Person:

Brown, Adam

Drug repositioning, the process of discovering, validating, and marketing previously approved drugs for new indications, is of growing interest to academia and industry due to reduced time and costs associated with repositioned drugs. Computational methods for repositioning are appealing because they putatively nominate the most promising candidate drugs for a given indication. Comparing the wide array of computational repositioning methods, however, is a challenge due to inconsistencies in method validation in the field. Furthermore, a common simplifying assumption, that all novel predictions are false, is intellectually unsatisfying and hinders reproducibility. We address this assumption by providing a gold standard database, repoDB, that consists of both true positives (approved drugs), and true negatives (failed drugs). We have made the full database and all code used to prepare it publicly available, and have developed a web application that allows users to browse subsets of the data (http://apps.chiragjpgroup.org/repoDB/).

Objective: Drug repositioning is a promising methodology for reducing the cost and duration of the drug discovery pipeline. We sought to develop a computational repositioning method leveraging annotations in the literature, such as Medical Subject Heading (MeSH) terms. Methods: We developed software to determine significantly co-occurring drug-MeSH term pairs and a method to estimate pair-wise literature-derived distances between drugs. Results: We found that literature-based drug-drug similarities predicted the number of shared indications across drug-drug pairs. Clustering drugs based on their similarity revealed both known and novel drug indications. We demonstrate the utility of our approach by generating repositioning hypotheses for the commonly used diabetes drug metformin. Conclusion: Our study demonstrates that literature-derived similarity is useful for identifying potential repositioning opportunities. We provided open-source code and deployed a free-to-use, interactive application to explore our database of similarity-based drug clusters (available at http://apps.chiragjpgroup.org/MeSHDD/).

Background: Repositioning approved drug and small molecules in novel therapeutic areas is of key interest to the pharmaceutical industry. A number of promising computational techniques have been developed to aid in repositioning, however, the majority of available methodologies require highly specific data inputs that preclude the use of many datasets and databases. There is a clear unmet need for a generalized methodology that enables the integration of multiple types of both gene expression data and database schema. Results: ksRepo eliminates the need for a single microarray platform as input and allows for the use of a variety of drug and chemical exposure databases. We tested ksRepo’s performance on a set of five prostate cancer datasets using the Comparative Toxicogenomics Database (CTD) as our database of gene-compound interactions. ksRepo successfully predicted significance for five frontline prostate cancer therapies, representing a significant enrichment from over 7000 CTD compounds, and achieved specificity similar to other repositioning methods. Conclusions: We present ksRepo, which enables investigators to use any data inputs for computational drug repositioning. ksRepo is implemented in a series of four functions in the R statistical environment under a BSD3 license. Source code is freely available at http://github.com/adam-sam-brown/ksRepo. A vignette is provided to aid users in performing ksRepo analysis.

Summary: Robust conversion between microarray platforms is needed to leverage the wide variety of microarray expression studies that have been conducted to date. Currently available conversion methods rely on manufacturer annotations, which are often incomplete, or on direct alignment of probes from different platforms, which often fail to yield acceptable genewise correlation. Here, we describe aRrayLasso, which uses the Lasso-penalized generalized linear model to model the relationships between individual probes in different probe sets. We have implemented aRrayLasso in a set of five open-source R functions that allow the user to acquire data from public sources such as Gene Expression Omnibus, train a set of Lasso models on that data and directly map one microarray platform to another. aRrayLasso significantly predicts expression levels with similar fidelity to technical replicates of the same RNA pool, demonstrating its utility in the integration of datasets from different platforms. Availability and implementation: All functions are available, along with descriptions, at https://github.com/adam-sam-brown/aRrayLasso. Contact: chirag_patel@hms.harvard.edu Supplementary information: Supplementary data are available at Bioinformatics online.