Approximating Probability Densities by Iterated Laplace Approximations

The Laplace approximation is an old, but frequently used method to approximate integrals for Bayesian calculations. In this paper we develop an extension of the Laplace approximation, by applying it iteratively to the residual, i.e., the difference between the current approximation and the true function. The final approximation is thus a linear combination of multivariate normal densities, where the coefficients are chosen to achieve a good fit to the target distribution. We illustrate on real and artificial examples that the proposed procedure is a computationally efficient alternative to current approaches for approximation of multivariate probability densities. The R-package iterLap implementing the methods described in this article is available from the CRAN servers.Comment: to appear in Journal of Computational and Graphical Statistics, http://pubs.amstat.org/loi/jcg

Subgroup identification in dose-finding trials via model-based recursive partitioning

An important task in early phase drug development is to identify patients, which respond better or worse to an experimental treatment. While a variety of different subgroup identification methods have been developed for the situation of trials that study an experimental treatment and control, much less work has been done in the situation when patients are randomized to different dose groups. In this article we propose new strategies to perform subgroup analyses in dose-finding trials and discuss the challenges, which arise in this new setting. We consider model-based recursive partitioning, which has recently been applied to subgroup identification in two arm trials, as a promising method to tackle these challenges and assess its viability using a real trial example and simulations. Our results show that model-based recursive partitioning can be used to identify subgroups of patients with different dose-response curves and improves estimation of treatment effects and minimum effective doses, when heterogeneity among patients is present.Comment: 23 pages, 6 figure

Response-adaptive dose-finding under model uncertainty

Dose-finding studies are frequently conducted to evaluate the effect of different doses or concentration levels of a compound on a response of interest. Applications include the investigation of a new medicinal drug, a herbicide or fertilizer, a molecular entity, an environmental toxin, or an industrial chemical. In pharmaceutical drug development, dose-finding studies are of critical importance because of regulatory requirements that marketed doses are safe and provide clinically relevant efficacy. Motivated by a dose-finding study in moderate persistent asthma, we propose response-adaptive designs addressing two major challenges in dose-finding studies: uncertainty about the dose-response models and large variability in parameter estimates. To allocate new cohorts of patients in an ongoing study, we use optimal designs that are robust under model uncertainty. In addition, we use a Bayesian shrinkage approach to stabilize the parameter estimates over the successive interim analyses used in the adaptations. This approach allows us to calculate updated parameter estimates and model probabilities that can then be used to calculate the optimal design for subsequent cohorts. The resulting designs are hence robust with respect to model misspecification and additionally can efficiently adapt to the information accrued in an ongoing study. We focus on adaptive designs for estimating the minimum effective dose, although alternative optimality criteria or mixtures thereof could be used, enabling the design to address multiple objectives.Comment: Published in at http://dx.doi.org/10.1214/10-AOAS445 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

Model Selection versus Model Averaging in Dose Finding Studies

Phase II dose finding studies in clinical drug development are typically conducted to adequately characterize the dose response relationship of a new drug. An important decision is then on the choice of a suitable dose response function to support dose selection for the subsequent Phase III studies. In this paper we compare different approaches for model selection and model averaging using mathematical properties as well as simulations. Accordingly, we review and illustrate asymptotic properties of model selection criteria and investigate their behavior when changing the sample size but keeping the effect size constant. In a large scale simulation study we investigate how the various approaches perform in realistically chosen settings. Finally, the different methods are illustrated with a recently conducted Phase II dosefinding study in patients with chronic obstructive pulmonary disease.Comment: Keywords and Phrases: Model selection; model averaging; clinical trials; simulation stud

On the efficiency of adaptive designs

In this paper we develop a method to investigate the efficiency of two-stage adaptive designs from a theoretical point of view. Our approach is based on an explicit expansion of the information matrix for an adaptive design. The results enables one to compare the performance of adaptive designs with non-adaptive designs, without having to rely on extensive simulation studies. We demonstrate that their relative efficiency depends sensitively on the statistical problem under investigation and derive some general conclusions when to prefer an adaptive or a non-adaptive design. In particular, we show that in nonlinear regression models with moderate or large variances the first stage sample size of an adaptive design should be chosen sufficiently large in order to address variability in the interim parameter estimates. We illustrate the methodology with several examples

Bayesian outlier detection in INGARCH time series

INGARCH models for time series of counts arising, e.g., in epidemiology assume the observations to be Poisson distributed conditionally on the past, with the conditional mean being an affinelinear function of the previous observations and the previous conditional means. We model outliers within such processes, assuming that we observe a contaminated process with additive Poisson distributed contamination, affecting each observation with a small probability. Our particular concern are additive outliers, which do not enter the dynamics of the process and can represent measurement artifacts and other singular events influencing a single observation. Such outliers are difficult to handle within a non-Bayesian framework since the uncontaminated values entering the dynamics of the process at contaminated time points are unobserved. We propose a Bayesian approach to outlier modeling in INGARCH processes, approximating the posterior distribution of the model parameters by application of a componentwise Metropolis- Hastings algorithm. Analyzing real and simulated data sets, we find Bayesian outlier detection with non-informative priors to work well if there are some outliers in the data

Using data mining to analyze job reviews

Job review websites like Glassdoor are not always clear on how well the company operates, especially as viewed from differing levels of employment. For instance, a middle or upper manager from Amazon may have an overall positive review of the company with minor issues about it, but someone who works in the warehouse may have a mixed experience. To solve this issue and determine any correlation between employee level and their review, data mining techniques were utilized such as website scraping and neural network training to develop a model that analyzes employee reviews