Outcome-based adaptive randomization for binary data in clinical trials---Compare and contrast

Monte Carlo simulation has been conducted to investigate parameter estimation and hypothesis testing in some well known adaptive randomization procedures. The four urn models studied are Randomized Play-the-Winner (RPW), Randomized Pôlya Urn (RPU), Birth and Death Urn with Immigration (BDUI), and Drop-the-Loses Urn (DL). Two sequential estimation methods, the sequential maximum likelihood estimation (SMLE) and the doubly adaptive biased coin design (DABC), are simulated at three optimal allocation targets that minimize the expected number of failures under the assumption of constant variance of simple difference (RSIHR), relative risk (ORR), and odds ratio (OOR) respectively. Log likelihood ratio test and three Wald-type tests (simple difference, log of relative risk, log of odds ratio) are compared in different adaptive procedures. ^ Simulation results indicates that although RPW is slightly better in assigning more patients to the superior treatment, the DL method is considerably less variable and the test statistics have better normality. When compared with SMLE, DABC has slightly higher overall response rate with lower variance, but has larger bias and variance in parameter estimation. Additionally, the test statistics in SMLE have better normality and lower type I error rate, and the power of hypothesis testing is more comparable with the equal randomization. Usually, RSIHR has the highest power among the 3 optimal allocation ratios. However, the ORR allocation has better power and lower type I error rate when the log of relative risk is the test statistics. The number of expected failures in ORR is smaller than RSIHR. It is also shown that the simple difference of response rates has the worst normality among all 4 test statistics. The power of hypothesis test is always inflated when simple difference is used. On the other hand, the normality of the log likelihood ratio test statistics is robust against the change of adaptive randomization procedures. ^

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.

Long-term dynamics of adaptive evolution in a globally important coccolithophore to ocean acidification

Recent evolution experiments have revealed that marine phytoplankton may adapt to global change, for example to ocean warming or acidification. Long-term adaptation to novel environments is a dynamic process and phenotypic change can take place thousands of generations after exposure to novel conditions. Using the longest evolution experiment performed in any marine species to date (4 yrs, = 2100 generations), we show that in the coccolithophore Emiliania huxleyi, long-term adaptation to ocean acidification is complex and initial phenotypic responses may revert for important traits. While fitness increased continuously, calcification was restored within the first 500 generations but later reduced in response to selection, enhancing physiological declines of calcification in response to ocean acidification. Interestingly, calcification was not constitutively reduced but revealed rates similar to control treatments when transferred back to present-day CO2 conditions. Growth rate increased with time in controls and adaptation treatments, although the effect size of adaptation assessed through reciprocal assay experiments varied. Several trait changes were associated with selection for higher cell division rates under laboratory conditions, such as reduced cell size and lower particulate organic carbon content per cell. Our results show that phytoplankton may evolve phenotypic plasticity that can affect biogeochemically important traits, such as calcification, in an unforeseen way under future ocean conditions.

DNA methylation and adaptive response in forest tree species

Progressive increase of temperatures as well as longer seasonal drought periods revealed by climate studies correspond to fast environmental changes that forest species face with their actual genetic background. Natural selective processes cannot develop an adaptive response within this time frame. Thus the capability of forest tree species to adapt to the new environments will depend on their genetic background, but also rely on their phenotypic plasticity. Several reports have shown the involvement of epigenetic modifiers as the basis of the phenotypic plasticity, and in particular to the adaptation to abiotic stresses. DNA methylation (methylation of cytosine residues)is one the most important epigenetic modification in eukaryotes. Itis involved in specific biological processes such as gene transcription regulation, gene silencing, mobile element control or genome imprinting.Therefore, there is a great interest in analyzing cytosine methylation levels and distribution within the genome

Analysis of adaptive responses of Pinus pinaster to changing environmental conditions in the Mediterranean region

Recent climate evolution studies highlight the progressive temperature increase and prevalence of seasonal drought, with specially incidence in the Mediterranean region. Although conifers are very important species regarding forest conservation, sustainability and productivity, given the large forest surface they cover in Spain and their active role in preventing soil erosion and desertification, we know little about the molecular mechanisms which control adaptation in this ancient taxonomic group

GEODA-GRUA: Adaptive Multibeam Conformal Antenna for Satellites Communications

The GEODA-GRUA is one conformal adaptive antenna array designed for satellite communications. Operating at 1.7 GHz with circular polarization, it is possible to track and communicate with several satellites at once being able to receive signals in full azimuth and within the range of 5° to broadside elevation thanks to its adaptive beam. The complex structure of the antenna array has 2700 radiating elements based on a set of 60 similar triangular arrays that are divided in 15 subarrays of 3 radiating elements. A control module governs each transmission/receiver (T/R) module associated to each cell in order to manage beam steering by shifting phases.

A Visual AGV-Urban Car using Fuzzy Control

The goal of the work described in this paper is to develop a visual line guided system for being used on-board an Autonomous Guided Vehicle (AGV) commercial car, controlling the steering and using just the visual information of a line painted below the car. In order to implement the control of the vehicle, a Fuzzy Logic controller has been implemented, that has to be robust against curvature changes and velocity changes. The only input information for the controller is the visual distance from the image center captured by a camera pointing downwards to the guiding line on the road, at a commercial frequency of 30Hz. The good performance of the controller has successfully been demonstrated in a real environment at urban velocities. The presented results demonstrate the capability of the Fuzzy controller to follow a circuit in urban environments without previous information about the path or any other information from additional sensors

PWM Control of a Buck Converter with an Amorphous Core Coil

Pulse-width modulation is widely used to control electronic converters. One of the most topologies used for high DC voltage/low DC voltage conversion is the Buck converter. It is obtained as a second order system with a LC filter between the switching subsystem and the load. The use of a coil with an amorphous magnetic material core instead of air core lets design converters with smaller size. If high switching frequencies are used for obtaining high quality voltage output, the value of the auto inductance L is reduced throughout the time. Then, robust controllers are needed if the accuracy of the converter response must not be affected by auto inductance and load variations. This paper presents a robust controller for a Buck converter based on a state space feedback control system combined with an additional virtual space variable which minimizes the effects of the inductance and load variations when a not-toohigh switching frequency is applied. The system exhibits a null steady-state average error response for the entire range of parameter variations. Simulation results are presented.

Catadioptric panoramic stereovision for humanoid robots

This paper proposes a novel design of a reconfigurable humanoid robot head, based on biological likeness of human being so that the humanoid robot could agreeably interact with people in various everyday tasks. The proposed humanoid head has a modular and adaptive structural design and is equipped with three main components: frame, neck motion system and omnidirectional stereovision system modules. The omnidirectional stereovision system module being the last module, a motivating contribution with regard to other computer vision systems implemented in former humanoids, it opens new research possibilities for achieving human-like behaviour. A proposal for a real-time catadioptric stereovision system is presented, including stereo geometry for rectifying the system configuration and depth estimation. The methodology for an initial approach for visual servoing tasks is divided into two phases, first related to the robust detection of moving objects, their depth estimation and position calculation, and second the development of attention-based control strategies. Perception capabilities provided allow the extraction of 3D information from a wide range of visions from uncontrolled dynamic environments, and work results are illustrated through a number of experiments.

AR drone identification and navigation control at CVG-UPM

This article presents the proposal of the Computer Vision Group to the first phase of the international competition “Concurso de Ingeniería de Control 2012, Control Aut ́onomo del seguimiento de trayectorias de un vehículo cuatrirrotor”. This phase consists mainly of two parts: identifying a model and designing a trajectory controller for the AR Drone quadrotor. For the identification task, two models are proposed: a simplified model that captures only the main dynamics of the quadrotor, and a second model based on the physical laws underlying the AR Drone behavior. The trajectory controller design is based on the simplified model, whereas the physical model is used to tune the controller to attain a certain level of robust stability to model uncertainties. The controller design is simplified by the hypothesis that accurate positions sensors will be available to implement a feedback controller.

Sistema de control borroso en lazo cerrado para terapias con insulina en diabetes tipo I

La diabetes mellitus es un trastorno del metabolismo de los carbohidratos producido por la insuficiente o nula producción de insulina o la reducida sensibilidad a esta hormona. Es una enfermedad crónica con una mayor prevalencia en los países desarrollados debido principalmente a la obesidad, la vida sedentaria y disfunciones en el sistema endocrino relacionado con el páncreas. La diabetes Tipo 1 es una enfermedad autoinmune en la que son destruidas las células beta del páncreas, que producen la insulina, y es necesaria la administración de insulina exógena. Un enfermo de diabetes Tipo 1 debe seguir una terapia con insulina administrada por la vía subcutánea que debe estar adaptada a sus necesidades metabólicas y a sus hábitos de vida, esta terapia intenta imitar el perfil insulínico de un páncreas no patológico. La tecnología actual permite abordar el desarrollo del denominado “páncreas endocrino artificial”, que aportaría precisión, eficacia y seguridad para los pacientes, en cuanto a la normalización del control glucémico y reducción del riesgo de hipoglucemias. Permitiría que el paciente no estuviera tan pendiente de su enfermedad. El páncreas artificial consta de un sensor continuo de glucosa, una bomba de infusión de insulina y un algoritmo de control, que calcula la insulina a infusionar usando la glucosa como información principal. Este trabajo presenta un método de control en lazo semi-cerrado mediante un sistema borroso experto basado en reglas. La regulación borrosa se fundamenta en la ambigüedad del lenguaje del ser humano. Esta incertidumbre sirve para la formación de una serie de reglas que representan el pensamiento humano, pero a la vez es el sistema que controla un proceso, en este caso el sistema glucorregulatorio. Este proyecto está enfocado en el diseño de un controlador borroso que haciendo uso de variables como la glucosa, insulina y dieta, sea capaz de restaurar la función endocrina del páncreas de forma tecnológica. La validación del algoritmo se ha realizado principalmente mediante experimentos en simulación utilizando una población de pacientes sintéticos, evaluando los resultados con estadísticos de primer orden y algunos más específicos como el índice de riesgo de Kovatchev, para después comparar estos resultados con los obtenidos por otros métodos de control anteriores. Los resultados demuestran que el control borroso (FBPC) mejora el control glucémico con respecto a un sistema predictivo experto basado en reglas booleanas (pBRES). El FBPC consigue reducir siempre la glucosa máxima y aumentar la mínima respecto del pBRES pero es en terapias desajustadas, donde el FBPC es especialmente robusto, hace descender la glucosa máxima 8,64 mg/dl, el uso de insulina es 3,92 UI menor, aumenta la glucosa mínima 3,32 mg/dl y lleva al rango de glucosa 80 – 110 mg/dl 15,33 muestras más. Por lo tanto se puede concluir que el FBPC realiza un mejor control glucémico que el controlador pBRES haciéndole especialmente efectivo, robusto y seguro en condiciones de desajustes de terapia basal y con gran capacidad de mejora futura. SUMMARY The diabetes mellitus is a metabolic disorder caused by a poor or null insulin secretion or a reduced sensibility to insulin. Diabetes is a chronic disease with a higher prevalence in the industrialized countries, mainly due to obesity, the sedentary life and endocrine disfunctions connected with the pancreas. Type 1 diabetes is a self-immune disease where the beta cells of the pancreas, which are the responsible of secreting insulin, are damaged. Hence, it is necessary an exogenous delivery of insulin. The Type 1 diabetic patient has to follow a therapy with subcutaneous insulin administration which should be adjusted to his/her metabolic needs and life style. This therapy tries to mimic the insulin profile of a non-pathological pancreas. Current technology lets the development of the so-called endocrine artificial pancreas that would provide accuracy, efficiency and safety to patients, in regards to the glycemic control normalization and reduction of the risk of hypoglycemic. In addition, it would help the patient not to be so concerned about his disease. The artificial pancreas has a continuous glucose sensor, an insulin infusion pump and a control algorithm, that calculates the insulin infusion using the glucose as main information. This project presents a method of control in semi-closed-loop, through an expert fuzzy system based on rules. The fuzzy regulation is based on the human language ambiguity. This uncertainty serves for construction of some rules that represent the human language besides it is the system that controls a process, in this case the glucoregulatory system. This project is focus on the design of a fuzzy controller that, using variables like glucose insulin and diet, will be able to restore the pancreas endocrine function with technology. The algorithm assessment has mainly been done through experiments in simulation using a population of synthetic patients, evaluating the results with first order statistical parameters and some other more specific such as the Kovatchev risk index, to compare later these results with the ones obtained in others previous methods of control. The results demonstrate that the fuzzy control (FBPC) improves the glycemic control connected with a predictive expert system based on Booleans rules (pBRES). The FBPC is always able to reduce the maximum level of glucose and increase the minimum level as compared with pBRES but it is in unadjusted therapies where FBPC is especially strong, it manages to decrease the maximum level of glucose and insulin used by 8,64 mg/dl and 3,92 UI respectively, also increases the value of minimum glucose by 3,32 mg/dl, getting 15,33 samples more inside the 80-110 mg/dl glucose rank. Therefore we can conclude that FBPC achieves a better glycemic control than the controller pBRES doing it especially effective, robust and safe in conditions of mismatch basal therapy and with a great capacity for future improvements.

Visual Tracking, Pose Estimation, and Control for Aerial Vehicles

El principal objetivo de esta tesis es dotar a los vehículos aéreos no tripulados (UAVs, por sus siglas en inglés) de una fuente de información adicional basada en visión. Esta fuente de información proviene de cámaras ubicadas a bordo de los vehículos o en el suelo. Con ella se busca que los UAVs realicen tareas de aterrizaje o inspección guiados por visión, especialmente en aquellas situaciones en las que no haya disponibilidad de estimar la posición del vehículo con base en GPS, cuando las estimaciones de GPS no tengan la suficiente precisión requerida por las tareas a realizar, o cuando restricciones de carga de pago impidan añadir sensores a bordo de los vehículos. Esta tesis trata con tres de las principales áreas de la visión por computador: seguimiento visual y estimación visual de la pose (posición y orientación), que a su vez constituyen la base de la tercera, denominada control servo visual, que en nuestra aplicación se enfoca en el empleo de información visual para controlar los UAVs. Al respecto, esta tesis se ocupa de presentar propuestas novedosas que permitan solucionar problemas relativos al seguimiento de objetos mediante cámaras ubicadas a bordo de los UAVs, se ocupa de la estimación de la pose de los UAVs basada en información visual obtenida por cámaras ubicadas en el suelo o a bordo, y también se ocupa de la aplicación de las técnicas propuestas para solucionar diferentes problemas, como aquellos concernientes al seguimiento visual para tareas de reabastecimiento autónomo en vuelo o al aterrizaje basado en visión, entre otros. Las diversas técnicas de visión por computador presentadas en esta tesis se proponen con el fin de solucionar dificultades que suelen presentarse cuando se realizan tareas basadas en visión con UAVs, como las relativas a la obtención, en tiempo real, de estimaciones robustas, o como problemas generados por vibraciones. Los algoritmos propuestos en esta tesis han sido probados con información de imágenes reales obtenidas realizando pruebas on-line y off-line. Diversos mecanismos de evaluación han sido empleados con el propósito de analizar el desempeño de los algoritmos propuestos, entre los que se incluyen datos simulados, imágenes de vuelos reales, estimaciones precisas de posición empleando el sistema VICON y comparaciones con algoritmos del estado del arte. Los resultados obtenidos indican que los algoritmos de visión por computador propuestos tienen un desempeño que es comparable e incluso mejor al de algoritmos que se encuentran en el estado del arte. Los algoritmos propuestos permiten la obtención de estimaciones robustas en tiempo real, lo cual permite su uso en tareas de control visual. El desempeño de estos algoritmos es apropiado para las exigencias de las distintas aplicaciones examinadas: reabastecimiento autónomo en vuelo, aterrizaje y estimación del estado del UAV. Abstract The main objective of this thesis is to provide Unmanned Aerial Vehicles (UAVs) with an additional vision-based source of information extracted by cameras located either on-board or on the ground, in order to allow UAVs to develop visually guided tasks, such as landing or inspection, especially in situations where GPS information is not available, where GPS-based position estimation is not accurate enough for the task to develop, or where payload restrictions do not allow the incorporation of additional sensors on-board. This thesis covers three of the main computer vision areas: visual tracking and visual pose estimation, which are the bases the third one called visual servoing, which, in this work, focuses on using visual information to control UAVs. In this sense, the thesis focuses on presenting novel solutions for solving the tracking problem of objects when using cameras on-board UAVs, on estimating the pose of the UAVs based on the visual information collected by cameras located either on the ground or on-board, and also focuses on applying these proposed techniques for solving different problems, such as visual tracking for aerial refuelling or vision-based landing, among others. The different computer vision techniques presented in this thesis are proposed to solve some of the frequently problems found when addressing vision-based tasks in UAVs, such as obtaining robust vision-based estimations at real-time frame rates, and problems caused by vibrations, or 3D motion. All the proposed algorithms have been tested with real-image data in on-line and off-line tests. Different evaluation mechanisms have been used to analyze the performance of the proposed algorithms, such as simulated data, images from real-flight tests, publicly available datasets, manually generated ground truth data, accurate position estimations using a VICON system and a robotic cell, and comparison with state of the art algorithms. Results show that the proposed computer vision algorithms obtain performances that are comparable to, or even better than, state of the art algorithms, obtaining robust estimations at real-time frame rates. This proves that the proposed techniques are fast enough for vision-based control tasks. Therefore, the performance of the proposed vision algorithms has shown to be of a standard appropriate to the different explored applications: aerial refuelling and landing, and state estimation. It is noteworthy that they have low computational overheads for vision systems.

Robust rolling stock under uncertain demand in rapid transit networks

This paper focuses on the railway rolling stock circulation problem in rapid transit networks where the known demand and train schedule must be met by a given fleet. In rapid transit networks the frequencies are high and distances are relatively short. Although the distances are not very large, service times are high due to the large number of intermediate stops required to allow proper passenger flow. The previous circumstances and the reduced capacity of the depot stations and that the rolling stock is shared between the different lines, force the introduction of empty trains and a careful control on shunting operation. In practice the future demand is generally unknown and the decisions must be based on uncertain forecast. We have developed a stochastic rolling stock formulation of the problem. The computational experiments were developed using a commercial line of the Madrid suburban rail network operated by RENFE (The main Spanish operator of suburban trains of passengers). Comparing the results obtained by deterministic scenarios and stochastic approach some useful conclusions may be obtained.

Adaptive cross-device videoconferencing solution for wireless networks based on QoS monitoring

The increase in CPU power and screen quality of todays smartphones as well as the availability of high bandwidth wireless networks has enabled high quality mobile videoconfer- encing never seen before. However, adapting to the variety of devices and network conditions that come as a result is still not a trivial issue. In this paper, we present a multiple participant videoconferencing service that adapts to different kind of devices and access networks while providing an stable communication. By combining network quality detection and the use of a multipoint control unit for video mixing and transcoding, desktop, tablet and mobile clients can participate seamlessly. We also describe the cost in terms of bandwidth and CPU usage of this approach in a variety of scenarios.

Variable structure control with chattering elimination and guaranteed stability for a generalized T-S model

In this paper, a fuzzy based Variable Structure Control (VSC) with guaranteed stability is presented. The main objective is to obtain an improved performance of highly non-linear unstable systems. The main contribution of this work is that, firstly, new functions for chattering reduction and error convergence without sacrificing invariant properties are proposed, which is considered the main drawback of the VSC control. Secondly, the global stability of the controlled system is guaranteed.The well known weighting parameters approach, is used in this paper to optimize local and global approximation and modeling capability of T-S fuzzy model.A one link robot is chosen as a nonlinear unstable system to evaluate the robustness, effectiveness and remarkable performance of optimization approach and the high accuracy obtained in approximating nonlinear systems in comparison with the original T-S model. Simulation results indicate the potential and generality of the algorithm. The application of the proposed FLC-VSC shows that both alleviation of chattering and robust performance are achieved with the proposed FLC-VSC controller. The effectiveness of the proposed controller is proven in front of disturbances and noise effects.