CSF tau and the CSF tau/ABeta ratio for the diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI).

BACKGROUND: Research suggests that measurable change in cerebrospinal fluid (CSF) biomarkers occurs years in advance of the onset of clinical symptoms (Beckett 2010). In this review, we aimed to assess the ability of CSF tau biomarkers (t-tau and p-tau) and the CSF tau (t-tau or p-tau)/ABeta ratio to enable the detection of Alzheimer's disease pathology in patients with mild cognitive impairment (MCI). These biomarkers have been proposed as important in new criteria for Alzheimer's disease dementia that incorporate biomarker abnormalities. OBJECTIVES: To determine the diagnostic accuracy of 1) CSF t-tau, 2) CSF p-tau, 3) the CSF t-tau/ABeta ratio and 4) the CSF p-tau/ABeta ratio index tests for detecting people with MCI at baseline who would clinically convert to Alzheimer's disease dementia or other forms of dementia at follow-up. SEARCH METHODS: The most recent search for this review was performed in January 2013. We searched MEDLINE (OvidSP), Embase (OvidSP), BIOSIS Previews (Thomson Reuters Web of Science), Web of Science Core Collection, including Conference Proceedings Citation Index (Thomson Reuters Web of Science), PsycINFO (OvidSP), and LILACS (BIREME). We searched specialized sources of diagnostic test accuracy studies and reviews. We checked reference lists of relevant studies and reviews for additional studies. We contacted researchers for possible relevant but unpublished data. We did not apply any language or data restriction to the electronic searches. We did not use any methodological filters as a method to restrict the search overall. SELECTION CRITERIA: We selected those studies that had prospectively well-defined cohorts with any accepted definition of MCI and with CSF t-tau or p-tau and CSF tau (t-tau or p-tau)/ABeta ratio values, documented at or around the time the MCI diagnosis was made. We also included studies which looked at data from those cohorts retrospectively, and which contained sufficient data to construct two by two tables expressing those biomarker results by disease status. Moreover, studies were only selected if they applied a reference standard for Alzheimer's disease dementia diagnosis, for example, the NINCDS-ADRDA or Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. DATA COLLECTION AND ANALYSIS: We screened all titles generated by the electronic database searches. Two review authors independently assessed the abstracts of all potentially relevant studies, and the full papers for eligibility. Two independent assessors performed data extraction and quality assessment. Where data allowed, we derived estimates of sensitivity at fixed values of specificity from the model we fitted to produce the summary receiver operating characteristic (ROC) curve. MAIN RESULTS: In total, 1282 participants with MCI at baseline were identified in the 15 included studies of which 1172 had analysable data; 430 participants converted to Alzheimer's disease dementia and 130 participants to other forms of dementia. Follow-up ranged from less than one year to over four years for some participants, but in the majority of studies was in the range one to three years. Conversion to Alzheimer's disease dementia The accuracy of the CSF t-tau was evaluated in seven studies (291 cases and 418 non-cases).The sensitivity values ranged from 51% to 90% while the specificity values ranged from 48% to 88%. At the median specificity of 72%, the estimated sensitivity was 75% (95% CI 67 to 85), the positive likelihood ratio was 2.72 (95% CI 2.43 to 3.04), and the negative likelihood ratio was 0.32 (95% CI 0.22 to 0.47).Six studies (164 cases and 328 non-cases) evaluated the accuracy of the CSF p-tau. The sensitivities were between 40% and 100% while the specificities were between 22% and 86%. At the median specificity of 47.5%, the estimated sensitivity was 81% (95% CI: 64 to 91), the positive likelihood ratio was 1.55 (CI 1.31 to 1.84), and the negative likelihood ratio was 0.39 (CI: 0.19 to 0.82).Five studies (140 cases and 293 non-cases) evaluated the accuracy of the CSF p-tau/ABeta ratio. The sensitivities were between 80% and 96% while the specificities were between 33% and 95%. We did not conduct a meta-analysis because the studies were few and small. Only one study reported the accuracy of CSF t-tau/ABeta ratio.Our findings are based on studies with poor reporting. A significant number of studies had unclear risk of bias for the reference standard, participant selection and flow and timing domains. According to the assessment of index test domain, eight of 15 studies were of poor methodological quality.The accuracy of these CSF biomarkers for 'other dementias' had not been investigated in the included primary studies. Investigation of heterogeneity The main sources of heterogeneity were thought likely to be reference standards used for the target disorders, sources of recruitment, participant sampling, index test methodology and aspects of study quality (particularly, inadequate blinding).We were not able to formally assess the effect of each potential source of heterogeneity as planned, due to the small number of studies available to be included. AUTHORS' CONCLUSIONS: The insufficiency and heterogeneity of research to date primarily leads to a state of uncertainty regarding the value of CSF testing of t-tau, p-tau or p-tau/ABeta ratio for the diagnosis of Alzheimer's disease in current clinical practice. Particular attention should be paid to the risk of misdiagnosis and overdiagnosis of dementia (and therefore over-treatment) in clinical practice. These tests, like other biomarker tests which have been subject to Cochrane DTA reviews, appear to have better sensitivity than specificity and therefore might have greater utility in ruling out Alzheimer's disease as the aetiology to the individual's evident cognitive impairment, as opposed to ruling it in. The heterogeneity observed in the few studies awaiting classification suggests our initial summary will remain valid. However, these tests may have limited clinical value until uncertainties have been addressed. Future studies with more uniformed approaches to thresholds, analysis and study conduct may provide a more homogenous estimate than the one that has been available from the included studies we have identified

Conceptualising organisational cultural lag: Marriage equality and Australian sport

This article develops a theoretical framework to understand how sexuality can be institutionalised through debates about marriage equality. We first examine 13 Australian sporting organisations concerning their support for marriage equality and sexual minority inclusion before showing they drew cultural capital from supporting episodes of equality exogenous to their organisation, while failing to promote internal inclusion. We use online content analysis alongside the identification of institutional speech acts within policy to analyse results through three conceptual lenses: Ahmed’s (2006) institutional diversity work, Ogburn’s (1922) cultural lag, and Evan’s (1966) organisational lag, from which we propose a hybrid, Organisational Cultural Lag, as a theoretical tool within social movement theory

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

Evidence synthesis to inform model-based cost-effectiveness evaluations of diagnostic tests: a methodological systematic review of health technology assessments

Background: Evaluations of diagnostic tests are challenging because of the indirect nature of their impact on patient outcomes. Model-based health economic evaluations of tests allow different types of evidence from various sources to be incorporated and enable cost-effectiveness estimates to be made beyond the duration of available study data. To parameterize a health-economic model fully, all the ways a test impacts on patient health must be quantified, including but not limited to diagnostic test accuracy. Methods: We assessed all UK NIHR HTA reports published May 2009-July 2015. Reports were included if they evaluated a diagnostic test, included a model-based health economic evaluation and included a systematic review and meta-analysis of test accuracy. From each eligible report we extracted information on the following topics: 1) what evidence aside from test accuracy was searched for and synthesised, 2) which methods were used to synthesise test accuracy evidence and how did the results inform the economic model, 3) how/whether threshold effects were explored, 4) how the potential dependency between multiple tests in a pathway was accounted for, and 5) for evaluations of tests targeted at the primary care setting, how evidence from differing healthcare settings was incorporated. Results: The bivariate or HSROC model was implemented in 20/22 reports that met all inclusion criteria. Test accuracy data for health economic modelling was obtained from meta-analyses completely in four reports, partially in fourteen reports and not at all in four reports. Only 2/7 reports that used a quantitative test gave clear threshold recommendations. All 22 reports explored the effect of uncertainty in accuracy parameters but most of those that used multiple tests did not allow for dependence between test results. 7/22 tests were potentially suitable for primary care but the majority found limited evidence on test accuracy in primary care settings. Conclusions: The uptake of appropriate meta-analysis methods for synthesising evidence on diagnostic test accuracy in UK NIHR HTAs has improved in recent years. Future research should focus on other evidence requirements for cost-effectiveness assessment, threshold effects for quantitative tests and the impact of multiple diagnostic tests

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

General Practice

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GENERAL PRACTICE

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International Medical Students: factors that enhance and inhibit learning

Aim: The aim of the research was to identify modifiable factors which affect learning experiences and outcomes for international medical students. Based on the results of the study, recommendations for improving the learning environment and student support services are made. Background: Previous studies have considered the economic and educational benefits of hosting international students on New Zealand institutions and ways to promote the frequency and quality of intercultural contact in universities. Little research has specifically investigated international medical students’ educational expectations, experiences and needs. There is anecdotal evidence to suggest that international students face special challenges pursuing medical education at Otago University and have unmet learning and educational needs. Proportionately more international students’ names appear than domestic students at the Student Progress Academic Committee meetings, which discuss how to help students who are struggling or failing assessments. The reasons for this over-representation are complex and relate to a combination of communication difficulties, learning styles and attitudinal issues. The research explores some of the challenges faced by international medical students to provide insight into factors which enhance and inhibit learning in order to recommend measures to improve the learning environment. Methods: Data for the study were collected at the University of Otago in 2009 on the experiences of international medical students. Funding came from two research grants. After obtaining ethical approval from the University and review by the Māori Ngai Tahu Committee, study participants were recruited by email, word of mouth and written information. Anonymity was assured. Questions in the semi-structured interview covered: factors that inhibited and enhanced learning, students’ experiences of accessing University support services, and students’ suggestions for improving the learning environment and support services to meet learning needs. Each interview was taped and transcribed. Thematic analysis of the data collected was initially undertaken using a software programme (Atlas-ti). Manual categorisation and coding of the thirty-one interviews was also carried out by the principal investigator to reveal common themes that were interpreted using both an inductive and deductive approach. Fifty-five students from nine different countries were interviewed at the Dunedin and Wellington campuses. There was a mix of group and individual interviews with students from Years 2-6 of the medical course. Results: International students were generally appreciative of the learning experience in New Zealand. Few instances of racism were reported within the University, but marginalisation by staff and students in learning and social contexts was reported. The more interactive learning style in New Zealand was contrasted to didactic teaching in many of the students’ home countries. Social events involving alcohol excluded many international students and inhibited integration with domestic students. Conclusion: Participants’ recommendations for improving the learning environment included: proof reading of written work, mentoring in years two and three, coaching for objective structured clinical examinations (OSCEs), and the organisation of social events without alcohol to facilitate socialisation with domestic students. There were also suggestions about preparing overseas students better for studying in New Zealand

International Medical Students: factors that enhance and inhibit learning

Aim: The aim of the research was to identify modifiable factors which affect learning experiences and outcomes for international medical students. Based on the results of the study, recommendations for improving the learning environment and student support services are made. Background: Previous studies have considered the economic and educational benefits of hosting international students on New Zealand institutions and ways to promote the frequency and quality of intercultural contact in universities. Little research has specifically investigated international medical students’ educational expectations, experiences and needs. There is anecdotal evidence to suggest that international students face special challenges pursuing medical education at Otago University and have unmet learning and educational needs. Proportionately more international students’ names appear than domestic students at the Student Progress Academic Committee meetings, which discuss how to help students who are struggling or failing assessments. The reasons for this over-representation are complex and relate to a combination of communication difficulties, learning styles and attitudinal issues. The research explores some of the challenges faced by international medical students to provide insight into factors which enhance and inhibit learning in order to recommend measures to improve the learning environment. Methods: Data for the study were collected at the University of Otago in 2009 on the experiences of international medical students. Funding came from two research grants. After obtaining ethical approval from the University and review by the Māori Ngai Tahu Committee, study participants were recruited by email, word of mouth and written information. Anonymity was assured. Questions in the semi-structured interview covered: factors that inhibited and enhanced learning, students’ experiences of accessing University support services, and students’ suggestions for improving the learning environment and support services to meet learning needs. Each interview was taped and transcribed. Thematic analysis of the data collected was initially undertaken using a software programme (Atlas-ti). Manual categorisation and coding of the thirty-one interviews was also carried out by the principal investigator to reveal common themes that were interpreted using both an inductive and deductive approach. Fifty-five students from nine different countries were interviewed at the Dunedin and Wellington campuses. There was a mix of group and individual interviews with students from Years 2-6 of the medical course. Results: International students were generally appreciative of the learning experience in New Zealand. Few instances of racism were reported within the University, but marginalisation by staff and students in learning and social contexts was reported. The more interactive learning style in New Zealand was contrasted to didactic teaching in many of the students’ home countries. Social events involving alcohol excluded many international students and inhibited integration with domestic students. Conclusion: Participants’ recommendations for improving the learning environment included: proof reading of written work, mentoring in years two and three, coaching for objective structured clinical examinations (OSCEs), and the organisation of social events without alcohol to facilitate socialisation with domestic students. There were also suggestions about preparing overseas students better for studying in New Zealand