Balancing the robustness and predictive performance of biomarkers.

Recent studies have highlighted the importance of assessing the robustness of putative biomarkers identified from experimental data. This has given rise to the concept of stable biomarkers, which are ones that are consistently identified regardless of small perturbations to the data. Since stability is not by itself a useful objective, we present a number of strategies that combine assessments of stability and predictive performance in order to identify biomarkers that are both robust and diagnostically useful. Moreover, by wrapping these strategies around logistic regression classifiers regularized by the elastic net penalty, we are able to assess the effects of correlations between biomarkers upon their perceived stability. We use a synthetic example to illustrate the properties of our proposed strategies. In this example, we find that: (i) assessments of stability can help to reduce the number of false-positive biomarkers, although potentially at the cost of missing some true positives; (ii) combining assessments of stability with assessments of predictive performance can improve the true positive rate; and (iii) correlations between biomarkers can have adverse effects on their stability and hence must be carefully taken into account when undertaking biomarker discovery. We then apply our strategies in a proteomics context to identify a number of robust candidate biomarkers for the human disease HTLV1-associated myelopathy/tropical spastic paraparesis (HAM/TSP)

Genes Suggest Ancestral Colour Polymorphisms Are Shared across Morphologically Cryptic Species in Arctic Bumblebees

email Suzanne orcd idCopyright: © 2015 Williams et al. This 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

Non-strategic ignorance: Considering the potential for a paradigm shift in evidence-based mental health

Randomised controlled trials form a central building block within the prevailing evidence-based mental health paradigm. Both methodology and paradigm have been widely problematised since their emergence in the mid-late twentieth century. We draw on the concept of ‘strategic ignorance’ to understand why the paradigm still prevails. We present focus group data gathered from 37 participants (service users, public, carers, general practitioners, commissioners) concerning the way they made sense of a randomised controlled trial of psychotherapy for treatment-resistant depression. Thematic analysis of the findings revealed an overall critique of randomised controlled trial methods which we refer to as ‘non-strategic ignorance’. Specifically, participants problematised the construct of depression, unseating the premise of the randomised controlled trial; they were sceptical about the purpose and highlighted its failure to show how therapy works or who might benefit; the randomised controlled trial was seen as inadequate for informing decisions about how to select a therapy. Participants assumed the treatment would be cost-effective given the client group and nature of the therapy, irrespective of any randomised controlled trial findings. Each area of lay (‘non-strategic’) critique has an analogous form within the methodological expert domain. We argue that ‘expert’ critiques have generally failed to have paradigmatic impact because they represent strategic ignorance. Yet parallel non-strategic critiques have common sense appeal, highlighting the potential power of lay voices. The discussion considers whether the evidence-based mental health paradigm is faced with epistemological problems of such complexity that the conditions exist for a new paradigm in which service user views are central and randomised controlled trials peripheral

Modified differentials and basic cohomology for Riemannian foliations

We define a new version of the exterior derivative on the basic forms of a Riemannian foliation to obtain a new form of basic cohomology that satisfies Poincar\'e duality in the transversally orientable case. We use this twisted basic cohomology to show relationships between curvature, tautness, and vanishing of the basic Euler characteristic and basic signature.Comment: 20 pages, references added, minor corrections mad

Observational Constraints on the Angular and Spectral Distributions of Photons in Gamma-Ray Burst Sources

The typical spectra of gamma-ray bursts (GRBs) are discussed in the context of the compactness problem for GRB sources and how it is resolved in the popular fireball model. In particular, observational (model-independent) constraints on the collimation of the gamma-rays and the dependence of the collimation angle on the photon energy are considered. The fact that the threshold for the creation of $e^{-}e^{+}$ pairs depends on the angle between the momenta of the annihilating photons in the GRB source provides an alternative solution to the compactness problem. A new approach to explaining GRBs, taking into account the angular dependence for pair creation, is proposed, and the main features of a scenario describing a GRB source with a total (photon) energy smaller or of the order of $10^{49}$ erg are laid out. Thus, we are dealing with an alternative to an ultra-relativistic fireball, if it turns out (as follows from observations) that all "long" GRBs are associated with normal (not peculiar) core-collapse supernovae. The effects of radiation pressure and the formation of jets as a consequence of even a small amount of anisotropy in the total radiation field in a (compact) GRB source are examined in this alternative model. Possible energy release mechanisms acting in regions smaller or of the order of $10^{8}$ cm in size (a compact model for a GRB) are discussed. New observational evidence for such compact energy release in the burst source is considered.Comment: 15 pages, no figures, no table

Chronic non-specific low back pain - sub-groups or a single mechanism?

Copyright 2008 Wand and O'Connell; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background: Low back pain is a substantial health problem and has subsequently attracted a considerable amount of research. Clinical trials evaluating the efficacy of a variety of interventions for chronic non-specific low back pain indicate limited effectiveness for most commonly applied interventions and approaches. Discussion: Many clinicians challenge the results of clinical trials as they feel that this lack of effectiveness is at odds with their clinical experience of managing patients with back pain. A common explanation for this discrepancy is the perceived heterogeneity of patients with chronic non-specific low back pain. It is felt that the effects of treatment may be diluted by the application of a single intervention to a complex, heterogeneous group with diverse treatment needs. This argument presupposes that current treatment is effective when applied to the correct patient. An alternative perspective is that the clinical trials are correct and current treatments have limited efficacy. Preoccupation with sub-grouping may stifle engagement with this view and it is important that the sub-grouping paradigm is closely examined. This paper argues that there are numerous problems with the sub-grouping approach and that it may not be an important reason for the disappointing results of clinical trials. We propose instead that current treatment may be ineffective because it has been misdirected. Recent evidence that demonstrates changes within the brain in chronic low back pain sufferers raises the possibility that persistent back pain may be a problem of cortical reorganisation and degeneration. This perspective offers interesting insights into the chronic low back pain experience and suggests alternative models of intervention. Summary: The disappointing results of clinical research are commonly explained by the failure of researchers to adequately attend to sub-grouping of the chronic non-specific low back pain population. Alternatively, current approaches may be ineffective and clinicians and researchers may need to radically rethink the nature of the problem and how it should best be managed

Deriving a mutation index of carcinogenicity using protein structure and protein interfaces

With the advent of Next Generation Sequencing the identification of mutations in the genomes of healthy and diseased tissues has become commonplace. While much progress has been made to elucidate the aetiology of disease processes in cancer, the contributions to disease that many individual mutations make remain to be characterised and their downstream consequences on cancer phenotypes remain to be understood. Missense mutations commonly occur in cancers and their consequences remain challenging to predict. However, this knowledge is becoming more vital, for both assessing disease progression and for stratifying drug treatment regimes. Coupled with structural data, comprehensive genomic databases of mutations such as the 1000 Genomes project and COSMIC give an opportunity to investigate general principles of how cancer mutations disrupt proteins and their interactions at the molecular and network level. We describe a comprehensive comparison of cancer and neutral missense mutations; by combining features derived from structural and interface properties we have developed a carcinogenicity predictor, InCa (Index of Carcinogenicity). Upon comparison with other methods, we observe that InCa can predict mutations that might not be detected by other methods. We also discuss general limitations shared by all predictors that attempt to predict driver mutations and discuss how this could impact high-throughput predictions. A web interface to a server implementation is publicly available at http://inca.icr.ac.uk/

Relativistic Calculation of the Meson Spectrum: a Fully Covariant Treatment Versus Standard Treatments

A large number of treatments of the meson spectrum have been tried that consider mesons as quark - anti quark bound states. Recently, we used relativistic quantum "constraint" mechanics to introduce a fully covariant treatment defined by two coupled Dirac equations. For field-theoretic interactions, this procedure functions as a "quantum mechanical transform of Bethe-Salpeter equation". Here, we test its spectral fits against those provided by an assortment of models: Wisconsin model, Iowa State model, Brayshaw model, and the popular semi-relativistic treatment of Godfrey and Isgur. We find that the fit provided by the two-body Dirac model for the entire meson spectrum competes with the best fits to partial spectra provided by the others and does so with the smallest number of interaction functions without additional cutoff parameters necessary to make other approaches numerically tractable. We discuss the distinguishing features of our model that may account for the relative overall success of its fits. Note especially that in our approach for QCD, the resulting pion mass and associated Goldstone behavior depend sensitively on the preservation of relativistic couplings that are crucial for its success when solved nonperturbatively for the analogous two-body bound-states of QED.Comment: 75 pages, 6 figures, revised content

How environmental managers perceive and approach the issue of invasive species: the case of Japanese knotweed s.l. (Rhône River, France)

We would like to thank Springer for publishing our article. The final publication is available at http://link.springer.com/article/10.1007%2Fs10530-015-0969-1International audienceStudying the perceptions of stakeholders or interested parties is a good way to better understand behaviours and decisions. This is especially true for the management of invasive species such as Japanese knotweed s.l. This plant has spread widely in the Rhône basin, where significant financial resources have been devoted to its management. However, no control technique is recognized as being particularly effective. Many uncertainties remain and many documents have been produced by environmental managers to disseminate current knowledge about the plant and its management. This article aims at characterizing the perceptions that environmental managers have of Japanese knotweed s.l. A discourse analysis was conducted on the printed documentation produced about Japanese knotweed s.l. by environmental managers working along the Rhône River (France). The corpus was both qualitatively and quantitatively analysed. The results indicated a diversity of perceptions depending on the type of environmental managers involved, as well as the geographicalareas and scales on which they acted. Whereas some focused on general knowledge relating to the origins and strategies of colonization, others emphasized the diversity and efficacy of the prospective eradication techniques. There is a real interest in implementing targeted actions to meet local issues. To do so, however, these issues must be better defined. This is a challenging task, as it must involve all types of stakeholders