Connectivity map data and associated methodologies have become a valuable tool in understanding drug mechanism of action (MOA) and discovering new indications for drugs. However, few systematic evaluations have been done to assess the accuracy of these methodologies. One of the difficulties has been the lack of benchmarking data sets. Iskar et al. (PLoS. Comput. Biol. 6, 2010) predicted the Anatomical Therapeutic Chemical (ATC) drug classification based on drug-induced gene expression profile similarity (DIPS), and quantified the accuracy of their method by computing the area under the curve (AUC) of the Receiver Operating Characteristic (ROC) curve. We adopt the same data and extend the methodology, by using a simpler eXtreme cosine (XCos) method, and find it does better in this limited setting than the Kolmogorov-Smirnov (KS) statistic. In fact, for partial AUC (a more relevant statistic for actual application to repositioning) XCos does 17% better than the DIPS method (p=1.2e-7). We also observe that smaller gene signatures (with 100 probes) do better than larger ones (with 500 probes), and that DMSO controls from within the same batch obviate the need for mean centering. As expected there is heterogeneity in the prediction accuracy amongst the various ATC codes. We find that good transcriptional response to drug treatment appears necessary but not sufficient to achieve high AUCs. Certain ATC codes, such as those corresponding to corticosteroids, had much higher AUCs possibly due to strong transcriptional responses and consistency in MOA.
Hidradenitis suppurativa (HS) is a common, debilitating inflammatory skin disease linked to immune dysregulation and abnormalities in follicular structure and function. Several studies have characterized the transcriptomic profile of affected and unaffected skin in small populations. In this study of 20 patients, RNA from lesional and matching non-lesional skin biopsies in 20 subjects were used to identify an expression-based HS disease signature. This was followed by differential expression and pathway enrichment analyses, as well as jointly reanalyzing our findings with previously published transcriptomic profiles. We establish an RNA-Seq based HS expression disease signature that is mostly consistent with previous reports. Bulk-RNA profiles from 104 subjects in 7 previously reported data sets identified a disease signature of 118 differentially regulated genes compared to three control data sets from non-lesional skin. We confirmed previously reported expression profiles and further characterized dysregulation in complement activation and host response to bacteria in disease pathogenesis. Changes in the transcriptome of lesional skin in this cohort of HS patients is consistent with smaller previously reported populations. The findings further support the significance of immune dysregulation, in particular with regard to bacterial response mechanisms. Joint analysis of this and previously reported cohorts indicate a remarkably consistent expression profile.
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