Systematic interrogation of diverse Omic data reveals interpretable, robust, and generalizable transcriptomic features of clinically successful therapeutic targets

Abstract

Target selection is the first and pivotal step in drug discovery. An incorrect choice may not manifest itself for many years after hundreds of millions of research dollars have been spent. We collected a set of 332 targets that succeeded or failed in phase III clinical trials, and explored whether Omic features describing the target genes could predict clinical success. We obtained features from the recently published comprehensive resource: Harmonizome. Nineteen features appeared to be significantly correlated with phase III clinical trial outcomes, but only 4 passed validation schemes that used bootstrapping or modified permutation tests to assess feature robustness and generalizability while accounting for target class selection bias. We also used classifiers to perform multivariate feature selection and found that classifiers with a single feature performed as well in cross-validation as classifiers with more features (AUROC=0.57 and AUPR=0.81). The two predominantly selected features were mean mRNA expression across tissues and standard deviation of expression across tissues, where successful targets tended to have lower mean expression and higher expression variance than failed targets. This finding supports the conventional wisdom that it is favorable for a target to be present in the tissue(s) affected by a disease and absent from other tissues. Overall, our results suggest that it is feasible to construct a model integrating interpretable target features to inform target selection. We anticipate deeper insights and better models in the future, as researchers can reuse the data we have provided to improve methods for handling sample biases and learn more informative features. Code, documentation, and data for this study have been deposited on GitHub athttps://github.com/arouillard/omic-features-successful-targets.AUTHOR SUMMARYDrug discovery often begins with a hypothesis that changing the abundance or activity of a target—a biological molecule, usually a protein—will cure a disease or ameliorate its symptoms. Whether a target hypothesis translates into a successful therapy depends in part on the characteristics of the target, but it is not completely understood which target characteristics are important for success. We sought to answer this question with a supervised machine learning approach. We obtained outcomes of target hypotheses tested in clinical trials, scoring targets as successful or failed, and then obtained thousands of features (i.e. properties or characteristics) of targets from dozens of biological datasets. We statistically tested which features differed between successful and failed targets, and built a computational model that used these features to predict success or failure of targets in clinical trials. We found that successful targets tended to have more variable mRNA abundance from tissue to tissue and lower average abundance across tissues than failed targets. Thus, it is probably favorable for a target to be present in the tissue(s) affected by a disease and absent from other tissues. Our work demonstrates the feasibility of predicting clinical trial outcomes from target features.

Artificial Intelligence in Drug Design: Algorithms, Applications, Challenges and Ethics

“…AI has reached advanced levels beyond theoretical investigations. It has been employed in myriad applications, particularly in the health sector, medicinal sciences and pharmacology, including: using virtual in silico screening for ligand-receptor complementarity and bioactivity [85]; developing new drug molecules or new molecules with potential biological activity [6,[85][86][87]; investigating new biomarkers [88]; improving chemical syntheses [89]; associating certain diseases with specific genes/receptors; multidimensional analyses for structure-activity relationships and druggability [89,90]; connecting gene expressions with clinical trial results [91]; and understanding the mechanisms of many biochemical phenomena, all of which are significant enough to involve companies such as Google and IBM in this business. Other companies that have implemented AI in drug design include Atomwise, Recursion, BenevolentAI, In-silico Medicine, Exscientia, twoXAR, Data2Discovery, Insitro and Collaborations Pharmaceuticals.…”