Browsing by Author "Posch, Martin"

Important objectives in the development of stratified medicines include the identification and confirmation of subgroups of patients with a beneficial treatment effect and a positive benefit-risk balance. We report the results of a literature review on methodological approaches to the design and analysis of clinical trials investigating a potential heterogeneity of treatment effects across subgroups. The identified approaches are classified based on certain characteristics of the proposed trial designs and analysis methods. We distinguish between exploratory and confirmatory subgroup analysis, frequentist, Bayesian and decision-theoretic approaches and, last, fixed-sample, group-sequential, and adaptive designs and illustrate the available trial designs and analysis strategies with published case studies.

Critical loads for acidification and eutrophication and their exceedances were determined for a selection of ecosystem effects monitoring sites in the Integrated Monitoring programme (UNECE ICP IM). The level of protection of these sites with respect to acidifying and eutrophying deposition was estimated for 2000 and 2020. In 2020 more sites were protected from acidification (67%) than in 2000(61%). However, due to the sensitivity of the sites, even the maximum technically feasible emission reductions scenario would not protect all sites from acidification. In 2000, around 20% of the IM sites were protected from eutrophication. In 2020, under reductions in accordance with current legislation, about one third of the sites would be protected, and at best, with the maximum technically feasible reductions, half of the sites would be protected from eutrophication. Data from intensively monitored sites, such as those in ICP IM, provide a connection between modelled critical thresholds and empirical observations, and thus an indication of the applicability of critical load estimates for natural ecosystems. Across the sites, there was good correlation between the exceedance of critical loads for acidification and key acidification parameters in runoff water, both with annual mean fluxes and concentrations. There was also evidence of a link between exceedances of critical loads of nutrient nitrogen and nitrogen leaching. The collected empirical data of the ICP IM thus allow testing and validation of key concepts used in the critical load calculations. This increases confidence in the European-scale critical loads mapping used in integrated assessment modelling to support emission reduction agreements. (C) 2012 Elsevier Ltd. All rights reserved.

With the advent of personalized medicine, clinical trials studying treatment effects in subpopulations are receiving increasing attention. The objectives of such studies are, besides demonstrating a treatment effect in the overall population, to identify subpopulations, based on biomarkers, where the treatment has a beneficial effect. Continuous biomarkers are often dichotomized using a threshold to define two subpopulations with low and high biomarker levels. If there is insufficient information on the dependence structure of the outcome on the biomarker, several thresholds may be investigated. The nested structure of such subpopulations is similar to the structure in group sequential trials. Therefore, it has been proposed to use the corresponding critical boundaries to test such nested subpopulations. We show that for biomarkers with a prognostic effect that is not adjusted for in the statistical model, the variability of the outcome may vary across subpopulations which may lead to an inflation of the family-wise type 1 error rate. Using simulations we quantify the potential inflation of testing procedures based on group sequential designs. Furthermore, alternative hypotheses tests that control the family-wise type 1 error rate under minimal assumptions are proposed. The methodological approaches are illustrated by a trial in depression.

Background: Randomized controlled trials (RCTs) are the gold standard design of clinical research to assess interventions. However, RCTs cannot always be applied for practical or ethical reasons. To investigate the current practices in rare diseases, we review evaluations of therapeutic interventions in paediatric multiple sclerosis (MS) and Creutzfeldt-Jakob disease (CJD). In particular, we shed light on the endpoints used, the study designs implemented and the statistical methodologies applied. Methods: We conducted literature searches to identify relevant primary studies. Data on study design, objectives, endpoints, patient characteristics, randomization and masking, type of intervention, control, withdrawals and statistical methodology were extracted from the selected studies. The risk of bias and the quality of the studies were assessed. Results: Twelve (seven) primary studies on paediatric MS (CJD) were included in the qualitative synthesis. No double-blind, randomized placebo-controlled trial for evaluating interventions in paediatric MS has been published yet. Evidence from one open-label RCT is available. The observational studies are before-after studies or controlled studies. Three of the seven selected studies on CJD are RCTs, of which two received the maximum mark on the Oxford Quality Scale. Four trials are controlled observational studies. Conclusions: Evidence from double-blind RCTs on the efficacy of treatments appears to be variable between rare diseases. With regard to paediatric conditions it remains to be seen what impact regulators will have through e.g., paediatric investigation plans. Overall, there is space for improvement by using innovative trial designs and data analysis techniques.