mCOPA: analysis of heterogeneous features in cancer expression data

Background Cancer outlier profile analysis (COPA) has proven to be an effective approach to analyzing cancer expression data, leading to the discovery of the TMPRSS2 and ETS family gene fusion events in prostate cancer. However, the original COPA algorithm did not identify down-regulated outliers, and the currently available R package implementing the method is similarly restricted to the analysis of over-expressed outliers. Here we present a modified outlier detection method, mCOPA, which contains refinements to the outlier-detection algorithm, identifies both over- and under-expressed outliers, is freely available, and can be applied to any expression dataset. Results We compare our method to other feature-selection approaches, and demonstrate that mCOPA frequently selects more-informative features than do differential expression or variance-based feature selection approaches, and is able to recover observed clinical subtypes more consistently. We demonstrate the application of mCOPA to prostate cancer expression data, and explore the use of outliers in clustering, pathway analysis, and the identification of tumour suppressors. We analyse the under-expressed outliers to identify known and novel prostate cancer tumour suppressor genes, validating these against data in Oncomine and the Cancer Gene Index. We also demonstrate how a combination of outlier analysis and pathway analysis can identify molecular mechanisms disrupted in individual tumours. Conclusions We demonstrate that mCOPA offers advantages, compared to differential expression or variance, in selecting outlier features, and that the features so selected are better able to assign samples to clinically annotated subtypes. Further, we show that the biology explored by outlier analysis differs from that uncovered in differential expression or variance analysis. mCOPA is an important new tool for the exploration of cancer datasets and the discovery of new cancer subtypes, and can be combined with pathway and functional analysis approaches to discover mechanisms underpinning heterogeneity in cancers

Circulating tumour cells, their role in metastasis and their clinical utility in lung cancer

Circulating tumour cells (CTCs) have attracted much recent interest in cancer research as a potential biomarker and as a means of studying the process of metastasis. It has long been understood that metastasis is a hallmark of malignancy, and conceptual theories on the basis of metastasis from the nineteenth century foretold the existence of a tumour "seed" which is capable of establishing discrete tumours in the "soil" of distant organs. This prescient "seed and soil" hypothesis accurately predicted the existence of CTCs; microscopic tumour fragments in the blood, at least some of which are capable of forming metastases. However, it is only in recent years that reliable, reproducible methods of CTC detection and analysis have been developed. To date, the majority of studies have employed the CellSearch™ system (Veridex LLC), which is an immunomagnetic purification method. Other promising techniques include microfluidic filters, isolation of tumour cells by size using microporous polycarbonate filters and flow cytometry-based approaches. While many challenges still exist, the detection of CTCs in blood is becoming increasingly feasible, giving rise to some tantalizing questions about the use of CTCs as a potential biomarker. CTC enumeration has been used to guide prognosis in patients with metastatic disease, and to act as a surrogate marker for disease response during therapy. Other possible uses for CTC detection include prognostication in early stage patients, identifying patients requiring adjuvant therapy, or in surveillance, for the detection of relapsing disease. Another exciting possible use for CTC detection assays is the molecular and genetic characterization of CTCs to act as a "liquid biopsy" representative of the primary tumour. Indeed it has already been demonstrated that it is possible to detect HER2, KRAS and EGFR mutation status in breast, colon and lung cancer CTCs respectively. In the course of this review, we shall discuss the biology of CTCs and their role in metastagenesis, the most commonly used techniques for their detection and the evidence to date of their clinical utility, with particular reference to lung cancer.

A novel DRD2 single-nucleotide polymorphism associated with schizophrenia predicts age of onset : HapMap tag-single-nucleotide polymorphism analysis

Background: Dopamine D2 receptor (DRD2) is thought to be critical in regulating the dopaminergic pathway in the brain which is known to be important in the aetiology of schizophrenia. It is therefore not surprising that most antipsychotic medication acts on the Dopamine D2 receptor. DRD2 is widely expressed in brain, levels are reduced in brains of schizophrenia patients and DRD2 polymorphisms have been associated with reduced brain expression. We have previously identified a genetic variant in DRD2, rs6277 to be strongly implicated in schizophrenia susceptibility. Methods: To identity new associations in the DRD2 gene with disease status and clinical severity, we genotyped seven single nucleotide polymorphisms (SNPs) in DRD2 using a multiplex mass spectrometry method. SNPs were chosen using a haplotype block-based gene-tagging approach so the entire DRD2 gene was represented. Results: One polymorphism rs2734839 was found to be significantly associated with schizophrenia as well as late onset age. Individuals carrying the genetic variation were more than twice as likely to have schizophrenia compared to controls. Conclusions: Our results suggest that DRD2 genetic variation is a good indicator for schizophrenia risk and may also be used as a predictor age of onset.

Uptake of skin self-examination and clinical examination behavior by outdoor workers

This study investigated the association between outdoor work and response to a behavioural skin cancer early detection intervention among men 50 years or older. Overall, 495 men currently working in outdoor, mixed or indoor occupations were randomised to a video-based intervention or control group. At 7 months post intervention, indoor workers reported the lowest proportion of whole-body skin self-examination (wbSSE; 20%). However, at 13 months mixed workers engaged more commonly in wbSSE (36%) compared to indoor (31%) and outdoor (32%) workers. In adjusted analysis, the uptake of early detection behaviours during the trial did not differ between men working in different settings. Outdoor workers compared to men in indoor or mixed work settings were similar in their response to an intervention encouraging uptake of secondary skin cancer prevention behaviours during this intervention trial.

Response to “Topical agent therapy for prevention and treatment of radiodermatitis : a meta-analysis”

To the Editor; It was with interest that I read the recent article by Zhang et al. published in Supportive Care in Cancer [1]. This paper highlighted the importance of radiodermatitis (RD) being an unresolved and distressing clinical issue in patients with cancer undergoing radiation therapy. However, I am concerned with a number of clinical and methodological issues within this paper: (i) the clinical and operational definition of prophylaxis and treatment of RD; (ii) the accuracy of the identification of trials; and (iii) the appropriateness of the conduct of the meta-analyses...

A confirmatory factor analysis of the Observer Alexithymia Scale in treatment seeking alcohol-dependent patients

Confirmatory factor analyses evaluated the factorial validity of the Observer Alexithymia Scale (OAS) in an alcohol-dependent sample. Observation was conducted by clinical psychologists. All models examined were rejected, given their poor fit. Given the psychometric limitations of the OAS shown in this study, the OAS may not be the most appropriate measure to use early in treatment among alcohol-dependent individuals.

Referral patterns and proximity to palliative care inpatient services by level of socio-economic disadvantage : a national study using spatial analysis

Background: A range of health outcomes at a population level are related to differences in levels of social disadvantage. Understanding the impact of any such differences in palliative care is important. The aim of this study was to assess, by level of socio-economic disadvantage, referral patterns to specialist palliative care and proximity to inpatient services. Methods: All inpatient and community palliative care services nationally were geocoded (using postcode) to one nationally standardised measure of socio-economic deprivation – Socio-Economic Index for Areas (SEIFA; 2006 census data). Referral to palliative care services and characteristics of referrals were described through data collected routinely at clinical encounters. Inpatient location was measured from each person’s home postcode, and stratified by socio-economic disadvantage. Results: This study covered July – December 2009 with data from 10,064 patients. People from the highest SEIFA group (least disadvantaged) were significantly less likely to be referred to a specialist palliative care service, likely to be referred closer to death and to have more episodes of inpatient care for longer time. Physical proximity of a person’s home to inpatient care showed a gradient with increasing distance by decreasing levels of socio-economic advantage. Conclusion: These data suggest that a simple relationship of low socioeconomic status and poor access to a referral-based specialty such as palliative care does not exist. Different patterns of referral and hence different patterns of care emerge.

Paramedics' perceptions of their role in palliative care : analysis of focus group transcripts

Paramedics play an important role in out-of-hospital health care. They provide unscheduled care, assisting both patients with minor injuries and those experiencing life-threatening emergencies. Increasingly, paramedics are called on to manage chronic and complex health needs, including symptom relief for patients at the end of life. However, paramedics may not be well prepared to offer palliative care, as practice guidelines and education tend to focus on the management of acute medical emergencies and major trauma. Emergency medical services that employ paramedics rarely have practice guidelines or protocols that deal specifically with palliative care.

Development of clinical competencies for emergency nurse practitioners : a pilot study

Background: Nurse practitioner education and practice has been guided by generic competency standards in Australia since 2006. Development of specialist competencies has been less structured and there are no formal standards to guide education and continuing professional development for specialty fields. There is limited international research and no Australian research into development of specialist nurse practitioner competencies. This pilot study aimed to test data collection methods, tools and processes in preparation for a larger national study to investigate specialist competency standards for emergency nurse practitioners. Research into specialist emergency nurse practitioner competencies has not been conducted in Australia. Methods: Mixed methods research was conducted with a sample of experienced emergency nurse practitioners. Deductive analysis of data from a focus group workshop informed development of a draft specialty competency framework. The framework was subsequently subjected to systematic scrutiny for consensus validation through a two round Delphi Study. Results: The Delphi study first round had a 100% response rate; the second round 75% response rate. The scoring for all items in both rounds was above the 80% cut off mark with the lowest mean score being 4.1 (82%) from the first round. Conclusion: The authors collaborated with emergency nurse practitioners to produce preliminary data on the formation of specialty competencies as a first step in developing an Australian framework.

Using ‘think aloud’ as a strategy for improving clinical reasoning in high fidelity case-based simulation for undergraduate nursing students.

Theme Paper for Curriculum innovation and enhancement theme AIM: This paper reports on a research project that trialled an educational strategy implemented in an undergraduate nursing curriculum. The project aimed to explore the effectiveness of ‘think aloud’ as a strategy for improving clinical reasoning for students in simulated clinical settings. BACKGROUND: Nurses are required to apply and utilise critical thinking skills to enable clinical reasoning and problem solving in the clinical setting (Lasater, 2007). Nursing students are expected to develop and display clinical reasoning skills in practice, but may struggle articulating reasons behind decisions about patient care. The ‘think aloud’ approach is an innovative learning/teaching method which can create an environment suitable for developing clinical reasoning skills in students (Banning, 2008, Lee and Ryan-Wenger, 1997). This project used the ‘think aloud’ strategy within a simulation context to provide a safe learning environment in which third year students were assisted to uncover cognitive approaches to assist in making effective patient care decisions, and improve their confidence, clinical reasoning and active critical reflection about their practice. MEHODS: In semester 2 2011 at QUT, third year nursing students undertook high fidelity simulation (some for the first time), commencing in September of 2011. There were two cohorts for strategy implementation (group 1= used think aloud as a strategy within the simulation, group 2= no specific strategy outside of nursing assessment frameworks used by all students) in relation to problem solving patient needs. The think aloud strategy was described to students in their pre-simulation briefing and allowed time for clarification of this strategy. All other aspects of the simulations remained the same, (resources, suggested nursing assessment frameworks, simulation session duration, size of simulation teams, preparatory materials). Ethics approval has been obtained for this project. RESULTS: Results of a qualitative analysis (in progress- will be completed by March 2012) of student and facilitator reports on students’ ability to meet the learning objectives of solving patient problems using clinical reasoning and experience with the ‘think aloud’ method will be presented. A comparison of clinical reasoning learning outcomes between the two groups will determine the effect on clinical reasoning for students responding to patient problems. CONCLUSIONS: In an environment of increasingly constrained clinical placement opportunities, exploration of alternate strategies to improve critical thinking skills and develop clinical reasoning and problem solving for nursing students is imperative in preparing nurses to respond to changing patient needs.

Injuries leading to hospitalisation in the first year of life : analysis by trimester of age using coded data and textual description

Objective: To describe unintentional injuries to children aged less than one year, using coded and textual information, in three-month age bands to reflect their development over the year. Methods: Data from the Queensland Injury Surveillance Unit was used. The Unit collects demographic, clinical and circumstantial details about injured persons presenting to selected emergency departments across the State. Only injuries coded as unintentional in children admitted to hospital were included for this analysis. Results: After editing, 1,082 children remained for analysis, 24 with transport-related injuries. Falls were the most common injury, but becoming proportionately less over the year, whereas burns and scalds and foreign body injuries increased. The proportion of injuries due to contact with persons or objects varied little, but poisonings were relatively more common in the first and fourth three-month periods. Descriptions indicated that family members were somehow causally involved in 16% of injuries. Our findings are in qualitative agreement with comparable previous studies. Conclusion: The pattern of injuries varies over the first year of life and is clearly linked to the child's increasing mobility. Implications: Injury patterns in the first year of life should be reported over shorter intervals. Preventive measures for young children need to be designed with their rapidly changing developmental stage in mind, using a variety of strategies, one of which could be opportunistic developmentally specific education of parents. Injuries in young children are of abiding concern given their immediate health and emotional effects, and potential for long-term adverse sequelae. In Australia, in the financial year 2006/07, 2,869 children less than 12 months of age were admitted to hospital for an unintentional injury, a rate of 10.6 per 1,000, representing a considerable economic and social burden. Given that many of these injuries are preventable, this is particularly concerning. Most epidemiologic studies analyse data in five-year age bands, so children less than five years of age are examined as a group. This study includes only those children younger than one year of age to identify injury detail lost in analyses of the larger group, as we hypothesised that the injury pattern varied with the developmental stage of the child. The authors of several North American studies have commented that in dealing with injuries in pre-school children, broad age groupings are inadequate to do justice to the rapid developmental changes in infancy and early childhood, and have in consequence analysed injuries in shorter intervals. To our knowledge, no similar analysis of Australian infant injuries has been published to date. This paper describes injury in children less than 12 months of age using data from the Queensland Injury Surveillance Unit (QISU).

Nutritional analysis of gastric contents and body condition score at a single time point in feral horses in Australia

Objective: To determine the impact of a free-choice diet on nutritional intake and body condition of feral horses. Animals: Cadavers of 41 feral horses from 5 Australian locations. Procedures: Body condition score (BCS) was determined (scale of 1 to 9), and the stomach was removed from horses during postmortem examination. Stomach contents were analyzed for nutritional variables and macroelement and microelement concentrations. Data were compared among the locations and also compared with recommended daily intakes for horses. Results: Mean BCS varied by location; all horses were judged to be moderately thin. The BCS for males was 1 to 3 points higher than that of females. Amount of protein in the stomach contents varied from 4.3% to 14.9% and was significantly associated with BCS. Amounts of water-soluble carbohydrate and ethanol-soluble carbohydrate in stomach contents of feral horses from all 5 locations were higher than those expected for horses eating high-quality forage. Some macroelement and microelement concentrations were grossly excessive, whereas others were grossly deficient. There was no evidence of ill health among the horses. Conclusions and Clinical Relevance: Results suggested that the diet for several populations of feral horses in Australia appeared less than optimal. However, neither low BCS nor trace mineral deficiency appeared to affect survival of the horses. Additional studies on food sources in these regions, including analysis of water-soluble carbohydrate, ethanol-soluble carbohydrate, and mineral concentrations, are warranted to determine the provenance of such rich sources of nutrients. Determination of the optimal diet for horses may need revision.

Phylodynamic analysis of the emergence and epidemiological impact of transmissible defective dengue viruses

Intra-host sequence data from RNA viruses have revealed the ubiquity of defective viruses in natural viral populations, sometimes at surprisingly high frequency. Although defective viruses have long been known to laboratory virologists, their relevance in clinical and epidemiological settings has not been established. The discovery of long-term transmission of a defective lineage of dengue virus type 1 (DENV-1) in Myanmar, first seen in 2001, raised important questions about the emergence of transmissible defective viruses and their role in viral epidemiology. By combining phylogenetic analyses and dynamical modelling, we investigate how evolutionary and ecological processes at the intra-host and inter-host scales shaped the emergence and spread of the defective DENV-1 lineage. We show that this lineage of defective viruses emerged between June 1998 and February 2001, and that the defective virus was transmitted primarily through co-transmission with the functional virus to uninfected individuals. We provide evidence that, surprisingly, this co-transmission route has a higher transmission potential than transmission of functional dengue viruses alone. Consequently, we predict that the defective lineage should increase overall incidence of dengue infection, which could account for the historically high dengue incidence reported in Myanmar in 2001-2002. Our results show the unappreciated potential for defective viruses to impact the epidemiology of human pathogens, possibly by modifying the virulence-transmissibility trade-off, or to emerge as circulating infections in their own right. They also demonstrate that interactions between viral variants, such as complementation, can open new pathways to viral emergence.

Qualitative analysis and eating disorders : Discourse analytic research on anorexia nervosa

The absence of qualitative analysis in mainstream research on eating disorders is discussed in the following article as being a weakness in developing theory and clinical practice. This article includes an analysis of interviews with British healthcare workers who manage anorexic patients. This analysis presents an example of qualitative methodology in the form of discourse analysis, which is argued to provide a systematic, yet flexible approach to research on eating disorders. The overwhelming prevalence of anorexia nervosa in women is specifically examined within the context of the identification of the "discourse of femininity. " The research findings are discussed in relation to the use of discursive practices that contribute to the maintenance and reproduction of clinical processes and their relative efficacy.

Australian dispensing doctors' prescribing : quantitative and qualitative analysis

Objective: To evaluate the prescribing practices of Australian dispensing doctors (DDs) and to explore their interpretations of the findings. Design, participants and setting: Sequential explanatory mixed methods. The quantitative phase comprised analysis of Pharmaceutical Benefits Scheme (PBS) claims data of DDs and non-DDs, 1 July 2005 30 June 2007. The qualitative phase involved semi-structured interviews with DDs in rural and remote general practice across Australian states, August 2009 February 2010. Main outcome measures: The number of PBS prescriptions per 1000 patients and use of Regulation 24 of the National Health (Pharmaceutical Benefits) Regulations 1960 (r. 24); DDs' interpretation of the findings. Results: 72 DDs' and 1080 non-DDs' PBS claims data were analysed quantitatively. DDs issued fewer prescriptions per 1000 patients (9452 v 15057; P = 0.003), even with a similar proportion of concessional patients and patients aged >65 years in their populations. DDs issued significantly more r. 24 prescriptions per 1000 prescriptions than non-DDs (314 v 67; P=0.008). Interviews with 22 DDs explained that the fewer prescriptions were due to perceived expectation from their peers regarding prescribing norms and the need to generate less administrative paperwork in small practices. Conclusions: Contrary to overseas findings, we found no evidence that Australian DDs overprescribed because of their additional dispensing role. MJA 2011; 195: 172-175