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PLoS Comput Biol. 2017 Jul 18;13(7):e1005653. doi: 10.1371/journal.pcbi.1005653. eCollection 2017 Jul.

CLIC, a tool for expanding biological pathways based on co-expression across thousands of datasets.

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Howard Hughes Medical Institute and Department of Molecular Biology and the Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States of America and Department of Systems Biology, Harvard Medical School, Boston, MA United States of America.
Department of Statistics, Harvard University, Cambridge, MA, United States of America.
Broad Institute, Cambridge, MA, United States of America.


In recent years, there has been a huge rise in the number of publicly available transcriptional profiling datasets. These massive compendia comprise billions of measurements and provide a special opportunity to predict the function of unstudied genes based on co-expression to well-studied pathways. Such analyses can be very challenging, however, since biological pathways are modular and may exhibit co-expression only in specific contexts. To overcome these challenges we introduce CLIC, CLustering by Inferred Co-expression. CLIC accepts as input a pathway consisting of two or more genes. It then uses a Bayesian partition model to simultaneously partition the input gene set into coherent co-expressed modules (CEMs), while assigning the posterior probability for each dataset in support of each CEM. CLIC then expands each CEM by scanning the transcriptome for additional co-expressed genes, quantified by an integrated log-likelihood ratio (LLR) score weighted for each dataset. As a byproduct, CLIC automatically learns the conditions (datasets) within which a CEM is operative. We implemented CLIC using a compendium of 1774 mouse microarray datasets (28628 microarrays) or 1887 human microarray datasets (45158 microarrays). CLIC analysis reveals that of 910 canonical biological pathways, 30% consist of strongly co-expressed gene modules for which new members are predicted. For example, CLIC predicts a functional connection between protein C7orf55 (FMC1) and the mitochondrial ATP synthase complex that we have experimentally validated. CLIC is freely available at We anticipate that CLIC will be valuable both for revealing new components of biological pathways as well as the conditions in which they are active.

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