Abstract
High-throughput in vitro screening experiments can be used to generate concentration-response data for large chemical libraries. It is often desirable to estimate the concentration needed to achieve a particular effect, or potency, for each chemical tested in an assay. Potency estimates can be used to directly compare chemical profiles and prioritize compounds for confirmation studies, or employed as input data for prediction modeling and association mapping. The concentration for half-maximal activity derived from the Hill equation model (i.e., AC50) is the most common potency measure applied in pharmacological research and toxicity testing. However, the AC50 parameter is subject to large uncertainty for many concentration-response relationships. In this study we introduce a new measure of potency based on a weighted Shannon entropy measure termed the weighted entropy score (WES). Our potency estimator (Point of Departure, PODWES) is defined as the concentration producing the maximum rate of change in weighted entropy along a concentration-response profile. This approach provides a new tool for potency estimation that does not depend on the assumption of monotonicity or any other pre-specified concentration-response relationship. PODWES estimates potency with greater precision and less bias compared to the conventional AC50 assessed across a range of simulated conditions.
Highlights
High-throughput in vitro screening experiments can be used to generate concentration-response data for large chemical libraries
More than 10,000 substances are being tested in 15-point concentration-response format in phase II of the Tox[21] collaboration, involving the U.S Environmental Protection Agency (EPA), the U.S Food and Drug Administration (FDA), the National Institutes of Health (NIH) National Center for Advancing Translational Sciences (NCATS) and the National Institute for Environmental Health Sciences (NIEHS)/National Toxicology Program (NTP)[4]
If the maximum observed response is less than the assay detection limit, PODWES is “undefined”, since a detectable response may have occurred if a larger range of test concentrations had been used
Summary
High-throughput in vitro screening experiments can be used to generate concentration-response data for large chemical libraries. Response profiles can be summarized by a measure of average activity across tested concentrations, such as the area under the curve (AUC) of concentration-response curves[5], a weighted version of AUC6, or a weighted entropy score (WES)[7] While these measures are useful for ranking compounds, it is often desirable to estimate the concentration at which a chemical induces a particular effect level using automated data analysis processes. Such potency measures can be applied for rapid identification of pharmacoactive hits or toxicological assessment, or used as input data for prediction modeling[8] or association mapping[5]. In qHTS studies there is usually very little, if any, replication at each tested concentration and it is often not appropriate to combine data across different experimental runs because conditions can change substantially between trials[4,10]
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