Target identification and validation is a pressing challenge in the pharmaceutical industry, with many of the programmes that fail for efficacy reasons showing poor association between the drug target and the disease. Computational prediction of successful targets could have a considerable impact on attrition rates in the drug discovery pipeline by significantly reducing the initial search space. Here, we explore whether gene–disease association data from the Open Targets platform is sufficient to predict therapeutic targets that are actively being pursued by pharmaceutical companies or are already on the market.
To test our hypothesis, we train four different classifiers (a random forest, a support vector machine, a neural network and a gradient boosting machine) on partially labelled data and evaluate their performance using nested cross-validation and testing on an independent set. We then select the best performing model and use it to make predictions on more than 15,000 genes. Finally, we validate our predictions by mining the scientific literature for proposed therapeutic targets.
We observe that the data types with the best predictive power are animal models showing a disease-relevant phenotype, differential expression in diseased tissue and genetic association with the disease under investigation. On a test set, the neural network classifier achieves over 71% accuracy with an AUC of 0.76 when predicting therapeutic targets in a semi-supervised learning setting. We use this model to gain insights into current and failed programmes and to predict 1431 novel targets, of which a highly significant proportion has been independently proposed in the literature.
Our in silico approach shows that data linking genes and diseases is sufficient to predict novel therapeutic targets effectively and confirms that this type of evidence is essential for formulating or strengthening hypotheses in the target discovery process. Ultimately, more rapid and automated target prioritisation holds the potential to reduce both the costs and the development times associated with bringing new medicines to patients.
Bio: After completing a BSc in Biotechnology and a MSc in Molecular Biotechnology at the University of Torino, Enrico started his PhD in Genetics and Systems Biology at the University of Cambridge. Here, he applied experimental and computational genomics approaches to study the role and the functional interactions of Sox transcription factors during the central nervous system development of the fruit fly. At GSK, Enrico works as a data scientist in the Computational Biology group within Target Sciences. He works across the Respiratory and Immuno-Inflammation therapeutic areas focusing on the application of data mining, machine learning and other computational biology approaches to identify and validate novel therapeutic targets.
Enrico Ferrero, PhD
Scientific Leader and Computational Biologist at GSK