Accelerated dimensionality reduction of single-cell RNA sequencing data with fastglmpca.

SUMMARY: Motivated by theoretical and practical issues that arise when applying Principal component analysis (PCA) to count data, Townes et al. introduced "Poisson GLM-PCA", a variation of PCA adapted to count data, as a tool for dimensionality reduction of single-cell RNA sequencing (scRNA-seq) data. However, fitting GLM-PCA is computationally challenging. Here we study this problem, and show that a simple algorithm, which we call "Alternating Poisson Regression" (APR), produces better quality fits, and in less time, than existing algorithms. APR is also memory-efficient and lends itself to parallel implementation on multi-core processors, both of which are helpful for handling large scRNA-seq datasets. We illustrate the benefits of this approach in three publicly available scRNA-seq datasets. The new algorithms are implemented in an R package, fastglmpca. AVAILABILITY AND IMPLEMENTATION: The fastglmpca R package is released on CRAN for Windows, macOS and Linux, and the source code is available at github.com/stephenslab/fastglmpca under the open source GPL-3 license. Scripts to reproduce the results in this paper are also available in the GitHub repository and on Zenodo.

Accelerated dimensionality reduction of single-cell RNA sequencing data with fastglmpca.

Summary: Motivated by theoretical and practical issues that arise when applying Principal Components Analysis (PCA) to count data, Townes et al introduced "Poisson GLM-PCA", a variation of PCA adapted to count data, as a tool for dimensionality reduction of single-cell RNA sequencing (RNA-seq) data. However, fitting GLM-PCA is computationally challenging. Here we study this problem, and show that a simple algorithm, which we call "Alternating Poisson Regression" (APR), produces better quality fits, and in less time, than existing algorithms. APR is also memory-efficient, and lends itself to parallel implementation on multi-core processors, both of which are helpful for handling large single-cell RNA-seq data sets. We illustrate the benefits of this approach in two published single-cell RNA-seq data sets. The new algorithms are implemented in an R package, fastglmpca. Availability and implementation: The fastglmpca R package is released on CRAN for Windows, macOS and Linux, and the source code is available at github.com/stephenslab/fastglmpca under the open source GPL-3 license. Scripts to reproduce the results in this paper are also available in the GitHub repository. Contact: mstephens@uchicago.edu. Supplementary information: Supplementary data are available on BioRxiv online.

Tradeoffs in Modeling Context Dependency in Complex Trait Genetics.

Genetic effects on complex traits may depend on context, such as age, sex, environmental exposures or social settings. However, it is often unclear if the extent of context dependency, or Gene-by-Environment interaction (GxE), merits more involved models than the additive model typically used to analyze data from genome-wide association studies (GWAS). Here, we suggest considering the utility of GxE models in GWAS as a tradeoff between bias and variance parameters. In particular, We derive a decision rule for choosing between competing models for the estimation of allelic effects. The rule weighs the increased estimation noise when context is considered against the potential bias when context dependency is ignored. In the empirical example of GxSex in human physiology, the increased noise of context-specific estimation often outweighs the bias reduction, rendering GxE models less useful when variants are considered independently. However, we argue that for complex traits, the joint consideration of context dependency across many variants mitigates both noise and bias. As a result, polygenic GxE models can improve both estimation and trait prediction. Finally, we exemplify (using GxDiet effects on longevity in fruit flies) how analyses based on independently ascertained "top hits" alone can be misleading, and that considering polygenic patterns of GxE can improve interpretation.