Title: Aggregate entropy scoring for quantifying activity across endpoints with irregular correlation structure.

Authors: Zhang, Guozhu; Marvel, Skylar; Truong, Lisa; Tanguay, Robert L; Reif, David M

Published In Reprod Toxicol, (2016 Jul)

Abstract: Robust computational approaches are needed to characterize systems-level responses to chemical perturbations in environmental and clinical toxicology applications. Appropriate characterization of response presents a methodological challenge when dealing with diverse phenotypic endpoints measured using in vivo systems. In this article, we propose an information-theoretic method named Aggregate Entropy (AggE) and apply it to scoring multiplexed, phenotypic endpoints measured in developing zebrafish (Danio rerio) across a broad concentration-response profile for a diverse set of 1060 chemicals. AggE accurately identified chemicals with significant morphological effects, including single-endpoint effects and multi-endpoint responses that would have been missed by univariate methods, while avoiding putative false-positives that confound traditional methods due to irregular correlation structure. By testing AggE in a variety of high-dimensional real and simulated datasets, we have characterized its performance and suggested implementation parameters that can guide its application across a wide range of experimental scenarios.

PubMed ID: 27132190

MeSH Terms: Animals; Embryo, Nonmammalian; Entropy; Flame Retardants/toxicity; High-Throughput Screening Assays*; Models, Theoretical*; Phenotype; Teratogens/toxicity*; Zebrafish/embryology*