Sequential genome-wide association studies for monitoring adverse events in the clinical evaluation of new drugs

Pharmacovigilance, the monitoring of adverse events (AEs), is an integral part in the clinical evaluation of a new drug. Until recently, attempts to relate the incidence of AEs to putative causes have been restricted to the evaluation of simple demographic and environmental factors. The advent of large-scale genotyping, however, provides an opportunity to look for associations between AEs and genetic markers, such as single nucleotides polymorphisms (SNPs). It is envisaged that a very large number of SNPs, possibly over 500 000, will be used in pharmacovigilance in an attempt to identify any genetic difference between patients who have experienced an AE and those who have not. We propose a sequential genome-wide association test for analysing AEs as they arise, allowing evidence-based decision-making at the earliest opportunity. This gives us the capability of quickly establishing whether there is a group of patients at high-risk of an AE based upon their DNA. Our method provides a valid test which takes account of linkage disequilibrium and allows for the sequential nature of the procedure. The method is more powerful than using a correction, such as idák, that assumes that the tests are independent. Copyright © 2006 John Wiley & Sons, Ltd.

Novel high-resolution characterization of ancient DNA reveals C > U-type base modification events as the sole cause of post mortem miscoding lesions

Ancient DNA (aDNA) research has long depended on the power of PCR to amplify trace amounts of surviving genetic material from preserved specimens. While PCR permits specific loci to be targeted and amplified, in many ways it can be intrinsically unsuited to damaged and degraded aDNA templates. PCR amplification of aDNA can produce highly-skewed distributions with significant contributions from miscoding lesion damage and non-authentic sequence artefacts. As traditional PCR-based approaches have been unable to fully resolve the molecular nature of aDNA damage over many years, we have developed a novel single primer extension (SPEX)-based approach to generate more accurate sequence information. SPEX targets selected template strands at defined loci and can generate a quantifiable redundancy of coverage; providing new insights into the molecular nature of aDNA damage and fragmentation. SPEX sequence data reveals inherent limitations in both traditional and metagenomic PCR-based approaches to aDNA, which can make current damage analyses and correct genotyping of ancient specimens problematic. In contrast to previous aDNA studies, SPEX provides strong quantitative evidence that C U-type base modifications are the sole cause of authentic endogenous damage-derived miscoding lesions. This new approach could allow ancient specimens to be genotyped with unprecedented accuracy.

Lag-1 sparing in the attentional blink: benefits and costs of integrating two events into a single episode

When people monitor a visual stream of rapidly presented stimuli for two targets (T1 and T2), they often miss T2 if it falls into a time window of about half a second after T1 onset-the attentional blink. However, if T2 immediately follows T1, performance is often reported being as good as that at long lags-the so-called Lag-1 sparing effect. Two experiments investigated the mechanisms underlying this effect. Experiment 1 showed that, at Lag 1, requiring subjects to correctly report both identity and temporal order of targets produces relatively good performance on T2 but relatively bad performance on T1. Experiment 2 confirmed that subjects often confuse target order at short lags, especially if the two targets are equally easy to discriminate. Results suggest that, if two targets appear in close succession, they compete for attentional resources. If the two competitors are of unequal strength the stronger one is more likely to win and be reported at the expense of the other. If the two are equally strong, however, they will often be integrated into the same attentional episode and thus get both access to attentional resources. But this comes with a cost, as it eliminates information about the targets' temporal order.

The roles of perirhinal cortex, postrhinal cortex, and the fornix in memory for objects, contexts, and events in the rat

Investigation of the anatomical substructure of the medial temporal lobe has revealed a number of highly interconnected areas, which has led some to propose that the region operates as a unitary memory system. However, here we outline the results of a number of studies from our laboratories, which investigate the contributions of the rat's perirhinal cortex and postrhinal cortex to memory, concentrating particularly on their respective roles in memory for objects. By contrasting patterns of impairment and spared abilities on a number of related tasks, we suggest that perirhinal cortex and postrhinal cortex make distinctive contributions to learning and memory: for example, that postrhinal cortex is important in learning about within-scene position and context. We also provide evidence that despite the strong connectivity between these cortical regions and the hippocampus, the hippocampus, as evidenced by lesions of the fornix, has a distinct function of its own-combining information about objects, positions, and contexts.

A fuzzy multi-criteria decision approach for enhanced auto-tracking of seismic events

The main activity carried out by the geophysicist when interpreting seismic data, in terms of both importance and time spent is tracking (or picking) seismic events. in practice, this activity turns out to be rather challenging, particularly when the targeted event is interrupted by discontinuities such as geological faults or exhibits lateral changes in seismic character. In recent years, several automated schemes, known as auto-trackers, have been developed to assist the interpreter in this tedious and time-consuming task. The automatic tracking tool available in modem interpretation software packages often employs artificial neural networks (ANN's) to identify seismic picks belonging to target events through a pattern recognition process. The ability of ANNs to track horizons across discontinuities largely depends on how reliably data patterns characterise these horizons. While seismic attributes are commonly used to characterise amplitude peaks forming a seismic horizon, some researchers in the field claim that inherent seismic information is lost in the attribute extraction process and advocate instead the use of raw data (amplitude samples). This paper investigates the performance of ANNs using either characterisation methods, and demonstrates how the complementarity of both seismic attributes and raw data can be exploited in conjunction with other geological information in a fuzzy inference system (FIS) to achieve an enhanced auto-tracking performance.

Export of dissolved organic carbon from an upland peatland during storm events: implications for flux estimates

Most of the dissolved organic carbon (DOC) exported from catchments is transported during storm events. Accurate assessments of DOC fluxes are essential to understand long-term trends in the transport of DOC from terrestrial to aquatic systems, and also the loss of carbon from peatlands to determine changes in the source/sink status of peatland carbon stores. However, many long-term monitoring programmes collect water samples at a frequency (e.g. weekly/monthly) less than the time period of a typical storm event (typically <1–2 days). As widespread observations in catchments dominated by organo-mineral soils have shown that both concentration and flux of DOC increases during storm events, lower frequency monitoring could result in substantial underestimation of DOC flux as the most dynamic periods of transport are missed. However, our intensive monitoring study in a UK upland peatland catchment showed a contrasting response to these previous studies. Our results showed that (i) DOC concentrations decreased during autumn storm events and showed a poor relationship with flow during other seasons; and that (ii) this decrease in concentrations during autumn storms caused DOC flux estimates based on weekly monitoring data to be over-estimated, rather than under-estimated, because of over rather than under estimation of the flow-weighted mean concentration used in flux calculations. However, as DOC flux is ultimately controlled by discharge volume, and therefore rainfall, and the magnitude of change in discharge was greater than the magnitude of decline in concentrations, DOC flux increased during individual storm events. The implications for long-term DOC trends are therefore contradictory, as increased rainfall could increase flux but cause an overall decrease in DOC concentrations from peatland streams. Care needs to be taken when interpreting long-term trends in DOC flux rather than concentration; as flux is calculated from discharge estimates, and discharge is controlled by rainfall, DOC flux and rainfall/discharge will always be well correlated.

Transfer of conceptualisation patterns in bilinguals: the construal of motion events in Turkish and German

We test Slobin's (2003) Thinking-for-Speaking hypothesis on data from different groups of Turkish-German bilinguals, those living in Germany and those who have returned to Germany.

A survey of gradual solar energetic particle events

We develop a database of 110 gradual solar energetic particle (SEP) events, over the period 1967–2006, providing estimates of event onset, duration, fluence, and peak flux for protons of energy E > 60 MeV. The database is established mainly from the energetic proton flux data distributed in the OMNI 2 data set; however, we also utilize the McMurdo neutron monitor and the energetic proton flux from GOES missions. To aid the development of the gradual SEP database, we establish a method with which the homogeneity of the energetic proton flux record is improved. A comparison between other SEP databases and the database developed here is presented which discusses the different algorithms used to define an event. Furthermore, we investigate the variation of gradual SEP occurrence and fluence with solar cycle phase, sunspot number (SSN), and interplanetary magnetic field intensity (Bmag) over solar cycles 20–23. We find that the occurrence and fluence of SEP events vary with the solar cycle phase. Correspondingly, we find a positive correlation between SEP occurrence and solar activity as determined by SSN and Bmag, while the mean fluence in individual events decreases with the same measures of solar activity. Therefore, although the number of events decreases when solar activity is low, the events that do occur at such times have higher fluence. Thus, large events such as the “Carrington flare” may be more likely at lower levels of solar activity. These results are discussed in the context of other similar investigations.

Changes in race-specific virulence in pseudomonas syringae pv. phaseolicola are Associated with a chimeric transposable element and rare deletion events in a plasmid-borne pathogenicity island

Virulence for bean and soybean is determined by effector genes in a plasmid-borne pathogenicity island (PAI) in race 7 strain 1449B of Pseudomonas syringae pv. phaseolicola. One of the effector genes, avrPphF, confers either pathogenicity, virulence, or avirulence depending on the plant host and is absent from races 2, 3, 4, 6, and 8 of this pathogen. Analysis of cosmid clones and comparison of DNA sequences showed that the absence of avrPphF from strain 1448A is due to deletion of a continuous 9.5-kb fragment. The remainder of the PAI is well conserved in strains 1448A and 1449B. The left junction of the deleted region consists of a chimeric transposable element generated from the fusion of homologs of IS1492 from Pseudomonas putida and IS1090 from Ralstonia eutropha. The borders of the deletion were conserved in 66 P. syringae pv. phaseolicola strains isolated in different countries and representing the five races lacking avrPphF. However, six strains isolated in Spain had a 10.5-kb deletion that extended 1 kb further from the right junction. The perfect conservation of the 28-nucleotide right repeat of the IS1090 homolog in the two deletion types and in the other 47 insertions of the IS1090 homolog in the 1448A genome strongly suggests that the avrPphF deletions were mediated by the activity of the chimeric mobile element. Our data strongly support a clonal origin for the races of P. syringae pv. phaseolicola lacking avrPphF.

Secondary uranium mineralization in southern Finland and its relationship to recent glacial events

Uranium series dating has been carried out on secondary uranyl silicate minerals formed during sub-glacial and post-glacial weathering of Proterozoic uraninite ores in south west Finland. The samples were obtained from two sites adjacent to the Salpauselkä III ice marginal formation and cover a range of depths, from the surface to more than 60 m. Measured ages fall into three distinct groups, 70–100 ka, 28–36 ka and < 2500 yr. The youngest set is associated with surface exposures and the crystals display clear evidence of re-working. The most likely trigger for uranium release at depths below the surface weathering zone is intrusion of oxidising glacial melt water. The latter is often characterised by very high discharge rates along channels, which close once the overpressure generated at the ice margin is released. There is excellent correspondence between the two Finnish sites and published data for similar deposits over a large area of southern and central Sweden. None of the seventy samples analysed gave a U–Th age between 40 and 70 ka; a second hiatus is apparent at 20 ka, coinciding with the Last Glacial Maximum. Thus, the process responsible for uranyl silicate formation was halted for significant periods, owing to a change in geochemical conditions or the hydrogeological regime. These data support the presence of interstadial conditions during the Early and Middle Weichselian since in the absence of major climatic perturbations the uranium phases at depth are stable. When viewed in conjunction with proxy data from mammoth remains it would appear that the region was ice-free prior to the Last Glacial Maximum.

Implications of non-cylindrical flux ropes for magnetic cloud reconstruction techniques and the interpretation of double flux rope events

Magnetic clouds (MCs) are a subset of interplanetary coronal mass ejections (ICMEs) which exhibit signatures consistent with a magnetic flux rope structure. Techniques for reconstructing flux rope orientation from single-point in situ observations typically assume the flux rope is locally cylindrical, e.g., minimum variance analysis (MVA) and force-free flux rope (FFFR) fitting. In this study, we outline a non-cylindrical magnetic flux rope model, in which the flux rope radius and axial curvature can both vary along the length of the axis. This model is not necessarily intended to represent the global structure of MCs, but it can be used to quantify the error in MC reconstruction resulting from the cylindrical approximation. When the local flux rope axis is approximately perpendicular to the heliocentric radial direction, which is also the effective spacecraft trajectory through a magnetic cloud, the error in using cylindrical reconstruction methods is relatively small (≈ 10∘). However, as the local axis orientation becomes increasingly aligned with the radial direction, the spacecraft trajectory may pass close to the axis at two separate locations. This results in a magnetic field time series which deviates significantly from encounters with a force-free flux rope, and consequently the error in the axis orientation derived from cylindrical reconstructions can be as much as 90∘. Such two-axis encounters can result in an apparent ‘double flux rope’ signature in the magnetic field time series, sometimes observed in spacecraft data. Analysing each axis encounter independently produces reasonably accurate axis orientations with MVA, but larger errors with FFFR fitting.