Missing channels in two-colour microarray experiments: combining single-channel and two-channel data.

BACKGROUND: There are mechanisms, notably ozone degradation, that can damage a single channel of two-channel microarray experiments. Resulting analyses therefore often choose between the unacceptable inclusion of poor quality data or the unpalatable exclusion of some (possibly a lot of) good quality data along with the bad. Two such approaches would be a single channel analysis using some of the data from all of the arrays, and an analysis of all of the data, but only from unaffected arrays. In this paper we examine a 'combined' approach to the analysis of such affected experiments that uses all of the unaffected data. RESULTS: A simulation experiment shows that while a single channel analysis performs relatively well when the majority of arrays are affected, and excluding affected arrays performs relatively well when few arrays are affected (as would be expected in both cases), the combined approach out-performs both. There are benefits to actively estimating the key-parameter of the approach, but whether these compensate for the increased computational cost and complexity over just setting that parameter to take a fixed value is not clear. Inclusion of ozone-affected data results in poor performance, with a clear spatial effect in the damage being apparent. CONCLUSION: There is no need to exclude unaffected data in order to remove those which are damaged. The combined approach discussed here is shown to out-perform more usual approaches, although it seems that if the damage is limited to very few arrays, or extends to very nearly all, then the benefits will be limited. In other circumstances though, large improvements in performance can be achieved by adopting such an approach.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

The epidemiology of reoperations for orthopaedic trauma.

Introduction: The Royal College of Surgeons of England (RCS) has issued guidance regarding the use of reoperation rates in the revalidation of UK-based orthopaedic surgeons. Currently, little has been published concerning acceptable rates of reoperation following primary surgical management of orthopaedic trauma, particularly with reference to revalidation. / Methods: A retrospective review was conducted of patients undergoing clearly defined reoperations following primary surgical management of trauma between 1 January 2010 and 31 December 2011. A full case note review was undertaken to establish the demographics, clinical course and context of reoperation. A review of the imaging was performed to establish whether the procedure performed was in line with accepted trauma practice and whether the technical execution was acceptable. / Results: A total of 3,688 patients underwent primary procedures within the time period studied while 70 (1.90%, 99% CI: 1.39–2.55) required an unplanned reoperation. Thirty-nine (56%) of these patients were male. The mean age of patients was 56 years (range: 18–98 years) and there was a median time to reoperation of 50 days (IQR: 13–154 days). Potentially avoidable reoperations occurred in 41 patients (58.6%, 99% CI: 43.2–72.6). This was largely due to technical errors (40 patients, 57.1%, 99% CI: 41.8–71.3), representing 1.11% (99% CI: 0.73–1.64) of the total trauma workload. Within RCS guidelines, 28-day reoperation rates for hip, wrist and ankle fractures were 1.4% (99% CI: 0.5–3.3), 3.5% (99% CI: 0.8%–12.1) and 1.86% (99% CI: 0.4–6.6) respectively. / Conclusions: We present novel work that has established baseline reoperation rates for index procedures required for revalidation of orthopaedic surgeons

The Metabochip, a Custom Genotyping Array for Genetic Studies of Metabolic, Cardiovascular, and Anthropometric Traits

PMCID: PMC3410907This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Philosophy and Science in Leibniz

This paper explores the question of Leibniz’s contribution to the rise of modern ‘science’. To be sure, it is now generally agreed that the modern category of ‘science’ did not exist in the early modern period. At the same time, this period witnessed a very important stage in the process from which modern science eventually emerged. My discussion will be aimed at uncovering the new enterprise, and the new distinctions which were taking shape in the early modern period under the banner of the old Aristotelian terminology. I will argue that Leibniz begins to theorize a distinction between physics and metaphysics that tracks our distinction between the autonomous enterprise of science in its modern meaning, and the enterprise of philosophy. I will try to show that, for Leibniz, physics proper is the study of natural phenomena in mathematical and mechanical terms without recourse for its explanations to metaphysical notions. This autonomy, however, does not imply for Leibniz that physics can say on its own all that there is to be said about the natural world. Quite the opposite. Leibniz inherits from the Aristotelian tradition the view that physics needs metaphysical roots or a metaphysical grounding. For Leibniz, what is ultimately real is reached by metaphysics, not by physics. This is, in my view, Leibniz’s chief insight: the new mathematical physics is an autonomous enterprise which offers its own kind of explanations but does not exhaust what can (and should) be said about the natural world

Differential expression of selected histone modifier genes in human solid cancers.

BACKGROUND: Post-translational modification of histones resulting in chromatin remodelling plays a key role in the regulation of gene expression. Here we report characteristic patterns of expression of 12 members of 3 classes of chromatin modifier genes in 6 different cancer types: histone acetyltransferases (HATs)- EP300, CREBBP, and PCAF; histone deacetylases (HDACs)- HDAC1, HDAC2, HDAC4, HDAC5, HDAC7A, and SIRT1; and histone methyltransferases (HMTs)- SUV39H1and SUV39H2. Expression of each gene in 225 samples (135 primary tumours, 47 cancer cell lines, and 43 normal tissues) was analysedby QRT-PCR, normalized with 8 housekeeping genes, and given as a ratio by comparison with a universal reference RNA. RESULTS: This involved a total of 13,000 PCR assays allowing for rigorous analysis by fitting a linear regression model to the data. Mutation analysis of HDAC1, HDAC2, SUV39H1, and SUV39H2 revealed only two out of 181 cancer samples (both cell lines) with significant coding-sequence alterations. Supervised analysis and Independent Component Analysis showed that expression of many of these genes was able to discriminate tumour samples from their normal counterparts. Clustering based on the normalized expression ratios of the 12 genes also showed that most samples were grouped according to tissue type. Using a linear discriminant classifier and internal cross-validation revealed that with as few as 5 of the 12 genes, SIRT1, CREBBP, HDAC7A, HDAC5 and PCAF, most samples were correctly assigned. CONCLUSION: The expression patterns of HATs, HDACs, and HMTs suggest these genes are important in neoplastic transformation and have characteristic patterns of expression depending on tissue of origin, with implications for potential clinical application.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial

IMPORTANCE: Secretory phospholipase A2(sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown. OBJECTIVE: To determine the effects of sPLA2inhibition with varespladib on cardiovascular outcomes. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America of 5145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012). INTERVENTIONS: Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies. MAIN OUTCOMES AND MEASURES: The primary efficacy measurewas a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated. RESULTS: At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95%CI, 0.97-1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95%CI, 1.16-2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04). CONCLUSIONS AND RELEVANCE: In patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01130246. Copyright 2014 American Medical Association. All rights reserved

Finality revived: powers and intentionality

Proponents of physical intentionality argue that the classic hallmarks of intentionality highlighted by Brentano are also found in purely physical powers. Critics worry that this idea is metaphysically obscure at best, and at worst leads to panpsychism or animism. I examine the debate in detail, finding both confusion and illumination in the physical intentionalist thesis. Analysing a number of the canonical features of intentionality, I show that they all point to one overarching phenomenon of which both the mental and the physical are kinds, namely finality. This is the finality of ‘final causes’, the long-discarded idea of universal action for an end to which recent proponents of physical intentionality are in fact pointing whether or not they realise it. I explain finality in terms of the concept of specific indifference, arguing that in the case of the mental, specific indifference is realised by the process of abstraction, which has no correlate in the case of physical powers. This analysis, I conclude, reveals both the strength and weakness of rational creatures such as us, as well as demystifying (albeit only partly) the way in which powers work