title: Aggregate entropy scoring for quantifying activity across endpoints with irregular correlation structure.
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.
authors.affiliation: Bioinformatics Research Center, North Carolina State University, Raleigh, NC, USA. Electronic address: gzhang6@ncsu.edu.
authors.forename: Guozhu
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Bioinformatics Research Center, North Carolina State University, Raleigh, NC, USA. Electronic address: swmarvel@ncsu.edu.
authors.forename: Skylar
authors.initials: S
authors.lastname: Marvel
authors.affiliation: Department of Environmental and Molecular Toxicology, Sinnhuber Aquatic Research Laboratory, Oregon State University, Corvallis, OR, USA. Electronic address: lisa.truong@oregonstate.edu.
authors.forename: Lisa
authors.initials: L
authors.lastname: Truong
authors.affiliation: Department of Environmental and Molecular Toxicology, Sinnhuber Aquatic Research Laboratory, Oregon State University, Corvallis, OR, USA. Electronic address: robert.tanguay@oregonstate.edu.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Tanguay
authors.affiliation: Bioinformatics Research Center, North Carolina State University, Raleigh, NC, USA; Department of Biological Sciences, Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, USA. Electronic address: dmreif@ncsu.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Reif
mesh_terms: D000818:Animals; D004625:Embryo, Nonmammalian; D019277:Entropy; D005411:Flame Retardants / Q000633:toxicity; D057166:High-Throughput Screening Assays; D008962:Models, Theoretical; D010641:Phenotype; D013723:Teratogens / Q000633:toxicity*; D015027:Zebrafish / Q000196:embryology*
chemical_list: D005411:Flame Retardants; D013723:Teratogens
keywords: Chemical biology; Developmental neurotoxicology; High throughput screening; Morphology; Multiplexed assays; ToxCast; Zebrafish