Each cluster generated by this procedure contains an ��exemplar��, a single member that best characterizes the pattern shared by the members of the group. To identify higherlevel relationships ICI 182780 between individual clusters, we further aggregated the data by recursively re-clustering these exemplars to attain a global view of the number of characteristic patterns of drug-induced gene expression changes in this collection. The clusters generated from the drug-induced gene expression profiles derived from the breast cancer cell line MCF7 are displayed in a network diagram in Figure 2A, where nodes represent individual drugs and edge weights represent the magnitude of similarity between a given drug��s expression profile and the exemplar of its cluster. We found that 2 of the 31 resulting clusters contained an enriched fraction of hERG inhibitors compared to randomized clusters of the same size. Even after correction for experimental batch effects described above, clustering of all drug-induced expression profiles demonstrates assortment by cell background, suggesting the existence of cell line-specific drug effects. However, as the exemplars of these subclusters are hierarchically merged, connections emerge between hERG inhibitor-enriched clusters derived from all three different cells lines, indicating the presence of general as well as cell background-specific responses. This interpretation is supported by a scatterplot of average expression changes in these five hERG inhibitor-enriched clusters in the three cell lines, which indicates that some differentially TWS119 purchase expressed genes are shared, as well as Venn diagrams indicating the overlap of DE genes between these sets. The clustering results for each of the networks in Figure 2 are given in Table S2. Further, we note that many of the exemplars of these hERG inhibitor-enriched clusters are preserved between cell lines. The enrichment of hERG blockers with previous experimental or clinical annotation among the five enriched clusters identified in Figure 2B were further quantified with the hypergeometric test, with resulting prediction statistics summarized in Table 2. Quantification of the resulting predictive power in Table 3 suggests an overall accuracy of 82% based on drugs for which experimental or clinical annotation is available, which is consistent with a test of ��good�� quality based on previously published metrics. While the pairwise gene expression profile correlations within the hERG inhibitor-enriched clusters are significantly higher than the correlations between enriched cluster drugs and non-enriched cluster drugs, the corresponding distributions of pairwise chemical similarities are statistically different yet possess approximately equal medians. Thus, this analysis highlights correlations in druginduced gene expression profiles that are not evident from chemical similarity alone. Intriguingly, we also noted that the MCF7 Astemizole-exemplar cluster includes Miconazole and Mefloquine, drugs which have been previously shown to inhibit hERG channels recombinantly expressed in cell lines, but did not appear in our lists of clinically annotated LQT contain false negatives which nevertheless cluster with other known inhibitors based on similarity in transcriptional responses.