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Nucleic Acids Res DOI:10.1093/nar/gku722

Multivariate inference of pathway activity in host immunity and response to therapeutics.

Publication TypeJournal Article
Year of Publication2014
AuthorsGoel, G, Conway, KL, Jaeger, M, Netea, MG, Xavier, RJ
JournalNucleic Acids Res
Volume42
Issue16
Pages10288-306
Date Published2014
ISSN1362-4962
KeywordsAlgorithms, Animals, Carrier Proteins, Cluster Analysis, Computational Biology, Epithelium, Gene Expression Profiling, Gene Expression Regulation, Gene-Environment Interaction, Humans, Immunity, Inflammatory Bowel Diseases, Mice, Microbiota, Multivariate Analysis, Niacinamide, Principal Component Analysis, Salmonella Infections, Animal, Transcription, Genetic, Wound Healing
Abstract

Developing a quantitative view of how biological pathways are regulated in response to environmental factors is central for understanding of disease phenotypes. We present a computational framework, named Multivariate Inference of Pathway Activity (MIPA), which quantifies degree of activity induced in a biological pathway by computing five distinct measures from transcriptomic profiles of its member genes. Statistical significance of inferred activity is examined using multiple independent self-contained tests followed by a competitive analysis. The method incorporates a new algorithm to identify a subset of genes that may regulate the extent of activity induced in a pathway. We present an in-depth evaluation of specificity, robustness, and reproducibility of our method. We benchmarked MIPA's false positive rate at less than 1%. Using transcriptomic profiles representing distinct physiological and disease states, we illustrate applicability of our method in (i) identifying gene-gene interactions in autophagy-dependent response to Salmonella infection, (ii) uncovering gene-environment interactions in host response to bacterial and viral pathogens and (iii) identifying driver genes and processes that contribute to wound healing and response to anti-TNFα therapy. We provide relevant experimental validation that corroborates the accuracy and advantage of our method.

URLhttp://nar.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=25147207
DOI10.1093/nar/gku722
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/25147207?dopt=Abstract

Alternate JournalNucleic Acids Res.
PubMed ID25147207
PubMed Central IDPMC4176341
Grant List310372 / / European Research Council / International
P30 DK043351 / DK / NIDDK NIH HHS / United States
AI089992 / AI / NIAID NIH HHS / United States
DK043351 / DK / NIDDK NIH HHS / United States