Decision-theoretic designs for phase II clinical trials allowing for competing studies

This article describes an approach to optimal design of phase II clinical trials using Bayesian decision theory. The method proposed extends that suggested by Stallard (1998, Biometrics54, 279–294) in which designs were obtained to maximize a gain function including the cost of drug development and the benefit from a successful therapy. Here, the approach is extended by the consideration of other potential therapies, the development of which is competing for the same limited resources. The resulting optimal designs are shown to have frequentist properties much more similar to those traditionally used in phase II trials.

Implementation of a Bayesian design in a dose-escalation study of an experimental agent in healthy volunteers

Bayesian decision procedures have recently been developed for dose escalation in phase I clinical trials concerning pharmacokinetic responses observed in healthy volunteers. This article describes how that general methodology was extended and evaluated for implementation in a specific phase I trial of a novel compound. At the time of writing, the study is ongoing, and it will be some time before the sponsor will wish to put the results into the public domain. This article is an account of how the study was designed in a way that should prove to be safe, accurate, and efficient whatever the true nature of the compound. The study involves the observation of two pharmacokinetic endpoints relating to the plasma concentration of the compound itself and of a metabolite as well as a safety endpoint relating to the occurrence of adverse events. Construction of the design and its evaluation via simulation are presented.

A Bayesian approach for dose-escalation in a phase I clinical trial incorporating pharmacodynamic endpoints

Bayesian decision procedures have already been proposed for and implemented in Phase I dose-escalation studies in healthy volunteers. The procedures have been based on pharmacokinetic responses reflecting the concentration of the drug in blood plasma and are conducted to learn about the dose-response relationship while avoiding excessive concentrations. However, in many dose-escalation studies, pharmacodynamic endpoints such as heart rate or blood pressure are observed, and it is these that should be used to control dose-escalation. These endpoints introduce additional complexity into the modeling of the problem relative to pharmacokinetic responses. Firstly, there are responses available following placebo administrations. Secondly, the pharmacodynamic responses are related directly to measurable plasma concentrations, which in turn are related to dose. Motivated by experience of data from a real study conducted in a conventional manner, this paper presents and evaluates a Bayesian procedure devised for the simultaneous monitoring of pharmacodynamic and pharmacokinetic responses. Account is also taken of the incidence of adverse events. Following logarithmic transformations, a linear model is used to relate dose to the pharmacokinetic endpoint and a quadratic model to relate the latter to the pharmacodynamic endpoint. A logistic model is used to relate the pharmacokinetic endpoint to the risk of an adverse event.

Comparative evaluation of a new effective population size estimator based on approximate Bayesian computation

We describe and evaluate a new estimator of the effective population size (N-e), a critical parameter in evolutionary and conservation biology. This new "SummStat" N-e. estimator is based upon the use of summary statistics in an approximate Bayesian computation framework to infer N-e. Simulations of a Wright-Fisher population with known N-e show that the SummStat estimator is useful across a realistic range of individuals and loci sampled, generations between samples, and N-e values. We also address the paucity of information about the relative performance of N-e estimators by comparing the SUMMStat estimator to two recently developed likelihood-based estimators and a traditional moment-based estimator. The SummStat estimator is the least biased of the four estimators compared. In 32 of 36 parameter combinations investigated rising initial allele frequencies drawn from a Dirichlet distribution, it has the lowest bias. The relative mean square error (RMSE) of the SummStat estimator was generally intermediate to the others. All of the estimators had RMSE > 1 when small samples (n = 20, five loci) were collected a generation apart. In contrast, when samples were separated by three or more generations and Ne less than or equal to 50, the SummStat and likelihood-based estimators all had greatly reduced RMSE. Under the conditions simulated, SummStat confidence intervals were more conservative than the likelihood-based estimators and more likely to include true N-e. The greatest strength of the SummStat estimator is its flexible structure. This flexibility allows it to incorporate any, potentially informative summary statistic from Population genetic data.

The Bayesian Foundations of solution concepts of games

We transform a non co-operati ve game into a -Bayesian decision problem for each player where the uncertainty faced by a player is the strategy choices of the other players, the pr iors of other players on the choice of other players, the priors over priors and so on.We provide a complete characterization between the extent of knowledge about the rationality of players and their ability to successfulIy eliminate strategies which are not best responses. This paper therefore provides the informational foundations of iteratively unàominated strategies and rationalizable strategic behavior (Bernheim (1984) and Pearce (1984». Moreover, sufficient condi tions are also found for Nash equilibrium behavior. We also provide Aumann's (1985) results on correlated equilibria .

Evolution of the landscape of Madeira Island: long-term vegetation dynamics

The aim of this thesis was to evaluate historical change of the landscape of Madeira Island and to assess spatial and temporal vegetation dynamics. In current research diverse “retrospective techniques”, such as landscape repeat photography, dendrochronology, and research of historical records were used. These, combined with vegetation relevés, aimed to gather information about landscape change, disturbance history, and vegetation successional patterns. It was found that landscape change, throughout 125 years, was higher in the last five decades manly driven by farming abandonment, building growth and exotic vegetation coverage increase. Pristine vegetation was greatly destroyed since early settlement and by the end of the nineteenth century native vegetation was highly devastated due to recurrent antropogenic disturbances. These actions also helped to block plant succession and to modify floristical assemblages, affecting as well as species richness. In places with less hemeroby, although significant growth of vegetation of lower seral stages was detected, the vegetation of most mature stages headed towards unbalance between recovery and loss, being also very vulnerable to exotic species encroachment. Recovery by native vegetation also occurred in areas formerly occupied by exotic plants and agriculture but it was almost negligible. Vegetation recovery followed the successional model currently proposed, attesting the model itself. Yet, succession was slower than espected, due to lack of favourable conditions and to recurrent disturbances. Probable tempus of each seral stage was obtained by growth rates of woody taxa estimated through dendrochronology. The exotic trees which were the dominant trees in the past (Castanea sativa and Pinus pinaster) almost vanished. Eucalyptus globulus, the current main tree of the exotic forest is being replaced by other cover types as Acacia mearnsii. The latter, along with Arundo donax, Cytisus scoparius and Pittosporum undulatum are currently the exotic species with higher invasive behaviour. However, many other exotic species have also proved to be highly pervasive and came together with the ones referred above to prevent native vegetation regeneration, to diminish biological diversity, and to block early successional phases delaying native forest recovery.

Variabilidade espacial de atributos químicos do solo sob diferentes usos e manejos

O uso e manejo do solo e da cultura são importantes condicionadores da variabilidade de atributos do solo. O trabalho foi desenvolvido em Selvíria (MS), com o objetivo de avaliar a variabilidade espacial do pH, potássio (K), cálcio (Ca), magnésio (Mg) e saturação por bases (V) em Latossolo Vermelho sob diferentes usos e manejos. Os solos foram amostrados em malha, com intervalos regulares de 2 m, perfazendo o total de 64 pontos, nas profundidades de 0,0-0,1 e 0,1-0,2 m, nas seguintes áreas: vegetação natural (Cerrado), plantio direto, plantio convencional e pastagem. As maiores variabilidades, medidas por meio do coeficiente de variação, foram observadas para K, Mg e Ca; o pH apresentou o menor coeficiente de variação nos diferentes usos e manejo do solo, e o atributo V, coeficiente de variação médio. Os sistemas preparo convencional e pastagem apresentaram os menores alcances quando comparado aos sistemas Cerrado e plantio direto.

A sucessão ecológica em ambientes florestais em restauração: estrutura e dinâmica da regeneração natural

Ecological restoration aims to restore the self-sustainability potential of degraded environments. The successional trajectory of areas in restoration may differ from the reference ecosystem on a number of factors, especially the disturbance history of the area and management techniques applied in order to reverse the degradation scenario. In this sense, the objective of this study was to characterize the dynamics of natural regeneration and the structure of the regenerating community in an area of ecological restoration for 25 years on the right bank of the Rio Grande in the Power Station in Camargos that belongs to the Companhia Energetica de Minas Gerais - CEMIG, Nazareno, MG, in order to identify the current state of environmental regeneration. In November 2014, there was the first community inventory of seedlings existing in regeneration subplots (2 x 2 m) within the inclusion criteria (height ≥ 10 cm and DBH <5 cm), divided into 44 subplots (11 plots) in two areas, one area in restoration (REF) and a fragment of native vegetation (FRAG). In October 2015, the second sampling was carried out, in which individuals were resampled and recruits and dead individuals quantified. The parameters abundance, floristic similarity, density, dominance, importance value, equability, richness and diversity were analyzed in both samples. The dynamics was evaluated for the number of individuals and basal area in the period of 2014-2015 and individuals distributed according to height. The history of usage area provoked different behavior between the study environments; the patterns of the FRAG and REF communities along the years allowed the distinction between environments and demonstrated great environmental diversity, with differences in the abundance of species, floristic similarity, richness, diversity, vertical structure and dynamics parameters. In the REF area, there was a considerable increase in the density of individuals along the years and the establishment of different species. In this sense, the evaluation of natural regeneration in REF has shown that resilience is gradually being resumed, a necessary condition to support the potential for environmental self-sustainability. However, given the disturbance history, it can be concluded that the environment moves to an alternative state, which is possibly different from that prior to degradation.

Variação de armazenagem de água num latossolo de cerrado em recuperação

Pós-graduação em Agronomia - FEIS

Diagnóstico ambiental da bacia hidrográfica do córrego do Bugre em Alumínio - SP

Pós-graduação em Ciências Ambientais - Sorocaba

Aplicação de análise multicriterial para determinação de áreas prioritárias à recomposição florestal

Using the Geographic Information System (GIS) and taking into account its capability to analyze spatial data, a database of updated spatial data from the sub-basin of the Descalvado stream, Botucatu, SP, was developed to provide an evaluation and diagnosis of the area concerning land use and the degradation processes therein. Through GIS, priority areas for forest recovery were defined by Multicriteria Evaluation and using the Ordered Weighted Average method. The latter allows the decision maker to define the area to be recovered, facing limitation of resources, among one of the proposed scenarios, or do it in stages. The study showed that there are accelerated erosion processes in the headwaters of the springs of water bodies; there is also fragmentation of native vegetation, especially in hillside areas, and little presence of native vegetation in riparian areas. The application of the multicriteria analysis using the Ordered Weighted Average was important as it systematized and discriminated scenarios of priority for forest recovery.

Degradação urbana decorrente da atividade de mineração para a construção civil em Teresina - PI

Pós-graduação em Geografia - IGCE

Retrospective Clinical Study of 988 Dual Acid-Etched Implants Placed in Grafted and Native Bone for Single-Tooth Replacement

Purpose: To evaluate the influence of sex, implant characteristics, and bone grafting on the survival rate of dual acid-etched (DAE) implants. Materials and Methods: Patients treated with internal-hex DAE implants for single-tooth replacement in a military dental clinic between January 2005 and December 2010 were included in this study. Clinical data related to implant characteristics, implant location, presence of grafted bone, and implant failures were collected. The primary outcome was implant loss. The survival rate was analyzed using the Kaplan-Meier method. Cox regression modeling was used to determine which factors would predict implant failure. Results: DAE implants were evaluated in a total of 988 patients (80.3% men). Twenty-four (2.4%) implants failed, most were cylindric (54.2%) with regular platforms (70.8%) and were 10 mm long (58.3%). The failure rate was 2.4% for the anterior maxilla, 3.3% for the posterior maxilla, 1.6% for the anterior mandible, and 2.0% for posterior mandible. The cumulative survival rate was 97.6%. The failure rate was 8.8% in implants placed after sinus augmentation, 7.3% in bone block-grafted areas, and 1.6% in native bone. Based on multivariable analysis (Cox regression), sinus augmentation and bone block grafting had a statistically significant effect on implant failure; the hazard ratios were 5.5 and 4.6, respectively. Conclusion: The results revealed that DAE implants had high survival rates, and no influence of sex, location, shape, diameter, or length on failure rates could be observed. However, a significant association was observed between failure and presence of bone graft in the implant area. Int J Oral Maxillofac Implants 2012;27:1243-1248

Operationalizing ecosystem services for the mitigation of soil threats: A proposed framework

Despite numerous research efforts over the last decades, integrating the concept of ecosystem servicesinto land management decision-making continues to pose considerable challenges. Researchers havedeveloped many different frameworks to operationalize the concept, but these are often specific to acertain issue and each has their own definitions and understandings of particular terms. Based on acomprehensive review of the current scientific debate, the EU FP7 project RECARE proposes an adaptedframework for soil-related ecosystem services that is suited for practical application in the preventionand remediation of soil degradation across Europe. We have adapted existing frameworks by integratingcomponents from soil science while attempting to introduce a consistent terminology that is understand-able to a variety of stakeholders. RECARE aims to assess how soil threats and prevention and remediationmeasures affect ecosystem services. Changes in the natural capital’s properties influence soil processes,which support the provision of ecosystem services. The benefits produced by these ecosystem servicesare explicitly or implicitly valued by individuals and society. This can influence decision- and policymak-ing at different scales, potentially leading to a societal response, such as improved land management.The proposed ecosystem services framework will be applied by the RECARE project in a transdisciplinaryprocess. It will assist in singling out the most beneficial land management measures and in identifyingtrade-offs and win–win situations resulting from and impacted by European policies. The framework thusreflects the specific contributions soils make to ecosystem services and helps reveal changes in ecosystemservices caused by soil management and policies impacting on soil. At the same time, the framework issimple and robust enough for practical application in assessing soil threats and their management withstakeholders at various levels.

Bayesian doubly optimal group sequential designs for randomized clinical trials

When conducting a randomized comparative clinical trial, ethical, scientific or economic considerations often motivate the use of interim decision rules after successive groups of patients have been treated. These decisions may pertain to the comparative efficacy or safety of the treatments under study, cost considerations, the desire to accelerate the drug evaluation process, or the likelihood of therapeutic benefit for future patients. At the time of each interim decision, an important question is whether patient enrollment should continue or be terminated; either due to a high probability that one treatment is superior to the other, or a low probability that the experimental treatment will ultimately prove to be superior. The use of frequentist group sequential decision rules has become routine in the conduct of phase III clinical trials. In this dissertation, we will present a new Bayesian decision-theoretic approach to the problem of designing a randomized group sequential clinical trial, focusing on two-arm trials with time-to-failure outcomes. Forward simulation is used to obtain optimal decision boundaries for each of a set of possible models. At each interim analysis, we use Bayesian model selection to adaptively choose the model having the largest posterior probability of being correct, and we then make the interim decision based on the boundaries that are optimal under the chosen model. We provide a simulation study to compare this method, which we call Bayesian Doubly Optimal Group Sequential (BDOGS), to corresponding frequentist designs using either O'Brien-Fleming (OF) or Pocock boundaries, as obtained from EaSt 2000. Our simulation results show that, over a wide variety of different cases, BDOGS either performs at least as well as both OF and Pocock, or on average provides a much smaller trial. ^