Specifying the target difference in the primary outcome for a randomised controlled trial: guidance for researchers.

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 Draft guidance was developed by the project steering and advisory groups utilising the results of the systematic review and surveys.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.

Methods for specifying the target difference in a randomised controlled trial: the Difference ELicitation in TriAls (DELTA) systematic review.

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.

Use of methods for specifying the target difference in randomised controlled trial sample size calculations: Two surveys of trialists' practice.

BACKGROUND: Central to the design of a randomised controlled trial (RCT) is a calculation of the number of participants needed. This is typically achieved by specifying a target difference, which enables the trial to identify a difference of a particular magnitude should one exist. Seven methods have been proposed for formally determining what the target difference should be. However, in practice, it may be driven by convenience or some other informal basis. It is unclear how aware the trialist community is of these formal methods or whether they are used. PURPOSE: To determine current practice regarding the specification of the target difference by surveying trialists. METHODS: Two surveys were conducted: (1) Members of the Society for Clinical Trials (SCT): participants were invited to complete an online survey through the society's email distribution list. Respondents were asked about their awareness, use of, and willingness to recommend methods; (2) Leading UK- and Ireland-based trialists: the survey was sent to UK Clinical Research Collaboration registered Clinical Trials Units, Medical Research Council UK Hubs for Trial Methodology Research, and the Research Design Services of the National Institute for Health Research. This survey also included questions about the most recent trial developed by the respondent's group. RESULTS: Survey 1: Of the 1182 members on the SCT membership email distribution list, 180 responses were received (15%). Awareness of methods ranged from 69 (38%) for health economic methods to 162 (90%) for pilot study. Willingness to recommend among those who had used a particular method ranged from 56% for the opinion-seeking method to 89% for the review of evidence-base method. Survey 2: Of the 61 surveys sent out, 34 (56%) responses were received. Awareness of methods ranged from 33 (97%) for the review of evidence-base and pilot methods to 14 (41%) for the distribution method. The highest level of willingness to recommend among users was for the anchor method (87%). Based upon the most recent trial, the target difference was usually one viewed as important by a stakeholder group, mostly also viewed as a realistic difference given the interventions under evaluation, and sometimes one that led to an achievable sample size. LIMITATIONS: The response rates achieved were relatively low despite the surveys being short, well presented, and having utilised reminders. CONCLUSION: Substantial variations in practice exist with awareness, use, and willingness to recommend methods varying substantially. The findings support the view that sample size calculation is a more complex process than would appear to be the case from trial reports and protocols. Guidance on approaches for sample size estimation may increase both awareness and use of appropriate formal methods.

Road traffic crashes and the protective effect of road curvature over small areas.

Road bends are known to cause traffic crashes, but the hypothesis in this study was that small geographical areas with many road bends have less, not more, road casualties than comparable areas with fewer bends. Data on road crashes involving fatal, serious and slight casualties in 571 wards in Eastern England were examined against four measures of average road curvature (mean angle per bend, cumulative angle per km, number of bends per km and ratio of road distance to straight distance) using regression analysis. Taking account of other risk factors, measures of average road curvature in wards were negatively associated with crash numbers, especially for fatal crashes. The strongest associations were with the cumulative angle turned per km. The results add to evidence suggesting that road casualty risk effects vary with geographical scale. Although individual road bends might be hazardous, frequent bends have a protective effect over a few kilometres of road.

Self-reported mental health-related quality of life and mortality in men and women in the European Prospective Investigation into Cancer (EPIC-Norfolk): a prospective population study.

OBJECTIVE: To explore the relationship between self-reported mental functional health and mortality. METHODS: Participants included 17,777 men and women aged 40 to 79 years at baseline who lived in Norfolk, UK, and had no known cardiovascular disease or cancer, and completed the anglicized Short Form 36-item questionnaire (UK SF-36) during 1996 to 2000 in the European Prospective Investigation into Cancer-Norfolk prospective population study. We examined the relationship between mental functional health derived from the mental component summary scores of the SF-36 and mortality from all causes, cardiovascular disease, cancer, and other causes during an average 6.5-year follow-up. RESULTS: There were 1065 deaths during a total of 115,550 person-years of follow-up. Impaired mental health-related quality of life was associated with increased risk of all-cause mortality in men and women. A decrease of 1 SD (10 points) in SF-36 mental component summary scores was associated with a 14% increase in all-cause mortality (hazards ratio = 1.14; 95% Confidence Interval: 1.07, 1.21) after controlling for age, gender, body mass index, systolic blood pressure, cholesterol, alcohol consumption, diabetes, smoking, social class, and physical functional health. CONCLUSION: Poor self-reported mental functional health is related to increased risk of all-cause mortality in men and women. Interpretation of this association requires further investigation.

Fruit and vegetable consumption and self-reported functional health in men and women in the European Prospective Investigation into Cancer-Norfolk (EPIC-Norfolk): a population-based cross-sectional study.

OBJECTIVES: To investigate the association between fruit and vegetable consumption and self-reported physical and mental functional health measured by an anglicised short-form 36-item questionnaire (UK SF-36). DESIGN: Population-based cross-sectional study. SETTING: General community in Norfolk, UK. SUBJECTS: A total of 16,792 men and women aged 40-79 years recruited from general practice population registers as part of the European Prospective Investigation into Cancer (EPIC)-Norfolk study, who completed food-frequency questionnaires in 1993-1997 and Health and Life Experiences Questionnaires 18 months later, were enrolled in the study. RESULTS: Mean SF-36 physical component summary scores increased significantly with increasing total fruit and vegetable consumption in both men and women (P < 0.0001 for trend). Men and women in the top quartile of consumption compared with the bottom quartile had a significantly higher likelihood of reporting good physical health (defined as a score > or = 55); odds ratio (OR) 1.30, 95% confidence interval (CI) 1.11-1.53 for men and OR 1.28, 95% CI 1.11-1.48 for women, after controlling for age, body mass index, smoking, education, social class, prevalent illness and total energy intake. Exclusion of current smokers and people with prevalent illness did not alter the associations. CONCLUSION: Higher fruit and vegetable consumption is associated with better self-reported physical functional health within a general population. Increasing daily intake by two portions of fruit and vegetables was associated with an 11% higher likelihood of good functional health. Since the current average consumption of fruit and vegetables in the UK is about three portions, the recommended 'five a day' strategy may have additional benefit for functional as well as other health outcomes in the population.

Modifiable lifestyle behaviors and functional health in the European Prospective Investigation into Cancer (EPIC)-Norfolk population study.

OBJECTIVE: To examine the association between modifiable lifestyle behaviors and functional health. METHOD: Population-based cross-sectional study in 16,678 men and women aged 40-79 years at baseline in 1993-1997 participating in the European Prospective Investigation into Cancer (EPIC)-Norfolk cohort. RESULTS: Smoking and physical inactivity were associated with poorer physical functional health, equivalent to being 7 years and 10-13 years older, respectively, and poorer mental functional health compared to non-smoking or being physically active. After adjusting for age, body mass index, social class, education, prevalent illness, and other lifestyles; men and women who currently smoke were more likely to report poor physical functional health compared to non-smokers {Odds Ratio (OR)=1.85 (95% confidence interval (CI): 1.49, 2.30) and 1.56 (1.30, 1.87)} and poor mental functional health {1.38 (1.12, 1.70); 1.77 (1.51, 2.07)}, respectively. The OR for good physical function in those who were physically active compared to inactive was 1.67 (1.41, 1.97) in men and 1.63 (1.39, 1.91) in women. Moderate alcohol consumption was positively associated with good physical and mental functional health. CONCLUSION: Modifiable behavioral factors are associated with substantial differences in the observed age-related decline in physical functional health and the prevalence of those in good and poor functional health in the community.

Obesity indices and self-reported functional health in men and women in the EPIC-Norfolk.

OBJECTIVE: To investigate the association between two indices of obesity, BMI and waist-to-hip ratio (WHR), and self-reported physical and mental functional health. RESEARCH METHODS AND PROCEDURES: We examined the relationship between obesity indices and self-reported physical and mental functional health measured by the Anglicized version of the Short-Form 36-item questionnaire in a population-based cross sectional study of 16,806 men and women 40 to 79 years old living in the general community in Norfolk, United Kingdom. RESULTS: Higher BMI and WHR were both independently associated with poorer self-reported physical functional health in men and women. The effect of BMI was greater in women compared with men, and the effect of WHR was greater in men compared with women, for poor physical functional health. Higher WHR but not BMI was associated with lower mental functional health in men and women. DISCUSSION: High BMI and WHR seem to be adversely related to self-perceived functional health in both men and women, although their relative impacts seem to differ by sex. Our findings also highlight the importance of using WHR in addition to BMI in assessing the impact of obesity on health outcome.

Impact of Helicobacter pylori eradication on dyspepsia, health resource use, and quality of life in the Bristol helicobacter project: randomised controlled trial.

OBJECTIVE: To determine the impact of a community based Helicobacter pylori screening and eradication programme on the incidence of dyspepsia, resource use, and quality of life, including a cost consequences analysis. DESIGN: H pylori screening programme followed by randomised placebo controlled trial of eradication. SETTING: Seven general practices in southwest England. PARTICIPANTS: 10,537 unselected people aged 20-59 years were screened for H pylori infection (13C urea breath test); 1558 of the 1636 participants who tested positive were randomised to H pylori eradication treatment or placebo, and 1539 (99%) were followed up for two years. INTERVENTION: Ranitidine bismuth citrate 400 mg and clarithromycin 500 mg twice daily for two weeks or placebo. MAIN OUTCOME MEASURES: Primary care consultation rates for dyspepsia (defined as epigastric pain) two years after randomisation, with secondary outcomes of dyspepsia symptoms, resource use, NHS costs, and quality of life. RESULTS: In the eradication group, 35% fewer participants consulted for dyspepsia over two years compared with the placebo group (55/787 v 78/771; odds ratio 0.65, 95% confidence interval 0.46 to 0.94; P = 0.021; number needed to treat 30) and 29% fewer participants had regular symptoms (odds ratio 0.71, 0.56 to 0.90; P = 0.05). NHS costs were 84.70 pounds sterling (74.90 pounds sterling to 93.91 pounds sterling) greater per participant in the eradication group over two years, of which 83.40 pounds sterling (146 dollars; 121 euro) was the cost of eradication treatment. No difference in quality of life existed between the two groups. CONCLUSIONS: Community screening and eradication of H pylori is feasible in the general population and led to significant reductions in the number of people who consulted for dyspepsia and had symptoms two years after treatment. These benefits have to be balanced against the costs of eradication treatment, so a targeted eradication strategy in dyspeptic patients may be preferable.

Randomised controlled trial of effects of Helicobacter pylori infection and its eradication on heartburn and gastro-oesophageal reflux: Bristol helicobacter project.

OBJECTIVES: To investigate the effects of Helicobacter pylori infection and its eradication on heartburn and gastro-oesophageal reflux. DESIGN: Cross sectional study, followed by a randomised placebo controlled trial. SETTING: Seven general practices in Bristol, England. PARTICIPANTS: 10,537 people, aged 20-59 years, with and without H pylori infection (determined by the (13)C-urea breath test). MAIN OUTCOME MEASURES: Prevalence of heartburn and gastro-oesophageal acid reflux at baseline and two years after treatment to eradicate H pylori infection. RESULTS: At baseline, H pylori infection was associated with increased prevalence of heartburn (odds ratio 1.14, 95% confidence interval 1.05 to 1.23) but not reflux (1.05, 0.97 to 1.14). In participants with H pylori infection, active treatment had no effect on the overall prevalence of heartburn (0.99, 0.88 to 1.12) or reflux (1.04, 0.91 to 1.19) and did not improve pre-existing symptoms of heartburn or reflux. CONCLUSIONS: H pylori infection is associated with a slightly increased prevalence of heartburn but not reflux. Treatment to eradicate H pylori has no net benefit in patients with heartburn or gastro-oesophageal reflux.

Inverse relationship between alcohol consumption and active Helicobacter pylori infection: the Bristol Helicobacter project.

OBJECTIVE: The aim of this study was to examine whether smoking or consumption of alcohol or coffee is associated with active Helicobacter pylori (H. pylori) infection. METHODS: This was a cross-sectional population study conducted as part of a randomized controlled trial of H. pylori infection eradication in southwest England. A total of 10,537 subjects, recruited from seven general practices, underwent 13C-urea breath testing for active infection with H. pylori and provided data on smoking, usual weekly consumption of alcohol, and daily intake of coffee. RESULTS: Smoking or coffee consumption were not related to active H. pylori infection. Total alcohol consumption was associated with a small, but not statistically significant, decrease in the odds of infection. After adjustment for age, sex, ethnic status, childhood and adult social class, smoking, coffee consumption, and intake of alcoholic beverages other than wine, subjects drinking 3-6 units of wine/wk had an 11% lower risk of H. pylori infection compared with those who took no wine: OR = 0.89, 95% CI = 0.80-0.99. Higher wine consumption was associated with a further 6% reduction in the risk of infection: OR = 0.83, 95% CI = 0.64-1.07. Intake of 3-6 units of beer (but no greater intake) was associated with a similar reduction in the risk of infection when compared to no beer intake (OR = 0.83, 95% CI = 0.75-0.91). CONCLUSIONS: This study indicates that modest consumption of wine and beer (approximately 7 units/wk) protects against H. pylori infection, presumably by facilitating eradication of the organism.

Pulmonary rehabilitation compared with brief advice given for severe chronic obstructive pulmonary disease.

PURPOSE: The objective of this study was to compare the effectiveness of a short-term pulmonary rehabilitation program with brief advice given to patients with severe ventilatory impairment due to chronic obstructive pulmonary disease (COPD). METHODS: One hundred three patients with severe COPD, defined as having forced expiratory volume in 1 second < 40% predicted, were randomly assigned to rehabilitation or to brief advice. Fifty-four patients attended a rehabilitation program twice a week for 6 weeks. Forty-nine patients attended a single session during which they were given printed educational materials and verbal advice and guidance about exercise. Subjects were reassessed at 3 months. RESULTS: The shuttle walking distance increased significantly in the rehabilitation group by 43 meters. The increase of 23 meters in the brief advice group was significantly less than in the rehabilitation group. Improvements in quality of life in the rehabilitation group were small and not clinically significant. CONCLUSIONS: In these patients with severe COPD, a short outpatient rehabilitation program of low intensity achieved small but significant improvement in shuttle walking distance, compared with brief advice. The improvements in quality of life were modest and did not reach statistical significance, although in some instances the confidence limits include differences that approach clinical significance. The relatively small effect may be due to the low intensity of the program or to the severity of the subjects' ventilatory impairment.

A placebo-controlled randomized trial of eradication of Helicobacter pylori in the general population: study design and response rates of the Bristol Helicobacter Project.

The Bristol Helicobacter Project is an ongoing, pragmatic, double-blind placebo-controlled trial of the effect of Helicobacter pylori eradication on symptoms of dyspepsia, health utilization and costs, and quality of life in the adult population. Commencing in 1996, 27,536 individuals ages 20-59 years who were registered with seven primary care centers in Bristol and the surrounding areas in southwest England were invited to undergo a 13C urea breath test. There was no selection on the basis of symptoms and 23.5% had dyspepsia on entry to the study. A total of 10,537 people were tested (38.3% of those invited), 1636 tested positive (15.5% of those tested), and 1558 (95.2% of those who tested positive) were randomized to H. pylori eradication therapy or placebo. The rate of participation in the screening phase increased with age (odds ratio [OR]: 1.42 per decade, 95% CI: 1.31 to 1.54) and female gender (OR: 1.35, 95% CI: 1.27 to 1.43) but decreased with lower socioeconomic status (OR: 0.70, 95% CI: 0.56 to 0.86 comparing lowest with highest category). H. pylori prevalence increased with age (OR: 1.69 per decade, 95% CI: 1.51 to 1.89) and lower socioeconomic status (OR: 1.33, 95% CI: 1.05 to 1.69) but was lower in women (OR: 0.87, 95% CI: 0.76 to 1.00). Population-based trials of H. pylori eradication are feasible but necessitate screening large numbers of people to identify those who are infected and who may benefit from eradication. In the Bristol Helicobacter Project the rate of participation varied inversely with both social deprivation and the prevalence of the infection.