Investigating and dealing with publication bias and other reporting biases in meta-analyses:a review

A P value, or the magnitude or direction of results can influence decisions about whether, when, and how research findings are disseminated. Regardless of whether an entire study or a particular study result is unavailable because investigators considered the results to be unfavourable, bias in a meta-analysis may occur when available results differ systematically from missing results. In this paper, we summarize the empirical evidence for various reporting biases that lead to study results being unavailable for inclusion in systematic reviews, with a focus on health research. These biases include publication bias and selective nonreporting bias. We describe processes that systematic reviewers can use to minimize the risk of bias due to missing results in meta-analyses of health research, such as comprehensive searches and prospective approaches to meta-analysis. We also outline methods that have been designed for assessing risk of bias due to missing results in meta-analyses of health research, including using tools to assess selective nonreporting of results, ascertaining qualitative signals that suggest not all studies were identified, and generating funnel plots to identify small-study effects, one cause of which is reporting bias. This article is protected by copyright. All rights reserved

Measuring sustainable employability:psychometric properties of the capability set for work questionnaire

BACKGROUND: The capability set for work questionnaire (CSWQ) is being used to measure the new model of sustainable employability building on the capability approach. However, previous studies on the psychometric properties of the instrument are limited and cross-sectional. This two-way study aimed to (1) evaluate the convergent validity of the CSWQ with the theoretically related constructs person-job fit, strengths use, and opportunity to craft and (2) test the predictive and incremental validity of the questionnaire for the well-established work outcomes, including work ability, work engagement, job satisfaction, and task performance. METHODS: A representative sample of 303 Dutch workers, chosen with probably random sampling, were surveyed using a one-month follow-up, cross-lagged design via the Longitudinal Internet Studies for the Social Sciences panel. The convergent validity was assessed by exploring the strength of associations between the capability set for work questionnaire and the theoretically related constructs using Pearson’s correlations. The predictive and incremental validity was evaluated by performing a series of linear hierarchical regression analyses. RESULTS: We found evidence of the convergent validity of the capability set score by moderate correlations with person-job fit, strengths use, and opportunity to craft (r = 0.51–0.52). A series of multiple regression analyses showed that Time 1 capability set score and its constituents (i.e., importance, ability, and enablement) generally had predictive and incremental validity for work ability, work engagement, job satisfaction, and task performance measured at Time 2. However, the incremental power of the CSWQ over and above conceptually related constructs was modest. CONCLUSIONS: The findings support the convergent, predictive, and incremental validity of the capability set for work questionnaire with not previously investigated work constructs. This provided further evidence to support its utility for assessing a worker’s sustainable employability for future research and practical interventions

Occupational physicians' perceived barriers and suggested solutions to improve adherence to a guideline on mental health problems: Analysis of a peer group training

Background: Despite the impact of mental health problems on sickness absence, only few occupational health guidelines addressing these problems are available. Moreover, adherence has found to be suboptimal. To improve adherence to the Dutch guideline on mental health problems a training was developed for Dutch occupational physicians (OPs) focusing on identifying barriers and addressing them. The aim of this study was to provide an overview of the barriers that OPs perceived in adhering to the Dutch guideline on mental health problems as well as their solutions to overcome them. Methods: A qualitative study was conducted using data from the peer group training. Thirty-two (6 groups of 4 to 6) OPs received a multiple-session interactive training over the course of a year, focusing on identifying and addressing barriers, using a Plan-Do-Check-Act approach. Sessions were audio-taped and transcribed verbatim. Thematic content analysis was performed by two researchers with a selection of 50 % (21 out of 42) of the transcripts to identify the perceived barriers and the suggested solutions, using AtlasTi 7.0. Results: Knowledge-related barriers were perceived regarding the content of all parts of the guideline. Commonly perceived attitude-related barriers were a lack of self-efficacy to perform certain guideline recommendations and difficulties with changing habits and routines. External barriers that were commonly perceived were work-contextual barriers, such as a lack of time/work pressure, tight contracts between occupational health services (OHSs) and employers, and conflicting policy of and a lack of collaboration with other parties (e.g. employer, other healthcare providers). The most often tested solutions by OPs during the training were sharing information, experiences, tips and tricks and referring to existing tools, or developing new tools to facilitate guideline usage. Conclusions: Dutch OPs perceive a range of knowledge-related, attitude-related and external barriers in adhering to the guideline on mental health problems. The tested solutions during the training particularly seemed to focus on knowledge and attitude-related barriers. To optimally implement this or similar mental health guidelines, it may be important to complement guideline training and education of individual or groups of OPs, with interventions that address external barriers such as changing

Combining the receptor tyrosine kinase inhibitor AEE788 and the mammalian target of rapamycin (mTOR) inhibitor RAD001 strongly inhibits adhesion and growth of renal cell carcinoma cells

Background Treatment options for metastatic renal cell carcinoma (RCC) are limited due to resistance to chemo- and radiotherapy. The development of small-molecule multikinase inhibitors have now opened novel treatment options. The influence of the receptor tyrosine kinase inhibitor AEE788, applied alone or combined with the mammalian target of rapamycin (mTOR) inhibitor RAD001, on RCC cell adhesion and proliferation in vitro has been evaluated. Methods RCC cell lines Caki-1, KTC-26 or A498 were treated with various concentrations of RAD001 or AEE788 and tumor cell proliferation, tumor cell adhesion to vascular endothelial cells or to immobilized extracellular matrix proteins (laminin, collagen, fibronectin) evaluated. The anti-tumoral potential of RAD001 combined with AEE788 was also investigated. Both, asynchronous and synchronized cell cultures were used to subsequently analyze drug induced cell cycle manipulation. Analysis of cell cycle regulating proteins was done by western blotting. Results RAD001 or AEE788 reduced adhesion of RCC cell lines to vascular endothelium and diminished RCC cell binding to immobilized laminin or collagen. Both drugs blocked RCC cell growth, impaired cell cycle progression and altered the expression level of the cell cycle regulating proteins cdk2, cdk4, cyclin D1, cyclin E and p27. The combination of AEE788 and RAD001 resulted in more pronounced RCC growth inhibition, greater rates of G0/G1 cells and lower rates of S-phase cells than either agent alone. Cell cycle proteins were much more strongly altered when both drugs were used in combination than with single drug application. The synergistic effects were observed in an asynchronous cell culture model, but were more pronounced in synchronous RCC cell cultures. Conclusions Potent anti-tumoral activitites of the multikinase inhibitors AEE788 or RAD001 have been demonstrated. Most importantly, the simultaneous use of both AEE788 and RAD001 offered a distinct combinatorial benefit and thus may provide a therapeutic advantage over either agent employed as a monotherapy for RCC treatment

Addressing social issues in a universal HIV test and treat intervention trial (ANRS 12249 TasP) in South Africa: methods for appraisal

Background: The Universal HIV Test and Treat (UTT) strategy represents a challenge for science, but is also a challenge for individuals and societies. Are repeated offers of provider-initiated HIV testing and immediate antiretroviral therapy (ART) socially-acceptable and can these become normalized over time? Can UTT be implemented without potentially adding to individual and community stigma, or threatening individual rights? What are the social, cultural and economic implications of UTT for households and communities? And can UTT be implemented within capacity constraints and other threats to the overall provision of HIV services? The answers to these research questions will be critical for routine implementation of UTT strategies. Methods/design: A social science research programme is nested within the ANRS 12249 Treatment-as-Prevention (TasP) cluster-randomised trial in rural South Africa. The programme aims to inform understanding of the (i) social, economic and environmental factors affecting uptake of services at each step of the continuum of HIV prevention, treatment and care and (ii) the causal impacts of the TasP intervention package on social and economic factors at the individual, household, community and health system level. We describe a multidisciplinary, multi-level, mixed-method research protocol that includes individual, household, community and clinic surveys, and combines quantitative and qualitative methods. Discussion: The UTT strategy is changing the overall approach to HIV prevention, treatment and care, and substantial social consequences may be anticipated, such as changes in social representations of HIV transmission, prevention, HIV testing and ART use, as well as changes in individual perceptions and behaviours in terms of uptake and frequency of HIV testing and ART initiation at high CD4. Triangulation of social science studies within the ANRS 12249 TasP trial will provide comprehensive insights into the acceptability and feasibility of the TasP intervention package at individual, community, patient and health system level, to complement the trial's clinical and epidemiological outcomes. It will also increase understanding of the causal impacts of UTT on social and economic outcomes, which will be critical for the long-term sustainability and routine UTT implementation. Trial registration: Clinicaltrials.gov: NCT01509508; South African Trial Register: DOH-27-0512-3974

Impact of the G84E variant on HOXB13 gene and protein expression in formalin-fixed, paraffin-embedded prostate tumours

The HOXB13 G84E variant is associated with risk of prostate cancer (PCa), however the role this variant plays in PCa development is unknown. This study examined 751 cases, 450 relatives and 355 controls to determine the contribution of this variant to PCa risk in Tasmania and investigated HOXB13 gene and protein expression in tumours from nine G84E heterozygote variant and 13 wild-type carriers. Quantitative PCR and immunohistochemistry showed that HOXB13 gene and protein expression did not differ between tumour samples from variant and wild-type carriers. Allele-specific transcription revealed that two of seven G84E carriers transcribed both the variant and wild-type allele, while five carriers transcribed the wild-type allele. Methylation of surrounding CpG sites was lower in the variant compared to the wild-type allele, however overall methylation across the region was very low. Notably, tumour characteristics were less aggressive in the two variant carriers that transcribed the variant allele compared to the five that did not. This study has shown that HOXB13 expression does not differ between tumour tissue of G84E variant carriers and non-carriers. Intriguingly, the G84E variant allele was rarely transcribed in carriers, suggesting that HOXB13 expression may be driven by the wild-type allele in the majority of carriers

Vitamin D and subsequent all-age and premature mortality: a systematic review

<br>Background: All-cause mortality in the population < 65 years is 30% higher in Glasgow than in equally deprived Liverpool and Manchester. We investigated a hypothesis that low vitamin D in this population may be associated with premature mortality via a systematic review and meta-analysis.</br> <br>Methods: Medline, EMBASE, Web of Science, the Cochrane Library and grey literature sources were searched until February 2012 for relevant studies. Summary statistics were combined in an age-stratified meta-analysis.</br> <br>Results: Nine studies were included in the meta-analysis, representing 24,297 participants, 5,324 of whom died during follow-up. The pooled hazard ratio for low compared to high vitamin D demonstrated a significant inverse association (HR 1.19, 95% CI 1.12-1.27) between vitamin D levels and all-cause mortality after adjustment for available confounders. In an age-stratified meta-analysis, the hazard ratio for older participants was 1.25 (95% CI 1.14-1.36) and for younger participants 1.12 (95% CI 1.01-1.24).</br> <br>Conclusions: Low vitamin D status is inversely associated with all-cause mortality but the risk is higher amongst older individuals and the relationship is prone to residual confounding. Further studies investigating the association between vitamin D deficiency and all-cause mortality in younger adults with adjustment for all important confounders (or using randomised trials of supplementation) are required to clarify this relationship.</br&gt

Prediction of cardiovascular risk using Framingham, ASSIGN and QRISK2: how well do they predict individual rather than population risk?

BACKGROUND: The objective of this study was to evaluate the performance of risk scores (Framingham, Assign and QRISK2) in predicting high cardiovascular disease (CVD) risk in individuals rather than populations. METHODS AND FINDINGS: This study included 1.8 million persons without CVD and prior statin prescribing using the Clinical Practice Research Datalink. This contains electronic medical records of the general population registered with a UK general practice. Individual CVD risks were estimated using competing risk regression models. Individual differences in the 10-year CVD risks as predicted by risk scores and competing risk models were estimated; the population was divided into 20 subgroups based on predicted risk. CVD outcomes occurred in 69,870 persons. In the subgroup with lowest risks, risk predictions by QRISK2 were similar to individual risks predicted using our competing risk model (99.9% of people had differences of less than 2%); in the subgroup with highest risks, risk predictions varied greatly (only 13.3% of people had differences of less than 2%). Larger deviations between QRISK2 and our individual predicted risks occurred with calendar year, different ethnicities, diabetes mellitus and number of records for medical events in the electronic health records in the year before the index date. A QRISK2 estimate of low 10-year CVD risk (<15%) was confirmed by Framingham, ASSIGN and our individual predicted risks in 89.8% while an estimate of high 10-year CVD risk (≥ 20%) was confirmed in only 48.6% of people. The majority of cases occurred in people who had predicted 10-year CVD risk of less than 20%. CONCLUSIONS: Application of existing CVD risk scores may result in considerable misclassification of high risk status. Current practice to use a constant threshold level for intervention for all patients, together with the use of different scoring methods, may inadvertently create an arbitrary classification of high CVD risk