Adaptive clinical trial design for targeted therapy development

The development of targeted therapy involve many challenges. Our study will address some of the key issues involved in biomarker identification and clinical trial design. In our study, we propose two biomarker selection methods, and then apply them in two different clinical trial designs for targeted therapy development. In particular, we propose a Bayesian two-step lasso procedure for biomarker selection in the proportional hazards model in Chapter 2. In the first step of this strategy, we use the Bayesian group lasso to identify the important marker groups, wherein each group contains the main effect of a single marker and its interactions with treatments. In the second step, we zoom in to select each individual marker and the interactions between markers and treatments in order to identify prognostic or predictive markers using the Bayesian adaptive lasso. In Chapter 3, we propose a Bayesian two-stage adaptive design for targeted therapy development while implementing the variable selection method given in Chapter 2. In Chapter 4, we proposed an alternate frequentist adaptive randomization strategy for situations where a large number of biomarkers need to be incorporated in the study design. We also propose a new adaptive randomization rule, which takes into account the variations associated with the point estimates of survival times. In all of our designs, we seek to identify the key markers that are either prognostic or predictive with respect to treatment. We are going to use extensive simulation to evaluate the operating characteristics of our methods.^

BAYESIAN STATISTICAL METHODS IN GENE-ENVIRONMENT AND GENE-GENE INTERACTION STUDIES

Complex diseases such as cancer result from multiple genetic changes and environmental exposures. Due to the rapid development of genotyping and sequencing technologies, we are now able to more accurately assess causal effects of many genetic and environmental factors. Genome-wide association studies have been able to localize many causal genetic variants predisposing to certain diseases. However, these studies only explain a small portion of variations in the heritability of diseases. More advanced statistical models are urgently needed to identify and characterize some additional genetic and environmental factors and their interactions, which will enable us to better understand the causes of complex diseases. In the past decade, thanks to the increasing computational capabilities and novel statistical developments, Bayesian methods have been widely applied in the genetics/genomics researches and demonstrating superiority over some regular approaches in certain research areas. Gene-environment and gene-gene interaction studies are among the areas where Bayesian methods may fully exert its functionalities and advantages. This dissertation focuses on developing new Bayesian statistical methods for data analysis with complex gene-environment and gene-gene interactions, as well as extending some existing methods for gene-environment interactions to other related areas. It includes three sections: (1) Deriving the Bayesian variable selection framework for the hierarchical gene-environment and gene-gene interactions; (2) Developing the Bayesian Natural and Orthogonal Interaction (NOIA) models for gene-environment interactions; and (3) extending the applications of two Bayesian statistical methods which were developed for gene-environment interaction studies, to other related types of studies such as adaptive borrowing historical data. We propose a Bayesian hierarchical mixture model framework that allows us to investigate the genetic and environmental effects, gene by gene interactions (epistasis) and gene by environment interactions in the same model. It is well known that, in many practical situations, there exists a natural hierarchical structure between the main effects and interactions in the linear model. Here we propose a model that incorporates this hierarchical structure into the Bayesian mixture model, such that the irrelevant interaction effects can be removed more efficiently, resulting in more robust, parsimonious and powerful models. We evaluate both of the 'strong hierarchical' and 'weak hierarchical' models, which specify that both or one of the main effects between interacting factors must be present for the interactions to be included in the model. The extensive simulation results show that the proposed strong and weak hierarchical mixture models control the proportion of false positive discoveries and yield a powerful approach to identify the predisposing main effects and interactions in the studies with complex gene-environment and gene-gene interactions. We also compare these two models with the 'independent' model that does not impose this hierarchical constraint and observe their superior performances in most of the considered situations. The proposed models are implemented in the real data analysis of gene and environment interactions in the cases of lung cancer and cutaneous melanoma case-control studies. The Bayesian statistical models enjoy the properties of being allowed to incorporate useful prior information in the modeling process. Moreover, the Bayesian mixture model outperforms the multivariate logistic model in terms of the performances on the parameter estimation and variable selection in most cases. Our proposed models hold the hierarchical constraints, that further improve the Bayesian mixture model by reducing the proportion of false positive findings among the identified interactions and successfully identifying the reported associations. This is practically appealing for the study of investigating the causal factors from a moderate number of candidate genetic and environmental factors along with a relatively large number of interactions. The natural and orthogonal interaction (NOIA) models of genetic effects have previously been developed to provide an analysis framework, by which the estimates of effects for a quantitative trait are statistically orthogonal regardless of the existence of Hardy-Weinberg Equilibrium (HWE) within loci. Ma et al. (2012) recently developed a NOIA model for the gene-environment interaction studies and have shown the advantages of using the model for detecting the true main effects and interactions, compared with the usual functional model. In this project, we propose a novel Bayesian statistical model that combines the Bayesian hierarchical mixture model with the NOIA statistical model and the usual functional model. The proposed Bayesian NOIA model demonstrates more power at detecting the non-null effects with higher marginal posterior probabilities. Also, we review two Bayesian statistical models (Bayesian empirical shrinkage-type estimator and Bayesian model averaging), which were developed for the gene-environment interaction studies. Inspired by these Bayesian models, we develop two novel statistical methods that are able to handle the related problems such as borrowing data from historical studies. The proposed methods are analogous to the methods for the gene-environment interactions on behalf of the success on balancing the statistical efficiency and bias in a unified model. By extensive simulation studies, we compare the operating characteristics of the proposed models with the existing models including the hierarchical meta-analysis model. The results show that the proposed approaches adaptively borrow the historical data in a data-driven way. These novel models may have a broad range of statistical applications in both of genetic/genomic and clinical studies.

The P-Adaptive BIEM Version in Elastostatics

This paper introduces the p-adaptive version of the boundary element method as a natural extension of the homonymous finite element approach. After a brief introduction to adaptive techniques through their finite element formulation in elastostatics, the concepts are cast into the boundary element environment. Thus, the p-adaptive version of boundary integral methods is shown to be a generalization of already well known ideas. In order to show the power of these numerical procedures, the results of two practical analysis using both methods are presented.

Remarks on methods for the computation of boundary-element integrals by co-ordinate transformation

It is well known that the evaluation of the influence matrices in the boundary-element method requires the computation of singular integrals. Quadrature formulae exist which are especially tailored to the specific nature of the singularity, i.e. log(*- x0)9 Ijx- JC0), etc. Clearly the nodes and weights of these formulae vary with the location Xo of the singular point. A drawback of this approach is that a given problem usually includes different types of singularities, and therefore a general-purpose code would have to include many alternative formulae to cater for all possible cases. Recently, several authors1"3 have suggested a type independent alternative technique based on the combination of standard Gaussian rules with non-linear co-ordinate transformations. The transformation approach is particularly appealing in connection with the p.adaptive version, where the location of the collocation points varies at each step of the refinement process. The purpose of this paper is to analyse the technique in eference 3. We show that this technique is asymptotically correct as the number of Gauss points increases. However, the method possesses a 'hidden' source of error that is analysed and can easily be removed.

P-Adaptive Boundary Elements

This paper presents the implementation of an adaptive philosophy to plane potential problems, using the direct boundary element method. After some considerations about the state of the art and a discussion of the standard approach features, the possibility of separately treating the modelling of variables and their interpolation through hierarchical shape functions is analysed. Then the proposed indicators and estimators are given, followed by a description of a small computer program written for an IBM PC. Finally, some examples show the kind of results to be expected.

3D hp-adaptive finite element simulations of a magic-T electromagnetic waveguide structure

This paper employs a 3D hp self-adaptive grid-refinement finite element strategy for the solution of a particular electromagnetic waveguide structure known as Magic-T. This structure is utilized as a power divider/combiner in communication systems as well as in other applications. It often incorporates dielectrics, metallic screws, round corners, and so on, which may facilitate its construction or improve its design, but significantly difficult its modeling when employing semi-analytical techniques. The hp-adaptive finite element method enables accurate modeling of a Magic-T structure even in the presence of these undesired materials/geometries. Numerical results demonstrate the suitability of the hp-adaptive method for modeling a Magic-T rectangular waveguide structure, delivering errors below 0.5% with a limited number of unknowns. Solutions of waveguide problems delivered by the self-adaptive hp-FEM are comparable to those obtained with semi-analytical techniques such as the Mode Matching method, for problems where the latest methods can be applied. At the same time, the hp-adaptive FEM enables accurate modeling of more complex waveguide structures.

A three-dimensional self-adaptive hp finite element method for the characterization of waveguide discontinuities

We propose the use of a highly-accurate three-dimensional (3D) fully automatic hp-adaptive finite element method (FEM) for the characterization of rectangular waveguide discontinuities. These discontinuities are either the unavoidable result of mechanical/electrical transitions or deliberately introduced in order to perform certain electrical functions in modern communication systems. The proposed numerical method combines the geometrical flexibility of finite elements with an accuracy that is often superior to that provided by semi-analytical methods. It supports anisotropic refinements on irregular meshes with hanging nodes, and isoparametric elements. It makes use of hexahedral elements compatible with high-order H(curl)H(curl) discretizations. The 3D hp-adaptive FEM is applied for the first time to solve a wide range of 3D waveguide discontinuity problems of microwave communication systems in which exponential convergence of the error is observed.

Adaptive Control for ZVS Three Phase Full Active Bridge Converter with ARCN

This paper presents an adaptive control for the auxiliary circuit, called ARCN (Auxiliary Resonant Commutating Network), used to achieve ZVS in full active bridge converters under a wide load range. Depending on the load conditions, the proposed control adapts the timing of the ARCN to minimize the losses. The principle of operation and implementation considerations are presented for a three phase full active bridge converter, proposing different methods to implement the control according to the specifications. The experimental results shown verify the proposed methodology.

Further Applications of P-Adaptive Boundary Elements

In previous BEM Conferences , the concepts, developments and organisation of the p-adaptive philosophy have been presented by the authors, as well as some interesting features of the hierarchisation of the solution, accuracy estimates and numerical computations optimization. This current paper is devoted to presenting some new developments and aplications in linear elastostatics, with emphasis on: a ) Efficient computation of influence coefficients, b) Efficient evaluation of the residuals by taking advantage of the hierarchy of the interpolation functions and e) New results regarding estimators and convergence ratios.In addition, several practical examples will be shown and discussed in order to point out the advantages of the method .

Subjective study of adaptive streaming strategies for 3DTV

Although the delivery of 3D video services to households is nowadays a reality thanks to frame-compatible formats, many efforts are being made to obtain efficient methods to transmit 3D content offering a high quality of experience to the end users. In this paper, a stereoscopic video streaming scenario is considered and the perceptual impact of various strategies applicable to adaptive streaming situations are compared. Specifically, the mechanisms are based on switching between copies of the content with different coding qualities, on discarding frames of the sequence, on switching from 3D to 2D and on using asymmetric coding of the stereo views. In addition, when video freezes happen, the possibility of keeping the end-to-end latency or maintaining the continuity of the video are considered. These aspects were evaluated carrying out a subjective assessment test considering also visual discomfort issues using a methodology designed to keep as far as possible domestic viewing conditions.

P-adaptive boundary elements for three-dimensional potential problems

This paper deals with the boundary element method (BEM) p-convergence approach applied to three-dimensional problems governed by Laplace's equation. The advantages derived from the boundary discretization and hierarchical interpolation functions are collated in order to minimize human effort in preparation of input data and improve numerical results.

Fully adaptive gaussian mixture metropolis-hastings algorithm

Markov Chain Monte Carlo methods are widely used in signal processing and communications for statistical inference and stochastic optimization. In this work, we introduce an efficient adaptive Metropolis-Hastings algorithm to draw samples from generic multimodal and multidimensional target distributions. The proposal density is a mixture of Gaussian densities with all parameters (weights, mean vectors and covariance matrices) updated using all the previously generated samples applying simple recursive rules. Numerical results for the one and two-dimensional cases are provided.

An adaptive population importance sampler

Monte Carlo (MC) methods are widely used in signal processing, machine learning and communications for statistical inference and stochastic optimization. A well-known class of MC methods is composed of importance sampling and its adaptive extensions (e.g., population Monte Carlo). In this work, we introduce an adaptive importance sampler using a population of proposal densities. The novel algorithm provides a global estimation of the variables of interest iteratively, using all the samples generated. The cloud of proposals is adapted by learning from a subset of previously generated samples, in such a way that local features of the target density can be better taken into account compared to single global adaptation procedures. Numerical results show the advantages of the proposed sampling scheme in terms of mean absolute error and robustness to initialization.

Adaptive designs in the time to event setting: The potential for benefit and risk

Thesis (Ph.D.)--University of Washington, 2016-06

Adaptive stepsize based on control theory for stochastic differential equations

The numerical solution of stochastic differential equations (SDEs) has been focussed recently on the development of numerical methods with good stability and order properties. These numerical implementations have been made with fixed stepsize, but there are many situations when a fixed stepsize is not appropriate. In the numerical solution of ordinary differential equations, much work has been carried out on developing robust implementation techniques using variable stepsize. It has been necessary, in the deterministic case, to consider the best choice for an initial stepsize, as well as developing effective strategies for stepsize control-the same, of course, must be carried out in the stochastic case. In this paper, proportional integral (PI) control is applied to a variable stepsize implementation of an embedded pair of stochastic Runge-Kutta methods used to obtain numerical solutions of nonstiff SDEs. For stiff SDEs, the embedded pair of the balanced Milstein and balanced implicit method is implemented in variable stepsize mode using a predictive controller for the stepsize change. The extension of these stepsize controllers from a digital filter theory point of view via PI with derivative (PID) control will also be implemented. The implementations show the improvement in efficiency that can be attained when using these control theory approaches compared with the regular stepsize change strategy. (C) 2004 Elsevier B.V. All rights reserved.