Sample size and statistical power considerations in high-dimensionality data settings: a comparative study of classification algorithms

Background: Data generated using ‘omics’ technologies are characterized by high dimensionality, where the number of features measured per subject vastly exceeds the number of subjects in the study. In this paper, we consider issues relevant in the design of biomedical studies in which the goal is the discovery of a subset of features and an associated algorithm that can predict a binary outcome, such as disease status. We compare the performance of four commonly used classifiers (K-Nearest Neighbors, Prediction Analysis for Microarrays, Random Forests and Support Vector Machines) in high-dimensionality data settings. We evaluate the effects of varying levels of signal-to-noise ratio in the dataset, imbalance in class distribution and choice of metric for quantifying performance of the classifier. To guide study design, we present a summary of the key characteristics of ‘omics’ data profiled in several human or animal model experiments utilizing high-content mass spectrometry and multiplexed immunoassay based techniques. Results: The analysis of data from seven ‘omics’ studies revealed that the average magnitude of effect size observed in human studies was markedly lower when compared to that in animal studies. The data measured in human studies were characterized by higher biological variation and the presence of outliers. The results from simulation studies indicated that the classifier Prediction Analysis for Microarrays (PAM) had the highest power when the class conditional feature distributions were Gaussian and outcome distributions were balanced. Random Forests was optimal when feature distributions were skewed and when class distributions were unbalanced. We provide a free open-source R statistical software library (MVpower) that implements the simulation strategy proposed in this paper. Conclusion: No single classifier had optimal performance under all settings. Simulation studies provide useful guidance for the design of biomedical studies involving high-dimensionality data

Student nurse selection and predictability of academic success : the Multiple Mini Interview project

BACKGROUND: With recent reports of public enquiries into failure to care, universities are under pressure to ensure that candidates selected for undergraduate nursing programmes demonstrate academic potential as well as characteristics and values such as compassion, empathy and integrity. The Multiple Mini Interview (MMI) was used in one university as a way of ensuring that candidates had the appropriate numeracy and literacy skills as well as a range of communication, empathy, decision-making and problem-solving skills as well as ethical insights and integrity, initiative and team-work. OBJECTIVES: To ascertain whether there is evidence of bias in MMIs (gender, age, nationality and location of secondary education) and to determine the extent to which the MMI is predictive of academic success in nursing. DESIGN: A longitudinal retrospective analysis of student demographics, MMI data and the assessment marks for years 1, 2 and 3. SETTINGS: One university in southwest London. PARTICIPANTS: One cohort of students who commenced their programme in September 2011, including students in all four fields of nursing (adult, child, mental health and learning disability). METHODS: Inferential statistics and a Bayesian Multilevel Model. RESULTS: MMI in conjunction with MMI numeracy test and MMI literacy test shows little or no bias in terms of ages, gender, nationality or location of secondary school education. Although MMI in conjunction with numeracy and literacy testing is predictive of academic success, it is only weakly predictive. CONCLUSIONS: The MMI used in conjunction with literacy and numeracy testing appears to be a successful technique for selecting candidates for nursing. However, other selection methods such as psychological profiling or testing of emotional intelligence may add to the extent to which selection methods are predictive of academic success on nursing

The Early Royal Society and Visual Culture

Recent studies have fruitfully examined the intersection between early modern science and visual culture by elucidating the functions of images in shaping and disseminating scientific knowledge. Given its rich archival sources, it is possible to extend this line of research in the case of the Royal Society to an examination of attitudes towards images as artefacts –manufactured objects worth commissioning, collecting and studying. Drawing on existing scholarship and material from the Royal Society Archives, I discuss Fellows’ interests in prints, drawings, varnishes, colorants, images made out of unusual materials, and methods of identifying the painter from a painting. Knowledge of production processes of images was important to members of the Royal Society, not only as connoisseurs and collectors, but also as those interested in a Baconian mastery of material processes, including a “history of trades”. Their antiquarian interests led to discussion of painters’ styles, and they gradually developed a visual memorial to an institution through portraits and other visual records.AH/M001938/1 (AHRC

A New Mechanistic Scenario for the Origin and Evolution of Vertebrate Cartilage

The appearance of cellular cartilage was a defining event in vertebrate evolution because it made possible the physical expansion of the vertebrate “new head”. Despite its central role in vertebrate evolution, the origin of cellular cartilage has been difficult to understand. This is largely due to a lack of informative evolutionary intermediates linking vertebrate cellular cartilage to the acellular cartilage of invertebrate chordates. The basal jawless vertebrate, lamprey, has long been considered key to understanding the evolution of vertebrate cartilage. However, histological analyses of the lamprey head skeleton suggest it is composed of modern cellular cartilage and a putatively unrelated connective tissue called mucocartilage, with no obvious transitional tissue. Here we take a molecular approach to better understand the evolutionary relationships between lamprey cellular cartilage, gnathostome cellular cartilage, and lamprey mucocartilage. We find that despite overt histological similarity, lamprey and gnathostome cellular cartilage utilize divergent gene regulatory networks (GRNs). While the gnathostome cellular cartilage GRN broadly incorporates Runx, Barx, and Alx transcription factors, lamprey cellular cartilage does not express Runx or Barx, and only deploys Alx genes in certain regions. Furthermore, we find that lamprey mucocartilage, despite its distinctive mesenchymal morphology, deploys every component of the gnathostome cartilage GRN, albeit in different domains. Based on these findings, and previous work, we propose a stepwise model for the evolution of vertebrate cellular cartilage in which the appearance of a generic neural crest-derived skeletal tissue was followed by a phase of skeletal tissue diversification in early agnathans. In the gnathostome lineage, a single type of rigid cellular cartilage became dominant, replacing other skeletal tissues and evolving via gene cooption to become the definitive cellular cartilage of modern jawed vertebrates

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Prime-boost immunization of rabbits with HIV-1 gp120 elicits potent neutralization activity against a primary viral isolate

<div><p>Development of a vaccine for HIV-1 requires a detailed understanding of the neutralizing antibody responses that can be experimentally elicited to difficult-to-neutralize primary isolates. Rabbits were immunized with the gp120 subunit of HIV-1 JR-CSF envelope (Env) using a DNA-prime protein-boost regimen. We analyzed five sera that showed potent autologous neutralizing activity (IC50s at ∼10³ to 10⁴ serum dilution) against pseudoviruses containing Env from the primary isolate JR-CSF but not from the related isolate JR-FL. Pseudoviruses were created by exchanging each variable and constant domain of JR-CSF gp120 with that of JR-FL or with mutations in putative N-glycosylation sites. The sera contained different neutralizing activities dependent on C3 and V5, C3 and V4, or V4 regions located on the glycan-rich outer domain of gp120. All sera showed enhanced neutralizing activity toward an Env variant that lacked a glycosylation site in V4. The JR-CSF gp120 epitopes recognized by the sera are generally distinct from those of several well characterized mAbs (targeting conserved sites on Env) or other type-specific responses (targeting V1, V2, or V3 variable regions). The activity of one serum requires specific glycans that are also important for 2G12 neutralization and this serum blocked the binding of 2G12 to gp120. Our findings show that different fine specificities can achieve potent neutralization of HIV-1, yet this strong activity does not result in improved breadth.</p> </div

James Britton’s theory of language and learning and the recent ’affective’ literary critics

This thesis examines the theories of some recent affective* literary critics in the light of James Britton's theory of language and learning. Until recently, literary criticism generally has not been concerned with the relationship between the text and the reader; it has concerned itself either with the poem as a static verbal object, as in New Criticism, or with the writer-text relationship, as in biographical criticism. With the neglect of the text-reader relationship, the study of literature has also ignored a basic aesthetic principle -- that the relationship between a work of art and its percipient is a dynamic interaction where 'ordinary' experience cannot be separated from aesthetic experience. Chapter I delineates this principle proposed primarily by John Dewey, whose theory is complemented by those of R.G. Collingwood, Susanne Langer, and George Kelly. Chapter II identifies and examines the recent theories of seven literary critics who discuss the 'affective' relationship between the reader and the text -- Norman Holland, Standly Fish, Roland Barthes, Wolfgang Iser, Georges Poulet, Wayne Booth, and Walter Slatoff. Two ideas emerge which are related to the aesthetic principle espoused by John Dewey and others: 1) our aesthetic responses to literature are natural extensions of our mundane selves; and 2) literature as art is still a linguistic utterance, and as such is related to other ordinary kinds of language use. But these ideas are rudimentary and fragmented and there is a need for a more general theory to integrate them. James Britton's theory of language in Chapter III, contained mainly in his book Language and Learning, provides a structure which subsumes these fragmented ideas so that a perspective can be gained on this new criticism. Britton puts forth the view that literature is a manifestation of man's linguistic activity in what he calls the 'spectator role*. This theory integrates the critical ideas arising out of Chapter II and also places literature in a new perspective with other of man's spectator role activities, both linguistic (gossip, personal letter-writing) and non-linguistic (play, dream, fantasy, ritual). Britton points to the importance of spectator role activities in personal development.Arts, Faculty ofEnglish, Department ofGraduat