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1.  Specifying the target difference in the primary outcome for a randomised controlled trial: guidance for researchers 
Trials  2015;16:12.
Background
Central to the design of a randomised controlled trial is the calculation of the number of participants needed. This is typically achieved by specifying a target difference and calculating the corresponding sample size, which provides reassurance that the trial will have the required statistical power (at the planned statistical significance level) to identify whether a difference of a particular magnitude exists. Beyond pure statistical or scientific concerns, it is ethically imperative that an appropriate number of participants should be recruited. Despite the critical role of the target difference for the primary outcome in the design of randomised controlled trials, its determination has received surprisingly little attention. This article provides guidance on the specification of the target difference for the primary outcome in a sample size calculation for a two parallel group randomised controlled trial with a superiority question.
Methods
This work was part of the DELTA (Difference ELicitation in TriAls) project. Draft guidance was developed by the project steering and advisory groups utilising the results of the systematic review and surveys. Findings were circulated and presented to members of the combined group at a face-to-face meeting, along with a proposed outline of the guidance document structure, containing recommendations and reporting items for a trial protocol and report. The guidance and was subsequently drafted and circulated for further comment before finalisation.
Results
Guidance on specification of a target difference in the primary outcome for a two group parallel randomised controlled trial was produced. Additionally, a list of reporting items for protocols and trial reports was generated.
Conclusions
Specification of the target difference for the primary outcome is a key component of a randomized controlled trial sample size calculation. There is a need for better justification of the target difference and reporting of its specification.
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-014-0526-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s13063-014-0526-8
PMCID: PMC4302137
Target difference; clinically important difference; sample size; randomised controlled trial; guidance
2.  Perceived difficulty and appropriateness of decision making by General Practitioners: a systematic review of scenario studies 
Background
Health-care quality in primary care depends largely on the appropriateness of General Practitioners’ (GPs; Primary Care or Family Physicians) decisions, which may be influenced by how difficult they perceive decisions to be. Patient scenarios (clinical or case vignettes) are widely used to investigate GPs’ decision making. This review aimed to identify the extent to which perceived decision difficulty, decision appropriateness, and their relationship have been assessed in scenario studies of GPs’ decision making; identify possible determinants of difficulty and appropriateness; and investigate the relationship between difficulty and appropriateness.
Methods
MEDLINE, EMBASE, PsycINFO, the Cochrane Library and Web of Science were searched for scenario studies of GPs’ decision making. One author completed article screening. Ten percent of titles and abstracts were checked by an independent volunteer, resulting in 91% agreement. Data on decision difficulty and appropriateness were extracted by one author and descriptively synthesised. Chi-squared tests were used to explore associations between decision appropriateness, decision type and decision appropriateness assessment method.
Results
Of 152 included studies, 66 assessed decision appropriateness and five assessed perceived difficulty. While no studies assessed the relationship between perceived difficulty and appropriateness, one study objectively varied the difficulty of the scenarios and assessed the relationship between a measure of objective difficulty and appropriateness. Across 38 studies where calculations were possible, 62% of the decisions were appropriate as defined by the appropriateness standard used. Chi-squared tests identified statistically significant associations between decision appropriateness, decision type and decision appropriateness assessment method. Findings suggested a negative relationship between decision difficulty and appropriateness, while interventions may have the potential to reduce perceived difficulty.
Conclusions
Scenario-based research into GPs’ decisions rarely considers the relationship between perceived decision difficulty and decision appropriateness. The links between these decisional components require further investigation.
Electronic supplementary material
The online version of this article (doi:10.1186/s12913-014-0621-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s12913-014-0621-2
PMCID: PMC4258016  PMID: 25471752
Systematic review; Clinical decision making; Decision difficulty; Decision appropriateness; General Practitioner; Primary care physician; Patient scenario; Vignette
3.  The effects of on-screen, point of care computer reminders on processes and outcomes of care 
Background
The opportunity to improve care by delivering decision support to clinicians at the point of care represents one of the main incentives for implementing sophisticated clinical information systems. Previous reviews of computer reminder and decision support systems have reported mixed effects, possibly because they did not distinguish point of care computer reminders from e-mail alerts, computer-generated paper reminders, and other modes of delivering ‘computer reminders’.
Objectives
To evaluate the effects on processes and outcomes of care attributable to on-screen computer reminders delivered to clinicians at the point of care.
Search methods
We searched the Cochrane EPOC Group Trials register, MEDLINE, EMBASE and CINAHL and CENTRAL to July 2008, and scanned bibliographies from key articles.
Selection criteria
Studies of a reminder delivered via a computer system routinely used by clinicians, with a randomised or quasi-randomised design and reporting at least one outcome involving a clinical endpoint or adherence to a recommended process of care.
Data collection and analysis
Two authors independently screened studies for eligibility and abstracted data. For each study, we calculated the median improvement in adherence to target processes of care and also identified the outcome with the largest such improvement. We then calculated the median absolute improvement in process adherence across all studies using both the median outcome from each study and the best outcome.
Main results
Twenty-eight studies (reporting a total of thirty-two comparisons) were included. Computer reminders achieved a median improvement in process adherence of 4.2% (interquartile range (IQR): 0.8% to 18.8%) across all reported process outcomes, 3.3% (IQR: 0.5% to 10.6%) for medication ordering, 3.8% (IQR: 0.5% to 6.6%) for vaccinations, and 3.8% (IQR: 0.4% to 16.3%) for test ordering. In a sensitivity analysis using the best outcome from each study, the median improvement was 5.6% (IQR: 2.0% to 19.2%) across all process measures and 6.2% (IQR: 3.0% to 28.0%) across measures of medication ordering.
In the eight comparisons that reported dichotomous clinical endpoints, intervention patients experienced a median absolute improvement of 2.5% (IQR: 1.3% to 4.2%). Blood pressure was the most commonly reported clinical endpoint, with intervention patients experiencing a median reduction in their systolic blood pressure of 1.0 mmHg (IQR: 2.3 mmHg reduction to 2.0 mmHg increase).
Authors’ conclusions
Point of care computer reminders generally achieve small to modest improvements in provider behaviour. A minority of interventions showed larger effects, but no specific reminder or contextual features were significantly associated with effect magnitude. Further research must identify design features and contextual factors consistently associated with larger improvements in provider behaviour if computer reminders are to succeed on more than a trial and error basis.
doi:10.1002/14651858.CD001096.pub2
PMCID: PMC4171964  PMID: 19588323
*Decision Support Systems, Clinical; *Outcome and Process Assessment (Health Care); *Point-of-Care Systems; *Reminder Systems; Decision Making, Computer-Assisted; Humans
4.  The use of segmented regression in analysing interrupted time series studies: an example in pre-hospital ambulance care 
Background
An interrupted time series design is a powerful quasi-experimental approach for evaluating effects of interventions introduced at a specific point in time. To utilize the strength of this design, a modification to standard regression analysis, such as segmented regression, is required. In segmented regression analysis, the change in intercept and/or slope from pre- to post-intervention is estimated and used to test causal hypotheses about the intervention. We illustrate segmented regression using data from a previously published study that evaluated the effectiveness of a collaborative intervention to improve quality in pre-hospital ambulance care for acute myocardial infarction (AMI) and stroke. In the original analysis, a standard regression model was used with time as a continuous variable. We contrast the results from this standard regression analysis with those from segmented regression analysis. We discuss the limitations of the former and advantages of the latter, as well as the challenges of using segmented regression in analysing complex quality improvement interventions.
Findings
Based on the estimated change in intercept and slope from pre- to post-intervention using segmented regression, we found insufficient evidence of a statistically significant effect on quality of care for stroke, although potential clinically important effects for AMI cannot be ruled out.
Conclusions
Segmented regression analysis is the recommended approach for analysing data from an interrupted time series study. Several modifications to the basic segmented regression analysis approach are available to deal with challenges arising in the evaluation of complex quality improvement interventions.
doi:10.1186/1748-5908-9-77
PMCID: PMC4068621  PMID: 24943919
Interrupted time series design; Segmented regression analysis; Quality improvement collaborative
5.  Methods for Specifying the Target Difference in a Randomised Controlled Trial: The Difference ELicitation in TriAls (DELTA) Systematic Review 
PLoS Medicine  2014;11(5):e1001645.
Jonathan Cook and colleagues systematically reviewed the literature for methods of determining the target difference for use in calculating the necessary sample size for clinical trials, and discuss which methods are best for various types of trials.
Please see later in the article for the Editors' Summary
Background
Randomised controlled trials (RCTs) are widely accepted as the preferred study design for evaluating healthcare interventions. When the sample size is determined, a (target) difference is typically specified that the RCT is designed to detect. This provides reassurance that the study will be informative, i.e., should such a difference exist, it is likely to be detected with the required statistical precision. The aim of this review was to identify potential methods for specifying the target difference in an RCT sample size calculation.
Methods and Findings
A comprehensive systematic review of medical and non-medical literature was carried out for methods that could be used to specify the target difference for an RCT sample size calculation. The databases searched were MEDLINE, MEDLINE In-Process, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane Methodology Register, PsycINFO, Science Citation Index, EconLit, the Education Resources Information Center (ERIC), and Scopus (for in-press publications); the search period was from 1966 or the earliest date covered, to between November 2010 and January 2011. Additionally, textbooks addressing the methodology of clinical trials and International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) tripartite guidelines for clinical trials were also consulted. A narrative synthesis of methods was produced. Studies that described a method that could be used for specifying an important and/or realistic difference were included. The search identified 11,485 potentially relevant articles from the databases searched. Of these, 1,434 were selected for full-text assessment, and a further nine were identified from other sources. Fifteen clinical trial textbooks and the ICH tripartite guidelines were also reviewed. In total, 777 studies were included, and within them, seven methods were identified—anchor, distribution, health economic, opinion-seeking, pilot study, review of the evidence base, and standardised effect size.
Conclusions
A variety of methods are available that researchers can use for specifying the target difference in an RCT sample size calculation. Appropriate methods may vary depending on the aim (e.g., specifying an important difference versus a realistic difference), context (e.g., research question and availability of data), and underlying framework adopted (e.g., Bayesian versus conventional statistical approach). Guidance on the use of each method is given. No single method provides a perfect solution for all contexts.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
A clinical trial is a research study in which human volunteers are randomized to receive a given intervention or not, and outcomes are measured in both groups to determine the effect of the intervention. Randomized controlled trials (RCTs) are widely accepted as the preferred study design because by randomly assigning participants to groups, any differences between the two groups, other than the intervention under study, are due to chance. To conduct a RCT, investigators calculate how many patients they need to enroll to determine whether the intervention is effective. The number of patients they need to enroll depends on how effective the intervention is expected to be, or would need to be in order to be clinically important. The assumed difference between the two groups is the target difference. A larger target difference generally means that fewer patients need to be enrolled, relative to a smaller target difference. The target difference and number of patients enrolled contribute to the study's statistical precision, and the ability of the study to determine whether the intervention is effective. Selecting an appropriate target difference is important from both a scientific and ethical standpoint.
Why Was This Study Done?
There are several ways to determine an appropriate target difference. The authors wanted to determine what methods for specifying the target difference are available and when they can be used.
What Did the Researchers Do and Find?
To identify studies that used a method for determining an important and/or realistic difference, the investigators systematically surveyed the research literature. Two reviewers screened each of the abstracts chosen, and a third reviewer was consulted if necessary. The authors identified seven methods to determine target differences. They evaluated the studies to establish similarities and differences of each application. Points about the strengths and limitations of the method and how frequently the method was chosen were also noted.
What Do these Findings Mean?
The study draws attention to an understudied but important part of designing a clinical trial. Enrolling the right number of patients is very important—too few patients and the study may not be able to answer the study question; too many and the study will be more expensive and more difficult to conduct, and will unnecessarily expose more patients to any study risks. The target difference may also be helpful in interpreting the results of the trial. The authors discuss the pros and cons of different ways to calculate target differences and which methods are best for which types of studies, to help inform researchers designing such studies.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001645.
Wikipedia has an entry on sample size determination that discusses the factors that influence sample size calculation, including the target difference and the statistical power of a study (statistical power is the ability of a study to find a difference between treatments when a true difference exists). (Note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages.)
The University of Ottawa has an article that explains how different factors influence the power of a study
doi:10.1371/journal.pmed.1001645
PMCID: PMC4019477  PMID: 24824338
6.  Evaluating an audit and feedback intervention for reducing antibiotic prescribing behaviour in general dental practice (the RAPiD trial): a partial factorial cluster randomised trial protocol 
Background
Antibiotic prescribing in dentistry accounts for 9% of total antibiotic prescriptions in Scottish primary care. The Scottish Dental Clinical Effectiveness Programme (SDCEP) published guidance in April 2008 (2nd edition, August 2011) for Drug Prescribing in Dentistry, which aims to assist dentists to make evidence-based antibiotic prescribing decisions. However, wide variation in prescribing persists and the overall use of antibiotics is increasing.
Methods
RAPiD is a 12-month partial factorial cluster randomised trial conducted in NHS General Dental Practices across Scotland. Its aim is to compare the effectiveness of individualised audit and feedback (A&F) strategies for the translation into practice of SDCEP recommendations on antibiotic prescribing. The trial uses routinely collected electronic healthcare data in five aspects of its design in order to: identify the study population; apply eligibility criteria; carry out stratified randomisation; generate the trial intervention; analyse trial outcomes.
Eligibility was determined on contract status and a minimum level of recent NHS treatment provision. All eligible dental practices in Scotland were simultaneously randomised at baseline either to current audit practice or to an intervention group. Randomisation was stratified by single-handed/multi-handed practices. General dental practitioners (GDPs) working at intervention practices will receive individualised graphical representations of their antibiotic prescribing rate from the previous 14 months at baseline and an update at six months. GDPs could not be blinded to their practice allocation. Intervention practices were further randomised using a factorial design to receive feedback with or without: a health board comparator; a supplementary text-based intervention; additional feedback at nine months. The primary outcome is the total antibiotic prescribing rate per 100 courses of treatment over the year following delivery of the baseline intervention.
A concurrent qualitative process evaluation will apply theory-based approaches using the Consolidated Framework for Implementation Research to explore the acceptability of the interventions and the Theoretical Domains Framework to identify barriers and enablers to evidence-based antibiotic prescribing behaviour by GDPs.
Discussion
RAPiD will provide a robust evaluation of A&F in dentistry in Scotland. It also demonstrates that linked administrative datasets have the potential to be used efficiently and effectively across all stages of an randomised controlled trial.
Trial registration
Current Controlled Trials ISRCTN49204710
doi:10.1186/1748-5908-9-50
PMCID: PMC4108126  PMID: 24758164
Prescribing; Antibiotics; Dental
7.  Theoretical and empirical dimensions of the Aberdeen Glaucoma Questionnaire: a cross sectional survey and principal component analysis 
BMC Ophthalmology  2013;13:72.
Background
To develop patient-reported outcome instruments, statistical techniques (e.g., principal components analysis; PCA) are used to examine correlations among items and identify interrelated item subsets (empirical factors). However, interpretation and labelling of empirical factors is a subjective process, lacking precision or conceptual basis. We report a novel and reproducible method for mapping between theoretical and empirical factor structures. We illustrate the method using the pilot Aberdeen Glaucoma Questionnaire (AGQ), a new measure of glaucoma-related disability developed using the International Classification of Functioning and Disability (ICF) as a theoretical framework and tested in a sample representing the spectrum of glaucoma severity.
Methods
We used the ICF to code AGQ item content before mailing the AGQ to a UK sample (N = 1349) selected to represent people with a risk factor for glaucoma and people with glaucoma across a range of severity. Reflecting uncertainty in the theoretical framework (items with multiple ICF codes), an exploratory PCA was conducted. The theoretical structure informed our interpretation of the empirical structure and guided the selection of theoretically-derived factor labels. We also explored the discrimination of the AGQ across glaucoma severity groups.
Results
656 (49%) completed questionnaires were returned. The data yielded a 7-factor solution with a simple structure (using cut-off point of a loading of 0.5) that together accounted for 63% of variance in the scores. The mapping process resulted in allocation of the following theoretically-derived factor labels: 1) Seeing Functions: Participation; 2) Moving Around & Communication; 3) Emotional Functions; 4) Walking Around Obstacles; 5) Light; 6) Seeing Functions: Domestic & Social Life; 7) Mobility. Using the seven factor scores as independent variables in a discriminant function analysis, the AGQ scores resulted in correct glaucoma severity grading of 32.5% of participants (p < 0.001).
Conclusions
This paper addresses a methodological gap in the application of classical test theory (CTT) techniques, such as PCA, in instrument development. Labels for empirically-derived factors are often selected intuitively whereas they can inform existing bodies of knowledge if selected on the basis of theoretical construct labels, which are more explicitly defined and which relate to each other in ways that are evidence based.
doi:10.1186/1471-2415-13-72
PMCID: PMC4222643  PMID: 24268026
8.  IQuaD dental trial; improving the quality of dentistry: a multicentre randomised controlled trial comparing oral hygiene advice and periodontal instrumentation for the prevention and management of periodontal disease in dentate adults attending dental primary care 
BMC Oral Health  2013;13:58.
Background
Periodontal disease is the most common oral disease affecting adults, and although it is largely preventable it remains the major cause of poor oral health worldwide. Accumulation of microbial dental plaque is the primary aetiological factor for both periodontal disease and caries. Effective self-care (tooth brushing and interdental aids) for plaque control and removal of risk factors such as calculus, which can only be removed by periodontal instrumentation (PI), are considered necessary to prevent and treat periodontal disease thereby maintaining periodontal health. Despite evidence of an association between sustained, good oral hygiene and a low incidence of periodontal disease and caries in adults there is a lack of strong and reliable evidence to inform clinicians of the relative effectiveness (if any) of different types of Oral Hygiene Advice (OHA). The evidence to inform clinicians of the effectiveness and optimal frequency of PI is also mixed. There is therefore an urgent need to assess the relative effectiveness of OHA and PI in a robust, sufficiently powered randomised controlled trial (RCT) in primary dental care.
Methods/Design
This is a 5 year multi-centre, randomised, open trial with blinded outcome evaluation based in dental primary care in Scotland and the North East of England. Practitioners will recruit 1860 adult patients, with periodontal health, gingivitis or moderate periodontitis (Basic Periodontal Examination Score 0–3). Dental practices will be cluster randomised to provide routine OHA or Personalised OHA. To test the effects of PI each individual patient participant will be randomised to one of three groups: no PI, 6 monthly PI (current practice), or 12 monthly PI.
Baseline measures and outcome data (during a three year follow-up) will be assessed through clinical examination, patient questionnaires and NHS databases.
The primary outcome measures at 3 year follow up are gingival inflammation/bleeding on probing at the gingival margin; oral hygiene self-efficacy and net benefits.
Discussion
IQuaD will provide evidence for the most clinically-effective and cost-effective approach to managing periodontal disease in dentate adults in Primary Care. This will support general dental practitioners and patients in treatment decision making.
Trial registration
Protocol ID: ISRCTN56465715
doi:10.1186/1472-6831-13-58
PMCID: PMC4015981  PMID: 24160246
Oral hygiene advice; Scale and polish; Prevention; Toothbrushing advice; Periodontal instrumentation; RCT; Primary care
9.  Developing the specifications of an Open Angle Glaucoma screening intervention in the United Kingdom: a Delphi approach 
Background
Glaucoma is a leading cause of blindness. Early detection is advocated but there is insufficient evidence from randomized controlled trials (RCTs) to inform health policy on population screening. Primarily, there is no agreed screening intervention. For a screening programme, agreement is required on the screening tests to be used, either individually or in combination, the person to deliver the test and the location where testing should take place. This study aimed to use ophthalmologists (who were experienced glaucoma subspecialists), optometrists, ophthalmic nurses and patients to develop a reduced set of potential screening tests and testing arrangements that could then be explored in depth in a further study of their feasibility for evaluation in a glaucoma screening RCT.
Methods
A two-round Delphi survey involving 38 participants was conducted. Materials were developed from a prior evidence synthesis. For round one, after some initial priming questions in four domains, specialists were asked to nominate three screening interventions, the intervention being a combination of the four domains; target population, (age and higher risk groups), site, screening test and test operator (provider). More than 250 screening interventions were identified. For round two, responses were condensed into 72 interventions and each was rated by participants on a 0-10 scale in terms of feasibility.
Results
Using a cut-off of a median rating of feasibility of ≥5.5 as evidence of agreement of intervention feasibility, six interventions were identified from round 2. These were initiating screening at age 50, with a combination of two or three screening tests (varying combinations of tonometry/measures of visual function/optic nerve damage) organized in a community setting with an ophthalmic trained technical assistant delivering the tests. An alternative intervention was a ‘glaucoma risk score’ ascertained by questionnaire. The advisory panel recommended that further exploration of the feasibility of screening higher risk populations and detailed specification of the screening tests was required.
Conclusions
With systematic use of expert opinions, a shortlist of potential screening interventions was identified. Views of users, service providers and cost-effectiveness modeling are now required to identify a feasible intervention to evaluate in a future glaucoma screening trial.
doi:10.1186/1472-6963-12-447
PMCID: PMC3563574  PMID: 23216983
10.  A Questionnaire Elicitation of Surgeons’ Belief about Learning within a Surgical Trial 
PLoS ONE  2012;7(11):e49178.
Introduction
Surgeons gain expertise as they repeatedly conduct a procedure. Such learning is widely acknowledged to pose a challenge to evaluating new surgical procedures. Most surgical trials report little if any information on learning. We elicited surgeons’ belief regarding learning within the context of a randomised trial which assessed two surgical procedures.
Materials and Methods
Surgeons participating in the UKUFF trial were sent a postal questionnaire requesting details on current practice, prior experience and their belief regarding acquiring proficiency and the learning curve of operation time for two surgical procedures (open and arthroscopic rotator cuff repair).
Results
In total 52 (58%) participating surgeons returned a completed questionnaire. The median (IQR) number of procedures required to acquire proficiency were 17 (10,23) and 35 (23,50) for the open and arthroscopic repairs respectively. The distribution of surgeons’ belief regarding the initial point had median (IQR) of 109 (69,128) and 145 (97,171) minutes for open and arthroscopic repair respectively. Corresponding values for the plateau point were 60 (46, 82) and 79 (58, 110).
Conclusions
We have shown that information on the current practice, prior experience and beliefs on the learning process of a surgical procedure can be elicited using a short questionnaire. The approach could aid the interpretation of trial results in terms of generalisability and be used a priori in the design of a trial.
doi:10.1371/journal.pone.0049178
PMCID: PMC3493499  PMID: 23145113
11.  Expert Opinion on Laparoscopic Surgery for Colorectal Cancer Parallels Evidence from a Cumulative Meta-Analysis of Randomized Controlled Trials 
PLoS ONE  2012;7(4):e35292.
Background
This study sought to synthesize survival outcomes from trials of laparoscopic and open colorectal cancer surgery, and to determine whether expert acceptance of this technology in the literature has parallel cumulative survival evidence.
Study Design
A systematic review of randomized trials was conducted. The primary outcome was survival, and meta-analysis of time-to-event data was conducted. Expert opinion in the literature (published reviews, guidelines, and textbook chapters) on the acceptability of laparoscopic colorectal cancer was graded using a 7-point scale. Pooled survival data were correlated in time with accumulating expert opinion scores.
Results
A total of 5,800 citations were screened. Of these, 39 publications pertaining to 23 individual trials were retained. As well, 414 reviews were included (28 guidelines, 30 textbook chapters, 20 systematic reviews, 336 narrative reviews). In total, 5,782 patients were randomized to laparoscopic (n = 3,031) and open (n = 2,751) colorectal surgery. Survival data were presented in 16 publications. Laparoscopic surgery was not inferior to open surgery in terms of overall survival (HR = 0.94, 95% CI 0.80, 1.09). Expert opinion in the literature pertaining to the oncologic acceptability of laparoscopic surgery for colon cancer correlated most closely with the publication of large RCTs in 2002–2004. Although increasingly accepted since 2006, laparoscopic surgery for rectal cancer remained controversial.
Conclusions
Laparoscopic surgery for colon cancer is non-inferior to open surgery in terms of overall survival, and has been so since 2004. The majority expert opinion in the literature has considered these two techniques to be equivalent since 2002–2004. Laparoscopic surgery for rectal cancer has been increasingly accepted since 2006, but remains controversial. Knowledge translation efforts in this field appear to have paralleled the accumulation of clinical trial evidence.
doi:10.1371/journal.pone.0035292
PMCID: PMC3332109  PMID: 22532846
12.  Evidence base for an intervention to maximise uptake of glaucoma testing: a theory-based cross-sectional survey 
BMJ Open  2012;2(2):e000710.
Objective
To identify factors associated with intention to attend a hypothetical eye health test and provide an evidence base for developing an intervention to maximise attendance, for use in studies evaluating glaucoma screening programmes.
Design
Theory-based cross-sectional survey, based on an extended Theory of Planned Behaviour (TPB) and the Common Sense Self-Regulation Model, conducted in June 2010.
Participants
General population including oversampling from low socioeconomic areas.
Setting
Aberdeenshire and the London Boroughs of Lewisham and Southwark, UK.
Results
From 867 questionnaires posted, 327 completed questionnaires were returned (38%). In hierarchical regression analysis, the three theoretical predictors in the TPB (Attitude, Subjective norm and Perceived Behavioural Control) accounted for two-thirds of the variance in intention scores (adjusted R2=0.65). All three predictors contributed significantly to prediction. Adding ‘Anticipated regret’ as a factor in the TPB model resulted in a significant increase in prediction (adjusted R2=0.74). In the Common Sense Self-Regulation Model, only illness representations about the personal consequences of glaucoma (How much do you think glaucoma would affect your life?) and illness concern (How concerned are you about getting glaucoma?) significantly predicted. The final model explained 75% of the variance in intention scores, with ethnicity significantly contributing to prediction.
Conclusions
In this population-based sample (including over-representation of lower socioeconomic groupings), the main predictors of intention to attend a hypothetical eye health test were Attitude, Perceived control over attendance, Anticipated regret if did not attend and black ethnicity. This evidence informs the design of a behavioural intervention with intervention components targeting low intentions and predicted to influence health-related behaviours.
Article summary
Article focus
The current UK practice of opportunistic case finding during routine sight tests misses a majority of those with glaucoma. Early detection and treatment of glaucoma reduces the risk of blindness.
The feasibility and cost-effectiveness of screening programmes is largely determined by uptake by the target population.
This study identified empirical evidence, based on models of behaviour change, to inform the design of an intervention to maximise uptake.
Key messages
Intention to attend an eye health check to detect glaucoma is associated with positive Attitude, Perceived control over screening attendance, Anticipated regret if test is not attended, perceived consequences of glaucoma and black ethnicity. These factors can be targeted in an intervention to maximise uptake.
Strengths and limitations of this study
This study is the largest of its kind and uses a robust methodology based on plausible models of change to identify potential barriers to attendance for eye care.
The response rate was 38%, which is higher than generally achieved in similar population-based surveys.
There was evidence to suggest that this sample was representative of the target population (general population with over-representation of black ethnicity or of low socioeconomic status).
doi:10.1136/bmjopen-2011-000710
PMCID: PMC3293143  PMID: 22382121
13.  The quality of research synthesis in surgery: the case of laparoscopic surgery for colorectal cancer 
Systematic Reviews  2012;1:14.
Background
Several systematic reviews and meta-analyses populate the literature on the effectiveness of laparoscopic surgery for colorectal cancer. The utility of this body of work is unclear. The objective of this study was to synthesize all such systematic reviews in terms of clinical effectiveness, to appraise their quality, and to determine whether areas of duplication exist across reviews.
Methods
Systematic reviews comparing laparoscopic and open surgery for colorectal cancer were identified using a comprehensive search protocol (1991 to 2008). The primary outcome was overall survival. The methodological quality of reviews was appraised using the Assessment of Multiple Systematic Reviews (AMSTAR) instrument. Abstraction and quality appraisal was carried out by two independent reviewers. Reviews were synthesized, and outcomes were compared qualitatively. A citation analysis was carried out using simple matrices to assess the comprehensiveness of each review.
Results
In total, 27 reviews were included; 13 reviews included only randomized controlled trials. Rectal cancer was addressed exclusively by four reviews. There was significant overlap between review purposes, populations and, outcomes. The mean AMSTAR score (out of 11) was 5.8 (95% CI: 4.6 to 7.0). Overall survival was evaluated by ten reviews, none of which found a significant difference. Three reviews provided a selective meta-analysis of time-to-event data. Previously published systematic reviews were poorly and highly selectively referenced (mean citation ratio 0.16, 95% CI: 0.093 to 0.22). Previously published trials were not comprehensively identified and cited (mean citation ratio 0.56, 95% CI: 0.46 to 0.65).
Conclusions
Numerous overlapping systematic reviews of laparoscopic and open surgery for colorectal cancer exist in the literature. Despite variable methods and quality, survival outcomes are congruent across reviews. A duplication of research efforts appears to exist in the literature. Further systematic reviews or meta-analyses are unlikely to be justified without specifying a significantly different research objective. This works lends support to the registration and updating of systematic reviews.
doi:10.1186/2046-4053-1-14
PMCID: PMC3351744  PMID: 22588035
colorectal cancer; laparoscopy; surgery; systematic review; umbrella review
14.  Participation in physical play and leisure: developing a theory- and evidence-based intervention for children with motor impairments 
BMC Pediatrics  2011;11:100.
Background
Children with motor impairments (e.g. difficulties with motor control, muscle tone or balance) experience significant difficulties in participating in physical play and leisure. Current interventions are often poorly defined, lack explicit hypotheses about why or how they might work, and have insufficient evidence about effectiveness. This project will identify (i) the 'key ingredients' of an effective intervention to increase participation in physical play and leisure in children with motor impairments; and (ii) how these ingredients can be combined in a feasible and acceptable intervention.
Methods/Design
The project draws on the WHO International Classification of Functioning, Disability and Health and the UK Medical Research Council guidance for developing 'complex interventions'. There will be five steps: 1) identifying biomedical, personal and environmental factors proposed to predict children's participation in physical play and leisure; 2) developing an explicit model of the key predictors; 3) selecting intervention strategies to target the predictors, and specifying the pathways to change; 4) operationalising the strategies in a feasible and acceptable intervention; and 5) modelling the intervention processes and outcomes within single cases.
Discussion
The primary output from this project will be a detailed protocol for an intervention. The intervention, if subsequently found to be effective, will support children with motor difficulties to attain life-long well-being and participation in society. The project will also be an exemplar of methodology for a systematic development of non-drug interventions for children.
doi:10.1186/1471-2431-11-100
PMCID: PMC3219724  PMID: 22061203
15.  Randomised Controlled Feasibility Trial of an Evidence-Informed Behavioural Intervention for Obese Adults with Additional Risk Factors 
PLoS ONE  2011;6(8):e23040.
Background
Interventions for dietary and physical activity changes in obese adults may be less effective for participants with additional obesity-related risk factors and co-morbidities than for otherwise healthy individuals. This study aimed to test the feasibility and acceptability of the recruitment, allocation, measurement, retention and intervention procedures of a randomised controlled trial of an intervention to improve physical activity and dietary practices amongst obese adults with additional obesity related risk factors.
Method
Pilot single centre open-labelled outcome assessor-blinded randomised controlled trial of obese (Body Mass Index (BMI)≥30 kg/m2) adults (age≥18 y) with obesity related co-morbidities such as type 2 diabetes, impaired glucose tolerance or hypertension. Participants were randomly allocated to a manual-based group intervention or a leaflet control condition in accordance to a 2∶1 allocation ratio. Primary outcome was acceptability and feasibility of trial procedures, secondary outcomes included measures of body composition, physical activity, food intake and psychological process measures.
Results
Out of 806 potentially eligible individuals identified through list searches in two primary care general medical practices N = 81 participants (63% female; mean-age = 56.56(11.44); mean-BMI = 36.73(6.06)) with 2.35(1.47) co-morbidities were randomised. Scottish Index of Multiple Deprivation (SIMD) was the only significant predictor of providing consent to take part in the study (higher chances of consent for invitees with lower levels of deprivation). Participant flowcharts, qualitative and quantitative feedback suggested good acceptance and feasibility of intervention procedures but 34.6% of randomised participants were lost to follow-up due to overly high measurement burden and sub-optimal retention procedures. Participants in the intervention group showed positive trends for most psychological, behavioural and body composition outcomes.
Conclusions
The intervention procedures were found to be acceptable and feasible. Attrition rates were unacceptably high and areas for improvements of trial procedures were identified.
Trial Registration
Controlled-Trials.com ISRCTN90101501
doi:10.1371/journal.pone.0023040
PMCID: PMC3163575  PMID: 21897841
16.  Pre-validation methods for developing a patient reported outcome instrument 
Background
Measures that reflect patients' assessment of their health are of increasing importance as outcome measures in randomised controlled trials. The methodological approach used in the pre-validation development of new instruments (item generation, item reduction and question formatting) should be robust and transparent. The totality of the content of existing PRO instruments for a specific condition provides a valuable resource (pool of items) that can be utilised to develop new instruments. Such 'top down' approaches are common, but the explicit pre-validation methods are often poorly reported. This paper presents a systematic and generalisable 5-step pre-validation PRO instrument methodology.
Methods
The method is illustrated using the example of the Aberdeen Glaucoma Questionnaire (AGQ). The five steps are: 1) Generation of a pool of items; 2) Item de-duplication (three phases); 3) Item reduction (two phases); 4) Assessment of the remaining items' content coverage against a pre-existing theoretical framework appropriate to the objectives of the instrument and the target population (e.g. ICF); and 5) qualitative exploration of the target populations' views of the new instrument and the items it contains.
Results
The AGQ 'item pool' contained 725 items. Three de-duplication phases resulted in reduction of 91, 225 and 48 items respectively. The item reduction phases discarded 70 items and 208 items respectively. The draft AGQ contained 83 items with good content coverage. The qualitative exploration ('think aloud' study) resulted in removal of a further 15 items and refinement to the wording of others. The resultant draft AGQ contained 68 items.
Conclusions
This study presents a novel methodology for developing a PRO instrument, based on three sources: literature reporting what is important to patient; theoretically coherent framework; and patients' experience of completing the instrument. By systematically accounting for all items dropped after the item generation phase, our method ensures that the AGQ is developed in a transparent, replicable manner and is fit for validation. We recommend this method to enhance the likelihood that new PRO instruments will be appropriate to the research context in which they are used, acceptable to research participants and likely to generate valid data.
doi:10.1186/1471-2288-11-112
PMCID: PMC3225127  PMID: 21827689
17.  Using the theory of planned behaviour as a process evaluation tool in randomised trials of knowledge translation strategies: A case study from UK primary care 
Background
Randomised trials of knowledge translation strategies for professional behaviour change can provide robust estimates of effectiveness, but offer little insight into the causal mechanisms by which any change is produced. To illustrate the applicability of causal methods within randomised trials, we undertook a theory-based process evaluation study within an implementation trial to explore whether the cognitions of primary care doctors' predicted their test requesting behaviours and, secondly, whether the trial results were mediated by the theoretical constructs.
Methods
The process evaluation comprised a cross-sectional questionnaire survey of a random 50% sample of the randomised groups of primary care practices in Grampian (NHS Grampian), UK, who took part in a trial of the effect of enhanced feedback and brief educational reminders on test requesting behaviour. The process evaluation was based upon the Theory of Planned Behaviour and focussed on three of the test requesting behaviours that were targeted in the trial -- ferritin, follicle stimulating hormone (FSH), and Helicobacter Pylori serology (HPS).
Results
The questionnaire was completed by 131 primary care doctors (56%) from 42 (98%) of the sampled practices. Behavioural intention, attitude, and subjective norm were highly correlated for all the tests. There was no evidence that perceived behavioural control was correlated with any of the other measures. Simple linear regression analysis of the rate of test requests on minimum behavioural intentions had R2 of 11.1%, 12.5%, and 0.1% for ferritin, FSH, and HPS requesting, respectively. Mediational analysis showed that the trial results for ferritin and FSH were partially mediated (between 23% and 78% mediation) through intentions. The HPS trial result was not mediated through intention.
Conclusions
This study demonstrated that a theory-based process evaluation can provide useful information on causal mechanisms that aid not only interpretation of the trial but also inform future evaluations and intervention development.
doi:10.1186/1748-5908-5-71
PMCID: PMC2959079  PMID: 20920277
18.  The translation research in a dental setting (TRiaDS) programme protocol 
Background
It is well documented that the translation of knowledge into clinical practice is a slow and haphazard process. This is no less true for dental healthcare than other types of healthcare. One common policy strategy to help promote knowledge translation is the production of clinical guidance, but it has been demonstrated that the simple publication of guidance is unlikely to optimise practice. Additional knowledge translation interventions have been shown to be effective, but effectiveness varies and much of this variation is unexplained. The need for researchers to move beyond single studies to develop a generalisable, theory based, knowledge translation framework has been identified.
For dentistry in Scotland, the production of clinical guidance is the responsibility of the Scottish Dental Clinical Effectiveness Programme (SDCEP). TRiaDS (Translation Research in a Dental Setting) is a multidisciplinary research collaboration, embedded within the SDCEP guidance development process, which aims to establish a practical evaluative framework for the translation of guidance and to conduct and evaluate a programme of integrated, multi-disciplinary research to enhance the science of knowledge translation.
Methods
Set in General Dental Practice the TRiaDS programmatic evaluation employs a standardised process using optimal methods and theory. For each SDCEP guidance document a diagnostic analysis is undertaken alongside the guidance development process. Information is gathered about current dental care activities. Key recommendations and their required behaviours are identified and prioritised. Stakeholder questionnaires and interviews are used to identify and elicit salient beliefs regarding potential barriers and enablers towards the key recommendations and behaviours. Where possible routinely collected data are used to measure compliance with the guidance and to inform decisions about whether a knowledge translation intervention is required. Interventions are theory based and informed by evidence gathered during the diagnostic phase and by prior published evidence. They are evaluated using a range of experimental and quasi-experimental study designs, and data collection continues beyond the end of the intervention to investigate the sustainability of an intervention effect.
Discussion
The TRiaDS programmatic approach is a significant step forward towards the development of a practical, generalisable framework for knowledge translation research. The multidisciplinary composition of the TRiaDS team enables consideration of the individual, organisational and system determinants of professional behaviour change. In addition the embedding of TRiaDS within a national programme of guidance development offers a unique opportunity to inform and influence the guidance development process, and enables TRiaDS to inform dental services practitioners, policy makers and patients on how best to translate national recommendations into routine clinical activities.
doi:10.1186/1748-5908-5-57
PMCID: PMC2920875  PMID: 20646275
19.  Investigating the missing data mechanism in quality of life outcomes: a comparison of approaches 
Background
Missing data is classified as missing completely at random (MCAR), missing at random (MAR) or missing not at random (MNAR). Knowing the mechanism is useful in identifying the most appropriate analysis. The first aim was to compare different methods for identifying this missing data mechanism to determine if they gave consistent conclusions. Secondly, to investigate whether the reminder-response data can be utilised to help identify the missing data mechanism.
Methods
Five clinical trial datasets that employed a reminder system at follow-up were used. Some quality of life questionnaires were initially missing, but later recovered through reminders. Four methods of determining the missing data mechanism were applied. Two response data scenarios were considered. Firstly, immediate data only; secondly, all observed responses (including reminder-response).
Results
In three of five trials the hypothesis tests found evidence against the MCAR assumption. Logistic regression suggested MAR, but was able to use the reminder-collected data to highlight potential MNAR data in two trials.
Conclusion
The four methods were consistent in determining the missingness mechanism. One hypothesis test was preferred as it is applicable with intermittent missingness. Some inconsistencies between the two data scenarios were found. Ignoring the reminder data could potentially give a distorted view of the missingness mechanism. Utilising reminder data allowed the possibility of MNAR to be considered.
doi:10.1186/1477-7525-7-57
PMCID: PMC2711047  PMID: 19545408
20.  Can't do it, won't do it! Developing a theoretically framed intervention to encourage better decontamination practice in Scottish dental practices 
Background
Guidance on the cleaning of dental instruments in primary care has recently been published. The aims of this study are to determine if the publication of the guidance document was enough to influence decontamination best practice and to design an implementation intervention strategy, should it be required.
Methods
A postal questionnaire assessing current decontamination practice and beliefs was sent to a random sample of 200 general dental practitioners.
Results
Fifty-seven percent (N = 113) of general dental practitioners responded. The survey showed large variation in what dentists self-reported doing, perceived as necessary or practical to do, were willing to do, felt able to do, as well as what they planned to change. Only 15% self-reported compliance with the five key guideline-recommended individual-level decontamination behaviours; only 2% reported compliance with all 11 key practice-level behaviours. The results also showed that our participants were almost equally split between dentists who were completely unmotivated to implement best decontamination practice or else highly motivated. The results suggested there was scope for further enhancing the implementation of decontamination guidance, and that an intervention with the greatest likelihood of success would require a tailored format, specifically targeting components of the theory of planned behaviour (attitude, perceived behavioural control, intention) and implementation intention theory (action planning).
Conclusion
Considerable resources are devoted to encouraging clinicians to implement evidence-based practice using interventions with erratic success records, or no known applicability to a specific clinical behaviour, selected mainly by means of researchers' intuition or optimism. The methodology used to develop this implementation intervention is not limited to decontamination or to a single segment of primary care. It is also in accordance with the preliminary stages of the framework for evaluating complex interventions suggested by the medical research council. The next phases of this work are to test the intervention feasibility and evaluate its effectiveness in a randomised control trial.
doi:10.1186/1748-5908-4-31
PMCID: PMC2701915  PMID: 19500342
21.  Minimal access surgery compared with medical management for chronic gastro-oesophageal reflux disease: UK collaborative randomised trial 
Objective To determine the relative benefits and risks of laparoscopic fundoplication surgery as an alternative to long term drug treatment for chronic gastro-oesophageal reflux disease (GORD).
Design Multicentre, pragmatic randomised trial (with parallel preference groups).
Setting 21 hospitals in the United Kingdom.
Participants 357 randomised participants (178 surgical, 179 medical) and 453 preference participants (261, 192); mean age 46; 66% men. All participants had documented evidence of GORD and symptoms for >12 months.
Intervention The type of laparoscopic fundoplication used was left to the discretion of the surgeon. Those allocated to medical treatment had their treatment reviewed and adjusted as necessary by a local gastroenterologist, and subsequent clinical management was at the discretion of the clinician responsible for care.
Main outcome measures The disease specific REFLUX quality of life score (primary outcome), SF-36, EQ-5D, and medication use, measured at time points equivalent to three and 12 months after surgery, and surgical complications.
Main results Randomised participants had received drugs for GORD for median of 32 months before trial entry. Baseline REFLUX scores were 63.6 (SD 24.1) and 66.8 (SD 24.5) in the surgical and medical randomised groups, respectively. Of those randomised to surgery, 111 (62%) actually had total or partial fundoplication. Surgical complications were uncommon with a conversion rate of 0.6% and no mortality. By 12 months, 38% (59/154) randomised to surgery (14% (14/104) among those who had fundoplication) were taking reflux medication versus 90% (147/164) randomised medical management. The REFLUX score favoured the randomised surgical group (14.0, 95% confidence interval 9.6 to 18.4; P<0.001). Differences of a third to half of 1 SD in other health status measures also favoured the randomised surgical group. Baseline scores in the preference for surgery group were the worst; by 12 months these were better than in the preference for medical treatment group.
Conclusion At least up to 12 months after surgery, laparoscopic fundoplication significantly increased measures of health status in patients with GORD.
Trial registration ISRCTN15517081.
doi:10.1136/bmj.a2664
PMCID: PMC2603580  PMID: 19074946
22.  Recruitment to publicly funded trials — Are surgical trials really different? 
Contemporary Clinical Trials  2008;29(5):631-634.
Background
Good recruitment is integral to the conduct of a high-quality randomised controlled trial. It has been suggested that recruitment is particularly difficult for evaluations of surgical interventions, a field in which there is a dearth of evidence from randomised comparisons. While there is anecdotal speculation to support the inference that recruitment to surgical trials is more challenging than for medical trials we are unaware of any formal assessment of this. In this paper, we compare recruitment to surgical and medical trials using a cohort of publicly funded trials.
Data
Overall recruitment to trials was assessed using of a cohort of publicly funded trials (n = 114). Comparisons were made by using the Recruitment Index, a simple measure of recruitment activity for multicentre randomised controlled trials. Recruitment at the centre level was also investigated through three example surgical trials.
Results
The Recruitment Index was found to be higher, though not statistically significantly, in the surgical group (n = 18, median = 38.0 IQR (10.7, 77.4)) versus (n = 81, median = 34.8 IQR (11.7, 98.0)) days per recruit for the medical group (median difference 1.7 (− 19.2, 25.1); p = 0.828). For the trials where the comparison was between a surgical and a medical intervention, the Recruitment Index was substantially higher (n = 6, 68.3 (23.5, 294.8)) versus (n = 93, 34.6 (11.7, 90.0); median difference 25.9 (− 35.5, 221.8); p = 0.291) for the other trials.
Conclusions
There was no clear evidence that surgical trials differ from medical trials in terms of recruitment activity. There was, however, support for the inference that medical versus surgical trials are more difficult to recruit to. Formal exploration of the recruitment data through a modelling approach may go some way to tease out where important differences exist.
doi:10.1016/j.cct.2008.02.005
PMCID: PMC2669413  PMID: 18397843
Randomised controlled trials; Surgery; Recruitment; Publicly funded
23.  A review of RCTs in four medical journals to assess the use of imputation to overcome missing data in quality of life outcomes 
Trials  2008;9:51.
Background
Randomised controlled trials (RCTs) are perceived as the gold-standard method for evaluating healthcare interventions, and increasingly include quality of life (QoL) measures. The observed results are susceptible to bias if a substantial proportion of outcome data are missing. The review aimed to determine whether imputation was used to deal with missing QoL outcomes.
Methods
A random selection of 285 RCTs published during 2005/6 in the British Medical Journal, Lancet, New England Journal of Medicine and Journal of American Medical Association were identified.
Results
QoL outcomes were reported in 61 (21%) trials. Six (10%) reported having no missing data, 20 (33%) reported ≤ 10% missing, eleven (18%) 11%–20% missing, and eleven (18%) reported >20% missing. Missingness was unclear in 13 (21%). Missing data were imputed in 19 (31%) of the 61 trials. Imputation was part of the primary analysis in 13 trials, but a sensitivity analysis in six. Last value carried forward was used in 12 trials and multiple imputation in two. Following imputation, the most common analysis method was analysis of covariance (10 trials).
Conclusion
The majority of studies did not impute missing data and carried out a complete-case analysis. For those studies that did impute missing data, researchers tended to prefer simpler methods of imputation, despite more sophisticated methods being available.
doi:10.1186/1745-6215-9-51
PMCID: PMC3225816  PMID: 18694492
24.  Effect of multivitamin and multimineral supplementation on cognitive function in men and women aged 65 years and over: a randomised controlled trial 
Nutrition Journal  2007;6:10.
Background
Observational studies have frequently reported an association between cognitive function and nutrition in later life but randomised trials of B vitamins and antioxidant supplements have mostly found no beneficial effect. We examined the effect of daily supplementation with 11 vitamins and 5 minerals on cognitive function in older adults to assess the possibility that this could help to prevent cognitive decline.
Methods
The study was carried out as part of a randomised double blind placebo controlled trial of micronutrient supplementation based in six primary care health centres in North East Scotland. 910 men and women aged 65 years and over living in the community were recruited and randomised: 456 to active treatment and 454 to placebo. The active treatment consisted of a single tablet containing eleven vitamins and five minerals in amounts ranging from 50–210 % of the UK Reference Nutrient Intake or matching placebo tablet taken daily for 12 months. Digit span forward and verbal fluency tests, which assess immediate memory and executive functioning respectively, were conducted at the start and end of the intervention period. Risk of micronutrient deficiency at baseline was assessed by a simple risk questionnaire.
Results
For digit span forward there was no evidence of an effect of supplements in all participants or in sub-groups defined by age or risk of deficiency. For verbal fluency there was no evidence of a beneficial effect in the whole study population but there was weak evidence for a beneficial effect of supplementation in the two pre-specified subgroups: in those aged 75 years and over (n 290; mean difference between supplemented and placebo groups 2.8 (95% CI -0.6, 6.2) units) and in those at increased risk of micronutrient deficiency assessed by the risk questionnaire (n 260; mean difference between supplemented and placebo groups 2.5 (95% CI -1.0, 6.1) units).
Conclusion
The results provide no evidence for a beneficial effect of daily multivitamin and multimineral supplements on these domains of cognitive function in community-living people over 65 years. However, the possibility of beneficial effects in older people and those at greater risk of nutritional deficiency deserves further attention.
doi:10.1186/1475-2891-6-10
PMCID: PMC1872030  PMID: 17474991
25.  Effect of multivitamin and multimineral supplements on morbidity from infections in older people (MAVIS trial): pragmatic, randomised, double blind, placebo controlled trial 
BMJ : British Medical Journal  2005;331(7512):324-329.
Objective To examine whether supplementation with multivitamins and multiminerals influences self reported days of infection, use of health services, and quality of life in people aged 65 or over.
Design Randomised, placebo controlled trial, with blinding of participants, outcome assessors, and investigators.
Setting Communities associated with six general practices in Grampian, Scotland.
Participants 910 men and women aged 65 or over who did not take vitamins or minerals.
Interventions Daily multivitamin and multimineral supplementation or placebo for one year.
Main outcome measures Primary outcomes were contacts with primary care for infections, self reported days of infection, and quality of life. Secondary outcomes included antibiotic prescriptions, hospital admissions, adverse events, and compliance.
Results Supplementation did not significantly affect contacts with primary care and days of infection per person (incidence rate ratio 0.96, 95% confidence interval 0.78 to 1.19 and 1.07, 0.90 to 1.27). Quality of life was not affected by supplementation. No statistically significant findings were found for secondary outcomes or subgroups.
Conclusion Routine multivitamin and multimineral supplementation of older people living at home does not affect self reported infection related morbidity.
Trial registration ISRCTN: 66376460.
PMCID: PMC1183131  PMID: 16081445

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