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1.  Vitamin D supplementation in children with asthma: a systematic review and meta-analysis 
BMC Research Notes  2015;8:23.
Background
Epidemiologic studies suggest an association between vitamin D deficiency and atopic diseases, including asthma. The objective of this study was to systematically review the benefits and harms of vitamin D supplementation in children with asthma.
Methods
We used standard Cochrane systematic review methodology. The search strategy included an electronic search in February 2013 of MEDLINE and EMBASE. Two reviewers completed in duplicate and independently study selection, data abstraction, and assessment of risk of bias. We pooled the results of trials using a random-effects model. We assessed the quality of evidence by outcome using the GRADE methodology.
Results
Four trials with a total of 149 children met eligibility criteria. The trials had major methodological limitations. Given the four studies reporting on asthma symptoms used different instruments to measure that outcome, we opted not to conduct a meta-analysis. Three of those studies reported improvement in asthma symptoms in the vitamin D supplemented group study, while the fourth reported no effect (very low quality evidence). For the lung function outcome, a meta-analysis of two trials assessing post treatment FEV-1 found a mean difference of 0.54 liters per second (95% CI -5.28; 4.19; low quality evidence). For the vitamin D level outcome, a meta-analysis of three trials found a mean difference of 6.56 ng/ml (95% CI -0.64; 13.77; very low quality evidence).
Conclusions
The available very low to low quality evidence does not confirm or rule out beneficial effects of vitamin D supplementation in children with asthma. Large-scale, well-designed and executed randomized controlled trials are needed to better understand the effectiveness and safety of vitamin D in children with asthma.
Electronic supplementary material
The online version of this article (doi:10.1186/s13104-014-0961-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s13104-014-0961-3
PMCID: PMC4328422  PMID: 25643669
Asthma; Allergy; Atopy; Vitamin D; Cholecalciferol; Calcitriol; Ergocalciferol; Children
2.  Impact of missing participant data for dichotomous outcomes on pooled effect estimates in systematic reviews: a protocol for a methodological study 
Systematic Reviews  2014;3(1):137.
Background
There is no consensus on how authors conducting meta-analysis should deal with trial participants with missing outcome data. The objectives of this study are to assess in Cochrane and non-Cochrane systematic reviews: (1) which categories of trial participants the systematic review authors consider as having missing participant data (MPD), (2) how trialists reported on participants with missing outcome data in trials, (3) whether systematic reviewer authors actually dealt with MPD in their meta-analyses of dichotomous outcomes consistently with their reported methods, and (4) the impact of different methods of dealing with MPD on pooled effect estimates in meta-analyses of dichotomous outcomes.
Methods/Design
We will conduct a methodological study of Cochrane and non-Cochrane systematic reviews. Eligible systematic reviews will include a group-level meta-analysis of a patient-important dichotomous efficacy outcome, with a statistically significant effect estimate. Teams of two reviewers will determine eligibility and subsequently extract information from each eligible systematic review in duplicate and independently, using standardized, pre-piloted forms. The teams will then use a similar process to extract information from the trials included in the meta-analyses of interest. We will assess first which categories of trial participants the systematic reviewers consider as having MPD. Second, we will assess how trialists reported on participants with missing outcome data in trials. Third, we will compare what systematic reviewers report having done, and what they actually did, in dealing with MPD in their meta-analysis. Fourth, we will conduct imputation studies to assess the effects of different methods of dealing with MPD on the pooled effect estimates of meta-analyses. We will specifically calculate for each method (1) the percentage of systematic reviews that lose statistical significance and (2) the mean change of effect estimates across systematic reviews.
Discussion
The impact of different methods of dealing with MPD on pooled effect estimates will help judge the associated risk of bias in systematic reviews. Our findings will inform recommendations regarding what assumptions for MPD should be used to test the robustness of meta-analytical results.
Electronic supplementary material
The online version of this article (doi:10.1186/2046-4053-3-137) contains supplementary material, which is available to authorized users.
doi:10.1186/2046-4053-3-137
PMCID: PMC4285551  PMID: 25423894
Missing participant data; Imputation; Risk of bias; Trials; Systematic reviews; Meta-analysis
3.  Assessment of faculty productivity in academic departments of medicine in the United States: a national survey 
BMC Medical Education  2014;14(1):205.
Background
Faculty productivity is essential for academic medical centers striving to achieve excellence and national recognition. The objective of this study was to evaluate whether and how academic Departments of Medicine in the United States measure faculty productivity for the purpose of salary compensation.
Methods
We surveyed the Chairs of academic Departments of Medicine in the United States in 2012. We sent a paper-based questionnaire along with a personalized invitation letter by postal mail. For non-responders, we sent reminder letters, then called them and faxed them the questionnaire. The questionnaire included 8 questions with 23 tabulated close-ended items about the types of productivity measured (clinical, research, teaching, administrative) and the measurement strategies used. We conducted descriptive analyses.
Results
Chairs of 78 of 152 eligible departments responded to the survey (51% response rate). Overall, 82% of respondents reported measuring at least one type of faculty productivity for the purpose of salary compensation. Amongst those measuring faculty productivity, types measured were: clinical (98%), research (61%), teaching (62%), and administrative (64%). Percentages of respondents who reported the use of standardized measurements units (e.g., Relative Value Units (RVUs)) varied from 17% for administrative productivity to 95% for research productivity. Departments reported a wide variation of what exact activities are measured and how they are monetarily compensated. Most compensation plans take into account academic rank (77%). The majority of compensation plans are in the form of a bonus on top of a fixed salary (66%) and/or an adjustment of salary based on previous period productivity (55%).
Conclusion
Our survey suggests that most academic Departments of Medicine in the United States measure faculty productivity and convert it into standardized units for the purpose of salary compensation. The exact activities that are measured and how they are monetarily compensated varied substantially across departments.
Electronic supplementary material
The online version of this article (doi:10.1186/1472-6920-14-205) contains supplementary material, which is available to authorized users.
doi:10.1186/1472-6920-14-205
PMCID: PMC4189191  PMID: 25257232
Faculty productivity; Salary compensation; Academia; Department of medicine; Survey
4.  Systematic reviews addressing identified health policy priorities in Eastern Mediterranean countries: a situational analysis 
Background
Systematic reviews can offer policymakers and stakeholders concise, transparent, and relevant evidence pertaining to pressing policy priorities to help inform the decision-making process. The production and the use of systematic reviews are specifically limited in the Eastern Mediterranean region. The extent to which published systematic reviews address policy priorities in the region is still unknown. This situational analysis exercise aims at assessing the extent to which published systematic reviews address policy priorities identified by policymakers and stakeholders in Eastern Mediterranean region countries. It also provides an overview about the state of systematic review production in the region and identifies knowledge gaps.
Methods
We conducted a systematic search of the Health System Evidence database to identify published systematic reviews on policy-relevant priorities pertaining to the following themes: human resources for health, health financing, the role of the non-state sector, and access to medicine. Priorities were identified from two priority-setting exercises conducted in the region. We described the distribution of these systematic reviews across themes, sub-themes, authors’ affiliations, and countries where included primary studies were conducted.
Results
Out of the 1,045 systematic reviews identified in Health System Evidence on selected themes, a total of 200 systematic reviews (19.1%) addressed the priorities from the Eastern Mediterranean region. The theme with the largest number of systematic reviews included was human resources for health (115) followed by health financing (33), access to medicine (27), and role of the non-state sector (25). Authors based in the region produced only three systematic reviews addressing regional priorities (1.5%). Furthermore, no systematic review focused on the Eastern Mediterranean region. Primary studies from the region had limited contribution to systematic reviews; 17 systematic reviews (8.5%) included primary studies conducted in the region.
Conclusions
There are still gaps in the production of systematic reviews addressing policymakers’ and stakeholders’ priorities in the Eastern Mediterranean region. Efforts should be directed towards better aligning systematic review production with policy needs and priorities. Study findings can inform the agendas of researchers, research institutions, and international funding agencies of priority areas where systematic reviews are required.
doi:10.1186/1478-4505-12-48
PMCID: PMC4237801  PMID: 25139256
Eastern Mediterranean region; Health policy and systems research; Policy priorities; Systematic reviews
6.  Shorter or longer anticoagulation to prevent recurrent venous thromboembolism: systematic review and meta-analysis 
BMJ Open  2014;4(7):e005674.
Introduction
Venous thromboembolism (VTE) is a major disease associated with short-term and long-term morbidity and mortality. Patients with a VTE provoked by surgery or immobilisation are at low risk of recurrence and do not require long-term anticoagulation; those with a VTE and metastatic cancer are at high risk of recurrence and require lifetime thromboprophylaxis. In those at intermediate risk of recurrence, it remains controversial whether prolonging anticoagulation and thus incurring treatment burden and bleeding risk is warranted.
Methods and analysis
We will conduct a systematic review and meta-analysis of randomised controlled trials enrolling patients with VTE at intermediate risk of recurrence and evaluating short-term anticoagulation (12 weeks to 9 months initial therapy) versus longer term anticoagulation (at least 6 months additional anticoagulation beyond the course of treatment in the shorter arm). Anticoagulation could consist of vitamin K antagonists or new oral anticoagulants. Outcomes of interest include recurrent non-fatal thrombosis (deep venous thrombosis and pulmonary embolism), major non-fatal bleeding and mortality. We will systematically search CINAHL, EMBASE, MEDLINE and the Cochrane Central Registry of Controlled Trials. Teams of two reviewers will, independently and in duplicate, screen titles and abstracts and complete full text reviews to determine eligibility, and subsequently abstract data and assess risk of bias in eligible trials. We will conduct meta-analyses to establish the effect of short-term versus long-term anticoagulation on the outcomes of interest and evaluate confidence in estimates (quality of evidence) using the GRADE (grading of recommendations, assessment, development and evaluation) approach.
Ethics and dissemination
Our review will facilitate evidence-based management of patients with unprovoked or recurrent VTE. For purposes of privacy and confidentiality, the systematic review will be limited to studies with deidentified data. The study will be disseminated by peer-review publication and conference presentation.
Trial registration number
PROSPERO (CRD42014007620).
doi:10.1136/bmjopen-2014-005674
PMCID: PMC4091261  PMID: 24996916
VASCULAR MEDICINE
7.  Legislative, educational, policy and other interventions targeting physicians’ interaction with pharmaceutical companies: a systematic review 
BMJ Open  2014;4(7):e004880.
Background
Pharmaceutical company representatives likely influence the prescribing habits and professional behaviour of physicians.
Objective
The objective of this study was to systematically review the effects of interventions targeting practising physicians’ interactions with pharmaceutical companies.
Eligibility criteria
We included observational studies, non-randomised controlled trials (non-RCTs) and RCTs evaluating legislative, educational, policy or other interventions targeting the interactions between physicians and pharmaceutical companies.
Data sources
The search strategy included an electronic search of MEDLINE and EMBASE. Two reviewers performed duplicate and independent study selection, data abstraction and assessment of risk of bias.
Appraisal and synthesis methods
We assessed the risk of bias in each included study. We summarised the findings narratively because the nature of the data did not allow a meta-analysis to be conducted. We assessed the quality of evidence by outcome using the GRADE methodology.
Results
Of 11 189 identified citations, one RCT and three observational studies met the eligibility criteria. All four studies specifically targeted one type of interaction with pharmaceutical companies, that is, interactions with drug representatives. The RCT provided moderate quality evidence of no effect of a ‘collaborative approach’ between the pharmaceutical industry and a health authority. The three observational studies provided low quality evidence suggesting a positive effect of policies aiming to reduce interaction between physicians and pharmaceutical companies (by restricting free samples, promotional material, and meetings with pharmaceutical company representatives) on prescription behaviour.
Limitations
We identified too few studies to allow strong conclusions.
Conclusions
Available evidence suggests a potential impact of policies aiming to reduce interaction between physicians and drug representatives on physicians’ prescription behaviour. We found no evidence concerning interventions affecting other types of interaction with pharmaceutical companies.
doi:10.1136/bmjopen-2014-004880
PMCID: PMC4091460  PMID: 24989618
Pharma; Gift giving; Conflict of interest; Drug industry; Primary care ; Physician
8.  Association between low vitamin D levels and the diagnosis of asthma in children: a systematic review of cohort studies 
Background
There is conflicting evidence about the association between low vitamin D levels in children and development of asthma in later life. The objective of this study was to systematically review the evidence for an epidemiological association between low serum levels of vitamin D and the diagnosis of asthma in children.
Methods
We used the Cochrane methodology for conducting systematic reviews. The search strategy included an electronic search of MEDLINE and EMBASE in February 2013. Two reviewers completed, in duplicate and independently, study selection, data abstraction, and assessment of risk of bias.
Results
Of 1081 identified citations, three cohort studies met eligibility criteria. Two studies found that low serum vitamin D level is associated with an increased risk of developing asthma late in childhood, while the third study found no association with either vitamin D2 or vitamin D3 levels. All three studies suffer from major methodological shortcomings that limit our confidence in their results.
Conclusions
Available epidemiological evidence suggests a potential association between low serum levels of vitamin D and the diagnosis of asthma in children. High quality studies are needed to reliably answer the question of interest.
doi:10.1186/1710-1492-10-31
PMCID: PMC4064110  PMID: 24955097
Asthma; Wheezing; Childhood; Pediatric; Vitamin D; Bronchial hyper responsiveness; Lung function tests; Systematic review; Cohort
9.  Guidelines 2.0: systematic development of a comprehensive checklist for a successful guideline enterprise 
Background:
Although several tools to evaluate the credibility of health care guidelines exist, guidance on practical steps for developing guidelines is lacking. We systematically compiled a comprehensive checklist of items linked to relevant resources and tools that guideline developers could consider, without the expectation that every guideline would address each item.
Methods:
We searched data sources, including manuals of international guideline developers, literature on guidelines for guidelines (with a focus on methodology reports from international and national agencies, and professional societies) and recent articles providing systematic guidance. We reviewed these sources in duplicate, extracted items for the checklist using a sensitive approach and developed overarching topics relevant to guidelines. In an iterative process, we reviewed items for duplication and omissions and involved experts in guideline development for revisions and suggestions for items to be added.
Results:
We developed a checklist with 18 topics and 146 items and a webpage to facilitate its use by guideline developers. The topics and included items cover all stages of the guideline enterprise, from the planning and formulation of guidelines, to their implementation and evaluation. The final checklist includes links to training materials as well as resources with suggested methodology for applying the items.
Interpretation:
The checklist will serve as a resource for guideline developers. Consideration of items on the checklist will support the development, implementation and evaluation of guidelines. We will use crowdsourcing to revise the checklist and keep it up to date.
doi:10.1503/cmaj.131237
PMCID: PMC3928232  PMID: 24344144
10.  Methodological survey of designed uneven randomization trials (DU-RANDOM): a protocol 
Trials  2014;15:33.
Background
Although even randomization (that is, approximately 1:1 randomization ratio in study arms) provides the greatest statistical power, designed uneven randomization (DUR), (for example, 1:2 or 1:3) is used to increase participation rates. Until now, no convincing data exists addressing the impact of DUR on participation rates in trials. The objective of this study is to evaluate the epidemiology and to explore factors associated with DUR.
Methods
We will search for reports of RCTs published within two years in 25 general medical journals with the highest impact factor according to the Journal Citation Report (JCR)-2010. Teams of two reviewers will determine eligibility and extract relevant information from eligible RCTs in duplicate and using standardized forms. We will report the prevalence of DUR trials, the reported reasons for using DUR, and perform a linear regression analysis to estimate the association between the randomization ratio and the associated factors, including participation rate, type of informed consent, clinical area, and so on.
Discussion
A clearer understanding of RCTs with DUR and its association with factors in trials, for example, participation rate, can optimize trial design and may have important implications for both researchers and users of the medical literature.
doi:10.1186/1745-6215-15-33
PMCID: PMC3902027  PMID: 24456965
Participation rate; Designed uneven randomization trials; Trial participation
11.  A methodological survey of the analysis, reporting and interpretation of Absolute Risk ReductiOn in systematic revieWs (ARROW): a study protocol 
Systematic Reviews  2013;2:113.
Background
Clinicians, providers and guideline panels use absolute effects to weigh the advantages and downsides of treatment alternatives. Relative measures have the potential to mislead readers. However, little is known about the reporting of absolute measures in systematic reviews. The objectives of our study are to determine the proportion of systematic reviews that report absolute measures of effect for the most important outcomes, and ascertain how they are analyzed, reported and interpreted.
Methods/design
We will conduct a methodological survey of systematic reviews published in 2010. We will conduct a 1:1 stratified random sampling of Cochrane vs. non-Cochrane systematic reviews. We will calculate the proportion of systematic reviews reporting at least one absolute estimate of effect for the most patient-important outcome for the comparison of interest. We will conduct multivariable logistic regression analyses with the reporting of an absolute estimate of effect as the dependent variable and pre-specified study characteristics as the independent variables. For systematic reviews reporting an absolute estimate of effect, we will document the methods used for the analysis, reporting and interpretation of the absolute estimate.
Discussion
Our methodological survey will inform current practices regarding reporting of absolute estimates in systematic reviews. Our findings may influence recommendations on reporting, conduct and interpretation of absolute estimates. Our results are likely to be of interest to systematic review authors, funding agencies, clinicians, guideline developers and journal editors.
doi:10.1186/2046-4053-2-113
PMCID: PMC3867670  PMID: 24330779
Systematic reviews; Meta-analysis; Statistical data; Evidence-based medicine; Numbers needed to treat; Data reporting; Absolute effect measures
12.  All That Glitters Isn't Gold: A Survey on Acknowledgment of Limitations in Biomedical Studies 
PLoS ONE  2013;8(11):e73623.
Background
Acknowledgment of all serious limitations to research evidence is important for patient care and scientific progress. Formal research on how biomedical authors acknowledge limitations is scarce.
Objectives
To assess the extent to which limitations are acknowledged in biomedical publications explicitly, and implicitly by investigating the use of phrases that express uncertainty, so-called hedges; to assess the association between industry support and the extent of hedging.
Design
We analyzed reporting of limitations and use of hedges in 300 biomedical publications published in 30 high and medium -ranked journals in 2007. Hedges were assessed using linguistic software that assigned weights between 1 and 5 to each expression of uncertainty.
Results
Twenty-seven percent of publications (81/300) did not mention any limitations, while 73% acknowledged a median of 3 (range 1–8) limitations. Five percent mentioned a limitation in the abstract. After controlling for confounders, publications on industry-supported studies used significantly fewer hedges than publications not so supported (p = 0.028).
Limitations
Detection and classification of limitations was – to some extent – subjective. The weighting scheme used by the hedging detection software has subjective elements.
Conclusions
Reporting of limitations in biomedical publications is probably very incomplete. Transparent reporting of limitations may protect clinicians and guideline committees against overly confident beliefs and decisions and support scientific progress through better design, conduct or analysis of new studies.
doi:10.1371/journal.pone.0073623
PMCID: PMC3854521  PMID: 24324540
13.  Initiation and continuation of randomized trials after the publication of a trial stopped early for benefit asking the same study question: STOPIT-3 study design 
Trials  2013;14:335.
Background
Randomized control trials (RCTs) stopped early for benefit (truncated RCTs) are increasingly common and, on average, overestimate the relative magnitude of benefit by approximately 30%. Investigators stop trials early when they consider it is no longer ethical to enroll patients in a control group. The goal of this systematic review is to determine how investigators of ongoing or planned RCTs respond to the publication of a truncated RCT addressing a similar question.
Methods/design
We will conduct systematic reviews to update the searches of 210 truncated RCTs to identify similar trials ongoing at the time of publication, or started subsequently, to the truncated trials ('subsequent RCTs’). Reviewers will determine in duplicate the similarity between the truncated and subsequent trials. We will analyze the epidemiology, distribution, and predictors of subsequent RCTs. We will also contact authors of subsequent trials to determine reasons for beginning, continuing, or prematurely discontinuing their own trials, and the extent to which they rely on the estimates from truncated trials.
Discussion
To the extent that investigators begin or continue subsequent trials they implicitly disagree with the decision to stop the truncated RCT because of an ethical mandate to administer the experimental treatment. The results of this study will help guide future decisions about when to stop RCTs early for benefit.
doi:10.1186/1745-6215-14-335
PMCID: PMC3874848  PMID: 24131702
Randomized controlled trials stopped early for benefit; RCT; Systematic review; Protocol
14.  Assessing and presenting summaries of evidence in Cochrane Reviews 
Systematic Reviews  2013;2:81.
Cochrane Reviews are intended to help providers, practitioners and patients make informed decisions about health care. The goal of the Cochrane Applicability and Recommendation Methods Group (ARMG) is to develop approaches, strategies and guidance that facilitate the uptake of information from Cochrane Reviews and their use by a wide audience with specific focus on developers of recommendations and on healthcare decision makers. This paper is part of a series highlighting developments in systematic review methodology in the 20 years since the establishment of The Cochrane Collaboration, and its aim is to present current work and highlight future developments in assessing and presenting summaries of evidence, with special focus on Summary of Findings (SoF) tables and Plain Language Summaries.
A SoF table provides a concise and transparent summary of the key findings of a review in a tabular format. Several studies have shown that SoF tables improve accessibility and understanding of Cochrane Reviews.
The ARMG and GRADE Working Group are working on further development of the SoF tables, for example by evaluating the degree of acceptable flexibility beyond standard presentation of SoF tables, developing SoF tables for diagnostic test accuracy reviews and interactive SoF tables (iSoF).
The plain language summary (PLS) is the other main building block for dissemination of review results to end-users. The PLS aims to summarize the results of a review in such a way that health care consumers can readily understand them. Current efforts include the development of a standardized language to describe statistical results, based on effect size and quality of supporting evidence.
Producing high quality PLS and SoF tables and making them compatible and linked would make it easier to produce dissemination products targeting different audiences (for example, providers, health policy makers, guideline developers).
Current issues of debate include optimal presentation formats of SoF tables, the training required to produce SoF tables, and the extent to which the authors of Cochrane Reviews should provide explicit guidance to target audiences of patients, clinicians and policy-makers.
doi:10.1186/2046-4053-2-81
PMCID: PMC3849859  PMID: 24059250
15.  Motives, beliefs and attitudes towards waterpipe tobacco smoking: a systematic review 
Background
In spite of the negative health effects of waterpipe tobacco smoking, its use is becoming more common. The objective of this study is to systematically review the medical literature for motives, beliefs and attitudes towards waterpipe tobacco smoking.
Methods
We electronically searched MEDLINE, EMBASE, and the ISI the Web of Science in January 2012. We included both quantitative and qualitative studies. We selected studies and abstracted data using standard systematic review methodology. We synthesized data qualitatively.
Results
We included 58 papers reporting on 56 studies. The main motives for waterpipe tobacco smoking were socializing, relaxation, pleasure and entertainment. Peer pressure, fashion, and curiosity were additional motives for university and school students while expression of cultural identity was an additional motive for people in the Middle East and for people of Middle Eastern descent in Western countries. Awareness of the potential health hazards of waterpipe smoking was common across settings. Most but not all studies found that the majority of people perceived waterpipe smoking as less harmful than cigarette smoking. Waterpipe smoking was generally socially acceptable and more acceptable than cigarette smoking in general. In Middle Eastern societies, it was particularly more acceptable for women’s use compared to cigarette use. A majority perceived waterpipe smoking as less addictive than cigarette smoking. While users were confident in their ability to quit waterpipe smoking at any time, willingness to quit varied across settings.
Conclusions
Socializing, relaxation, pleasure and entertainment were the main motives for waterpipe use. While waterpipe users were aware of the health hazards of waterpipe smoking, they perceived it as less harmful, less addictive and more socially acceptable than cigarette smoking and were confident about their ability to quit.
doi:10.1186/1477-7517-10-12
PMCID: PMC3706388  PMID: 23816366
Tobacco; Waterpipe; Addiction; Motives; Beliefs; Attitudes
16.  Addressing Dichotomous Data for Participants Excluded from Trial Analysis: A Guide for Systematic Reviewers 
PLoS ONE  2013;8(2):e57132.
Introduction
Systematic reviewer authors intending to include all randomized participants in their meta-analyses need to make assumptions about the outcomes of participants with missing data.
Objective
The objective of this paper is to provide systematic reviewer authors with a relatively simple guidance for addressing dichotomous data for participants excluded from analyses of randomized trials.
Methods
This guide is based on a review of the Cochrane handbook and published methodological research. The guide deals with participants excluded from the analysis who were considered ‘non-adherent to the protocol’ but for whom data are available, and participants with missing data.
Results
Systematic reviewer authors should include data from ‘non-adherent’ participants excluded from the primary study authors' analysis but for whom data are available. For missing, unavailable participant data, authors may conduct a complete case analysis (excluding those with missing data) as the primary analysis. Alternatively, they may conduct a primary analysis that makes plausible assumptions about the outcomes of participants with missing data. When the primary analysis suggests important benefit, sensitivity meta-analyses using relatively extreme assumptions that may vary in plausibility can inform the extent to which risk of bias impacts the confidence in the results of the primary analysis. The more plausible assumptions draw on the outcome event rates within the trial or in all trials included in the meta-analysis. The proposed guide does not take into account the uncertainty associated with assumed events.
Conclusions
This guide proposes methods for handling participants excluded from analyses of randomized trials. These methods can help in establishing the extent to which risk of bias impacts meta-analysis results.
doi:10.1371/journal.pone.0057132
PMCID: PMC3581575  PMID: 23451162
17.  Systematic evaluation of the methodology of randomized controlled trials of anticoagulation in patients with cancer 
BMC Cancer  2013;13:76.
Background
Randomized controlled trials (RCTs) that are inappropriately designed or executed may provide biased findings and mislead clinical practice. In view of recent interest in the treatment and prevention of thrombotic complications in cancer patients we evaluated the characteristics, risk of bias and their time trends in RCTs of anticoagulation in patients with cancer.
Methods
We conducted a comprehensive search, including a search of four electronic databases (MEDLINE, EMBASE, ISI the Web of Science, and CENTRAL) up to February 2010. We included RCTs in which the intervention and/or comparison consisted of: vitamin K antagonists, unfractionated heparin (UFH), low molecular weight heparin (LMWH), direct thrombin inhibitors or fondaparinux. We performed descriptive analyses and assessed the association between the variables of interest and the year of publication.
Results
We included 67 RCTs with 24,071 participants. In twenty one trials (31%) DVT diagnosis was triggered by clinical suspicion; the remaining trials either screened for DVT or were unclear about their approach. 41 (61%), 22 (33%), and 11 (16%) trials respectively reported on major bleeding, minor bleeding, and thrombocytopenia. The percentages of trials satisfying risk of bias criteria were: adequate sequence generation (85%), adequate allocation concealment (61%), participants’ blinding (39%), data collectors’ blinding (44%), providers’ blinding (41%), outcome assessors’ blinding (75%), data analysts’ blinding (15%), intention to treat analysis (57%), no selective outcome reporting (12%), no stopping early for benefit (97%). The mean follow-up rate was 96%. Adequate allocation concealment and the reporting of intention to treat analysis were the only two quality criteria that improved over time.
Conclusions
Many RCTs of anticoagulation in patients with cancer appear to use insufficiently rigorous outcome assessment methods and to have deficiencies in key methodological features. It is not clear whether this reflects a problem in the design, conduct or the reporting of these trials, or both. Future trials should avoid the shortcomings described in this article.
doi:10.1186/1471-2407-13-76
PMCID: PMC3579688  PMID: 23406262
18.  Current experience with applying the GRADE approach to public health interventions: an empirical study 
BMC Public Health  2013;13:9.
Background
The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach has been adopted by many national and international organisations as a systematic and transparent framework for evidence-based guideline development. With reference to an ongoing debate in the literature and within public health organisations, this study reviews current experience with the GRADE approach in rating the quality of evidence in the field of public health and identifies challenges encountered.
Methods
We conducted semi-structured interviews with individuals/groups that have applied the GRADE approach in the context of systematic reviews or guidelines in the field of public health, as well as with representatives of groups or organisations that actively decided against its use. We initially contacted potential participants by email. Responses were obtained by telephone interview or email, and written interview summaries were validated with participants. We analysed data across individual interviews to distil common themes and challenges.
Results
Based on 25 responses, we undertook 18 interviews and obtained 15 in-depth responses relating to specific systematic reviews or guideline projects; a majority of the latter were contributed by groups within the World Health Organization. All respondents that have used the GRADE approach appreciated the systematic and transparent process of assessing the quality of the evidence. However, respondents reported a range of minor and major challenges relating to complexity of public health interventions, choice of outcomes and outcome measures, ability to discriminate between different types of observational studies, use of non-epidemiological evidence, GRADE terminology and the GRADE and guideline development process. Respondents’ suggestions to make the approach more applicable to public health interventions included revisiting terminology, offering better guidance on how to apply GRADE to complex interventions and making modifications to the current grading scheme.
Conclusions
Our findings suggest that GRADE principles are applicable to public health and well-received but also highlight common challenges. They provide a starting point for exploring options for improvements and, where applicable, testing these across different types of public health interventions. Several public health organisations are currently testing GRADE, and the GRADE Working Group is eager to engage with these groups to find ways to address concerns.
doi:10.1186/1471-2458-13-9
PMCID: PMC3546302  PMID: 23294803
19.  Inconsistent Definitions for Intention-To-Treat in Relation to Missing Outcome Data: Systematic Review of the Methods Literature 
PLoS ONE  2012;7(11):e49163.
Background
Authors of randomized trial reports seem to hold a variety of views regarding the relationship between missing outcome data (MOD) and intention to treat (ITT). The objectives of this study were to systematically investigate how authors of methodology articles define ITT in the presence of MOD, how they recommend handling MOD under ITT, and to make a proposal for potential improvement in the definition and use of ITT in relation to MOD.
Methods and Findings
We systematically searched MEDLINE in February 2009 for methodological articles written in English that devoted at least one paragraph to ITT and two other paragraphs to either ITT or MOD. We excluded original trial reports, observational studies, and clinical systematic reviews. Working in teams of two, we independently extracted relevant information from each eligible article. Of 1007 titles and abstracts reviewed, 66 articles met eligibility criteria. Five (8%) did not provide a definition of ITT; 25 (38%) mentioned MOD but did not discuss its relationship to ITT; and 36 (55%) discussed the relationship of MOD with ITT. These 36 articles described one or more of three statements: complete follow-up is required for ITT (58%); ITT and MOD are separate issues (17%); and ITT requires a specific strategy for handling MOD (78%); 17 (47%) endorsed more than one relationship. The most frequently mentioned strategies for handling MOD within ITT were: using the last outcome carried forward (50%); sensitivity analysis (50%); and use of available data to impute missing data (46%).
Conclusion
We found that there is no consensus on the definition of ITT in relation to MOD. For conceptual clarity, we suggest that both reports of randomized trials and systematic reviews separately consider and describe how they deal with participants with complete data and those with MOD.
doi:10.1371/journal.pone.0049163
PMCID: PMC3499557  PMID: 23166608
20.  Learning from failure - rationale and design for a study about discontinuation of randomized trials (DISCO study) 
Background
Randomized controlled trials (RCTs) may be discontinued because of apparent harm, benefit, or futility. Other RCTs are discontinued early because of insufficient recruitment. Trial discontinuation has ethical implications, because participants consent on the premise of contributing to new medical knowledge, Research Ethics Committees (RECs) spend considerable effort reviewing study protocols, and limited resources for conducting research are wasted. Currently, little is known regarding the frequency and characteristics of discontinued RCTs.
Methods/Design
Our aims are, first, to determine the prevalence of RCT discontinuation for specific reasons; second, to determine whether the risk of RCT discontinuation for specific reasons differs between investigator- and industry-initiated RCTs; third, to identify risk factors for RCT discontinuation due to insufficient recruitment; fourth, to determine at what stage RCTs are discontinued; and fifth, to examine the publication history of discontinued RCTs.
We are currently assembling a multicenter cohort of RCTs based on protocols approved between 2000 and 2002/3 by 6 RECs in Switzerland, Germany, and Canada. We are extracting data on RCT characteristics and planned recruitment for all included protocols. Completion and publication status is determined using information from correspondence between investigators and RECs, publications identified through literature searches, or by contacting the investigators. We will use multivariable regression models to identify risk factors for trial discontinuation due to insufficient recruitment. We aim to include over 1000 RCTs of which an anticipated 150 will have been discontinued due to insufficient recruitment.
Discussion
Our study will provide insights into the prevalence and characteristics of RCTs that were discontinued. Effective recruitment strategies and the anticipation of problems are key issues in the planning and evaluation of trials by investigators, Clinical Trial Units, RECs and funding agencies. Identification and modification of barriers to successful study completion at an early stage could help to reduce the risk of trial discontinuation, save limited resources, and enable RCTs to better meet their ethical requirements.
doi:10.1186/1471-2288-12-131
PMCID: PMC3528626  PMID: 22928744
Randomized controlled trial; Trial discontinuation; Slow recruitment; Ethics committees; Trial protocols
21.  Anterior Cervical Discectomy with Arthroplasty versus Arthrodesis for Single-Level Cervical Spondylosis: A Systematic Review and Meta-Analysis 
PLoS ONE  2012;7(8):e43407.
Objective
To estimate the effectiveness of anterior cervical discectomy with arthroplasty (ACDA) compared to anterior cervical discectomy with fusion (ACDF) for patient-important outcomes for single-level cervical spondylosis.
Data sources
Electronic databases (MEDLINE, EMBASE, Cochrane Register for Randomized Controlled Trials, BIOSIS and LILACS), archives of spine meetings and bibliographies of relevant articles.
Study selection
We included RCTs of ACDF versus ACDA in adult patients with single-level cervical spondylosis reporting at least one of the following outcomes: functionality, neurological success, neck pain, arm pain, quality of life, surgery for adjacent level degeneration (ALD), reoperation and dysphonia/dysphagia. We used no language restrictions. We performed title and abstract screening and full text screening independently and in duplicate.
Data synthesis
We used random-effects model to pool data using mean difference (MD) for continuous outcomes and relative risk (RR) for dichotomous outcomes. We used GRADE to evaluate the quality of evidence for each outcome.
Results
Of 2804 citations, 9 articles reporting on 9 trials (1778 participants) were eligible. ACDA is associated with a clinically significant lower incidence of neurologic failure (RR  = 0.53, 95% CI  = 0.37–0.75, p = 0.0004) and improvement in the Neck pain visual analogue scale (VAS) (MD  = 6.56, 95% CI  = 3.22–9.90, p = 0.0001; Minimal clinically important difference (MCID)  = 2.5. ACDA is associated with a statistically but not clinically significant improvement in Arm pain VAS and SF-36 physical component summary. ACDA is associated with non-statistically significant higher improvement in the Neck Disability Index Score and lower incidence of ALD requiring surgery, reoperation, and dysphagia/dysphonia.
Conclusions
There is no strong evidence to support the routine use of ACDA over ACDF in single-level cervical spondylosis. Current trials lack long-term data required to assess safety as well as surgery for ALD. We suggest that ACDA in patients with single level cervical spondylosis is an option although its benefits and indication over ACDF remain in question.
doi:10.1371/journal.pone.0043407
PMCID: PMC3422251  PMID: 22912869
22.  Effects of assessing the productivity of faculty in academic medical centres: a systematic review 
Background:
Many academic medical centres have introduced strategies to assess the productivity of faculty as part of compensation schemes. We conducted a systematic review of the effects of such strategies on faculty productivity.
Methods:
We searched the MEDLINE, Healthstar, Embase and PsycInfo databases from their date of inception up to October 2011. We included studies that assessed academic productivity in clinical, research, teaching and administrative activities, as well as compensation, promotion processes and satisfaction.
Results:
Of 531 full-text articles assessed for eligibility, we included 9 articles reporting on eight studies. The introduction of strategies for assessing academic productivity as part of compensation schemes resulted in increases in clinical productivity (in six of six studies) in terms of clinical revenue, the work component of relative-value units (these units are nonmonetary standard units of measure used to indicate the value of services provided), patient satisfaction and other departmentally used standards. Increases in research productivity were noted (in five of six studies) in terms of funding and publications. There was no change in teaching productivity (in two of five studies) in terms of educational output. Such strategies also resulted in increases in compensation at both individual and group levels (in three studies), with two studies reporting a change in distribution of compensation in favour of junior faculty. None of the studies assessed effects on administrative productivity or promotion processes. The overall quality of evidence was low.
Interpretation:
Strategies introduced to assess productivity as part of a compensation scheme appeared to improve productivity in research activities and possibly improved clinical productivity, but they had no effect in the area of teaching. Compensation increased at both group and individual levels, particularly among junior faculty. Higher quality evidence about the benefits and harms of such assessment strategies is needed.
doi:10.1503/cmaj.111123
PMCID: PMC3414625  PMID: 22641686
23.  Willingness of Lebanese physicians in the United States to relocate to Lebanon 
Background
We recently proposed that Lebanon could become a regional ‘academic hub’ through the repatriation of emigrated Lebanese physicians who would then provide clinical services in the Arab Gulf region on a locum tenens basis. The objectives of this study were to assess the willingness of Lebanese medical graduates practicing in the United States of America to relocate to Lebanon and the Arab Gulf region and to explore the factors associated with this willingness.
Methods
In 2009 we surveyed Lebanese medical graduates practicing medicine in the United States. The questionnaire included questions about their willingness to relocate to Lebanon and to the Arab Gulf region and the associated timeframes. The questionnaire also included questions about family factors. We linked responders’ answers to their personal, educational, and practice characteristics provided by the American Medical Association Physicians’ Dataset. We conducted both descriptive and regression analyses.
Results
A total of 286 physicians participated in the survey (57% response rate). A majority (61%) was willing to relocate to Lebanon (51% possibly, 10% definitely). A third (33%) were willing to relocate to the Arab Gulf region (31% possibly, 2% definitely). About half (54%) were willing to relocate to Lebanon as a base for clinical missions to the Arab Gulf region (49% possibly, 5% definitely). Willingness to relocate to Lebanon was independently associated with Lebanese citizenship and the birthplace of the spouse being Lebanon, and inversely associated with US citizenship. Willingness to relocate to the Arab Gulf region was independently associated with being board certified, and inversely associated with being married, the age of the oldest child, and practicing in direct patient care. Willingness to relocate to Lebanon as a base was not independently associated with any factor.
Conclusions
The findings of this study support the feasibility of the proposal of Lebanon becoming a regional ‘academic hub’. Future research should explore other factors important for the feasibility of the proposal as well as actual relocation.
doi:10.1186/1478-4491-10-15
PMCID: PMC3549762  PMID: 22780903
Physician migration; Repatriation; Lebanese physician workforce
24.  An emigration versus a globalization perspective of the Lebanese physician workforce: a qualitative study 
Background
Lebanon is witnessing an increased emigration of physicians. The objective of this study was to understand the perceptions of Lebanese policymakers of this emigration, and elicit their proposals for future policies and strategies to deal with this emigration.
Methods
We conducted semi-structured individual interviews with the deans of Lebanon’s seven medical schools, the presidents of the two physicians professional associations, and governmental officials. We analyzed the results qualitatively.
Results
Participants differed in the assessment of the extent and gravity of emigration. Lebanon has a surplus of physicians, driven largely by the over-production of graduates by a growing number of medical schools. Participants cited advantages and disadvantages of the emigration on the personal, financial, medical education system, healthcare system, and national levels. Proposed strategies included limiting the number of students entering medical schools, creating job opportunities for graduating students, and implementing quality standards. Most participants acknowledged the globalization of the Lebanese physician workforce, including exchanges with the Gulf region, exchanges with developed countries, and the involvement of North American medical education institutions in the region.
Conclusion
Many Lebanese policy makers, particularly deans of medical schools, perceive the emigration of the physician workforce as an opportunity in the context of the globalization of the profession.
doi:10.1186/1472-6963-12-135
PMCID: PMC3414743  PMID: 22646478
Emigration and immigration; Health manpower; Medical education; Physicians
25.  Evaluating patient values and preferences for thromboprophylaxis decision making during pregnancy: a study protocol 
Background
Pregnant women with prior venous thromboembolism (VTE) are at risk of recurrence. Low molecular weight heparin (LWMH) reduces the risk of pregnancy-related VTE. LMWH prophylaxis is, however, inconvenient, uncomfortable, costly, medicalizes pregnancy, and may be associated with increased risks of obstetrical bleeding. Further, there is uncertainty in the estimates of both the baseline risk of pregnancy-related recurrent VTE and the effects of antepartum LMWH prophylaxis. The values and treatment preferences of pregnant women, crucial when making recommendations for prophylaxis, are currently unknown. The objective of this study is to address this gap in knowledge.
Methods
We will perform a multi-center cross-sectional interview study in Canada, USA, Norway and Finland. The study population will consist of 100 women with a history of lower extremity deep vein thrombosis (DVT) or pulmonary embolism (PE), and who are either pregnant, planning pregnancy, or may in the future consider pregnancy (women between 18 and 45 years). We will exclude individuals who are on full dose anticoagulation or thromboprophylaxis, who have undergone surgical sterilization, or whose partners have undergone vasectomy. We will determine each participant's willingness to receive LMWH prophylaxis during pregnancy through direct choice exercises based on real life and hypothetical scenarios, preference-elicitation using a visual analog scale (“feeling thermometer”), and a probability trade-off exercise. The primary outcome will be the minimum reduction (threshold) in VTE risk at which women change from declining to accepting LMWH prophylaxis. We will explore possible determinants of this choice, including educational attainment, the characteristics of the women’s prior VTE, and prior experience with LMWH. We will determine the utilities that women place on the burden of LMWH prophylaxis, pregnancy-related DVT, pregnancy-related PE and pregnancy-related hemorrhage. We will generate a “personalized decision analysis” using participants’ utilities and their personalized risk of recurrent VTE as inputs to a decision analytic model. We will compare the personalized decision analysis to the participant’s stated choice.
Discussion
The preferences of pregnant women at risk of VTE with respect to the use of antithrombotic therapy remain unexplored. This research will provide explicit, quantitative expressions of women's valuations of health states related to recurrent VTE and its prevention with LMWH. This information will be crucial for both guideline developers and for clinicians.
doi:10.1186/1471-2393-12-40
PMCID: PMC3495041  PMID: 22646475

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