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Ludwig A Hothorn

Publications and source records attributed to Ludwig A Hothorn.

14 recordsLinked to original sources
PubMed2006

Power and sample size computations in simultaneous tests for non-inferiority based on relative margins.

In this paper, we address the problem of calculating power and sample sizes associated with simultaneous tests for non-inferiority. We consider the case of comparing several experimental treatments with an active control. The approach is based on the ratio view, where the common non-inferiority margin is chosen to be some percentage of the mean of the control treatment. Two power definitions in multiple hypothesis testing, namely, complete power and minimal power, are used in the computations. The sample sizes associated with the ratio-based inference are also compared with that of a comparable inference based on the difference of means for various scenarios. It is found that the sample size required for ratio-based inferences is smaller than that of difference-based inferences when the relative non-inferiority margin is less than one and when large response values indicate better treatment effects. The results are illustrated with examples.

Data Interpretation, Statistical↗
PubMed2006

Multiple comparisons and multiple contrasts in randomized dose-response trials--confidence interval oriented approaches.

According to the ICH E9 recommendation, the evaluation of randomized dose-finding trials focuses on the graphical presentation of different kinds of simultaneous confidence intervals: i) superiority of at least one dose vs. placebo with and without the assumption of order restriction, ii) noninferiority of at least one dose vs. active control, iii) identification of the minimum effective dose, iv) identification of the peak dose, v) identification of the maximum safe dose for a safety endpoint, and vi) estimation of simultaneous confidence intervals for "many-to-one-by-condition interaction contrasts." Moreover, global tests for a monotone trend or a trend with a possible downturn effect are discussed. The basic approach involved obtaining multiple contrasts for different problem-related contrast definitions. For all approaches, definitions of relevance margins for superiority or noninferiority are needed. Because consensus on margins only exists for selected therapeutic areas and the definition of absolute thresholds may be difficult, simultaneous confidence intervals for ratio to placebo were also used. All approaches are demonstrated in an example-based manner using the R-packages multcomp (difference), for hypotheses based on difference, and mratios (ratio), for hypotheses based on ratios.

Algorithms↗
PubMed2006

Impact of Bt maize pollen (MON810) on lepidopteran larvae living on accompanying weeds.

Environmental risks of Bt maize, particularly pollen drift from Bt maize, were assessed for nontarget lepidopteran larvae in maize field margins. In our experimental approach, we carried out 3-year field trials on 6 ha total. Three treatments were used in a randomized block design with eight replications resulting in 24 plots: (i) near-isogenic control variety without insecticide (control), (ii) near-isogenic control variety with chemical insecticide (Baytroid) and (iii) Bt maize expressing the recombinant toxin. We established a weed strip (20 x 1 m) in every plot consisting of a Chenopodium album (goosefoot)/Sinapis alba (mustard) mixture. In these strips we measured diversity and abundance of lepidopteran larvae during maize bloom and pollen shed. C. album hosted five species but all in very low densities; therefore data were not suitable for statistical analysis. S. alba hosted nine species in total. Most abundant were Plutella xylostella and Pieris rapae. For these species no differences were detected between the Bt treatment and the control, but the chemical insecticide treatment reduced larval abundance significantly. Conclusions regarding experimental methodology and results are discussed in regard to environmental risk assessment and monitoring of genetically modified organisms.

Animals↗
PubMed2005

Statistical analysis used in the nutritional assessment of novel food using the proof of safety.

The safety assessment of Novel Food, including GM biotechnology-derived crops, starts with the comparison of the Novel Food with a traditional counterpart that is generally accepted as safe based on a history of human food use. Substantial equivalence is established if no meaningful difference from the conventional counterpart was found, leading to the conclusion that the Novel Food is as safe and nutritious as its traditional counterpart. In general, the non-significance of p value is used for the proof of safety. From a statistical perspective, the problems connected with such an approach are demonstrated, namely that quite different component-specific false negative error rates result. As an alternative, the proof of safety is discussed with the inherently related definition of safety thresholds. Moreover, parametric and non-parametric confidence intervals for the difference and the ratio to control (conventional line) are described in detail. Finally, the treatment of multiple components for a global proof of safety is explained.

Consumer Product Safety↗
PubMed2003

Identifying effective and/or safe doses by stepwise confidence intervals for ratios.

Typical randomized clinical dose-finding studies consist of the comparison of several doses of a drug versus a placebo. Interest lies in estimating relevant doses among those under investigation for efficacy and safety variables, such as the minimum effective dose or the maximum safe dose (or estimating both doses simultaneously). Step-down procedures have been proposed for comparing the standardized differences of the dose groups against placebo. In this paper we consider the ratio of population means and propose stepwise confidence intervals for these ratios. These confidence intervals do not require multiplicity adjustments and yield the same decisions as the associated test procedures. In addition, several power concepts are investigated within the present framework. The results allow sample size determination in the design phase of a study for the probability of estimating correctly the dose of interest. Auxiliary results of a numerical study show the range of application of these methods.

Allylamine↗
PubMed2003

Analyzing randomized dose finding studies with a primary and a secondary endpoint.

The identification of the minimum effective dose for both the primary and secondary endpoint under a priori importance ordering assumption is described. Stepwise testing procedures, which conditionally test each elementary hypotheses at level alpha, but control the experimentwise Type I error rate, can be used.

Dose-Response Relationship, Drug↗
PubMed2003

Protocol designed subgroup analyses in multiarmed clinical trials: multiplicity aspects.

Subgroup analyses are quite common in clinical trials although the subgroup findings are usually presented without adjustment for the multiple analyses, which increases the chance of false positive findings. This paper is focused on the multiplicity aspects of subgroup analyses in multiarmed randomized clinical trials and provides some guidance to practitioners.

Female↗
PubMed2003

Statistics of interlaboratory in vitro toxicological studies.

Interlaboratory studies are common in toxicology, particularly for the introduction of alternative assays. Numerous papers are available on the statistical analysis of interlaboratory studies, but these deal primarily with the case of a replicated single sample studied in several laboratories. This approach can be used for some assays, but for the majority, the results will be unsatisfactory, i.e. involving great variability between both the dose groups and the laboratories. However, the primary objective of toxicological assays is to achieve similarity between the sizes of effects, rather than to determine absolute values. In the parametric model, the sizes of effects are the studentised differences from the negative control or, for the commonly used dose-response designs, the similarity of the slopes of the dose-response curves. Standard approaches for the estimation of intralaboratory and interlaboratory variability, including Mandel plots, are introduced, and new approaches are presented for demonstrating similarity of effect sizes, with or without assuming a dose-response model. One approach is based on a modification of the parallel-line assay, the other is based on a modification of the interaction contrasts of the analysis of variance. SAS programs are given for all approaches, and real data from an interlaboratory immunotoxicological study are analysed as a demonstration.

Animal Testing Alternatives↗
PubMed2003

Two-stage testing of safety: a statistical view.

Sample sizes given in regulatory guidelines are not based on statistical reasoning. However, from an ethical, scientific, and regulatory point of view, a mutagenicity experiment must have a reasonable chance of supporting the decision as to whether a result is negative or positive. Consequently, the sample size should be based on type I and type II errors, the underlying variability, and the specific size of a treatment effect. A two-stage adaptive interim analysis is presented, which permits an adaptive choice of sample size after an interim analysis of the data from the first stage. Because the sample size of the first stage is considered to be a minimum requirement, this stage can also be regarded as a pilot study.

Animal Testing Alternatives↗
PubMed2003

Dose-response and thresholds in mutagenicity studies: a statistical testing approach.

The analysis of dose-response relationships is an important objective in toxicology, and one in which both modelling and testing approaches are used. One particular question is whether a threshold exists at low doses. The concept of a pragmatic threshold is used, i.e. low doses with biologically unimportant effects are assumed to be threshold doses. "Biologically unimportant" means, in statistical terms, a lower effect than the effect of the negative control, or at least a just-tolerable margin delta higher than the effect of the negative control. Therefore, threshold doses can be tested in terms of a one-sided hypothesis of equivalence. A new approach is proposed, assuming, at the least, that the low dose is a threshold dose, and the highest dose is superior to the negative control. By analogy to the k-fold rule commonly used in mutagenicity studies, tests on ratio-to-control are used. The a priori definition of the threshold margin is inherently needed. A further approach proposes the analysis of dose-response relationships by means of order-restricted inference (the so-called trend test). A modification of a multiple-contrast test is used, in which only those contrasts are included that are sensitive for no effects at low doses. A further modification treats the complicated, but real, problem of simultaneous existence of a threshold, a monotonic increase, and a downturn effect at high dose(s). A parametric procedure is considered, together with an extension for proportions. The important problem of a priori sample size definition is discussed. The approaches are demonstrated by means of examples based on real data.

Animal Testing Alternatives↗
PubMed2002

Detecting dose-response using contrasts: asymptotic power and sample size determination for binomial data.

Recently, Stewart and Ruberg proposed the use of contrast tests for detecting dose-response relationships. They considered in particular bivariate contrasts for healing rates and gave several possibilities of defining adequate sets of coefficients. This paper extends their work in several directions. First, asymptotic power expressions for both single and multiple contrast tests are derived. Secondly, well known trend tests are rewritten as multiple contrast tests, thus alleviating the inherent problem of choosing adequate contrast coefficients. Thirdly, recent results on the efficient calculation of multivariate normal probabilities overcome the traditional simulation-based methods for the numerical computations. Modifications of the power formulae allow the calculation of sample sizes for given type I and II errors, the spontaneous rate, and the dose-response shape. Some numerical results of a power study for small to moderate sample sizes show that the nominal power is a reasonably good approximation to the actual power. An example from a clinical trial illustrates the practical use of the results.

Cabergoline↗
PubMed2002

Selected biostatistical aspects of the validation of in vitro toxicological assays.

An overview is presented on selected biostatistical aspects of the validation of in vitro toxicological assays. Primarily, the statistical analysis of single assays is discussed. Several approaches are compared for the possible non-monotonic dose-response relationship with a priori unknown shapes. The use of confidence intervals instead of p values for toxicologically appropriate decision making is explained. New methods are discussed for demonstrating interlaboratory similarity for dose-response designs are discussed. For validation, the inappropriateness of the concordance coefficient is shown, and sensitive and specificity as well as predictive values are proposed as alternatives. The problem of the missing gold standard is highlighted.

Animal Testing Alternatives↗
PubMed2002

Effects of treatment with ibandronate on bone mass, architecture, biomechanical properties, and bone concentration of ibandronate in ovariectomized aged rats.

OBJECTIVE: To investigate the effects of treatment with ibandronate, a highly potent nitrogen-containing bisphosphonate, on bone loss, bone quality, biomechanical properties, and bone concentrations in aged ovariectomized rats. METHODS: Eight-month-old female Wistar rats were ovariectomized (Ovx) or sham-operated. Treatment was started 10 weeks following Ovx with subcutaneous ibandronate in doses of 0.2, 1.0, 5.0, or 25 micro g/kg/day for 12 mo. Additional groups received 25 or 125 micro g/kg intermittently every 25 days, resulting in the same total dose as compared to 1.0 or 5.0 micro g/kg/day, respectively. Bone analyses by x-ray densitometry, peripheral quantitative computed tomography (pQCT), dual energy x-ray absorptiometry (DEXA), histomorphometry, 3-point bending, and compression tests were performed in femora, tibiae, and lumbar vertebrae in separate groups at the beginning and the end of treatment. Ibandronate concentration in tibiae and vertebrae was determined by gas chromatography mass spectroscopy at the end of the study. RESULTS: Ovariectomy resulted in a significant reduction in bone mass (p <or= 0.0001) and strength (p < 0.05) by 10 weeks after surgery in long bones, while only a trend was present in vertebrae. When compared to age matched Ovx controls, ibandronate resulted in a dose dependent increase in bone mineral density (BMD), trabecular bone volume and trabecular number, load to failure (Fmax), and yield load in long bones and vertebrae. The lowest significant dose, which was different from Ovx controls, ranged between 0.2 and 1.0 micro g/kg/day, with higher doses not differing from sham controls. Increased trabecular separation (p <or= 0.0001) was fully prevented by all doses. Vertebral BMD (pQCT and DEXA) positively correlated with Fmax by r = 0.88 (p <or= 0.0001) both; correlation of femoral Fmax versus cortical BMD was r = 0.61 (p <or= 0.0001). CONCLUSION: Bone concentrations of ibandronate were linear with the dose, suggesting linear kinetics in the applied dose range. In general, the same total cumulative ibandronate dose given provided equivalent results, independent of the administration schedule.

Absorptiometry, Photon↗