Statistical design and analysis of pharmacogenetic trials

Pharmacogenetic trials investigate the effect of genotype on treatment response. When there are two or more treatment groups and two or more genetic groups, investigation of gene-treatment interactions is of key interest. However, calculation of the power to detect such interactions is complicated because this depends not only on the treatment effect size within each genetic group, but also on the number of genetic groups, the size of each genetic group, and the type of genetic effect that is both present and tested for. The scale chosen to measure the magnitude of an interaction can also be problematic, especially for the binary case. Elston et al. proposed a test for detecting the presence of gene-treatment interactions for binary responses, and gave appropriate power calculations. This paper shows how the same approach can also be used for normally distributed responses. We also propose a method for analysing and performing sample size calculations based on a generalized linear model (GLM) approach. The power of the Elston et al. and GLM approaches are compared for the binary and normal case using several illustrative examples. While more sensitive to errors in model specification than the Elston et al. approach, the GLM approach is much more flexible and in many cases more powerful. Copyright © 2005 John Wiley & Sons, Ltd.

Wnt6 controls amniote neural crest induction through the non-canonical signaling pathway

The neural crest is a multipotent embryonic cell population that arises from neural ectoderm and forms derivatives essential for vertebrate function. Neural crest induction requires an ectodermal signal, thought to be a Writ ligand, but the identity of the Wnt that performs this function in amniotes is unknown. Here, we demonstrate that Wnt6, derived from the ectoderm, is necessary for chick neural crest induction. Crucially, we also show that Wnt6 acts through the non-canonical pathway and not the beta-catenin-dependant pathway. Surprisingly, we found that canonical Wnt signaling inhibited neural crest production in the chick embryo. In light of studies in anamniotes demonstrating that canonical Wnt signaling induces neural crest, these results indicate a significant and novel change in the mechanism of neural crest induction during vertebrate evolution. These data also highlight a key role for noncanonical Wnt signaling in cell type specification from a stem population during development.

Restricted expression of NADPH oxidase/peroxidase gene (Duox) in zone VII of the ascidian endostyle

The ascidian Ciona intestinalis, a marine invertebrate chordate, is an emerging model system for developmental and evolutionary studies. The endostyle, one of the characteristic organs of ascidians, is a pharyngeal structure with iodine-concentrating and peroxidase activities and is therefore considered to be homologous to the follicular thyroid of higher vertebrates. We have previously reported that a limited part of the endostyle (zone VII) is marked by the expression of orthologs of the thyroid peroxidase (TPO) and thyroid transcription factor-2 (TTF-2/FoxE) genes. In this study, we have identified the Ciona homolog of NADPH oxidase/peroxidase (Duox), which provides hydrogen peroxide (H2O2) for iodine metabolism by TPO in the vertebrate thyroid. Expression patterns assessed by in situ hybridization have revealed that Ciona Duox (Ci-Duox) is predominantly expressed in the dorsal part of zone VII of the endostyle. Furthermore, two-color fluorescent in situ hybridization with Ci-Duox and Ciona TPO (CiTPO) has revealed that the ventral boundary of the Ci-Duox domain of expression is more dorsal than that of CiTPO. We have also characterized several genes, such as Ci-Fgf8/17/18, 5HT7, and Ci-NK4, which are predominantly expressed in the ventral part of zone VII, in a region complementary to the Ci-Duox expression domain. These observations suggest that, at the molecular level, zone VII has a complex organization that might have some impact on the specification of cell types and functions in this thyroid-equivalent element of the ascidian endostyle.

Graphical tracking systems revisited: a practical approach to computer scheduling in horticulture

Graphical tracking is a technique for crop scheduling where the actual plant state is plotted against an ideal target curve which encapsulates all crop and environmental characteristics. Management decisions are made on the basis of the position of the actual crop against the ideal position. Due to the simplicity of the approach it is possible for graphical tracks to be developed on site without the requirement for controlled experimentation. Growth models and graphical tracks are discussed, and an implementation of the Richards curve for graphical tracking described. In many cases, the more intuitively desirable growth models perform sub-optimally due to problems with the specification of starting conditions, environmental factors outside the scope of the original model and the introduction of new cultivars. Accurate specification for a biological model requires detailed and usually costly study, and as such is not adaptable to a changing cultivar range and changing cultivation techniques. Fitting of a new graphical track for a new cultivar can be conducted on site and improved over subsequent seasons. Graphical tracking emphasises the current position relative to the objective, and as such does not require the time consuming or system specific input of an environmental history, although it does require detailed crop measurement. The approach is flexible and could be applied to a variety of specification metrics, with digital imaging providing a route for added value. For decision making regarding crop manipulation from the observed current state, there is a role for simple predictive modelling over the short term to indicate the short term consequences of crop manipulation.

Modelling fatigue damage distribution to inform slip and cut policy for riser tensioner ropes

The paper describes a method whereby the distribution of fatigue damage along riser tensioner ropes is calculated, taking account of heave motion, set tension, system geometry, tidal range and rope specification. From these data the distribution of damage along the rope is calculated for a given time period using a Miner’s summation method. This information can then be used to help the operator decide on the length of rope to ‘slip and cut’ whereby a length from the end of the rope is removed and the rope moved through the system from a storage drum such that sections of rope that have already suffered significant fatigue damage are not moved to positions where there is another peak in the distribution. There are two main advantages to be gained by using the fatigue damage model. The first is that it shows the amount of fatigue damage accumulating at different points along the rope, enabling the most highly damaged section to be removed well before failure. The second is that it makes for greater efficiency, as damage can be spread more evenly along the rope over time, avoiding the need to scrap long sections of undamaged rope.

Enabling older people to stay at home: The costs of substituting and supplementing care with assistive technology

A wide-ranging multiprofessional research project explored issues relating to the introduction of assistive technology into the existing homes of older people in order to provide them with the opportunity to remain at home. The financial relationship between assistive technology and packages of formal care was also explored. The costs of residential care and those of a number of packages containing differing quantities of assistive technology, formal care and informal care were compared. The analyses provide a strong financial case for substituting and/or supplementing formal care with assistive technology, even for individuals with quite disabling conditions. Although needs and hence the cost of provision rise with an increasing level of disability, the savings in care costs accrue quickly. The consideration of a variety of users with different needs and informal care provision, and occupying a very wide range of housing, leads to the conclusion that in comparison with traditional care packages, at worst, incorporating significant amounts of assistive technology into care packages is cost neutral, but that with careful specification of assistive technology major savings are feasible.

MPJ express: Towards thread safe Java HPC

MPJ Express is a thread-safe Java messaging library that provides a full implementation of the mpiJava 1.2 API specification. This specification defines a MPI-like bindings for the Java language. We have implemented two communication devices as part of our library, the first, called niodev is based on the Java New I/O package and the second, called mxdev is based on the Myrinet eXpress library MPJ Express comes with an experimental runtitne, which allows portable bootstrapping of Java Virtual Machines across a cluster or network of computers. In this paper we describe the implementation of MPJ Express. Also, we present a performance comparison against various other C and Java messaging systems. A beta version of MPJ Express was released in September 2005.

Perspex machine VIII: axioms of transreal arithmetic

Transreal arithmetic is a total arithmetic that contains real arithmetic, but which has no arithmetical exceptions. It allows the specification of the Universal Perspex Machine which unifies geometry with the Turing Machine. Here we axiomatise the algebraic structure of transreal arithmetic so that it provides a total arithmetic on any appropriate set of numbers. This opens up the possibility of specifying a version of floating-point arithmetic that does not have any arithmetical exceptions and in which every number is a first-class citizen. We find that literal numbers in the axioms are distinct. In other words, the axiomatisation does not require special axioms to force non-triviality. It follows that transreal arithmetic must be defined on a set of numbers that contains{-8,-1,0,1,8,&pphi;} as a proper subset. We note that the axioms have been shown to be consistent by machine proof.

Applying semiotic analysis to the design and modeling of distributed multimedia systems

Semiotics is the study of signs. Application of semiotics in information systems design is based on the notion that information systems are organizations within which agents deploy signs in the form of actions according to a set of norms. An analysis of the relationships among the agents, their actions and the norms would give a better specification of the system. Distributed multimedia systems (DMMS) could be viewed as a system consisted of many dynamic, self-controlled normative agents engaging in complex interaction and processing of multimedia information. This paper reports the work of applying the semiotic approach to the design and modeling of DMMS, with emphasis on using semantic analysis under the semiotic framework. A semantic model of DMMS describing various components and their ontological dependencies is presented, which then serves as a design model and implemented in a semantic database. Benefits of using the semantic database are discussed with reference to various design scenarios.

Determining information requirements for e-business Systems - from activity space to information space

The study of information requirements for e-business systems reveals that the level of detail, granularity, format of presentation, and a broad range of information types are required for the applications. The provision of relevant information affects how e-business systems can efficiently support the business goals and processes. This paper presents an approach for determining information requirements for e-business systems (DIRES) which will allow the user to describe the core business processes, whose specification maps onto a business activity space. It further aids a configuration of information requirements into an information space. A case study of a logistics company in China demonstrates the use of DIRES techniques and assesses the validity of the research.

Design of highly parallel architecture with Alpha and Handel

We propose a bridge between two important parallel programming paradigms: data parallelism and communicating sequential processes (CSP). Data parallel pipelined architectures obtained with the Alpha language can be embedded in a control intensive application expressed in CSP-based Handel formalism. The interface is formally defined from the semantics of the languages Alpha and Handel. This work will ease the design of compute intensive applications on FPGAs.

A compositional framework for hardware/software co-design

We describe a compositional framework, together with its supporting toolset, for hardware/software co-design. Our framework is an integration of a formal approach within a traditional design flow. The formal approach is based on Interval Temporal Logic and its executable subset, Tempura. Refinement is the key element in our framework because it will derive from a single formal specification of the system the software and hardware parts of the implementation, while preserving all properties of the system specification. During refinement simulation is used to choose the appropriate refinement rules, which are applied automatically in the HOL system. The framework is illustrated with two case studies. The work presented is part of a UK collaborative research project between the Software Technology Research Laboratory at the De Montfort University and the Oxford University Computing Laboratory.

Spectral design and verification of HIRDLS filters and antireflection coatings using an integrated system performance approach

The HIRDLS instrument contains 21 spectral channels spanning a wavelength range from 6 to 18mm. For each of these channels the spectral bandwidth and position are isolated by an interference bandpass filter at 301K placed at an intermediate focal plane of the instrument. A second filter cooled to 65K positioned at the same wavelength but designed with a wider bandwidth is placed directly in front of each cooled detector element to reduce stray radiation from internally reflected in-band signals, and to improve the out-of-band blocking. This paper describes the process of determining the spectral requirements for the two bandpass filters and the antireflection coatings used on the lenses and dewar window of the instrument. This process uses a system throughput performance approach taking the instrument spectral specification as a target. It takes into account the spectral characteristics of the transmissive optical materials, the relative spectral response of the detectors, thermal emission from the instrument, and the predicted atmospheric signal to determine the radiance profile for each channel. Using this design approach an optimal design for the filters can be achieved, minimising the number of layers to improve the in-band transmission and to aid manufacture. The use of this design method also permits the instrument spectral performance to be verified using the measured response from manufactured components. The spectral calculations for an example channel are discussed, together with the spreadsheet calculation method. All the contributions made by the spectrally active components to the resulting instrument channel throughput are identified and presented.