0000000000954525
AUTHOR
Antje Jahn-eimermacher
Statistical analysis of latency outcomes in behavioral experiments
In experimental designs of animal models, memory is often assessed by the time for a performance measure to occur (latency). Depending on the cognitive test, this may be the time it takes an animal to escape to a hidden platform (water maze), an escape tunnel (Barnes maze) or to enter a dark component (passive avoidance test). Latency outcomes are usually statistically analyzed using ANOVAs. Besides strong distributional assumptions, ANOVA cannot properly deal with animals not showing the performance measure within the trial time, potentially causing biased and misleading results. We propose an alternative approach for statistical analyses of latency outcomes. These analyses have less distr…
Opportunities and challenges of combined effect measures based on prioritized outcomes
Many authors have proposed different approaches to combine multiple endpoints in a univariate outcome measure in the literature. In case of binary or time-to-event variables, composite endpoints, which combine several event types within a single event or time-to-first-event analysis are often used to assess the overall treatment effect. A main drawback of this approach is that the interpretation of the composite effect can be difficult as a negative effect in one component can be masked by a positive effect in another. Recently, some authors proposed more general approaches based on a priority ranking of outcomes, which moreover allow to combine outcome variables of different scale levels. …
Performance of adaptive sample size adjustment with respect to stopping criteria and time of interim analysis
The benefit of adjusting the sample size in clinical trials on the basis of treatment effects observed in interim analysis has been the subject of several recent papers. Different conclusions were drawn about the usefulness of this approach for gaining power or saving sample size, because of differences in trial design and setting. We examined the benefit of sample size adjustment in relation to trial design parameters such as 'time of interim analysis' and 'choice of stopping criteria'. We compared the adaptive weighted inverse normal method with classical group sequential methods for the most common and for optimal stopping criteria in early, half-time and late interim analyses. We found …
High dose infusion of activated protein C (rhAPC) fails to improve neuronal damage and cognitive deficit after global cerebral ischemia in rats
Abstract Purpose : Recent studies demonstrated anticoagulatory, antiinflammatory, antiapoptotic, and neuroprotective properties of activated protein C (APC) in rodent models of acute neurodegenerative diseases, suggesting APC as promising broad acting therapeutic agent. Unfortunately, continuous infusion of recombinant human APC (rhAPC) failed to improve brain damage following cardiac arrest in rats. The present study was designed to investigate the neuroprotective effect after global cerebral ischemia (GI) with an optimized infusion protocol. Methods : Rats were subjected to bilateral clip occlusion of the common carotid arteries (BCAO) and controlled hemorrhagic hypotension to 40 mmHg for…
Comparison of different quantification methods to determine hippocampal damage after cerebral ischemia
Abstract Background Experimental stroke studies use multiple techniques to evaluate histopathological damage. Unfortunately, sensitivity and reproducibility of these techniques are poorly characterized despite pivotal influence on results. Method The present study compared several quantification methods to differentiate between two severities of global cerebral ischemia and reperfusion. Male Sprague-Dawley rats were randomized to moderate (10 min) or severe (14 min) ischemia by bilateral carotid occlusion (BCAO) with hemorrhagic hypotension. Neuronal cell count was determined in hippocampus at bregma −3.14 mm and −3.8 mm on day 3 and 28 post insult by counting neurons in the whole CA1 or in…
Marginal hazard ratio estimates in joint frailty models for heart failure trials
Abstract This work is motivated by clinical trials in chronic heart failure disease, where treatment has effects both on morbidity (assessed as recurrent non‐fatal hospitalisations) and on mortality (assessed as cardiovascular death, CV death). Recently, a joint frailty proportional hazards model has been proposed for these kind of efficacy outcomes to account for a potential association between the risk rates for hospital admissions and CV death. However, more often clinical trial results are presented by treatment effect estimates that have been derived from marginal proportional hazards models, that is, a Cox model for mortality and an Andersen–Gill model for recurrent hospitalisations. …
Assessing vaccine efficacy for the prevention of acute otitis media by pneumococcal vaccination in children: a methodological overview of statistical practice in randomized controlled clinical trials.
Acute otitis media (AOM) is the most common bacterial infectious disease among children. Vaccination is proposed to prevent otitis and several clinical trials were performed to assess the efficacy of pneumococcal vaccines. The way vaccine efficacy is analysed varies among trials. However, the clinical meaning of an estimate of vaccine effect and its statistical test depends on the applied statistical method. We aim to bring the meaning and validity of statistical trial results to the attention of researchers. We consider all methodological approaches for analysing vaccine efficacy applied in pneumococcal vaccination trials included in a recent Cochrane Review. We demonstrate how different m…
Comparison of the Andersen–Gill model with poisson and negative binomial regression on recurrent event data
Many generalizations of the Cox proportional hazard method have been elaborated to analyse recurrent event data. The Andersen-Gill model was proposed to handle event data following Poisson processes. This method is compared with non-survival approaches, such as Poisson and negative binomial regression. The comparison is performed on data simulated according to various event-generating processes and differing in subject heterogeneity. When robust standard error estimates are applied, for Poisson processes the Andersen-Gill approach is comparable to a negative binomial regression, whereas the poisson regression has comparable coverage probabilities of confidence intervals, but increased type …
Adaptive trial design: a general methodology for censored time to event data.
Adaptive designs allow a clinical trial design to be changed according to interim findings without inflating type I error. The Inverse Normal method can be considered as an adaptive generalization of classical group sequential designs. The use of the Inverse Normal method for censored survival data was demonstrated only for the logrank statistic. However, the logrank statistic is inefficient in the presence of nuisance covariates affecting survival. We demonstrate, how the Inverse Normal method can be applied to Cox regression analysis. The required independence between test statistics of the different stages of the trial can be obtained by two different approaches. One is using the indepen…
Sample size in cluster-randomized trials with time to event as the primary endpoint
In cluster-randomized trials, groups of individuals (clusters) are randomized to the treatments or interventions to be compared. In many of those trials, the primary objective is to compare the time for an event to occur between randomized groups, and the shared frailty model well fits clustered time-to-event data. Members of the same cluster tend to be more similar than members of different clusters, causing correlations. As correlations affect the power of a trial to detect intervention effects, the clustered design has to be considered in planning the sample size. In this publication, we derive a sample size formula for clustered time-to-event data with constant marginal baseline hazards…
Association of smoking but not HLA-DRB1*15:01, APOE or body mass index with brain atrophy in early multiple sclerosis
Background: The course of multiple sclerosis (MS) shows substantial inter-individual variability. The underlying determinants of disease severity likely involve genetic and environmental factors. Objective: The aim of this study was to assess the impact of APOE and HLA polymorphisms as well as smoking and body mass index (BMI) in the very early MS course. Methods: Untreated patients ( n = 263) with a recent diagnosis of relapsing-remitting (RR) MS or clinically isolated syndrome underwent standardized magnetic resonance imaging (MRI). Genotyping was performed for single-nucleotide polymorphisms (SNPs) rs3135388 tagging the HLA-DRB1*15:01 haplotype and rs7412 (Ɛ2) and rs429358 (Ɛ4) in APOE. …
Single administration of tripeptide α-MSH(11-13) attenuates brain damage by reduced inflammation and apoptosis after experimental traumatic brain injury in mice.
Following traumatic brain injury (TBI) neuroinflammatory processes promote neuronal cell loss. Alpha-melanocyte-stimulating hormone (α-MSH) is a neuropeptide with immunomodulatory properties, which may offer neuroprotection. Due to short half-life and pigmentary side-effects of α-MSH, the C-terminal tripeptide α-MSH(11-13) may be an anti-inflammatory alternative. The present study investigated the mRNA concentrations of the precursor hormone proopiomelanocortin (POMC) and of melanocortin receptors 1 and 4 (MC1R/MC4R) in naive mice and 15 min, 6, 12, 24, and 48 h after controlled cortical impact (CCI). Regulation of POMC and MC4R expression did not change after trauma, while MC1R levels incr…
Computational issues in fitting joint frailty models for recurrent events with an associated terminal event.
Abstract Background and objective: Joint frailty regression models are intended for the analysis of recurrent event times in the presence of informative drop-outs. They have been proposed for clinical trials to estimate the effect of some treatment on the rate of recurrent heart failure hospitalisations in the presence of drop-outs due to cardiovascular death. Whereas a R-software-package for fitting joint frailty models is available, some technical issues have to be solved in order to use SASⓇ 1 software, which is required in the regulatory environment of clinical trials. Methods: First, we demonstrate how to solve these issues by deriving proper likelihood-decompositions, in particular fo…
A comparison of semiparametric approaches to evaluate composite endpoints in heart failure trials
In heart failure trials efficacy is usually proven by a composite endpoint including cardiovascular death (CVD) and recurrent heart failure hospitalisations (HFH), evaluated with time-to-first-event analysis based on a Cox model. As a considerable fraction of events is ignored that way, recurrent event[for full text, please go to the a.m. URL]
Abstract WP200: Development and Validation of a Score to Detect Paroxysmal Atrial Fibrillation During Long-term Holter-monitoring After Acute Ischemic Stroke
Introduction: Atrial fibrillation remains one of the most common causes of ischemic stroke. The diagnosis of paroxysmal atrial fibrillation (pAF) frequently escapes routine diagnostic due to its intermittent and asymptomatic occurrence. Currently prolonged monitoring times (72h) are recommended, but did not find their way into everyday practice. Therefore an individual patient selection for prolonged ECG-monitoring might increase the diagnostic yield of pAF in a resource-saving and cost-effective manner. Methods: We used individual patient data from three prospective studies (n total =1556) which performed a prolonged Holter ECG-monitoring (at least 72 h) and centralized data evaluation af…
MSJ763541_supplementary_material – Supplemental material for Association of smoking but not HLA-DRB1*15:01, APOE or body mass index with brain atrophy in early multiple sclerosis
Supplemental material, MSJ763541_supplementary_material for Association of smoking but not HLA-DRB1*15:01, APOE or body mass index with brain atrophy in early multiple sclerosis by Christiane Graetz, Adriane Gröge, Felix Luessi, Anke Salmen, Daniela Zöller, Janine Schultz, Nelly Siller, Vinzenz Fleischer, Barbara Bellenberg, Achim Berthele, Viola Biberacher, Joachim Havla, Michael Hecker, Reinhard Hohlfeld, Carmen Infante-Duarte, Jan S Kirschke, Tania Kümpfel, Ralf Linker, Friedemann Paul, Steffen Pfeuffer, Philipp Sämann, Gerrit Toenges, Frank Weber, Uwe K Zettl, Antje Jahn-Eimermacher, Gisela Antony, Sergiu Groppa, Heinz Wiendl, Bernhard Hemmer, Mark Mühlau, Carsten Lukas, Ralf Gold, Chri…
Sample-size calculation and reestimation for a semiparametric analysis of recurrent event data taking robust standard errors into account
In some clinical trials, the repeated occurrence of the same type of event is of primary interest and the Andersen-Gill model has been proposed to analyze recurrent event data. Existing methods to determine the required sample size for an Andersen-Gill analysis rely on the strong assumption that all heterogeneity in the individuals' risk to experience events can be explained by known covariates. In practice, however, this assumption might be violated due to unknown or unmeasured covariates affecting the time to events. In these situations, the use of a robust variance estimate in calculating the test statistic is highly recommended to assure the type I error rate, but this will in turn decr…
Mild Hypothermia Has No Long-Term Impact on Postischemic Neurogenesis in Rats
Postischemic improvement of functional outcome by therapeutic hypothermia may be related to cerebral regeneration by postischemic neurogenesis. We investigated whether mild peri-ischemic hypothermia leads to a long-term increase in postischemic neurogenesis.Seventy male sevoflurane-anesthetized Sprague Dawley rats were randomly assigned to the following treatment groups: normothermic ischemia, intraischemic hypothermia, and postischemic hypothermia with corresponding sham-operated controls. Fifteen naïve rats were investigated as reference for natural neurogenesis. Forebrain ischemia was induced by bilateral common carotid artery occlusion and hemorrhagic hypotension. In normothermic groups…
The novel video-assisted intubating laryngeal mask Totaltrack compared to the intubating laryngeal mask Fastrach - a controlled randomized manikin study.
BACKGROUND The novel Totaltrack combines a supraglottic airway device with video laryngoscopic tracheal intubation. The intubation laryngeal mask Fastrach is an established device without visual control of intubation. We hypothesized that supraglottic ventilation success with Totaltrack would be similar to Fastrach, but intubation would be performed faster due to visual control of the procedure. METHODS Fifty-five anaesthesiologists were randomized into one of two study arms: Fastrach Totaltrack. After a standardized introduction, six consecutive attempts of supraglottic ventilation and intubation attempts with each of one of the devices were performed on an airway manikin. The combined pri…
Comparison of speed-vacuum method and heat-drying method to measure brain water content of small brain samples
Abstract Background A reliable measurement of brain water content (wet-to-dry ratio) is an important prerequisite for conducting research on mechanisms of brain edema formation. The conventionally used oven-drying method suffers from several limitations, especially in small samples. A technically demanding and time-consuming alternative is freeze-drying. New method Centrifugal vacuum concentrators (e.g. SpeedVac/speed-vacuum drying) are a combination of vacuum-drying and centrifugation, used to reduce the boiling temperature. These concentrators have the key advantages of improving the freeze-drying speed and maintaining the integrity of dried samples, thus, allowing e.g. DNA analyses. In t…