Decision-theoretic designs for phase II clinical trials allowing for competing studies

This article describes an approach to optimal design of phase II clinical trials using Bayesian decision theory. The method proposed extends that suggested by Stallard (1998, Biometrics54, 279–294) in which designs were obtained to maximize a gain function including the cost of drug development and the benefit from a successful therapy. Here, the approach is extended by the consideration of other potential therapies, the development of which is competing for the same limited resources. The resulting optimal designs are shown to have frequentist properties much more similar to those traditionally used in phase II trials.

Large supersaturated designs

A supersaturated design (SSD) is an experimental plan, useful for evaluating the main effects of m factors with n experimental units when m > n - 1, each factor has two levels and when the first-order effects of only a few factors are expected to have dominant effects on the response. Use of these plans can be extremely cost-effective when it is necessary to screen hundreds or thousands of factors with a limited amount of resources. In this article we describe how to use cyclic balanced incomplete block designs and regular graph designs to construct E (s(2)) optimal and near optimal SSDs when m is a multiple of n - 1. We also provide a table that can be used to construct these designs for screening thousands of factors. We also explain how to obtain SSDs when m is not a multiple of n - 1. Using the table and the approaches given in this paper, SSDs can be developed for designs with up to 24 runs and up to 12,190 factors.

Decadal predictability of the Atlantic Ocean in a coupled GCM: forecast skill and optimal perturbations using Linear Inverse Modelling

The decadal predictability of three-dimensional Atlantic Ocean anomalies is examined in a coupled global climate model (HadCM3) using a Linear Inverse Modelling (LIM) approach. It is found that the evolution of temperature and salinity in the Atlantic, and the strength of the meridional overturning circulation (MOC), can be effectively described by a linear dynamical system forced by white noise. The forecasts produced using this linear model are more skillful than other reference forecasts for several decades. Furthermore, significant non-normal amplification is found under several different norms. The regions from which this growth occurs are found to be fairly shallow and located in the far North Atlantic. Initially, anomalies in the Nordic Seas impact the MOC, and the anomalies then grow to fill the entire Atlantic basin, especially at depth, over one to three decades. It is found that the structure of the optimal initial condition for amplification is sensitive to the norm employed, but the initial growth seems to be dominated by MOC-related basin scale changes, irrespective of the choice of norm. The consistent identification of the far North Atlantic as the most sensitive region for small perturbations suggests that additional observations in this region would be optimal for constraining decadal climate predictions.

Estimating the spatial scales of regionalized variables by nested sampling, hierarchical analysis of variance and residual maximum likelihood

The variogram is essential for local estimation and mapping of any variable by kriging. The variogram itself must usually be estimated from sample data. The sampling density is a compromise between precision and cost, but it must be sufficiently dense to encompass the principal spatial sources of variance. A nested, multi-stage, sampling with separating distances increasing in geometric progression from stage to stage will do that. The data may then be analyzed by a hierarchical analysis of variance to estimate the components of variance for every stage, and hence lag. By accumulating the components starting from the shortest lag one obtains a rough variogram for modest effort. For balanced designs the analysis of variance is optimal; for unbalanced ones, however, these estimators are not necessarily the best, and the analysis by residual maximum likelihood (REML) will usually be preferable. The paper summarizes the underlying theory and illustrates its application with data from three surveys, one in which the design had four stages and was balanced and two implemented with unbalanced designs to economize when there were more stages. A Fortran program is available for the analysis of variance, and code for the REML analysis is listed in the paper. (c) 2005 Elsevier Ltd. All rights reserved.

Estimating the spatial scales of regionalized variables by nested sampling, hierarchical analysis of variance and residual maximum likelihood

The variogram is essential for local estimation and mapping of any variable by kriging. The variogram itself must usually be estimated from sample data. The sampling density is a compromise between precision and cost, but it must be sufficiently dense to encompass the principal spatial sources of variance. A nested, multi-stage, sampling with separating distances increasing in geometric progression from stage to stage will do that. The data may then be analyzed by a hierarchical analysis of variance to estimate the components of variance for every stage, and hence lag. By accumulating the components starting from the shortest lag one obtains a rough variogram for modest effort. For balanced designs the analysis of variance is optimal; for unbalanced ones, however, these estimators are not necessarily the best, and the analysis by residual maximum likelihood (REML) will usually be preferable. The paper summarizes the underlying theory and illustrates its application with data from three surveys, one in which the design had four stages and was balanced and two implemented with unbalanced designs to economize when there were more stages. A Fortran program is available for the analysis of variance, and code for the REML analysis is listed in the paper. (c) 2005 Elsevier Ltd. All rights reserved.

Copyright issues on the protection of architectural works and designs

Architects and engineers depend on copyright law to protect their original works. Copyright protection is automatic once a tangible medium of expression in any form of an innovative material, conforming the Copyright Designs and Patents Act 1988, is created. In terms of architectural works, they are protected as literary works (design drawings and plans) and as artistic works (the building or model of the building). The case law on the concept of “originality” however discloses that it may be difficult for certain artistic works of architecture to achieve copyright protection. Although copyright law provides automatic protection to all original architectural plans, the limitation is that it only protects the expression of ideas but not the ideas themselves. The purpose of this research is to explore how effective the UK’s copyright law regime is for protecting the rights and interests of architects in their works. In addition, the United States system of copyright law will be analysed to determine whether it provides more effective protection for architects and engineers with regard to architectural works. The key objective in carrying out this comparison is to compare and contrast the extent to which the two systems protect the rights and interests of architects against copyright infringement. This comparative analysis concludes by considering the possibility of copyright law reform in the UK.

Optimal inverter design for an induction machine using resonant frequency matching

The frequency responses of two 50 Hz and one 400 Hz induction machines have been measured experimentally over a frequency range of 1 kHz to 400 kHz. This study has shown that the stator impedances of the machines behave in a similar manner to a parallel resonant circuit, and hence have a resonant point at which the Input impedance of the machine is at a maximum. This maximum impedance point was found experimentally to be as low as 33 kHz, which is well within the switching frequency ranges of modern inverter drives. This paper investigates the possibility of exploiting the maximum impedance point of the machine, by taking it into consideration when designing an inverter, in order to minimize ripple currents due to the switching frequency. Minimization of the ripple currents would reduce torque pulsation and losses, increasing overall performance. A modified machine model was developed to take into account the resonant point, and this model was then simulated with an inverter to demonstrate the possible advantages of matching the inverter switching frequency to the resonant point. Finally, in order to experimentally verify the simulated results, a real inverter with a variable switching frequency was used to drive an induction machine. Experimental results are presented.

Who owns the copyright of architectural works and designs?

Copyright protects the rights and interests of authors on their original works of authorship such as literary, dramatic, musical, artistic, and certain other intellectual works including architectural works and designs. It is automatic once a tangible medium of expression in any form of an innovative material, which conforms the Copyright Designs and Patents Act 1988 (CDPA 1988), is created. This includes the building, the architectural plans and drawings. There is no official copyright registry, no requirements on any fees need to be paid and they can be published or unpublished materials. Copyrights owners have the rights to control the reproduction, display, publication, and even derivation of the design. However, there are limitations on the rights of the copyright owners concerning copyrights infringements. Infringement of copyright is an unauthorised violation of the exclusive rights of the copyright author. Architects and engineers depend on copyright law to protect their works and design. Copyrights are protected on the arrangements of spaces and elements as well as the overall form of the architectural design. However, it does not cover the design of functional elements and standard features. Although copyright law provides automatic protection to all original architectural plans, the limitation is that copyright only protects the expression of ideas but not the ideas themselves. It can be argued that architectural drawings and design, including models are recognised categories of artistic works which are protected under the copyright law. This research investigates to what extent copyrights protect the rights and interests of the designers on architectural works and design.

Improved and optimal dual circular 32-QAM for MB-OFDM

Quadrature Phase Shift Keying (QPSK) and Dual Carrier Modulation (DCM) are currently used as the modulation schemes for Multiband Orthogonal Frequency Division Multiplexing (MB-OFDM) in the ECMA-368 defined Ultra-Wideband (UWB) radio platform. ECMA-368 has been chosen as the physical radio platform for many systems including Wireless USB (W-USB), Bluetooth 3.0 and Wireless HDMI; hence ECMA-368 is an important issue to consumer electronics and the users’ experience of these products. To enable the transport of high-rate USB, ECMA-368 offers up to 480 Mb/s instantaneous bit rate to the Medium Access Control (MAC) layer, but depending on radio channel conditions dropped packets unfortunately result in a lower throughput. This paper presents improvement on a high data rate modulation scheme that fits within the configuration of the current standard increasing system throughput by achieving 600 Mb/s (reliable to 3.2 meters) thus maintaining the high rate USB throughput even with a moderate level of dropped packets. The modulation system is termed improved and optimal Dual Circular 32-QAM (DC 32-QAM). The system performance for improved and optimal DC 32-QAM modulation is presented and compared with previous DC 32- QAM, 16-QAM and DCM.

Optimal protection of stabilised dry live bacteria from bile toxicity in oral dosage forms by bile acid adsorbent resins

We previously found that dried live bacteria of a vaccine strain can be temporarily sensitive to bile acids and suggested that Bile Adsorbing Resins (BAR) can be used in oral vaccine tablets to protect dried bacteria from intestinal bile. Here, we report a quantitative analysis of the ability of BAR to exclude the dye bromophenol blue from penetrating into matrix tablets and also sections of hard capsule shells. Based on this quantitative analysis, we made a fully optimised formulation, comprising 25% w/w of cholestyramine in Vcaps™ HPMC capsules. This gave effectively 100% protection of viability from 4% bile, with 4200-fold more live bacteria recovered from this formulation compared to unprotected dry bacteria. From the image analysis, we found that the filler material or compaction force used had no measurable effect on dye exclusion but did affect the rate of tablet hydration. Increasing the mass fraction of BAR gave more exclusion of dye up to 25% w/w, after which a plateau was reached and no further dye exclusion was seen. More effective dye exclusion was seen with smaller particle sizes (i.e. cholestyramine) and when the BAR was thoroughly dried and disaggregated. Similar results were found when imaging dye penetration into capsule sections or tablets. The predictions of the dye penetration study were tested using capsules filled with dried attenuated Salmonella vaccine plus different BAR types, and the expected protection from bile was found, validating the imaging study. Surprisingly, depending on the capsule shell material, some protection was given by the capsule alone without adding BAR, with Vcaps™ HPMC capsules providing up to 174-fold protection against 1% bile; faster releasing Vcaps Plus™ HPMC capsules and Coni Snap™ gelatin capsules gave less protection.