Estimating Potency in High-Throughput Screening Experiments by Maximizing the Rate of Change in Weighted Shannon Entropy.
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.
Biostatistics and Computational Biology Branch, The National Institute of Environmental Health Sciences, National Institutes of Health, 111 T. W. Alexander Drive, Research Triangle Park, NC 27709, USA.
Keith R
KR
Shockley
D002460:Cell Line; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D019277:Entropy; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D005867:Gestrinone / Q000494:pharmacology; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D008962:Models, Theoretical; D010636:Phenols / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000378:metabolism; D015203:Reproducibility of Results; D054852:Small Molecule Libraries / Q000494:pharmacology*
D010636:Phenols; D011960:Receptors, Estrogen; D054852:Small Molecule Libraries; D005867:Gestrinone; D004958:Estradiol; C041594:4-nonylphenol