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1.  Do Baseline P-Values Follow a Uniform Distribution in Randomised Trials? 
PLoS ONE  2013;8(10):e76010.
Background
The theory has been put forward that if a null hypothesis is true, P-values should follow a Uniform distribution. This can be used to check the validity of randomisation.
Method
The theory was tested by simulation for two sample t tests for data from a Normal distribution and a Lognormal distribution, for two sample t tests which are not independent, and for chi-squared and Fisher’s exact test using small and using large samples.
Results
For the two sample t test with Normal data the distribution of P-values was very close to the Uniform. When using Lognormal data this was no longer true, and the distribution had a pronounced mode. For correlated tests, even using data from a Normal distribution, the distribution of P-values varied from simulation run to simulation run, but did not look close to Uniform in any realisation. For binary data in a small sample, only a few probabilities were possible and distribution was very uneven. With a sample of two groups of 1,000 observations, there was great unevenness in the histogram and a poor fit to the Uniform.
Conclusions
The notion that P-values for comparisons of groups using baseline data in randomised clinical trials should follow a Uniform distribution if the randomisation is valid has been found to be true only in the context of independent variables which follow a Normal distribution, not for Lognormal data, correlated variables, or binary data using either chi-squared or Fisher’s exact tests. This should not be used as a check for valid randomisation.
doi:10.1371/journal.pone.0076010
PMCID: PMC3788030  PMID: 24098419
2.  Acupuncture and Counselling for Depression in Primary Care: A Randomised Controlled Trial 
PLoS Medicine  2013;10(9):e1001518.
In a randomized controlled trial, Hugh MacPherson and colleagues investigate the effectiveness of acupuncture and counseling compared with usual care alone for the treatment of depression symptoms in primary care settings.
Please see later in the article for the Editors' Summary
Background
Depression is a significant cause of morbidity. Many patients have communicated an interest in non-pharmacological therapies to their general practitioners. Systematic reviews of acupuncture and counselling for depression in primary care have identified limited evidence. The aim of this study was to evaluate acupuncture versus usual care and counselling versus usual care for patients who continue to experience depression in primary care.
Methods and Findings
In a randomised controlled trial, 755 patients with depression (Beck Depression Inventory BDI-II score ≥20) were recruited from 27 primary care practices in the North of England. Patients were randomised to one of three arms using a ratio of 2∶2∶1 to acupuncture (302), counselling (302), and usual care alone (151). The primary outcome was the difference in mean Patient Health Questionnaire (PHQ-9) scores at 3 months with secondary analyses over 12 months follow-up. Analysis was by intention-to-treat.
PHQ-9 data were available for 614 patients at 3 months and 572 patients at 12 months. Patients attended a mean of ten sessions for acupuncture and nine sessions for counselling. Compared to usual care, there was a statistically significant reduction in mean PHQ-9 depression scores at 3 months for acupuncture (−2.46, 95% CI −3.72 to −1.21) and counselling (−1.73, 95% CI −3.00 to −0.45), and over 12 months for acupuncture (−1.55, 95% CI −2.41 to −0.70) and counselling (−1.50, 95% CI −2.43 to −0.58). Differences between acupuncture and counselling were not significant. In terms of limitations, the trial was not designed to separate out specific from non-specific effects. No serious treatment-related adverse events were reported.
Conclusions
In this randomised controlled trial of acupuncture and counselling for patients presenting with depression, after having consulted their general practitioner in primary care, both interventions were associated with significantly reduced depression at 3 months when compared to usual care alone.
Trial Registration
Controlled-Trials.com ISRCTN63787732
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Depression–overwhelming sadness and hopelessness–is responsible for a substantial proportion of the global disease burden and is a major cause of suicide. It affects more than 350 million people worldwide and about one in six people will have an episode of depression during their lifetime. Depression is different from everyday mood fluctuations. For people who are clinically depressed, feelings of severe sadness, anxiety, hopelessness, and worthlessness can last for months and years. Affected individuals lose interest in activities they used to enjoy and sometimes have physical symptoms such as disturbed sleep. Clinicians can diagnose depression and determine its severity by asking patients to complete a questionnaire (for example, the Beck Depression Inventory [BDI-II] or the Patient Health Questionnaire 9 [PHQ-9]) about their feelings and symptoms. The answer to each question is given a score and the total score from the questionnaire (“depression rating scale”) indicates the severity of depression. Antidepressant drugs are usually the front-line treatment for depression in primary care.
Why Was This Study Done?
Unfortunately, antidepressants don't work for more than half of patients. Moreover, many patients would like to be offered non-pharmacological treatment options for depression such as acupuncture–a therapy originating from China in which fine needles are inserted into the skin at specific points of the body–and counseling–a “talking therapy” that provides patients with a safe, non-judgmental place to express feelings and emotions and that helps them recognize their capacity for growth and fulfillment. However, it is unclear whether either of these treatments is effective in depression. In this pragmatic randomized controlled trial, the researchers investigate the clinical effectiveness of acupuncture or counseling in patients with depression compared to usual care in primary care in northern England. A randomized controlled trial compares outcomes in groups of patients who are assigned to different interventions through the play of chance. A pragmatic trial asks whether the intervention works under real-life conditions. Patient selection reflects routine practice and some aspects of the intervention are left to the discretion of clinician, By contrast, an explanatory trial asks whether an intervention works under ideal conditions and involves a strict protocol for patient selection and treatment.
What Did the Researchers Do and Find?
The researchers recruited 755 patients who had consulted their primary health care provider about depression within the past 5 years and who had a score of more than 20 on the BDI-II–a score that is defined as moderate-to-severe depression on this depression rating scale–at the start of the study. Patients were randomized to receive up to 12 weekly sessions of acupuncture plus usual care (302 patients), up to 12 weekly sessions of counseling plus usual care (302 patients), or usual care alone (151 patients). Both the acupuncture protocol and the counseling protocols allowed for some individualization of treatment. Usual care, including antidepressants, was available according to need and monitored in all three groups. Compared to usual care alone, there was a significant reduction (a reduction unlikely to have occurred by chance) in the average PHQ-9 scores at both 3 and 6 months for both the acupuncture and counseling interventions. The difference between the mean PHQ-9 score for acupuncture and counseling was not significant. At 9 months and 12 months, because of improvements in the PHQ-9 scores in the usual care group, acupuncture and counseling were no longer significantly better than usual care.
What Do These Findings Mean?
These findings suggest that, compared to usual care alone, both acupuncture and counseling when provided alongside usual care provided significant benefits at 3 months in primary care to patients with recurring depression. Because this trial was a pragmatic trial, these findings cannot indicate which aspects of acupuncture and counseling are likely to be most or least beneficial. Nevertheless they do provide an estimate of the overall effects of these complex interventions, an estimate that is of most interest to patients, practitioners, and health care providers. Moreover, because this trial only considers the effect of these interventions on patients with moderate-to-severe depression as classified by the BDI-II; it provides no information about the effectiveness of acupuncture or counseling compared to usual care for patients with mild depression. Importantly, however, these findings suggest that further research into optimal treatment regimens for the treatment of depression with acupuncture and counseling is merited.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001518.
The US National Institute of Mental Health provides information on all aspects of depression (in English and Spanish)
The UK National Health Service Choices website provides detailed information about depression, including personal stories about depression, and information on counseling and acupuncture
The UK charity Mind provides information on depression, on talking treatments, and on complementary and alternative therapies including acupuncture; Mind also includes personal stories about depression on its website
More personal stories about depression are available from Healthtalkonline
MedlinePlus provides links to other resources about depression and about acupuncture (in English and Spanish)
doi:10.1371/journal.pmed.1001518
PMCID: PMC3782410  PMID: 24086114
3.  Copper Bracelets and Magnetic Wrist Straps for Rheumatoid Arthritis – Analgesic and Anti-Inflammatory Effects: A Randomised Double-Blind Placebo Controlled Crossover Trial 
PLoS ONE  2013;8(9):e71529.
Background
Folklore remedies for pain and inflammation in rheumatoid arthritis include the application of magnets and copper to the skin. Despite the popular use of devices containing magnets or copper for this purpose, little research has been conducted to evaluate the efficacy of such treatments.
Objective
To investigate whether the practice of wearing magnetic wrists straps, or copper bracelets, offers any specific therapeutic benefit for patients with rheumatoid arthritis.
Design
Randomised double-blind placebo-controlled crossover trial.
Methods
70 patients, aged 33 to 79 years and predominantly female (n = 52), with painful rheumatoid arthritis were recruited from general practices within Yorkshire. Participants were randomly allocated to wear four devices in a different order. Devices tested were: a standard (1502 to 2365 gauss) magnetic wrist strap, a demagnetised (<20 gauss) wrist strap, an attenuated (250 to 350 gauss) magnetic wrist strap, and a copper bracelet. Devices were each worn for five weeks, with treatment phases being separated by one week wash-out periods. The primary outcome measured was pain using a 100 mm visual analogue scale. Secondary pain measures were the McGill Pain Questionnaire and tender joint count. Inflammation was assessed using C-reactive protein and plasma viscosity blood tests and by swollen joint count. Physical function was assessed using the Health Assessment Questionnaire (Disability Index). Disease activity and medication use was also measured.
Results
65 participants provided complete self-report outcome data for all devices, four participants provided partial data. Analysis of treatment outcomes did not reveal any statistically significant differences (P>0.05) between the four devices in terms of their effects on pain, inflammation, physical function, disease activity, or medication use.
Conclusions
Wearing a magnetic wrist strap or a copper bracelet did not appear to have any meaningful therapeutic effect, beyond that of a placebo, for alleviating symptoms and combating disease activity in rheumatoid arthritis.
Trial Registration
Controlled-Trials.com ISRCTN51459023 ISRCTN51459023.
doi:10.1371/journal.pone.0071529
PMCID: PMC3774818  PMID: 24066023
4.  Comparison of Pooled Risk Estimates for Adverse Effects from Different Observational Study Designs: Methodological Overview 
PLoS ONE  2013;8(8):e71813.
Background
A diverse range of study designs (e.g. case-control or cohort) are used in the evaluation of adverse effects. We aimed to ascertain whether the risk estimates from meta-analyses of case-control studies differ from that of other study designs.
Methods
Searches were carried out in 10 databases in addition to reference checking, contacting experts, and handsearching key journals and conference proceedings. Studies were included where a pooled relative measure of an adverse effect (odds ratio or risk ratio) from case-control studies could be directly compared with the pooled estimate for the same adverse effect arising from other types of observational studies.
Results
We included 82 meta-analyses. Pooled estimates of harm from the different study designs had 95% confidence intervals that overlapped in 78/82 instances (95%). Of the 23 cases of discrepant findings (significant harm identified in meta-analysis of one type of study design, but not with the other study design), 16 (70%) stemmed from significantly elevated pooled estimates from case-control studies. There was associated evidence of funnel plot asymmetry consistent with higher risk estimates from case-control studies. On average, cohort or cross-sectional studies yielded pooled odds ratios 0.94 (95% CI 0.88–1.00) times lower than that from case-control studies.
Interpretation
Empirical evidence from this overview indicates that meta-analysis of case-control studies tend to give slightly higher estimates of harm as compared to meta-analyses of other observational studies. However it is impossible to rule out potential confounding from differences in drug dose, duration and populations when comparing between study designs.
doi:10.1371/journal.pone.0071813
PMCID: PMC3748094  PMID: 23977151
5.  Alexander Technique Lessons, Acupuncture Sessions or usual care for patients with chronic neck pain (ATLAS): study protocol for a randomised controlled trial 
Trials  2013;14:209.
Background
Chronic neck pain is a common condition in the adult population. More research is needed to evaluate interventions aiming to facilitate beneficial long-term change. We propose to evaluate the effect of Alexander Technique lessons and acupuncture in a rigorously conducted pragmatic trial with an embedded qualitative study.
Methods/Design
We will recruit 500 patients who have been diagnosed with neck pain in primary care, who have continued to experience neck pain for at least three months with 28% minimum cut-off score on the Northwick Park Neck Pain Questionnaire (NPQ). We will exclude patients with serious underlying pathology, prior cervical spine surgery, history of psychosis, rheumatoid arthritis, ankylosing spondylitis, osteoporosis, haemophilia, cancer, HIV or hepatitis, or with alcohol or drug dependency currently or in the last 12 months, or actively pursuing compensation or with pending litigation.
The York Trials Unit will randomly allocate participants using a secure computer-based system. We will use block randomisation with allocation to each intervention arm being unambiguously concealed from anyone who might subvert the randomisation process.
Participants will be randomised in equal proportions to Alexander Technique lessons, acupuncture or usual care alone. Twenty 30-minute Alexander Technique lessons will be provided by teachers registered with the Society of Teachers of the Alexander Technique and twelve 50-minute sessions of acupuncture will be provided by acupuncturists registered with the British Acupuncture Council. All participants will continue to receive usual GP care.
The primary outcome will be the NPQ at 12 months, with the secondary time point at 6 months, and an area-under-curve analysis will include 3, 6 and 12 month time-points. Adverse events will be documented. Potential intervention effect modifiers and mediators to be explored include: self-efficacy, stress management, and the incorporation of practitioner advice about self-care and lifestyle. Qualitative material will be used to address issues of safety, acceptability and factors that impact on longer term outcomes.
Discussion
This study will provide robust evidence on whether there are significant clinical benefits to patients, economic benefits demonstrating value for money, and sufficient levels of acceptability and safety.
Trial registration
Current Controlled Trials ISRCTN15186354
doi:10.1186/1745-6215-14-209
PMCID: PMC3720220  PMID: 23841901
6.  The effect of improving task representativeness on capturing nurses’ risk assessment judgements: a comparison of written case simulations and physical simulations 
Background
The validity of studies describing clinicians’ judgements based on their responses to paper cases is questionable, because - commonly used - paper case simulations only partly reflect real clinical environments. In this study we test whether paper case simulations evoke similar risk assessment judgements to the more realistic simulated patients used in high fidelity physical simulations.
Methods
97 nurses (34 experienced nurses and 63 student nurses) made dichotomous assessments of risk of acute deterioration on the same 25 simulated scenarios in both paper case and physical simulation settings. Scenarios were generated from real patient cases. Measures of judgement ‘ecology’ were derived from the same case records. The relationship between nurses’ judgements, actual patient outcomes (i.e. ecological criteria), and patient characteristics were described using the methodology of judgement analysis. Logistic regression models were constructed to calculate Lens Model Equation parameters. Parameters were then compared between the modeled paper-case and physical-simulation judgements.
Results
Participants had significantly less achievement (ra) judging physical simulations than when judging paper cases. They used less modelable knowledge (G) with physical simulations than with paper cases, while retaining similar cognitive control and consistency on repeated patients. Respiration rate, the most important cue for predicting patient risk in the ecological model, was weighted most heavily by participants.
Conclusions
To the extent that accuracy in judgement analysis studies is a function of task representativeness, improving task representativeness via high fidelity physical simulations resulted in lower judgement performance in risk assessments amongst nurses when compared to paper case simulations. Lens Model statistics could prove useful when comparing different options for the design of simulations used in clinical judgement analysis. The approach outlined may be of value to those designing and evaluating clinical simulations as part of education and training strategies aimed at improving clinical judgement and reasoning.
doi:10.1186/1472-6947-13-62
PMCID: PMC3674950  PMID: 23718556
Written case simulation; Physical simulation; Representative design; Clinical judgement analysis; Risk assessment; Lens model equation; Logistic regression; Clinical vignettes
7.  The effect of clinical experience, judgment task difficulty and time pressure on nurses’ confidence calibration in a high fidelity clinical simulation 
Background
Misplaced or poorly calibrated confidence in healthcare professionals’ judgments compromises the quality of health care. Using higher fidelity clinical simulations to elicit clinicians’ confidence 'calibration' (i.e. overconfidence or underconfidence) in more realistic settings is a promising but underutilized tactic. In this study we examine nurses’ calibration of confidence with judgment accuracy for critical event risk assessment judgments in a high fidelity simulated clinical environment. The study also explores the effects of clinical experience, task difficulty and time pressure on the relationship between confidence and accuracy.
Methods
63 student and 34 experienced nurses made dichotomous risk assessments on 25 scenarios simulated in a high fidelity clinical environment. Each nurse also assigned a score (0–100) reflecting the level of confidence in their judgments. Scenarios were derived from real patient cases and classified as easy or difficult judgment tasks. Nurses made half of their judgments under time pressure. Confidence calibration statistics were calculated and calibration curves generated.
Results
Nurse students were underconfident (mean over/underconfidence score −1.05) and experienced nurses overconfident (mean over/underconfidence score 6.56), P = 0.01. No significant differences in calibration and resolution were found between the two groups (P = 0.80 and P = 0.51, respectively). There was a significant interaction between time pressure and task difficulty on confidence (P = 0.008); time pressure increased confidence in easy cases but reduced confidence in difficult cases. Time pressure had no effect on confidence or accuracy. Judgment task difficulty impacted significantly on nurses’ judgmental accuracy and confidence. A 'hard-easy' effect was observed: nurses were overconfident in difficult judgments and underconfident in easy judgments.
Conclusion
Nurses were poorly calibrated when making risk assessment judgments in a high fidelity simulated setting. Nurses with more experience tended toward overconfidence. Whilst time pressure had little effect on calibration, nurses’ over/underconfidence varied significantly with the degree of task difficulty. More research is required to identify strategies to minimize such cognitive biases.
doi:10.1186/1472-6947-12-113
PMCID: PMC3547784  PMID: 23034048
High fidelity clinical simulation; Confidence calibration; Clinical experience; Overconfidence; Underconfidence; Time pressure; Clinical judgment; Hard-easy effect
9.  Meta-analyses of Adverse Effects Data Derived from Randomised Controlled Trials as Compared to Observational Studies: Methodological Overview 
PLoS Medicine  2011;8(5):e1001026.
Su Golder and colleagues carry out an overview of meta-analyses to assess whether estimates of the risk of harm outcomes differ between randomized trials and observational studies. They find that, on average, there is no difference in the estimates of risk between overviews of observational studies and overviews of randomized trials.
Background
There is considerable debate as to the relative merits of using randomised controlled trial (RCT) data as opposed to observational data in systematic reviews of adverse effects. This meta-analysis of meta-analyses aimed to assess the level of agreement or disagreement in the estimates of harm derived from meta-analysis of RCTs as compared to meta-analysis of observational studies.
Methods and Findings
Searches were carried out in ten databases in addition to reference checking, contacting experts, citation searches, and hand-searching key journals, conference proceedings, and Web sites. Studies were included where a pooled relative measure of an adverse effect (odds ratio or risk ratio) from RCTs could be directly compared, using the ratio of odds ratios, with the pooled estimate for the same adverse effect arising from observational studies. Nineteen studies, yielding 58 meta-analyses, were identified for inclusion. The pooled ratio of odds ratios of RCTs compared to observational studies was estimated to be 1.03 (95% confidence interval 0.93–1.15). There was less discrepancy with larger studies. The symmetric funnel plot suggests that there is no consistent difference between risk estimates from meta-analysis of RCT data and those from meta-analysis of observational studies. In almost all instances, the estimates of harm from meta-analyses of the different study designs had 95% confidence intervals that overlapped (54/58, 93%). In terms of statistical significance, in nearly two-thirds (37/58, 64%), the results agreed (both studies showing a significant increase or significant decrease or both showing no significant difference). In only one meta-analysis about one adverse effect was there opposing statistical significance.
Conclusions
Empirical evidence from this overview indicates that there is no difference on average in the risk estimate of adverse effects of an intervention derived from meta-analyses of RCTs and meta-analyses of observational studies. This suggests that systematic reviews of adverse effects should not be restricted to specific study types.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Whenever patients consult a doctor, they expect the treatments they receive to be effective and to have minimal adverse effects (side effects). To ensure that this is the case, all treatments now undergo exhaustive clinical research—carefully designed investigations that test new treatments and therapies in people. Clinical investigations fall into two main groups—randomized controlled trials (RCTs) and observational, or non-randomized, studies. In RCTs, groups of patients with a specific disease or condition are randomly assigned to receive the new treatment or a control treatment, and the outcomes (for example, improvements in health and the occurrence of specific adverse effects) of the two groups of patients are compared. Because the patients are randomly chosen, differences in outcomes between the two groups are likely to be treatment-related. In observational studies, patients who are receiving a specific treatment are enrolled and outcomes in this group are compared to those in a similar group of untreated patients. Because the patient groups are not randomly chosen, differences in outcomes between cases and controls may be the result of a hidden shared characteristic among the cases rather than treatment-related (so-called confounding variables).
Why Was This Study Done?
Although data from individual trials and studies are valuable, much more information about a potential new treatment can be obtained by systematically reviewing all the evidence and then doing a meta-analysis (so-called evidence-based medicine). A systematic review uses predefined criteria to identify all the research on a treatment; meta-analysis is a statistical method for combining the results of several studies to yield “pooled estimates” of the treatment effect (the efficacy of a treatment) and the risk of harm. Treatment effect estimates can differ between RCTs and observational studies, but what about adverse effect estimates? Can different study designs provide a consistent picture of the risk of harm, or are the results from different study designs so disparate that it would be meaningless to combine them in a single review? In this methodological overview, which comprises a systematic review and meta-analyses, the researchers assess the level of agreement in the estimates of harm derived from meta-analysis of RCTs with estimates derived from meta-analysis of observational studies.
What Did the Researchers Do and Find?
The researchers searched literature databases and reference lists, consulted experts, and hand-searched various other sources for studies in which the pooled estimate of an adverse effect from RCTs could be directly compared to the pooled estimate for the same adverse effect from observational studies. They identified 19 studies that together covered 58 separate adverse effects. In almost all instances, the estimates of harm obtained from meta-analyses of RCTs and observational studies had overlapping 95% confidence intervals. That is, in statistical terms, the estimates of harm were similar. Moreover, in nearly two-thirds of cases, there was agreement between RCTs and observational studies about whether a treatment caused a significant increase in adverse effects, a significant decrease, or no significant change (a significant change is one unlikely to have occurred by chance). Finally, the researchers used meta-analysis to calculate that the pooled ratio of the odds ratios (a statistical measurement of risk) of RCTs compared to observational studies was 1.03. This figure suggests that there was no consistent difference between risk estimates obtained from meta-analysis of RCT data and those obtained from meta-analysis of observational study data.
What Do These Findings Mean?
The findings of this methodological overview suggest that there is no difference on average in the risk estimate of an intervention's adverse effects obtained from meta-analyses of RCTs and from meta-analyses of observational studies. Although limited by some aspects of its design, this overview has several important implications for the conduct of systematic reviews of adverse effects. In particular, it suggests that, rather than limiting systematic reviews to certain study designs, it might be better to evaluate a broad range of studies. In this way, it might be possible to build a more complete, more generalizable picture of potential harms associated with an intervention, without any loss of validity, than by evaluating a single type of study. Such a picture, in combination with estimates of treatment effects also obtained from systematic reviews and meta-analyses, would help clinicians decide the best treatment for their patients.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001026.
The US National Institutes of Health provide information on clinical research; the UK National Health Service Choices Web site also has a page on clinical trials and medical research
The Cochrane Collaboration produces and disseminates systematic reviews of health-care interventions
Medline Plus provides links to further information about clinical trials (in English and Spanish)
doi:10.1371/journal.pmed.1001026
PMCID: PMC3086872  PMID: 21559325
10.  Acupuncture for irritable bowel syndrome: A protocol for a pragmatic randomised controlled trial 
BMC Gastroenterology  2010;10:63.
Background
There is insufficient evidence on the effectiveness of acupuncture for irritable bowel syndrome (IBS) for conclusions to be drawn. Given the current interest in acupuncture by patients, it is in the public interest to establish more rigorous evidence. Building on the positive findings from a pilot study, in this paper we present the protocol for a fully-powered trial designed to establish whether or not acupuncture is effective and cost-effective.
Methods/Design
In this pragmatic randomised controlled trial we will randomise patients recruited directly from GP databases to either 10 sessions of acupuncture plus usual GP care or to usual GP care alone. The primary clinical outcome will be the IBS Symptom Severity Score (SSS) (maximum score 500) at three months, and at 12 month assessing whether there is an overall benefit. We estimate the sample size required to detect a minimum clinical difference at 90% power and 5% significance to be 188 patients. To allow for loss to follow up we will recruit 220 patients drawn from an estimated primary care population of 140 000. Analysis will be by intention-to-treat, and multiple imputation is to be used for missing data.
In a nested qualitative study using in-depth interviews, we will explore how patients, acupuncturists, and GPs explain and subsequently understand acupuncture to work. We will use purposive sampling to identify patients and flexible topic guides for the interviews. The data analysis will lead to a thematic description of how patients and practitioners explain how acupuncture works, and whether or not the explanations influence treatment outcome and/or referrals.
We will undertake a cost-effectiveness analysis at 12 months by comparing resource use in the two groups with any treatment benefit. We will use the EQ-5D to measure health-related quality of life and convert into quality adjusted life years (QALYs). We will generate cost effectiveness acceptability curves (CEACs) exploring the probability that acupuncture will produce an acceptable cost per QALY at different cost-effectiveness thresholds.
Discussion
The trial has received NHS ethics approval and recruited 233 patients between November 2008 and June 2009. Results are expected in 2011.
Trial Registration
Current Controlled Trials ISRCTN08827905
doi:10.1186/1471-230X-10-63
PMCID: PMC2909152  PMID: 20565790
11.  Childhood obesity: should primary school children be routinely screened? A systematic review and discussion of the evidence 
Archives of Disease in Childhood  2007;92(5):416-422.
Background
Population monitoring has been introduced in UK primary schools in an effort to track the growing obesity epidemic. It has been argued that parents should be informed of their child's results, but is there evidence that moving from monitoring to screening would be effective? We describe what is known about the effectiveness of monitoring and screening for overweight and obesity in primary school children and highlight areas where evidence is lacking and research should be prioritised.
Design
Systematic review with discussion of evidence gaps and future research.
Data sources
Published and unpublished studies (any language) from electronic databases (inception to July 2005), clinical experts, Primary Care Trusts and Strategic Health Authorities, and reference lists of retrieved studies.
Review methods
We included any study that evaluated measures of overweight and obesity as part of a population‐level assessment and excluded studies whose primary outcome measure was prevalence.
Results
There were no trials assessing the effectiveness of monitoring or screening for overweight and obesity. Studies focussed on the diagnostic accuracy of measurements. Information on the attitudes of children, parents and health professionals to monitoring was extremely sparse.
Conclusions
Our review found a lack of data on the potential impact of population monitoring or screening for obesity and more research is indicated. Identification of effective weight reduction strategies for children and clarification of the role of preventative measures are priorities. It is difficult to see how screening to identify individual children can be justified without effective interventions.
doi:10.1136/adc.2006.113589
PMCID: PMC2083728  PMID: 17449522
obesity; overweight; monitoring; screening; BMI
12.  Screening and brief interventions for hazardous and harmful alcohol use in probation services: a cluster randomised controlled trial protocol 
BMC Public Health  2009;9:418.
Background
A large number of randomised controlled trials in health settings have consistently reported positive effects of brief intervention in terms of reductions in alcohol use. However, although alcohol misuse is common amongst offenders, there is limited evidence of alcohol brief interventions in the criminal justice field. This factorial pragmatic cluster randomised controlled trial with Offender Managers (OMs) as the unit of randomisation will evaluate the effectiveness and cost-effectiveness of different models of screening to identify hazardous and harmful drinkers in probation and different intensities of brief intervention to reduce excessive drinking in probation clients.
Methods and design
Ninety-six OMs from 9 probation areas across 3 English regions (the North East Region (n = 4) and London and the South East Regions (n = 5)) will be recruited. OMs will be randomly allocated to one of three intervention conditions: a client information leaflet control condition (n = 32 OMs); 5-minute simple structured advice (n = 32 OMs) and 20-minute brief lifestyle counselling delivered by an Alcohol Health Worker (n = 32 OMs). Randomisation will be stratified by probation area. To test the relative effectiveness of different screening methods all OMs will be randomised to either the Modified Single Item Screening Questionnaire (M-SASQ) or the Fast Alcohol Screening Test (FAST). There will be a minimum of 480 clients recruited into the trial. There will be an intention to treat analysis of study outcomes at 6 and 12 months post intervention. Analysis will include client measures (screening result, weekly alcohol consumption, alcohol-related problems, re-offending, public service use and quality of life) and implementation measures from OMs (the extent of screening and brief intervention beyond the minimum recruitment threshold will provide data on acceptability and feasibility of different models of brief intervention). We will also examine the practitioner and organisational factors associated with successful implementation.
Discussion
The trial will evaluate the impact of screening and brief alcohol intervention in routine probation work and therefore its findings will be highly relevant to probation teams and thus the criminal justice system in the UK.
Ethical approval was given by Northern & Yorkshire REC
Trial Registration number
ISRCTN 19160244
doi:10.1186/1471-2458-9-418
PMCID: PMC2784463  PMID: 19922618
13.  Screening and brief interventions for hazardous and harmful alcohol use in primary care: a cluster randomised controlled trial protocol 
BMC Public Health  2009;9:287.
Background
There have been many randomized controlled trials of screening and brief alcohol intervention in primary care. Most trials have reported positive effects of brief intervention, in terms of reduced alcohol consumption in excessive drinkers. Despite this considerable evidence-base, key questions remain unanswered including: the applicability of the evidence to routine practice; the most efficient strategy for screening patients; and the required intensity of brief intervention in primary care. This pragmatic factorial trial, with cluster randomization of practices, will evaluate the effectiveness and cost-effectiveness of different models of screening to identify hazardous and harmful drinkers in primary care and different intensities of brief intervention to reduce excessive drinking in primary care patients.
Methods and design
GPs and nurses from 24 practices across the North East (n = 12), London and South East (n = 12) of England will be recruited. Practices will be randomly allocated to one of three intervention conditions: a leaflet-only control group (n = 8); brief structured advice (n = 8); and brief lifestyle counselling (n = 8). To test the relative effectiveness of different screening methods all practices will also be randomised to either a universal or targeted screening approach and to use either a modified single item (M-SASQ) or FAST screening tool. Screening randomisation will incorporate stratification by geographical area and intervention condition. During the intervention stage of the trial, practices in each of the three arms will recruit at least 31 hazardous or harmful drinkers who will receive a short baseline assessment followed by brief intervention. Thus there will be a minimum of 744 patients recruited into the trial.
Discussion
The trial will evaluate the impact of screening and brief alcohol intervention in routine practice; thus its findings will be highly relevant to clinicians working in primary care in the UK. There will be an intention to treat analysis of study outcomes at 6 and 12 months after intervention. Analyses will include patient measures (screening result, weekly alcohol consumption, alcohol-related problems, public service use and quality of life) and implementation measures from practice staff (the acceptability and feasibility of different models of brief intervention.) We will also examine organisational factors associated with successful implementation.
Trial registration
Current Controlled Trials ISRCTN06145674.
doi:10.1186/1471-2458-9-287
PMCID: PMC2734851  PMID: 19664255
14.  Screening and brief interventions for hazardous alcohol use in accident and emergency departments: a randomised controlled trial protocol 
Background
There is a wealth of evidence regarding the detrimental impact of excessive alcohol consumption on the physical, psychological and social health of the population. There also exists a substantial evidence base for the efficacy of brief interventions aimed at reducing alcohol consumption across a range of healthcare settings. Primary research conducted in emergency departments has reinforced the current evidence regarding the potential effectiveness and cost-effectiveness. Within this body of evidence there is marked variation in the intensity of brief intervention delivered, from very minimal interventions to more intensive behavioural or lifestyle counselling approaches. Further the majority of primary research has been conducted in single centre and there is little evidence of the wider issues of generalisability and implementation of brief interventions across emergency departments.
Methods/design
The study design is a prospective pragmatic factorial cluster randomised controlled trial. Individual Emergency Departments (ED) (n = 9) are randomised with equal probability to a combination of screening tool (M-SASQ vs FAST vs SIPS-PAT) and an intervention (Minimal intervention vs Brief advice vs Brief lifestyle counselling). The primary hypothesis is that brief lifestyle counselling delivered by an Alcohol Health Worker (AHW) is more effective than Brief Advice or a minimal intervention delivered by ED staff. Secondary hypotheses address whether short screening instruments are more acceptable and as efficient as longer screening instruments and the cost-effectiveness of screening and brief interventions in ED. Individual participants will be followed up at 6 and 12 months after consent. The primary outcome measure is performance using a gold-standard screening test (AUDIT). Secondary outcomes include; quantity and frequency of alcohol consumed, alcohol-related problems, motivation to change, health related quality of life and service utilisation.
Discussion
This paper presents a protocol for a large multi-centre pragmatic factorial cluster randomised trial to evaluate the effectiveness and cost-effectiveness of screening and brief interventions for hazardous alcohol users attending emergency departments.
Trial Registration
ISRCTN 93681536
doi:10.1186/1472-6963-9-114
PMCID: PMC2712466  PMID: 19575791
15.  The effectiveness and cost-effectiveness of opportunistic screening and stepped care interventions for older hazardous alcohol users in primary care (AESOPS) – A randomised control trial protocol 
Background
There is a wealth of evidence regarding the detrimental impact of excessive alcohol consumption. In older populations excessive alcohol consumption is associated with increased risk of coronary heart disease, hypertension, stroke and a range of cancers. Alcohol consumption is also associated with an increased risk of falls, early onset of dementia and other cognitive deficits. Physiological changes that occur as part of the ageing process mean that older people experience alcohol related problems at lower consumption levels. There is a strong evidence base for the effectiveness of brief psychosocial interventions in reducing alcohol consumption in populations identified opportunistically in primary care settings. Stepped care interventions involve the delivery of more intensive interventions only to those in the population who fail to respond to less intensive interventions and provide a potentially resource efficient means of meeting the needs of this population.
Methods/design
The study design is a pragmatic prospective multi-centre two arm randomised controlled trial. The primary hypothesis is that stepped care interventions for older hazardous alcohol users reduce alcohol consumption compared with a minimal intervention at 12 months post randomisation. Potential participants are identified using the AUDIT questionnaire. Eligible and consenting participants are randomised with equal probability to either a minimal intervention or a three step treatment approach. The step treatment approach incorporates as step 1 behavioural change counselling, step 2 three sessions of motivational enhancement therapy and step 3 referral to specialist services. The primary outcome is measured using average standard drinks per day and secondary outcome measures include the Drinking Problems Index, health related quality of life and health utility. The study incorporates a comprehensive economic analysis to assess the relative cost-effectiveness of the interventions.
Discussion
The paper presents a protocol for the first pragmatic randomised controlled trial evaluating the effectiveness and cost-effectiveness of stepped care interventions for older hazardous alcohol users in primary care.
Trial registration
ISRCTN52557360
doi:10.1186/1472-6963-8-129
PMCID: PMC2442836  PMID: 18549492
16.  Acupuncture for chronic neck pain: a pilot for a randomised controlled trial 
Background
Acupuncture is increasingly being used for many conditions including chronic neck pain. However the evidence remains inconclusive, indicating the need for further well-designed research. The aim of this study was to conduct a pilot randomised controlled parallel arm trial, to establish key features required for the design and implementation of a large-scale trial on acupuncture for chronic neck pain.
Methods
Patients whose GPs had diagnosed neck pain were recruited from one general practice, and randomised to receive usual GP care only, or acupuncture (up to 10 treatments over 3 months) as an adjunctive treatment to usual GP care. The primary outcome measure was the Northwick Park Neck Pain Questionnaire (NPQ) at 3 months. The primary analysis was to determine the sample size for the full scale study.
Results
Of the 227 patients with neck pain identified from the GP database, 28 (12.3%) consenting patients were eligible to participate in the pilot and 24 (10.5%) were recruited to the trial. Ten patients were randomised to acupuncture, receiving an average of eight treatments from one of four acupuncturists, and 14 were randomised to usual GP care alone. The sample size for the full scale trial was calculated from a clinically meaningful difference of 5% on the NPQ and, from this pilot, an adjusted standard deviation of 15.3%. Assuming 90% power at the 5% significance level, a sample size of 229 would be required in each arm in a large-scale trial when allowing for a loss to follow-up rate of 14%. In order to achieve this sample, one would need to identify patients from databases of GP practices with a total population of 230,000 patients, or approximately 15 GP practices roughly equal in size to the one involved in this study (i.e. 15,694 patients).
Conclusion
This pilot study has allowed a number of recommendations to be made to facilitate the design of a large-scale trial, which in turn will help to clarify the existing evidence base on acupuncture for neck pain.
doi:10.1186/1471-2474-7-99
PMCID: PMC1713236  PMID: 17156464
17.  Retrospective cohort study of false alarm rates associated with a series of heart operations: the case for hospital mortality monitoring groups 
BMJ : British Medical Journal  2004;328(7436):375.
Objective To examine the efficacy of different methods of detecting a high death rate and determining whether an increase in deaths after heart transplantation could be explained by chance.
Design Retrospective analysis of deaths after heart transplantation. Seven methods were used: mortality above national average, mortality excessively above national average, test of moving average mortality, test of number of consecutive deaths, sequential probability ratio test (SPRT), cusum graph with v-mask, and CRAM chart. The national average mortality was not available and a rate of 15% was used instead as the benchmark.
Setting Regional cardiothoracic unit.
Participants All 371 patients who received a heart transplant in the programme, 1986-2000.
Main outcome measures 30 day survival after transplantation.
Results All methods provided evidence that the 30 day mortality had been high at some stage. The probability that the finding was a false positive depended on which test was used. At the end of the series the average mortality, sequential probability ratio, and cusum tests indicated a level of deaths higher than the benchmark while the remaining four tests yielded negative results.
Conclusions If the decision to test for outlying mortality is made retrospectively, in the light of the data, it is not possible to determine the false positive rate. Prospective on-site mortality monitoring with the CRAM chart is recommended as this method can quantify the death rate and identify periods when an audit of cases is indicated, even when data from other institutions are not available. A hospital mortality monitoring group can routinely monitor all deaths in the hospital, by specialty, using hospital episode statistics (HES) data and appropriate statistical methods.
doi:10.1136/bmj.37956.520567.44
PMCID: PMC341384  PMID: 14751918
18.  WMA should not retreat on use of placebos 
BMJ : British Medical Journal  2002;324(7331):240.
PMCID: PMC1122151  PMID: 11809661
20.  Fatigue and psychological distress  
BMJ : British Medical Journal  2000;320(7233):515.
PMCID: PMC1127546  PMID: 10678880
25.  Effectiveness of screening and brief alcohol intervention in primary care (SIPS trial): pragmatic cluster randomised controlled trial 
Objective To evaluate the effectiveness of different brief intervention strategies at reducing hazardous or harmful drinking in primary care. The hypothesis was that more intensive intervention would result in a greater reduction in hazardous or harmful drinking.
Design Pragmatic cluster randomised controlled trial.
Setting Primary care practices in the north east and south east of England and in London.
Participants 3562 patients aged 18 or more routinely presenting in primary care, of whom 2991 (84.0%) were eligible to enter the trial: 900 (30.1%) screened positive for hazardous or harmful drinking and 756 (84.0%) received a brief intervention. The sample was predominantly male (62%) and white (92%), and 34% were current smokers.
Interventions Practices were randomised to three interventions, each of which built on the previous one: a patient information leaflet control group, five minutes of structured brief advice, and 20 minutes of brief lifestyle counselling. Delivery of the patient leaflet and brief advice occurred directly after screening and brief lifestyle counselling in a subsequent consultation.
Main outcome measures The primary outcome was patients’ self reported hazardous or harmful drinking status as measured by the alcohol use disorders identification test (AUDIT) at six months. A negative AUDIT result (score <8) indicated non-hazardous or non-harmful drinking. Secondary outcomes were a negative AUDIT result at 12 months, experience of alcohol related problems (alcohol problems questionnaire), health utility (EQ-5D), service utilisation, and patients’ motivation to change drinking behaviour (readiness to change) as measured by a modified readiness ruler.
Results Patient follow-up rates were 83% at six months (n=644) and 79% at 12 months (n=617). At both time points an intention to treat analysis found no significant differences in AUDIT negative status between the three interventions. Compared with the patient information leaflet group, the odds ratio of having a negative AUDIT result for brief advice was 0.85 (95% confidence interval 0.52 to 1.39) and for brief lifestyle counselling was 0.78 (0.48 to 1.25). A per protocol analysis confirmed these findings.
Conclusions All patients received simple feedback on their screening outcome. Beyond this input, however, evidence that brief advice or brief lifestyle counselling provided important additional benefit in reducing hazardous or harmful drinking compared with the patient information leaflet was lacking.
Trial registration Current Controlled Trials ISRCTN06145674.
doi:10.1136/bmj.e8501
PMCID: PMC3541471  PMID: 23303891

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