Sequentially testing for a gene-drug interaction in a genomewide analysis

Assaying a large number of genetic markers from patients in clinical trials is now possible in order to tailor drugs with respect to efficacy. The statistical methodology for analysing such massive data sets is challenging. The most popular type of statistical analysis is to use a univariate test for each genetic marker, once all the data from a clinical study have been collected. This paper presents a sequential method for conducting an omnibus test for detecting gene-drug interactions across the genome, thus allowing informed decisions at the earliest opportunity and overcoming the multiple testing problems from conducting many univariate tests. We first propose an omnibus test for a fixed sample size. This test is based on combining F-statistics that test for an interaction between treatment and the individual single nucleotide polymorphism (SNP). As SNPs tend to be correlated, we use permutations to calculate a global p-value. We extend our omnibus test to the sequential case. In order to control the type I error rate, we propose a sequential method that uses permutations to obtain the stopping boundaries. The results of a simulation study show that the sequential permutation method is more powerful than alternative sequential methods that control the type I error rate, such as the inverse-normal method. The proposed method is flexible as we do not need to assume a mode of inheritance and can also adjust for confounding factors. An application to real clinical data illustrates that the method is computationally feasible for a large number of SNPs. Copyright (c) 2007 John Wiley & Sons, Ltd.

Sequential methods for pharmacogenetic studies

A study or experiment can be described as sequential if its design includes one or more interim analyses at which it is possible to stop the study, having reached a definitive conclusion concerning the primary question of interest. The potential of the sequential study to terminate earlier than the equivalent fixed sample size study means that, typically, there are ethical and economic advantages to be gained from using a sequential design. These advantages have secured a place for the methodology in the conduct of many clinical trials of novel therapies. Recently, there has been increasing interest in pharmacogenetics: the study of how DNA variation in the human genome affects the safety and efficacy of drugs. The potential for using sequential methodology in pharmacogenetic studies is considered and the conduct of candidate gene association studies, family-based designs and genome-wide association studies within the sequential setting is explored. The objective is to provide a unified framework for the conduct of these types of studies as sequential designs and hence allow experimenters to consider using sequential methodology in their future pharmacogenetic studies.

Are power calculations useful? A multicentre neuroimaging study

There are now many reports of imaging experiments with small cohorts of typical participants that precede large-scale, often multicentre studies of psychiatric and neurological disorders. Data from these calibration experiments are sufficient to make estimates of statistical power and predictions of sample size and minimum observable effect sizes. In this technical note, we suggest how previously reported voxel-based power calculations can support decision making in the design, execution and analysis of cross-sectional multicentre imaging studies. The choice of MRI acquisition sequence, distribution of recruitment across acquisition centres, and changes to the registration method applied during data analysis are considered as examples. The consequences of modification are explored in quantitative terms by assessing the impact on sample size for a fixed effect size and detectable effect size for a fixed sample size. The calibration experiment dataset used for illustration was a precursor to the now complete Medical Research Council Autism Imaging Multicentre Study (MRC-AIMS). Validation of the voxel-based power calculations is made by comparing the predicted values from the calibration experiment with those observed in MRC-AIMS. The effect of non-linear mappings during image registration to a standard stereotactic space on the prediction is explored with reference to the amount of local deformation. In summary, power calculations offer a validated, quantitative means of making informed choices on important factors that influence the outcome of studies that consume significant resources.

Cross-sector surveys assessing perceptions of key stakeholders towards barriers, concerns and facilitators to the appropriate use of adaptive designs in confirmatory trials

Background Appropriately conducted adaptive designs (ADs) offer many potential advantages over conventional trials. They make better use of accruing data, potentially saving time, trial participants, and limited resources compared to conventional, fixed sample size designs. However, one can argue that ADs are not implemented as often as they should be, particularly in publicly funded confirmatory trials. This study explored barriers, concerns, and potential facilitators to the appropriate use of ADs in confirmatory trials among key stakeholders. Methods We conducted three cross-sectional, online parallel surveys between November 2014 and January 2015. The surveys were based upon findings drawn from in-depth interviews of key research stakeholders, predominantly in the UK, and targeted Clinical Trials Units (CTUs), public funders, and private sector organisations. Response rates were as follows: 30(55 %) UK CTUs, 17(68 %) private sector, and 86(41 %) public funders. A Rating Scale Model was used to rank barriers and concerns in order of perceived importance for prioritisation. Results Top-ranked barriers included the lack of bridge funding accessible to UK CTUs to support the design of ADs, limited practical implementation knowledge, preference for traditional mainstream designs, difficulties in marketing ADs to key stakeholders, time constraints to support ADs relative to competing priorities, lack of applied training, and insufficient access to case studies of undertaken ADs to facilitate practical learning and successful implementation. Associated practical complexities and inadequate data management infrastructure to support ADs were reported as more pronounced in the private sector. For funders of public research, the inadequate description of the rationale, scope, and decision-making criteria to guide the planned AD in grant proposals by researchers were all viewed as major obstacles. Conclusions There are still persistent and important perceptions of individual and organisational obstacles hampering the use of ADs in confirmatory trials research. Stakeholder perceptions about barriers are largely consistent across sectors, with a few exceptions that reflect differences in organisations’ funding structures, experiences and characterisation of study interventions. Most barriers appear connected to a lack of practical implementation knowledge and applied training, and limited access to case studies to facilitate practical learning. Keywords: Adaptive designs; flexible designs; barriers; surveys; confirmatory trials; Phase 3; clinical trials; early stopping; interim analyses

Exploring block construction and mental imagery: evidence of atypical orientation discrimination in Williams syndrome

The visuospatial perceptual abilities of individuals with Williams syndrome (WS) were investigated in two experiments. Experiment I measured the ability of participants to discriminate between oblique and between nonoblique orientations. Individuals with WS showed a smaller effect of obliqueness in response time, when compared to controls matched for nonverbal mental age. Experiment 2 investigated the possibility that this deviant pattern of orientation discrimination accounts for the poor ability to perform mental rotation in WS (Farran, Jarrold, & Gathercole, 2001). A size transformation task was employed, which shares the image transformation requirements of mental rotation, but not the orientation discrimination demands. Individuals with WS performed at the same level as controls. The results suggest a deviance at the perceptual level in WS, in processing orientation, which fractionates from the ability to mentally transform images.

PIC based detection for distributed space-time block coding under imperfect synchronisation

A parallel interference cancellation (PIC) detection scheme is proposed to suppress the impact of imperfect synchronisation. By treating as interference the extra components in the received signal caused by timing misalignment, the PIC detector not only offers much improved performance but also retains a low structural and computational complexity.

Distributed space-time block coding with incremental relay: performance improvement under imperfect synchronisation

This paper addresses the impact of imperfect synchronisation on D-STBC when combined with incremental relay. To suppress such an impact, a novel detection scheme is proposed, which retains the two key features of the STBC principle: simplicity (i.e. linear computational complexity), and optimality (i.e. maximum likelihood). These two features make the new detector very suitable for low power wireless networks (e.g. sensor networks).

A simple optimum detector for distributed space-time block coding under imperfect synchronisation

Most research on D-STBC has assumed that cooperative relay nodes are perfectly synchronised. Since such an assumption is difficult to achieve in many practical systems, this paper proposes a simple yet optimum detector for the case of two relay nodes, which proves to be much more robust against timing misalignment than the conventional STBC detector.

Distributed space-time block coding for 3 and 4 relay nodes: Imperfect synchronisation and a solution

Most research on distributed space time block coding (STBC) has so far focused on the case of 2 relay nodes and assumed that the relay nodes are perfectly synchronised at the symbol level. By applying STBC to 3-or 4-relay node systems, this paper shows that imperfect synchronisation causes significant performance degradation to the conventional detector. To this end, we propose a new STBC detection solution based on the principle of parallel interference cancellation (PIC). The PIC detector is moderate in computational complexity but is very effective in suppressing the impact of imperfect synchronisation.

A block coprocessor for user data rate improvements to GPRS coding scheme 4

The general packet radio service (GPRS) has been developed to allow packet data to be transported efficiently over an existing circuit-switched radio network, such as GSM. The main application of GPRS are in transporting Internet protocol (IP) datagrams from web servers (for telemetry or for mobile Internet browsers). Four GPRS baseband coding schemes are defined to offer a trade-off in requested data rates versus propagation channel conditions. However, data rates in the order of > 100 kbits/s are only achievable if the simplest coding scheme is used (CS-4) which offers little error detection and correction (EDC) (requiring excellent SNR) and the receiver hardware is capable of full duplex which is not currently available in the consumer market. A simple EDC scheme to improve the GPRS block error rate (BLER) performance is presented, particularly for CS-4, however gains in other coding schemes are seen. For every GPRS radio block that is corrected by the EDC scheme, the block does not need to be retransmitted releasing bandwidth in the channel and improving the user's application data rate. As GPRS requires intensive processing in the baseband, a viable field programmable gate array (FPGA) solution is presented in this paper.

PIC detector for distributed space-time block coding under imperfect synchronisation

A parallel interference cancellation (PIC) detection scheme is proposed to suppress the impact of imperfect synchronisation. By treating as interference the extra components in the received signal caused by timing misalignment, the PIC detector not only offers much improved performance but also retains a low structural and computational complexity.

Near-optimum detection for distributed space-time block coding under imperfect synchronization

Significant performance gain can potentially be achieved by employing distributed space-time block coding (D-STBC) in ad hoc or mesh networks. So far, however, most research on D-STBC has assumed that cooperative relay nodes are perfectly synchronized. Considering the difficulty in meeting such an assumption in many practical systems, this paper proposes a simple and near-optimum detection scheme for the case of two relay nodes, which proves to be able to handle far greater timing misalignment than the conventional STBC detector.

Signal detection for distributed space-time block coding: 4 relay nodes under quasi-synchronisation

Most research on Distributed Space-Time Block Coding (D-STBC) has so far focused on the case of 2 relay nodes and assumed that the relay nodes are perfectly synchronised at the symbol level. This paper applies STBC to 4-relaynode systems under quasi-synchronisation and derives a new detector based on parallel interference cancellation, which proves to be very effective in suppressing the impact of imperfect synchronisation.

Signal detection for orthogonal space-time block coding over time-selective fading channels: the H(i) systems

One major assumption in all orthogonal space-time block coding (O-STBC) schemes is that the channel remains static over the length of the code word. However, time-selective fading channels do exist, and in such case conventional O-STBC detectors can suffer from a large error floor in the high signal-to-noise ratio (SNR) cases. As a sequel to the authors' previous papers on this subject, this paper aims to eliminate the error floor of the H(i)-coded O-STBC system (i = 3 and 4) by employing the techniques of: 1) zero forcing (ZF) and 2) parallel interference cancellation (PIC). It is. shown that for an H(i)-coded system the PIC is a much better choice than the ZF in terms of both performance and computational complexity. Compared with the, conventional H(i) detector, the PIC detector incurs a moderately higher computational complexity, but this can well be justified by the enormous improvement.