arXiv subjects

Lucia Ameis

Publications and source records attributed to Lucia Ameis.

3 recordsLinked to original sources

arXiv2026

Estimating effect thresholds and beyond: A flexible framework for multivariate alert detection

Evaluating the influence of continuous covariates, like exposure time or dose, on a response variable is a pivotal objective in the assessment of a compound's effect, particularly when determining toxicity in pre-clinical research or pharmacokinetics in clinical trials. The determination of an alert, such as the ED50 value, at which a pre-specified threshold of the response variable is crossed, is an important tool for the evaluation process. In practice, response data might be available for combinations of different covariates and the alert depending on both is of interest. In this case, it is crucial to use all available information and extrapolate between cases to ensure the optimal utilization of the data. In this paper, we introduce a parametric approach that allows alerts to be estimated in a multidimensional setting. For time-dose-response data, for instance, alert doses at a given time can be determined, even when there are no measurements available at that exact time. Likewise, it allows estimation of alert times for a given dose. More generally, the method makes it possible to characterize the complete alert relationship between covariates by leveraging all available data. This is achieved by fitting a parametric model and constructing either a confidence band for the two-dimensional curve given for example a fixed time or dose or by constructing a confidence plane for the three-dimensional model fit. The initial model fit is achieved by the flexible framework of Generalized Additive Models for Location, Scale and Shape (GAMLSS), which offers the possibility to account for a plethora of complex three-dimensional data structures. We demonstrate the validity of our approach through a simulation study and present an application to data from a study investigating the relevance of the exposure duration on cytotoxicity in primary human hepatocytes.

stat.ME↗

arXiv2024

Identification of changes in gene expression

Evaluating the change in gene expression is a common goal in many research areas, such as in toxicological studies as well as in clinical trials. In practice, the analysis is often based on multiple t-tests evaluated at the observed time points. This severely limits the accuracy of determining the time points at which the gene changes in expression. Even if a parametric approach is chosen, the analysis is often restricted to identifying the onset of an effect. In this paper, we propose a parametric method to identify the time frame where the gene expression significantly changes. This is achieved by fitting a parametric model to the time-response data and constructing a confidence band for its first derivative. The confidence band is derived by a flexible two step bootstrap approach, which can be applied to a wide variety of possible curves. Our method focuses on the first derivative, since it provides an easy to compute and reliable measure for the change in response. It is summarised in terms of a hypothesis test, such that rejecting the null hypothesis means detecting a significant change in gene expression. Furthermore, a method for calculating confidence intervals for time points of interest (e.g. the beginning and end of significant change) is developed. We demonstrate the validity of our approach through a simulation study and present a variety of different applications to mouse gene expression data from a study investigating the effect of a Western diet on the progression of non-alcoholic fatty liver disease.

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arXiv2023

A non-parametric proportional risk model to assess a treatment effect in time-to-event data

Time-to-event analysis often relies on prior parametric assumptions, or, if a non-parametric approach is chosen, Cox's model. This is inherently tied to the assumption of proportional hazards, with the analysis potentially invalidated if this assumption is not fulfilled. In addition, most interpretations focus on the hazard ratio, that is often misinterpreted as the relative risk. In this paper, we introduce an alternative to current methodology for assessing a treatment effect in a two-group situation, not relying on the proportional hazards assumption but assuming proportional risks. Precisely, we propose a new non-parametric model to directly estimate the relative risk of two groups to experience an event under the assumption that the risk ratio is constant over time. In addition to this relative measure, our model allows for calculating the number needed to treat as an absolute measure, providing the possibility of an easy and holistic interpretation of the data. We demonstrate the validity of the approach by means of a simulation study and present an application to data from a large randomized controlled trial investigating the effect of dapagliflozin on the risk of first hospitalization for heart failure.

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