FUNNEL-GSEA: FUNctioNal ELastic-net regression in time-course gene set enrichment analysis.
BACKGROUND
Gene set enrichment analyses (GSEAs) are widely used in genomic research to identify underlying biological mechanisms (defined by the gene sets), such as Gene Ontology terms and molecular pathways. There are two caveats in the currently available methods: (i) they are typically designed for group comparisons or regression analyses, which do not utilize temporal information efficiently in time-series of transcriptomics measurements; and (ii) genes overlapping in multiple molecular pathways are considered multiple times in hypothesis testing.


RESULTS
We propose an inferential framework for GSEA based on functional data analysis, which utilizes the temporal information based on functional principal component analysis, and disentangles the effects of overlapping genes by a functional extension of the elastic-net regression. Furthermore, the hypothesis testing for the gene sets is performed by an extension of Mann-Whitney U test which is based on weighted rank sums computed from correlated observations. By using both simulated datasets and a large-scale time-course gene expression data on human influenza infection, we demonstrate that our method has uniformly better receiver operating characteristic curves, and identifies more pathways relevant to immune-response to human influenza infection than the competing approaches.


METHODS
The methods are implemented in R package FUNNEL, freely and publicly available at: https://github.com/yunzhang813/FUNNEL-GSEA-R-Package .


BACKGROUND
xing_qiu@urmc.rochester.edu or juilee_thakar@urmc.rochester.edu.


BACKGROUND
Supplementary data are available at Bioinformatics online.
Department of Biostatistics and Computational Biology.
Yun
Y
Zhang
Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, USA.
David J
DJ
Topham
Department of Biostatistics and Computational Biology.|Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, USA.
Juilee
J
Thakar
Department of Biostatistics and Computational Biology.
Xing
X
Qiu
D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation; D063990:Gene Ontology; D006801:Humans; D007251:Influenza, Human / Q000235:genetics; D017423:Sequence Analysis, RNA / Q000379:methods; D012984:Software