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

Asymptotic properties of robust complex covariance matrix estimates

In many statistical signal processing applications, the estimation of nuisance parameters and parameters of interest is strongly linked to the resulting performance. Generally, these applications deal with complex data. This paper focuses on covariance matrix estimation problems in non-Gaussian environments and particularly, the M-estimators in the context of elliptical distributions. Firstly, this paper extends to the complex case the results of Tyler in [1]. More precisely, the asymptotic distribution of these estimators as well as the asymptotic distribution of any homogeneous function of degree 0 of the M-estimates are derived. On the other hand, we show the improvement of such results on two applications: DOA (directions of arrival) estimation using the MUSIC (MUltiple SIgnal Classification) algorithm and adaptive radar detection based on the ANMF (Adaptive Normalized Matched Filter) test

Spike-and-Slab Priors for Function Selection in Structured Additive Regression Models

Structured additive regression provides a general framework for complex Gaussian and non-Gaussian regression models, with predictors comprising arbitrary combinations of nonlinear functions and surfaces, spatial effects, varying coefficients, random effects and further regression terms. The large flexibility of structured additive regression makes function selection a challenging and important task, aiming at (1) selecting the relevant covariates, (2) choosing an appropriate and parsimonious representation of the impact of covariates on the predictor and (3) determining the required interactions. We propose a spike-and-slab prior structure for function selection that allows to include or exclude single coefficients as well as blocks of coefficients representing specific model terms. A novel multiplicative parameter expansion is required to obtain good mixing and convergence properties in a Markov chain Monte Carlo simulation approach and is shown to induce desirable shrinkage properties. In simulation studies and with (real) benchmark classification data, we investigate sensitivity to hyperparameter settings and compare performance to competitors. The flexibility and applicability of our approach are demonstrated in an additive piecewise exponential model with time-varying effects for right-censored survival times of intensive care patients with sepsis. Geoadditive and additive mixed logit model applications are discussed in an extensive appendix

Fully computable a posteriori error bounds for hybridizable discontinuous Galerkin finite element approximations

We derive a posteriori error estimates for the hybridizable discontinuous Galerkin (HDG) methods, including both the primal and mixed formulations, for the approximation of a linear second-order elliptic problem on conforming simplicial meshes in two and three dimensions. We obtain fully computable, constant free, a posteriori error bounds on the broken energy seminorm and the HDG energy (semi)norm of the error. The estimators are also shown to provide local lower bounds for the HDG energy (semi)norm of the error up to a constant and a higher-order data oscillation term. For the primal HDG methods and mixed HDG methods with an appropriate choice of stabilization parameter, the estimators are also shown to provide a lower bound for the broken energy seminorm of the error up to a constant and a higher-order data oscillation term. Numerical examples are given illustrating the theoretical results

Dense and accurate motion and strain estimation in high resolution speckle images using an image-adaptive approach

Digital image processing methods represent a viable and well acknowledged alternative to strain gauges and interferometric techniques for determining full-field displacements and strains in materials under stress. This paper presents an image adaptive technique for dense motion and strain estimation using high-resolution speckle images that show the analyzed material in its original and deformed states. The algorithm starts by dividing the speckle image showing the original state into irregular cells taking into consideration both spatial and gradient image information present. Subsequently the Newton-Raphson digital image correlation technique is applied to calculate the corresponding motion for each cell. Adaptive spatial regularization in the form of the Geman-McClure robust spatial estimator is employed to increase the spatial consistency of the motion components of a cell with respect to the components of neighbouring cells. To obtain the final strain information, local least-squares fitting using a linear displacement model is performed on the horizontal and vertical displacement fields. To evaluate the presented image partitioning and strain estimation techniques two numerical and two real experiments are employed. The numerical experiments simulate the deformation of a specimen with constant strain across the surface as well as small rigid-body rotations present while real experiments consist specimens that undergo uniaxial stress. The results indicate very good accuracy of the recovered strains as well as better rotation insensitivity compared to classical techniques