Bayesian adaptive designs for drug combinations in early phase clinical trials

Treating patients with combined agents is a growing trend in cancer clinical trials. Evaluating the synergism of multiple drugs is often the primary motivation for such drug-combination studies. Focusing on the drug combination study in the early phase clinical trials, our research is composed of three parts: (1) We conduct a comprehensive comparison of four dose-finding designs in the two-dimensional toxicity probability space and propose using the Bayesian model averaging method to overcome the arbitrariness of the model specification and enhance the robustness of the design; (2) Motivated by a recent drug-combination trial at MD Anderson Cancer Center with a continuous-dose standard of care agent and a discrete-dose investigational agent, we propose a two-stage Bayesian adaptive dose-finding design based on an extended continual reassessment method; (3) By combining phase I and phase II clinical trials, we propose an extension of a single agent dose-finding design. We model the time-to-event toxicity and efficacy to direct dose finding in two-dimensional drug-combination studies. We conduct extensive simulation studies to examine the operating characteristics of the aforementioned designs and demonstrate the designs' good performances in various practical scenarios.^

Bayesian adaptive designs in early phase clinical trials

There are two practical challenges in the phase I clinical trial conduct: lack of transparency to physicians, and the late onset toxicity. In my dissertation, Bayesian approaches are used to address these two problems in clinical trial designs. The proposed simple optimal designs cast the dose finding problem as a decision making process for dose escalation and deescalation. The proposed designs minimize the incorrect decision error rate to find the maximum tolerated dose (MTD). For the late onset toxicity problem, a Bayesian adaptive dose-finding design for drug combination is proposed. The dose-toxicity relationship is modeled using the Finney model. The unobserved delayed toxicity outcomes are treated as missing data and Bayesian data augment is employed to handle the resulting missing data. Extensive simulation studies have been conducted to examine the operating characteristics of the proposed designs and demonstrated the designs' good performances in various practical scenarios.^

Adaptive liquid-crystal phase-only passive devices

This PhD work is focused on liquid crystal based tunable phase devices with special emphasis on their design and manufacturing. In the course of the work a number of new manufacturing technologies have been implemented in the UPM clean room facilities, leading to an important improvement in the range of devices being manufactured in the laboratory. Furthermore, a number of novel phase devices have been developed, all of them including novel electrodes, and/or alignment layers. The most important manufacturing progress has been the introduction of reactive ion etching as a tool for achieving high resolution photolithography on indium-tin-oxide (ITO) coated glass and quartz substrates. Another important manufacturing result is the successful elaboration of a binding protocol of anisotropic conduction adhesives. These have been employed in high density interconnections between ITO-glass and flexible printed circuits. Regarding material characterization, the comparative study of nonstoichiometric silicon oxide (SiOx) and silica (SiO2) inorganic alignment layers, as well as the relationship between surface layer deposition, layer morphology and liquid crystal electrooptical response must be highlighted, together with the characterization of the degradation of liquid crystal devices in simulated space mission environment. A wide variety of phase devices have been developed, with special emphasis on beam steerers. One of these was developed within the framework of an ESA project, and consisted of a high density reconfigurable 1D blaze grating, with a spatial separation of the controlling microelectronics and the active, radiation exposed, area. The developed devices confirmed the assumption that liquid crystal devices with such a separation of components, are radiation hard, and can be designed to be both vibration and temperature sturdy. In parallel to the above, an evenly variable analog beam steering device was designed, manufactured and characterized, providing a narrow cone diffraction free beam steering. This steering device is characterized by a very limited number of electrodes necessary for the redirection of a light beam. As few as 4 different voltage levels were needed in order to redirect a light beam. Finally at the Wojskowa Akademia Techniczna (Military University of Technology) in Warsaw, Poland, a wedged analog tunable beam steering device was designed, manufactured and characterized. This beam steerer, like the former one, was designed to resist the harsh conditions both in space and in the context of the shuttle launch. Apart from the beam steering devices, reconfigurable vortices and modal lens devices have been manufactured and characterized. In summary, during this work a large number of liquid crystal devices and liquid crystal device manufacturing technologies have been developed. Besides their relevance in scientific publications and technical achievements, most of these new devices have demonstrated their usefulness in the actual work of the research group where this PhD has been completed. El presente trabajo de Tesis se ha centrado en el diseño, fabricación y caracterización de nuevos dispositivos de fase basados en cristal líquido. Actualmente se están desarrollando dispositivos basados en cristal líquido para aplicaciones diferentes a su uso habitual como displays. Poseen la ventaja de que los dispositivos pueden ser controlados por bajas tensiones y no necesitan elementos mecánicos para su funcionamiento. La fabricación de todos los dispositivos del presente trabajo se ha realizado en la cámara limpia del grupo. La cámara limpia ha sido diseñada por el grupo de investigación, es de dimensiones reducidas pero muy versátil. Está dividida en distintas áreas de trabajo dependiendo del tipo de proceso que se lleva a cabo. La cámara limpia está completamente cubierta de un material libre de polvo. Todas las entradas de suministro de gas y agua están selladas. El aire filtrado es constantemente bombeado dentro de la zona limpia, a fin de crear una sobrepresión evitando así la entrada de aire sin filtrar. Las personas que trabajan en esta zona siempre deben de estar protegidas con un traje especial. Se utilizan trajes especiales que constan de: mono, máscara, guantes de látex, gorro, patucos y gafas de protección UV, cuando sea necesario. Para introducir material dentro de la cámara limpia se debe limpiar con alcohol y paños especiales y posteriormente secarlos con nitrógeno a presión. La fabricación debe seguir estrictamente unos pasos determinados, que pueden cambiar dependiendo de los requerimientos de cada dispositivo. Por ello, la fabricación de dispositivos requiere la formulación de varios protocolos de fabricación. Estos protocolos deben ser estrictamente respetados a fin de obtener repetitividad en los experimentos, lo que lleva siempre asociado un proceso de fabricación fiable. Una célula de cristal líquido está compuesta (de forma general) por dos vidrios ensamblados (sándwich) y colocados a una distancia determinada. Los vidrios se han sometido a una serie de procesos para acondicionar las superficies internas. La célula se llena con cristal líquido. De forma resumida, el proceso de fabricación general es el siguiente: inicialmente, se cortan los vidrios (cuya cara interna es conductora) y se limpian. Después se imprimen las pistas sobre el vidrio formando los píxeles. Estas pistas conductoras provienen del vidrio con la capa conductora de ITO (óxido de indio y estaño). Esto se hace a través de un proceso de fotolitografía con una resina fotosensible, y un desarrollo y ataque posterior del ITO sin protección. Más tarde, las caras internas de los vidrios se acondicionan depositando una capa, que puede ser orgánica o inorgánica (un polímero o un óxido). Esta etapa es crucial para el funcionamiento del dispositivo: induce la orientación de las moléculas de cristal líquido. Una vez que las superficies están acondicionadas, se depositan espaciadores en las mismas: son pequeñas esferas o cilindros de tamaño calibrado (pocos micrómetros) para garantizar un espesor homogéneo del dispositivo. Después en uno de los sustratos se deposita un adhesivo (gasket). A continuación, los sustratos se ensamblan teniendo en cuenta que el gasket debe dejar una boca libre para que el cristal líquido se introduzca posteriormente dentro de la célula. El llenado de la célula se realiza en una cámara de vacío y después la boca se sella. Por último, la conexión de los cables a la célula y el montaje de los polarizadores se realizan fuera de la sala limpia (Figura 1). Dependiendo de la aplicación, el cristal líquido empleado y los demás componentes de la célula tendrán unas características particulares. Para el diseño de los dispositivos de este trabajo se ha realizado un estudio de superficies inorgánicas de alineamiento del cristal líquido, que será de gran importancia para la preparación de los dispositivos de fase, dependiendo de las condiciones ambientales en las que vayan a trabajar. Los materiales inorgánicos que se han estudiado han sido en este caso SiOx y SiO2. El estudio ha comprendido tanto los factores de preparación influyentes en el alineamiento, el comportamiento del cristal líquido al variar estos factores y un estudio de la morfología de las superficies obtenidas.

Iterative determination of clinical beam phase space from dose measurements

Monte Carlo (MC) method can accurately compute the dose produced by medical linear accelerators. However, these calculations require a reliable description of the electron and/or photon beams delivering the dose, the phase space (PHSP), which is not usually available. A method to derive a phase space model from reference measurements that does not heavily rely on a detailed model of the accelerator head is presented. The iterative optimization process extracts the characteristics of the particle beams which best explains the reference dose measurements in water and air, given a set of constrains

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.

Debonding detection of FRP strengthened concrete beams by using impedance measurements and an ensemble PSO adaptive spectral model

An impedance-based midspan debonding identification method for RC beams strengthened with FRP strips is presented in this paper using piezoelectric ceramic (PZT) sensor?actuators. To reach this purpose, firstly, a two-dimensional electromechanical impedance model is proposed to predict the electrical admittance of the PZT transducer bonded to the FRP strips of an RC beam. Considering the impedance is measured in high frequencies, a spectral element model of the bonded-PZT?FRP strengthened beam is developed. This model, in conjunction with experimental measurements of PZT transducers, is used to present an updating methodology to quantitatively detect interfacial debonding of these kinds of structures. To improve the performance and accuracy of the detection algorithm in a challenging problem such as ours, the structural health monitoring approach is solved with an ensemble process based on particle of swarm. An adaptive mesh scheme has also been developed to increase the reliability in locating the area in which debonding initiates. Predictions carried out with experimental results have showed the effectiveness and potential of the proposed method to detect prematurely at its earliest stages a critical failure mode such as that due to midspan debonding of the FRP strip.

Transient thermal analysis during the ascent phase of a balloon-borne payload. Comparison with SUNRISE test flight measurements

The thermal design of stratospheric balloon payloads usually focuses on the cruise phase of the missions, that is, the floating altitude conditions. The ascent phase usually takes between 2 and 4 h, a very small period compared to the duration of the whole mission, which can last up to 4 weeks. However, during this phase payloads are subjected to very harsh conditions due mainly to the convective cooling that occurs as the balloon passes through the cold atmosphere, with minimum temperatures in the tropopause. The aim of this work is to study the thermal behaviour of a payload carried by a long duration balloon during the ascent phase. Its temperature has been calculated as a function of the altitude from sea level to floating conditions. To perform this analysis it has been assumed that the thermal interactions (convection and radiation) depend on the altitude, on the environmental conditions (which in turn depend also on the altitude) and on the temperature of the system itself. The results have been compared with the measurements taken during the SUNRISE test flight, launched in October 2007 by CSBF from Fort Sumner (New Mexico).

Effect of level of fiber of the rearing phase diets on egg production, digestive tract traits, and body measurements of brown egg-laying hens fed diets differing in energy concentration

This research studied the effects of additional fiber in the rearing phase diets on egg production, gastrointestinal tract (GIT) traits, and body measurements of brown egg-laying hens fed diets varying in energy concentration from 17 to 46 wk of age. The experiment was completely randomized with 10 treatments arranged as a 5 × 2 factorial with 5 rearing phase diets and 2 laying phase diets. During the rearing phase, treatments consisted of a control diet based on cereals and soybean meal and 4 additional diets with a combination of 2 fiber sources (cereal straw and sugar beet pulp, SBP) at 2 levels (2 and 4%). During the laying phase, diets differed in energy content (2,650 vs. 2,750 kcal AMEn/kg) but had the same amino acid content per unit of energy. The rearing diet did not affect any production trait except egg production that was lower in birds fed SBP than in birds fed straw (91.6 and 94.1%, respectively; P < 0.05). Laying hens fed the high energy diet had lower feed intake (P < 0.001), better feed conversion (P < 0.01), and greater BW gain (P < 0.05) than hens fed the low energy diet but egg production and egg weight were not affected. At 46 wk of age, none of the GIT traits was affected by previous dietary treatment. At this age, hen BW was positively related with body length (r = 0.500; P < 0.01), tarsus length (r = 0.758; P < 0.001), and body mass index (r = 0.762; P < 0.001) but no effects of type of diet on these traits were detected. In summary, the inclusion of up to 4% of a fiber source in the rearing diets did not affect GIT development of the hens but SBP reduced egg production. An increase in the energy content of the laying phase diet reduced ADFI and improved feed efficiency but did not affect any of the other traits studied.

Transportable setup for amplifier phase fidelity measurements

One possible laser source for the Laser Interferometer Space Antenna (LISA) consists of an Ytterbium-doped fiber amplifier originally developed for inter-satellite communication, seeded by the laser used for the technology demonstrator mission LISA Pathfinder. LISA needs to transmit clock information between its three spacecraft to correct for phase noise between the clocks on the individual spacecraft. For this purpose phase modulation sidebands at GHz frequencies will be imprinted on the laser beams between spacecraft. Differential phase noise between the carrier and a sideband introduced within the optical chain must be very low. We report on a transportable setup to measure the phase fidelity of optical amplifiers.

Nested Sampling and its Applications in Stable Compressive Covariance Estimation and Phase Retrieval with Near-Minimal Measurements

Compressed covariance sensing using quadratic samplers is gaining increasing interest in recent literature. Covariance matrix often plays the role of a sufficient statistic in many signal and information processing tasks. However, owing to the large dimension of the data, it may become necessary to obtain a compressed sketch of the high dimensional covariance matrix to reduce the associated storage and communication costs. Nested sampling has been proposed in the past as an efficient sub-Nyquist sampling strategy that enables perfect reconstruction of the autocorrelation sequence of Wide-Sense Stationary (WSS) signals, as though it was sampled at the Nyquist rate. The key idea behind nested sampling is to exploit properties of the difference set that naturally arises in quadratic measurement model associated with covariance compression. In this thesis, we will focus on developing novel versions of nested sampling for low rank Toeplitz covariance estimation, and phase retrieval, where the latter problem finds many applications in high resolution optical imaging, X-ray crystallography and molecular imaging. The problem of low rank compressive Toeplitz covariance estimation is first shown to be fundamentally related to that of line spectrum recovery. In absence if noise, this connection can be exploited to develop a particular kind of sampler called the Generalized Nested Sampler (GNS), that can achieve optimal compression rates. In presence of bounded noise, we develop a regularization-free algorithm that provably leads to stable recovery of the high dimensional Toeplitz matrix from its order-wise minimal sketch acquired using a GNS. Contrary to existing TV-norm and nuclear norm based reconstruction algorithms, our technique does not use any tuning parameters, which can be of great practical value. The idea of nested sampling idea also finds a surprising use in the problem of phase retrieval, which has been of great interest in recent times for its convex formulation via PhaseLift, By using another modified version of nested sampling, namely the Partial Nested Fourier Sampler (PNFS), we show that with probability one, it is possible to achieve a certain conjectured lower bound on the necessary measurement size. Moreover, for sparse data, an l1 minimization based algorithm is proposed that can lead to stable phase retrieval using order-wise minimal number of measurements.

Remote sensing the vertical profile of cloud droplet effective radius, thermodynamic phase, and temperature

Cloud-aerosol interaction is a key issue in the climate system, affecting the water cycle, the weather, and the total energy balance including the spatial and temporal distribution of latent heat release. Information on the vertical distribution of cloud droplet microphysics and thermodynamic phase as a function of temperature or height, can be correlated with details of the aerosol field to provide insight on how these particles are affecting cloud properties and their consequences to cloud lifetime, precipitation, water cycle, and general energy balance. Unfortunately, today's experimental methods still lack the observational tools that can characterize the true evolution of the cloud microphysical, spatial and temporal structure in the cloud droplet scale, and then link these characteristics to environmental factors and properties of the cloud condensation nuclei. Here we propose and demonstrate a new experimental approach (the cloud scanner instrument) that provides the microphysical information missed in current experiments and remote sensing options. Cloud scanner measurements can be performed from aircraft, ground, or satellite by scanning the side of the clouds from the base to the top, providing us with the unique opportunity of obtaining snapshots of the cloud droplet microphysical and thermodynamic states as a function of height and brightness temperature in clouds at several development stages. The brightness temperature profile of the cloud side can be directly associated with the thermodynamic phase of the droplets to provide information on the glaciation temperature as a function of different ambient conditions, aerosol concentration, and type. An aircraft prototype of the cloud scanner was built and flew in a field campaign in Brazil. The CLAIM-3D (3-Dimensional Cloud Aerosol Interaction Mission) satellite concept proposed here combines several techniques to simultaneously measure the vertical profile of cloud microphysics, thermodynamic phase, brightness temperature, and aerosol amount and type in the neighborhood of the clouds. The wide wavelength range, and the use of multi-angle polarization measurements proposed for this mission allow us to estimate the availability and characteristics of aerosol particles acting as cloud condensation nuclei, and their effects on the cloud microphysical structure. These results can provide unprecedented details on the response of cloud droplet microphysics to natural and anthropogenic aerosols in the size scale where the interaction really happens.

Metal-insulator transition in Nd(1-x) Eu(x) NiO(3) probed by specific heat and anelastic measurements

Oxides RNiO(3) (R - rare-earth, R not equal La) exhibit a metal-insulator (MI) transition at a temperature T(MI) and an antiferromagnetic (AF) transition at T(N). Specific heat (C(P)) and anelastic spectroscopy measurements were performed in samples of Nd(1-x)Eu(x)NiO(3), 0 <= x <= 0.35. For x - 0, a peak in C(P) is observed upon cooling and warming at essentially the same temperature T(MI) - T(N) similar to 195 K, although the cooling peak is much smaller. For x >= 0.25, differences between the cooling and warming curves are negligible, and two well defined peaks are clearly observed: one at lower temperatures that define T(N), and the other one at T(MI). An external magnetic field of 9 T had no significant effect on these results. The elastic compliance (s) and the reciprocal of the mechanical quality factor (Q(-1)) of NdNiO(3), measured upon warming, showed a very sharp peak at essentially the same temperature obtained from C(P), and no peak is observed upon cooling. The elastic modulus hardens below T(MI) much more sharply upon warming, while the cooling and warming curves are reproducible above T(MI). Conversely, for the sample with x - 0.35, s and Q(-1) curves are very similar upon warming and cooling. The results presented here give credence to the proposition that the MI phase transition changes from first to second order with increasing Eu doping. (C) 2011 American Institute of Physics. [doi: 10.1063/1.3549615]