title: A data-driven weighting scheme for multivariate phenotypic endpoints recapitulates zebrafish developmental cascades.
abstract: Zebrafish have become a key alternative model for studying health effects of environmental stressors, partly due to their genetic similarity to humans, fast generation time, and the efficiency of generating high-dimensional systematic data. Studies aiming to characterize adverse health effects in zebrafish typically include several phenotypic measurements (endpoints). While there is a solid biomedical basis for capturing a comprehensive set of endpoints, making summary judgments regarding health effects requires thoughtful integration across endpoints. Here, we introduce a Bayesian method to quantify the informativeness of 17 distinct zebrafish endpoints as a data-driven weighting scheme for a multi-endpoint summary measure, called weighted Aggregate Entropy (wAggE). We implement wAggE using high-throughput screening (HTS) data from zebrafish exposed to five concentrations of all 1060 ToxCast chemicals. Our results show that our empirical weighting scheme provides better performance in terms of the Receiver Operating Characteristic (ROC) curve for identifying significant morphological effects and improves robustness over traditional curve-fitting approaches. From a biological perspective, our results suggest that developmental cascade effects triggered by chemical exposure can be recapitulated by analyzing the relationships among endpoints. Thus, wAggE offers a powerful approach for analysis of multivariate phenotypes that can reveal underlying etiological processes.
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: krroell@ncsu.edu.
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Roell
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; D008962:Models, Theoretical; D015999:Multivariate Analysis; D010641:Phenotype; D015027:Zebrafish / Q000196:embryology*
keywords: Bayesian; Developmental cascade; High-dimensional; Multiple endpoints; Multivariate; Risk assessment; Scoring; ToxRefDB; Zebrafish