation of differential transcript usage from RNA-seq data
- Searching for alternative splicing with a joint model on probe measurability and expression intensities
- Quantifying alternative splicing from paired-end RNA-sequencing data
- Yanagi: transcript segment library construction for RNA-seq quantification
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