Use compatibility intervals in regulatory toxicology

Hothorn, Ludwig A.; Pirow, Ralph

doi:10.1016/j.yrtph.2020.104720

Cited by 17 publications

(9 citation statements)

References 16 publications

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“…However, it is accepted or even preferred to the NOAEL approach due to its benefits, as laid out in the introduction. Further, statistical testing itself is scrutinized when used as a naïve binary decision criterion (e.g., Wasserstein, Schirm & Lazar, 2019 ; Wasserstein & Lazar, 2016 ) and with respect to toxicology ( Kluxen & Hothorn, 2020 ; Hothorn & Pirow, 2020 ; Kluxen, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

bmd: an R package for benchmark dose estimation

Jensen

Kluxen²,

Streibig

et al. 2020

PeerJ

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The benchmark dose (BMD) methodology is used to derive a hazard characterization measure for risk assessment in toxicology or ecotoxicology. The present paper’s objective is to introduce the R extension package bmd, which facilitates the estimation of BMD and the benchmark dose lower limit for a wide range of dose-response models via the popular package drc. It allows using the most current statistical methods for BMD estimation, including model averaging. The package bmd can be used for BMD estimation for binomial, continuous, and count data in a simple set up or from complex hierarchical designs and is introduced using four examples. While there are other stand-alone software solutions available to estimate BMDs, the package bmd facilitates easy estimation within the established and flexible statistical environment R. It allows the rapid implementation of available, novel, and future statistical methods and the integration of other statistical analyses.

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Section: Discussionmentioning

confidence: 99%

bmd: an R package for benchmark dose estimation

Jensen

Kluxen²,

Streibig

et al. 2020

PeerJ

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show abstract

“…Random experiments with a single primary proportion p i , k = 2 were used to estimate the per-pairs power Π 01 , Π 02 , Π 03 for several strict monotonic alternatives and two shapes with a downturn effect at the high dose as well as the empirical FWER estimate under global and partial H 0 based on 5000 samples drawn independently from binomial distributions Bin(n i ; π i ). Common simulation studies on MCTs compare the any-pair power [7] or average power [17]. These concepts simplifies power comparisons considerably, but is not target-oriented, since which particular comparison is in the alternative is not considered.…”

Section: Simulation Studymentioning

confidence: 99%

Comparisons of proportions in k dose groups against a negative control assuming order restriction: Williams-type test vs. closed test procedures

Hothorn

2020

Preprint

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The comparison of proportions is considered in the asymptotic generalized linear model with the odds ratio as effect size. When several doses are compared with a control assuming an order restriction, a Williams-type trend test can be used. As an alternative, two variants of the closed testing approach are considered, one using global Williams-tests in the partition hypotheses, one with pairwise contrasts. Their advantages in terms of power and simplicity are demonstrated. Related R-code is provided.

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“…were compared according to their FWER and any-pairs power (5000/2000 runs). Common simulation studies on MCTs compare the any-pair power [11] or average power [22] only. These concepts simplifies power comparisons considerably, but are not target-oriented, since which comparison is in the alternative is not considered.…”

Section: Simulation Studymentioning

confidence: 99%

Comparisons of multiple treatment groups with a negative control or placebo group: Dunnett test vs. closed test procedur

Hothorn

2020

Preprint

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Several treatments are usually compared with a control using the Dunnett test. As an alternative, three variants of the closed testing approach are considered, one with ANOVA-F-tests, one with MCT-GrandMean and one with global Dunnett-tests in the partition hypotheses. The problemComparisons of multiple treatment groups with a control (or placebo) group are frequently performed in biomedical experiments: in a plant molecular experiment new mutants were compared with the wild type [24], in a toxicological assay selected clinical chemistry endpoints in three dose groups with disodium adenosine-triphosphate were compared with a water control [13] and in neurological clinical trial three candidate drugs amiloride, fluoxetine, and riluzole were compared with a placebo group for the primary endpoint volumetric MRI percentage brain volume change [6]. Typically, the Dunnett procedure is used [7] in such randomized one-way designs. The main advantage is the availability of simultaneous confidence intervals, alternatively to the multiplicity-adjusted p-values. An alternative is the closed testing procedure (CTP) [15], because it is available for any test in the GLM (particularly its small n i approximations [19]) and can be easily generalized to further joint analysis, e.g. considering multiple endpoints [5]. Three test versions are considered here for the global and partition hypotheses: the common ANOVA F-test, the global multiple contrast test for comparisons against the grand mean [18] and the global Dunnett test. Since the last two are based on multiple contrast tests, subset contrasts can be formulated for all k-samples, allowing the entire degree of freedom to be used in all sub-tests.

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Use compatibility intervals in regulatory toxicology

Cited by 17 publications

References 16 publications

bmd: an R package for benchmark dose estimation

bmd: an R package for benchmark dose estimation

Comparisons of proportions in k dose groups against a negative control assuming order restriction: Williams-type test vs. closed test procedures

Comparisons of multiple treatment groups with a negative control or placebo group: Dunnett test vs. closed test procedur

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