Gaining acceptability for the Bayesian decision-theoretic approach in dose-escalation studies

There has recently been increasing demand for better designs to conduct first-into-man dose-escalation studies more efficiently, more accurately and more quickly. The authors look into the Bayesian decision-theoretic approach and use simulation as a tool to investigate the impact of compromises with conventional practice that might make the procedures more acceptable for implementation. Copyright © 2005 John Wiley & Sons, Ltd.

Bayesian decision procedures for dose-escalation based on evidence of undesirable events and therapeutic benefit.

In this paper, Bayesian decision procedures are developed for dose-escalation studies based on bivariate observations of undesirable events and signs of therapeutic benefit. The methods generalize earlier approaches taking into account only the undesirable outcomes. Logistic regression models are used to model the two responses, which are both assumed to take a binary form. A prior distribution for the unknown model parameters is suggested and an optional safety constraint can be included. Gain functions to be maximized are formulated in terms of accurate estimation of the limits of a therapeutic window or optimal treatment of the next cohort of subjects, although the approach could be applied to achieve any of a wide variety of objectives. The designs introduced are illustrated through simulation and retrospective implementation to a completed dose-escalation study. Copyright © 2006 John Wiley & Sons, Ltd.

An evaluation of a Bayesian method of dose escalation based on bivariate binary responses

Recently, various approaches have been suggested for dose escalation studies based on observations of both undesirable events and evidence of therapeutic benefit. This article concerns a Bayesian approach to dose escalation that requires the user to make numerous design decisions relating to the number of doses to make available, the choice of the prior distribution, the imposition of safety constraints and stopping rules, and the criteria by which the design is to be optimized. Results are presented of a substantial simulation study conducted to investigate the influence of some of these factors on the safety and the accuracy of the procedure with a view toward providing general guidance for investigators conducting such studies. The Bayesian procedures evaluated use logistic regression to model the two responses, which are both assumed to be binary. The simulation study is based on features of a recently completed study of a compound with potential benefit to patients suffering from inflammatory diseases of the lung.

An evaluation of Bayesian designs for dose-escalation studies in healthy volunteers

In this paper, Bayesian decision procedures previously proposed for dose-escalation studies in healthy volunteers are reviewed and evaluated. Modifications are made to the expression of the prior distribution in order to make the procedure simpler to implement and a more relevant criterion for optimality is introduced. The results of an extensive simulation exercise to establish the proper-ties of the procedure and to aid choice between designs are summarized, and the way in which readers can use simulation to choose a design for their own trials is described. The influence of the value of the within-subject correlation on the procedure is investigated and the use of a simple prior to reflect uncertainty about the correlation is explored. Copyright (c) 2005 John Wiley & Sons, Ltd.

A hierarchical Bayesian model for predicting the functional consequences of amino-acid polymorphisms

Genetic polymorphisms in deoxyribonucleic acid coding regions may have a phenotypic effect on the carrier, e.g. by influencing susceptibility to disease. Detection of deleterious mutations via association studies is hampered by the large number of candidate sites; therefore methods are needed to narrow down the search to the most promising sites. For this, a possible approach is to use structural and sequence-based information of the encoded protein to predict whether a mutation at a particular site is likely to disrupt the functionality of the protein itself. We propose a hierarchical Bayesian multivariate adaptive regression spline (BMARS) model for supervised learning in this context and assess its predictive performance by using data from mutagenesis experiments on lac repressor and lysozyme proteins. In these experiments, about 12 amino-acid substitutions were performed at each native amino-acid position and the effect on protein functionality was assessed. The training data thus consist of repeated observations at each position, which the hierarchical framework is needed to account for. The model is trained on the lac repressor data and tested on the lysozyme mutations and vice versa. In particular, we show that the hierarchical BMARS model, by allowing for the clustered nature of the data, yields lower out-of-sample misclassification rates compared with both a BMARS and a frequen-tist MARS model, a support vector machine classifier and an optimally pruned classification tree.

Decision-making in a phase II clinical trial: a new approach combining Bayesian and frequentist concepts

The aim of a phase H clinical trial is to decide whether or not to develop an experimental therapy further through phase III clinical evaluation. In this paper, we present a Bayesian approach to the phase H trial, although we assume that subsequent phase III clinical trials will hat,e standard frequentist analyses. The decision whether to conduct the phase III trial is based on the posterior predictive probability of a significant result being obtained. This fusion of Bayesian and frequentist techniques accepts the current paradigm for expressing objective evidence of therapeutic value, while optimizing the form of the phase II investigation that leads to it. By using prior information, we can assess whether a phase II study is needed at all, and how much or what sort of evidence is required. The proposed approach is illustrated by the design of a phase II clinical trial of a multi-drug resistance modulator used in combination with standard chemotherapy in the treatment of metastatic breast cancer. Copyright (c) 2005 John Wiley & Sons, Ltd.

Uptake pathways: the potential of Bayesian belief networks to assist the management, monitoring and evaluation of development-orientated research

The effectiveness of development assistance has come under renewed scrutiny in recent years. In an era of growing economic liberalisation, research organisations are increasingly being asked to account for the use of public funds by demonstrating achievements. However, in the natural resources (NR) research field, conventional economic assessment techniques have focused on quantifying the impact achieved rather understanding the process that delivered it. As a result, they provide limited guidance for planners and researchers charged with selecting and implementing future research. In response, “pathways” or logic models have attracted increased interest in recent years as a remedy to this shortcoming. However, as commonly applied these suffer from two key limitations in their ability to incorporate risk and assess variance from plan. The paper reports the results of a case study that used a Bayesian belief network approach to address these limitations and outlines its potential value as a tool to assist the planning, monitoring and evaluation of development-orientated research.

Forecast calibration and combination: a simple Bayesian approach for ENSO

This study presents a new simple approach for combining empirical with raw (i.e., not bias corrected) coupled model ensemble forecasts in order to make more skillful interval forecasts of ENSO. A Bayesian normal model has been used to combine empirical and raw coupled model December SST Niño-3.4 index forecasts started at the end of the preceding July (5-month lead time). The empirical forecasts were obtained by linear regression between December and the preceding July Niño-3.4 index values over the period 1950–2001. Coupled model ensemble forecasts for the period 1987–99 were provided by ECMWF, as part of the Development of a European Multimodel Ensemble System for Seasonal to Interannual Prediction (DEMETER) project. Empirical and raw coupled model ensemble forecasts alone have similar mean absolute error forecast skill score, compared to climatological forecasts, of around 50% over the period 1987–99. The combined forecast gives an increased skill score of 74% and provides a well-calibrated and reliable estimate of forecast uncertainty.

Adaptive approximate Bayesian computation

Sequential techniques can enhance the efficiency of the approximate Bayesian computation algorithm, as in Sisson et al.'s (2007) partial rejection control version. While this method is based upon the theoretical works of Del Moral et al. (2006), the application to approximate Bayesian computation results in a bias in the approximation to the posterior. An alternative version based on genuine importance sampling arguments bypasses this difficulty, in connection with the population Monte Carlo method of Cappe et al. (2004), and it includes an automatic scaling of the forward kernel. When applied to a population genetics example, it compares favourably with two other versions of the approximate algorithm.

Epidemiological risk assessment using linked network and grid based modelling: Phytophthora ramorum and Phytophthora kernoviae in the UK

We developed a stochastic simulation model incorporating most processes likely to be important in the spread of Phytophthora ramorum and similar diseases across the British landscape (covering Rhododendron ponticum in woodland and nurseries, and Vaccinium myrtillus in heathland). The simulation allows for movements of diseased plants within a realistically modelled trade network and long-distance natural dispersal. A series of simulation experiments were run with the model, representing an experiment varying the epidemic pressure and linkage between natural vegetation and horticultural trade, with or without disease spread in commercial trade, and with or without inspections-with-eradication, to give a 2 x 2 x 2 x 2 factorial started at 10 arbitrary locations spread across England. Fifty replicate simulations were made at each set of parameter values. Individual epidemics varied dramatically in size due to stochastic effects throughout the model. Across a range of epidemic pressures, the size of the epidemic was 5-13 times larger when commercial movement of plants was included. A key unknown factor in the system is the area of susceptible habitat outside the nursery system. Inspections, with a probability of detection and efficiency of infected-plant removal of 80% and made at 90-day intervals, reduced the size of epidemics by about 60% across the three sectors with a density of 1% susceptible plants in broadleaf woodland and heathland. Reducing this density to 0.1% largely isolated the trade network, so that inspections reduced the final epidemic size by over 90%, and most epidemics ended without escape into nature. Even in this case, however, major wild epidemics developed in a few percent of cases. Provided the number of new introductions remains low, the current inspection policy will control most epidemics. However, as the rate of introduction increases, it can overwhelm any reasonable inspection regime, largely due to spread prior to detection. (C) 2009 Elsevier B.V. All rights reserved.

Spatiotemporal modelling of CheY complexes in Escherichia coli chemotaxis

The chemotaxis pathway of Escherichia coli is one of the best studied and modelled biological signalling pathways. Here we extend existing modelling approaches by explicitly including a description of the formation and subcellular localization of intermediary complexes in the phosphotransfer pathway. The inclusion of these complexes shows that only about 60% of the total output response regulator (CheY) is uncomplexed at any moment and hence free to interact with its target, the flagellar motor. A clear strength of this model is its ability to predict the experimentally observable subcellular localization of CheY throughout a chemotactic response. We have found good agreement between the model output and experimentally determined CheY localization patterns. (C) 2009 Elsevier Ltd. All rights reserved.

Monthly average temperature modelling

This research is associated with the goal of the horticultural sector of the Colombian southwest, which is to obtain climatic information, specifically, to predict the monthly average temperature in sites where it has not been measured. The data correspond to monthly average temperature, and were recorded in meteorological stations at Valle del Cauca, Colombia, South America. Two components are identified in the data of this research: (1) a component due to the temporal aspects, determined by characteristics of the time series, distribution of the monthly average temperature through the months and the temporal phenomena, which increased (El Nino) and decreased (La Nina) the temperature values, and (2) a component due to the sites, which is determined for the clear differentiation of two populations, the valley and the mountains, which are associated with the pattern of monthly average temperature and with the altitude. Finally, due to the closeness between meteorological stations it is possible to find spatial correlation between data from nearby sites. In the first instance a random coefficient model without spatial covariance structure in the errors is obtained by month and geographical location (mountains and valley, respectively). Models for wet periods in mountains show a normal distribution in the errors; models for the valley and dry periods in mountains do not exhibit a normal pattern in the errors. In models of mountains and wet periods, omni-directional weighted variograms for residuals show spatial continuity. The random coefficient model without spatial covariance structure in the errors and the random coefficient model with spatial covariance structure in the errors are capturing the influence of the El Nino and La Nina phenomena, which indicates that the inclusion of the random part in the model is appropriate. The altitude variable contributes significantly in the models for mountains. In general, the cross-validation process indicates that the random coefficient model with spatial spherical and the random coefficient model with spatial Gaussian are the best models for the wet periods in mountains, and the worst model is the model used by the Colombian Institute for Meteorology, Hydrology and Environmental Studies (IDEAM) to predict temperature.