Abstract
A key unmet challenge in interpreting omics experiments is inferring biological meaning in the context of public functional genomics data. We developed a computational framework, Your Evidence Tailored Integration (YETI; http://yeti.princeton.edu/), which creates specialized functional interaction maps from large public datasets relevant to an individual omics experiment. Using this tailored integration, we predicted and experimentally confirmed an unexpected divergence in viral replication after seasonal or pandemic human influenza virus infection.
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Data availability
The virus infection microarray data are available in GEO under accession GSE55278. Researchers may submit their data of interest for YETI analysis at http://yeti.princeton.edu/. Visualization and exploration of their YETI network and precomputed YETI networks are also available at http://yeti.princeton.edu. All data used in this study are available from the corresponding author on request.
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Acknowledgements
We thank R. Dannenfelser for help in processing the TCGA RNA-seq datasets and A. Krishnan for discussions regarding the network evaluations. We greatly appreciate all members of the Troyanskaya lab for their valuable advice and discussions. This work was supported in part by the NIH (grant NIH U19 AI117873 to S.C.S.; grant NIH R01 GM071966 to O.G.T.). O.G.T. is a senior fellow of the Genetic Networks program of the Canadian Institute for Advanced Research (CIFAR).
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Y.-s.L., E.Z., S.C.S., and O.G.T. conceived and designed the research. Y.-s.L. performed the computational analyses with contributions from C.Y.P. A.K.W., A.T., and Y.-s.L. developed the web interface. B.M.H., V.A.D., and I.R. performed the molecular experiments. Y.-s.L., E.Z., S.C.S., and O.G.T. wrote the manuscript with revisions from all other authors.
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Integrated supplementary information
Supplementary Figure 1 Overview of other approaches.
(left) Coexpression networks are based entirely on the correlated expression in a specific dataset. This yields functional relationships that are highly relevant to the specific dataset but does not capture accurately biological pathway interactions. (right) A generic Bayesian integration using a global data compendium accurately identifies biological pathway interactions, but the functional relationships in this network have a low specificity to any specific dataset.
Supplementary Figure 2 YETI computational framework to construct dataset-specific functional networks.
Known functional interactions are categorized into 237 distinctive biological processes spanning the multifaceted interaction landscape of the human genome. The context-specific interaction network of each biological process is learned through Bayesian integration of the public data compendium. These 237 Bayesian functional networks (i.e. source networks) are then selected based on similar interaction patterns in the user dataset of interest.
Supplementary Figure 3 Example work-through of the YETI webserver.
The user first submits her omics dataset of interest in a simple tab-separated values (TSV) format with genes in rows and omics assays in columns. The web server then integrates the public data compendium in accordance to the latent data structure of the input dataset. The user can then easily explore the dataset-relevant source networks and the dataset-specific functional map of query genes to gain deeper insight into the omics dataset used as input.
Supplementary Figure 4 Effect of exclusion of a single dataset from generic or YETI integrations.
Distribution of the Dataset Specificity Score for including the dataset, excluding it, and using YETI are shown. The center line represents the median, the lower and upper hinges indicate the first and third quartiles, the upper whisker extends to the largest value less than 1.5 x IQR and the lower whisker extends to the smallest value at most 1.5 x IQR. 10 of the 362 GEO datasets used for evaluation in Fig. 2 were chosen at random to be excluded from or included into the generic integrations that were evaluated over the MeSH terms relevant to each dataset (See Supplemental Online Methods). YETI achieved significantly improved dataset specificity over generic integration (**p = 3.1 x 10-4, one-tailed paired t test), and including the dataset of interest in the generic integration had no effect on specificity (p = 0.87, one-tailed paired t test). N.S. = not significant.
Supplementary Figure 5 Evaluation of YETI network performance robustness to the number of directly relevant datasets in the data compendium.
Accuracy score of YETI networks from disease datasets were grouped by the number of datasets annotated to the disease, excluding the user dataset used for YETI analysis. Boxplots were drawn as in Supplementary Fig. 3. The sample sizes of boxplots from left to right are: 52, 36, 64, 35, and 249.
Supplementary Figure 6 Evaluation of vulnerability of the density of YETI networks and co-expression networks to dataset size.
(a) Network densities of co-expression networks exponentially decreased with greater dataset size. (b) Network densities of YETI networks were consistently low even across input datasets of different sizes.
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–6
Supplementary Data 1
Name and description of datasets included in the public data compendium
Supplementary Data 2
ID and name of the 237 source networks
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Lee, Ys., Wong, A.K., Tadych, A. et al. Interpretation of an individual functional genomics experiment guided by massive public data. Nat Methods 15, 1049–1052 (2018). https://doi.org/10.1038/s41592-018-0218-5
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DOI: https://doi.org/10.1038/s41592-018-0218-5
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Olga Troyanskaya
Nature Methods (2018)
