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Inference for the existence of hormetic dose-response relationships in toxicology studies.

ABSTRACT: In toxicology studies hormesis refers to a dose-response relationship with a stimulatory response at low doses and an inhibitory response at high doses. In this manuscript, we particularly focus on a J-shaped dose-response relationship for binary cancer responses. We propose and examine two new flexible models for testing the hypothesis of hormesis in a Bayesian framework. The first model is parametric and enhances the flexibility of modeling a hormetic zone by using a non-linear predictor in a multistage model. The second model is non-parametric and allows multiple model specifications, weighting the contribution of each model via Bayesian model averaging (BMA). Simulation studies show that the non-parametric modeling approach with BMA provides robust sensitivity and specificity for detecting hormesis relative to the parametric approach, regardless of the shape of a hormetic zone.

SUBMITTER: Kim SB

PROVIDER: S-EPMC4915611 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Inference for the existence of hormetic dose-response relationships in toxicology studies.

Kim Steven B SB Bartell Scott M SM Gillen Daniel L DL

Biostatistics (Oxford, England) 20160212 3

In toxicology studies hormesis refers to a dose-response relationship with a stimulatory response at low doses and an inhibitory response at high doses. In this manuscript, we particularly focus on a J-shaped dose-response relationship for binary cancer responses. We propose and examine two new flexible models for testing the hypothesis of hormesis in a Bayesian framework. The first model is parametric and enhances the flexibility of modeling a hormetic zone by using a non-linear predictor in a ...[more]

PMID: 26873961

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Project description:BackgroundTwo hormetic modifications of a monotonically decreasing log-logistic dose-response function are most often used to model stimulatory effects of low dosages of a toxicant in plant biology. As just one of these empirical models is yet properly parameterized to allow inference about quantities of interest, this study contributes the parameterized functions for the second hormetic model and compares the estimates of effective dosages between both models based on 23 hormetic data sets. Based on this, the impact on effective dosage estimations was evaluated, especially in case of a substantially inferior fit by one of the two models.Methodology/principal findingsThe data sets evaluated described the hormetic responses of four different test plant species exposed to 15 different chemical stressors in two different experimental dose-response test designs. Out of the 23 data sets, one could not be described by any of the two models, 14 could be better described by one of the two models, and eight could be equally described by both models. In cases of misspecification by any of the two models, the differences between effective dosages estimates (0-1768%) greatly exceeded the differences observed when both models provided a satisfactory fit (0-26%). This suggests that the conclusions drawn depending on the model used may diverge considerably when using an improper hormetic model especially regarding effective dosages quantifying hormesis.Conclusions/significanceThe study showed that hormetic dose responses can take on many shapes and that this diversity can not be captured by a single model without risking considerable misinterpretation. However, the two empirical models considered in this paper together provide a powerful means to model, prove, and now also to quantify a wide range of hormetic responses by reparameterization. Despite this, they should not be applied uncritically, but after statistical and graphical assessment of their adequacy.

Dataset Information

Inference for the existence of hormetic dose-response relationships in toxicology studies.

Publications

Inference for the existence of hormetic dose-response relationships in toxicology studies.

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