Dose Response Signal Detection under Model Uncertainty

Dette, Holger; Titoff, Stefanie; Volgushev, Stanislav; Bretz, Frank

doi:10.1111/biom.12357

Cited by 9 publications

(21 citation statements)

References 47 publications

(69 reference statements)

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“…The BMD represents an estimate of the dose corresponding to a specified level of increased response (the benchmark response [BMR]), which is derived from the dose–response curve fitted to data (EFSA, ). The regression method is a mathematical approach to simulate and apply a parametric model with continuous variables, which presumes that the dose is responsible for the response (Dette, Titoff, Volgushev, & Bretz, ). In the present study, NOAEL/LOAEL method and BMD method were both used to derive the recommended HBGV, in this case, TDI for NP.…”

Section: Resultsmentioning

confidence: 99%

An updated weight of evidence approach for deriving a health‐based guidance value for 4‐nonylphenol

Huo

Liu

et al. 2018

J of Applied Toxicology

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4-Nonylphenol (NP) is a persistent estrogen-active compound. Human exposure to NP is primarily through water and food. Although risk assessments of NP have been conducted by the European Union and a few other countries, only the Danish Veterinary and Food Administration, in 2000, proposed a tolerable daily intake of 0.005 mg kg body weight (bw) day . New data have been accumulated since then, prompting an update on the risk assessment of NP. A weight of evidence approach is recommended for use in scientific assessments by several agencies, e.g., European Food Safety Authority, etc. Based on the results of a weight of evidence approach, two methods were used to derive the health-based guidance value (HBGV) for NP in this study, namely a no observed adverse effects level/lowest observable adverse effect level method, and a benchmark dose method. Considering the considerable uncertainty of benchmark dose model fitting of the available data, a tolerable daily intake value of 0.025 mg kg bw day was derived as a provisional HBGV for NP based on the lowest observable adverse effect level value of 15 mg kg bw day of the renal toxicity in rats, together with the uncertainty factor of 600. However, the HBGV of NP still needs further investigation.

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Section: Resultsmentioning

confidence: 99%

An updated weight of evidence approach for deriving a health‐based guidance value for 4‐nonylphenol

Huo

Liu

et al. 2018

J of Applied Toxicology

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“…This is addressed as LR contrast test in their paper (Dette et al, 2015). They use likelihood ratio test instead of the test used in the PoC testing step.…”

Section: Methods Based On Lr Contrast Test (Mclra)mentioning

confidence: 99%

“…But it is well known that classical asymptotic theory are not applicable when parameters are unidentifiable under null hypothesis of the above set up (Andrews & Ploberger, 1994;Chernoff, 1954;Davies, 1987;Lindsay, 1995). The derivations are described in detail in the original manuscript (Dette et al, 2015). They have shown that the asymptotic distribution of the likelihood ratio test statistic (1) corresponding to each model can be approximated by a functional of a stochastic process.…”

Section: Methods Based On Lr Contrast Test (Mclra)mentioning

confidence: 99%

“…The first approach suggested by Dette, Titoff, Volgushev, and Bretz (2015) is a variation of the MCP-Mod approach that uses likelihood ratio tests instead of prespecified contrasts tests used in the original MCP-Mod. The first approach suggested by Dette, Titoff, Volgushev, and Bretz (2015) is a variation of the MCP-Mod approach that uses likelihood ratio tests instead of prespecified contrasts tests used in the original MCP-Mod.…”

Section: Introductionmentioning

confidence: 99%

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Comparison of different approaches for dose response analysis

Saha

Brannath

2018

Biometrical J

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Characterizing an appropriate dose-response relationship and identifying the right dose in a clinical trial are two main goals of early drug-development. MCP-Mod is one of the pioneer approaches developed within the last 10 years that combines the modeling techniques with multiple comparison procedures to address the above goals in clinical drug development. The MCP-Mod approach begins with a set of potential dose-response models, tests for a significant dose-response effect (proof of concept, PoC) using multiple linear contrasts tests and selects the "best" model among those with a significant contrast test. A disadvantage of the method is that the parameter values of the candidate models need to be fixed a priori for the contrasts tests. This may lead to a loss in power and unreliable model selection. For this reason, several variations of the MCP-Mod approach and a hierarchical model selection approach have been suggested where the parameter values need not be fixed in the proof of concept testing step and can be estimated after the model selection step. This paper provides a numerical comparison of the different MCP-Mod variants and the hierarchical model selection approach with regard to their ability of detecting the dose-response trend, their potential to select the correct model and their accuracy in estimating the dose response shape and minimum effective dose. Additionally, as one of the approaches is based on two-sided model comparisons only, we make it more consistent with the common goals of a PoC study, by extending it to one-sided comparisons between the constant and alternative candidate models in the proof of concept step.

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“…A number of approaches address model specification uncertainty when the possibility that the model used in a model-based approach might be incorrect (Bornkamp, Bretz, Dette, & Pinheiro, 2011;Bretz, Pinheiro, & Branson, 2005;Dette, Titoff, Volgushev, & Bretz, 2015;Faes et al, 2007;Klingenberg, 2009;Link & Albers, 2007;Morales et al, 2006;Ohlssen & Racine, 2015;Pinheiro, Bornkamp, & Bretz, 2006;Verrier, Sivapregassam, & Solente, 2014). A number of approaches address model specification uncertainty when the possibility that the model used in a model-based approach might be incorrect (Bornkamp, Bretz, Dette, & Pinheiro, 2011;Bretz, Pinheiro, & Branson, 2005;Dette, Titoff, Volgushev, & Bretz, 2015;Faes et al, 2007;Klingenberg, 2009;Link & Albers, 2007;Morales et al, 2006;Ohlssen & Racine, 2015;Pinheiro, Bornkamp, & Bretz, 2006;Verrier, Sivapregassam, & Solente, 2014).…”

Section: Introductionmentioning

confidence: 99%

BMA‐Mod: A Bayesian model averaging strategy for determining dose‐response relationships in the presence of model uncertainty

Gould¹

2018

Biometrical J

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Successful pharmaceutical drug development requires finding correct doses. The issues that conventional dose-response analyses consider, namely whether responses are related to doses, which doses have responses differing from a control dose response, the functional form of a dose-response relationship, and the dose(s) to carry forward, do not need to be addressed simultaneously. Determining if a dose-response relationship exists, regardless of its functional form, and then identifying a range of doses to study further may be a more efficient strategy. This article describes a novel estimation-focused Bayesian approach (BMA-Mod) for carrying out the analyses when the actual dose-response function is unknown. Realizations from Bayesian analyses of linear, generalized linear, and nonlinear regression models that may include random effects and covariates other than dose are optimally combined to produce distributions of important secondary quantities, including test-control differences, predictive distributions of possible outcomes from future trials, and ranges of doses corresponding to target outcomes. The objective is similar to the objective of the hypothesis-testing based MCP-Mod approach, but provides more model and distributional flexibility and does not require testing hypotheses or adjusting for multiple comparisons. A number of examples illustrate the application of the method. K E Y W O R D SBayesian model averaging, likelihood principle, MCMC, nonnormal distributions, predictive distributions

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Dose Response Signal Detection under Model Uncertainty

Cited by 9 publications

References 47 publications

An updated weight of evidence approach for deriving a health‐based guidance value for 4‐nonylphenol

An updated weight of evidence approach for deriving a health‐based guidance value for 4‐nonylphenol

Comparison of different approaches for dose response analysis

BMA‐Mod: A Bayesian model averaging strategy for determining dose‐response relationships in the presence of model uncertainty

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