Assessing methods to specify the target difference for a randomised controlled trial: DELTA (Difference ELicitation in TriAls) review.

BACKGROUND: The randomised controlled trial (RCT) is widely considered to be the gold standard study for comparing the effectiveness of health interventions. Central to the design and validity of a RCT is a calculation of the number of participants needed (the sample size). The value used to determine the sample size can be considered the 'target difference'. From both a scientific and an ethical standpoint, selecting an appropriate target difference is of crucial importance. Determination of the target difference, as opposed to statistical approaches to calculating the sample size, has been greatly neglected though a variety of approaches have been proposed the current state of the evidence is unclear. OBJECTIVES: The aim was to provide an overview of the current evidence regarding specifying the target difference in a RCT sample size calculation. The specific objectives were to conduct a systematic review of methods for specifying a target difference; to evaluate current practice by surveying triallists; to develop guidance on specifying the target difference in a RCT; and to identify future research needs. DESIGN: The biomedical and social science databases searched were MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Methodology Register, PsycINFO, Science Citation Index, EconLit, Education Resources Information Center (ERIC) and Scopus for in-press publications. All were searched from 1966 or the earliest date of the database coverage and searches were undertaken between November 2010 and January 2011. There were three interlinked components: (1) systematic review of methods for specifying a target difference for RCTs - a comprehensive search strategy involving an electronic literature search of biomedical and some non-biomedical databases and clinical trials textbooks was carried out; (2) identification of current trial practice using two surveys of triallists - members of the Society for Clinical Trials (SCT) were invited to complete an online survey and respondents were asked about their awareness and use of, and willingness to recommend, methods; one individual per triallist group [UK Clinical Research Collaboration (UKCRC)-registered Clinical Trials Units (CTUs), Medical Research Council (MRC) UK Hubs for Trials Methodology Research and National Institute for Health Research (NIHR) UK Research Design Services (RDS)] was invited to complete a survey; (3) production of a structured guidance document to aid the design of future trials - the draft guidance was developed utilising the results of the systematic review and surveys by the project steering and advisory groups. SETTING: Methodological review incorporating electronic searches, review of books and guidelines, two surveys of experts (membership of an international society and UK- and Ireland-based triallists) and development of guidance. PARTICIPANTS: The two surveys were sent out to membership of the SCT and UK- and Ireland-based triallists. INTERVENTIONS: The review focused on methods for specifying the target difference in a RCT. It was not restricted to any type of intervention or condition. MAIN OUTCOME MEASURES: Methods for specifying the target difference for a RCT were considered. RESULTS: The search identified 11,485 potentially relevant studies. In total, 1434 were selected for full-text assessment and 777 were included in the review. Seven methods to specify the target difference for a RCT were identified - anchor, distribution, health economic, opinion-seeking, pilot study, review of evidence base (RoEB) and standardised effect size (SES) - each having important variations in implementation. A total of 216 of the included studies used more than one method. A total of 180 (15%) responses to the SCT survey were received, representing 13 countries. Awareness of methods ranged from 38% (n =69) for the health economic method to 90% (n =162) for the pilot study. Of the 61 surveys sent out to UK triallist groups, 34 (56%) responses were received. Awareness ranged from 97% (n =33) for the RoEB and pilot study methods to only 41% (n =14) for the distribution method. Based on the most recent trial, all bar three groups (91%, n =30) used a formal method. Guidance was developed on the use of each method and the reporting of the sample size calculation in a trial protocol and results paper. CONCLUSIONS: There is a clear need for greater use of formal methods to determine the target difference and better reporting of its specification. Raising the standard of RCT sample size calculations and the corresponding reporting of them would aid health professionals, patients, researchers and funders in judging the strength of the evidence and ensuring better use of scarce resources. FUNDING: The Medical Research Council UK and the National Institute for Health Research Joint Methodology Research programme.

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.

The unintended consequences of cervical screening: distress in women undergoing cytologic surveillance.

OBJECTIVE: It is well known that receipt of an initial abnormal cervical cytology test can trigger considerable anxiety among women. Less is known about the impact of follow-up by repeat cytology tests. We quantified prevalence, and identified predictors, of distress after repeat cytologic testing in women with a single low-grade test. METHODS: Within the framework of the TOMBOLA randomized controlled trial of alternative managements, 844 women aged 20 to 59 years with a single routine cytology test showing borderline nuclear abnormalities (BNA; broadly equivalent to atypical squamous cells of undetermined significance) were assigned to follow-up by repeat cytology in primary care (the first test was due 6 months after the initial BNA result). Women completed sociodemographic and psychosocial questionnaires at recruitment and the Impact of Event Scale (IES) 6 weeks after their first follow-up cytology test. Factors associated with significant psychologic distress (IES ≥ 9) were identified using logistic regression. RESULTS: The response rate was 74% (n = 621/844). Of all the respondents, 39% scored in the range for significant distress. Distress varied by follow-up cytology result: negative, 36%; BNA or mild dyskaryosis, 42%; other (including high grade and inadequate), 55%. After adjusting for the cytology result, risk of distress was significantly raised in women who had significant anxiety at recruitment, reported experiencing pain after the follow-up cytology, had children, or were dissatisfied with support they had received after their initial BNA test. CONCLUSIONS: Substantial proportions of women experience surveillance-related psychologic distress after a follow-up cytology test, even when the result is negative. This is an important, albeit unintended, consequence of cervical screening. Strategies to alleviate this distress merit attention.

Using databases in medical education research: AMEE Guide No. 77.

This AMEE Guide offers an introduction to the use of databases in medical education research. It is intended for those who are contemplating conducting research in medical education but are new to the field. The Guide is structured around the process of planning your research so that data collection, management and analysis are appropriate for the research question. Throughout we consider contextual possibilities and constraints to educational research using databases, such as the resources available, and provide concrete examples of medical education research to illustrate many points. The first section of the Guide explains the difference between different types of data and classifying data, and addresses the rationale for research using databases in medical education. We explain the difference between qualitative research and qualitative data, the difference between categorical and quantitative data, and the difference types of data which fall into these categories. The Guide reviews the strengths and weaknesses of qualitative and quantitative research. The next section is structured around how to work with quantitative and qualitative databases and provides guidance on the many practicalities of setting up a database. This includes how to organise your database, including anonymising data and coding, as well as preparing and describing your data so it is ready for analysis. The critical matter of the ethics of using databases in medical educational research, including using routinely collected data versus data collected for research purposes, and issues of confidentiality, is discussed. Core to the Guide is drawing out the similarities and differences in working with different types of data and different types of databases. Future AMEE Guides in the research series will address statistical analysis of data in more detail.

Breast-feeding and childhood-onset type 1 diabetes: a pooled analysis of individual participant data from 43 observational studies.

OBJECTIVE: To investigate if there is a reduced risk of type 1 diabetes in children breastfed or exclusively breastfed by performing a pooled analysis with adjustment for recognized confounders. RESEARCH DESIGN AND METHODS: Relevant studies were identified from literature searches using MEDLINE, Web of Science, and EMBASE. Authors of relevant studies were asked to provide individual participant data or conduct prespecified analyses. Meta-analysis techniques were used to combine odds ratios (ORs) and investigate heterogeneity between studies. RESULTS: Data were available from 43 studies including 9,874 patients with type 1 diabetes. Overall, there was a reduction in the risk of diabetes after exclusive breast-feeding for >2 weeks (20 studies; OR = 0.75, 95% CI 0.64-0.88), the association after exclusive breast-feeding for >3 months was weaker (30 studies; OR = 0.87, 95% CI 0.75-1.00), and no association was observed after (nonexclusive) breast-feeding for >2 weeks (28 studies; OR = 0.93, 95% CI 0.81-1.07) or >3 months (29 studies; OR = 0.88, 95% CI 0.78-1.00). These associations were all subject to marked heterogeneity (I(2) = 58, 76, 54, and 68%, respectively). In studies with lower risk of bias, the reduced risk after exclusive breast-feeding for >2 weeks remained (12 studies; OR = 0.86, 95% CI 0.75-0.99), and heterogeneity was reduced (I(2) = 0%). Adjustments for potential confounders altered these estimates very little. CONCLUSIONS: The pooled analysis suggests weak protective associations between exclusive breast-feeding and type 1 diabetes risk. However, these findings are difficult to interpret because of the marked variation in effect and possible biases (particularly recall bias) inherent in the included studies.

Long term outcomes in men screened for abdominal aortic aneurysm: prospective cohort study.

OBJECTIVE: To determine whether there is a relation between aortic diameter and morbidity and mortality in men screened for abdominal aortic aneurysm. DESIGN: Prospective cohort study. SETTING: Highland and Western Isles (a large, sparsely populated area of Scotland). PARTICIPANTS: 8146 men aged 65-74. MAIN OUTCOME MEASURES: Morbidity and mortality in relation to presence of abdominal aortic aneurysm and three categories of aortic diameter (≤ 24 mm, 25-29 mm, and ≥ 30 mm). RESULTS: When screened, 414 men (5.1%) had an aneurysm (diameter ≥ 30 mm), 669 (8.2%) an aortic diameter of 25-29 mm, and 7063 (86.7%) an aortic diameter of ≤ 24 mm. The cohort was followed up for a median of 7.4 (interquartile range 6.9-8.2) years. Mortality was significantly associated with aortic diameter: 512 (7.2%) men in the ≤ 24 mm group died compared with 69 (10.3%) in the 25-29 mm group and 73 (17.6%) in the ≥ 30 mm group. The mortality risk in men with an aneurysm or with an aorta measuring 25-29 mm was significantly higher than in men with an aorta of ≤ 24 mm. The increased mortality risk in the 25-29 mm group was reduced when taking confounders such as smoking and known heart disease into account. After adjustment, compared with men with an aortic diameter of ≤ 24 mm, the risk of hospital admission for cardiovascular disease and chronic obstructive pulmonary disease was significantly higher in men with aneurysm and those with aortas measuring 25-29 mm. Men with an aneurysm also had an increased risk of hospital admission for cerebrovascular disease, atherosclerosis, peripheral arterial disease, and respiratory disease. In men with aortas measuring 25-29 mm, the risk of hospital admission with abdominal aortic aneurysm was significantly higher than in men with an aorta of ≤ 24 mm (adjusted hazard ratio 6.7, 99% confidence interval 3.4 to 13.2) and this increased risk became apparent two years after screening. CONCLUSIONS: Men with abdominal aortic aneurysm and those with aortic diameters measuring 25-29 mm have an increased risk of mortality and subsequent hospital admissions compared with men with an aorta diameter of ≤ 24 mm. Consideration should be given to control of risk factors and to rescreening men with aortas measuring 25-29 mm at index scanning.

Maternal and neonatal risk factors for childhood type 1 diabetes: a matched case-control study.

BACKGROUND: An interaction between genetic susceptibility and environmental factors is thought to be involved in the aetiology of type 1 diabetes. The aim of this study was to investigate maternal and neonatal risk factors for type 1 diabetes in children under 15 years old in Grampian, Scotland. METHODS: A matched case-control study was conducted by record linkage. Cases (n = 361) were children born in Aberdeen Maternity Hospital from 1972 to 2002, inclusive, who developed type 1 diabetes, identified from the Scottish Study Group for the Care of Diabetes in the Young Register. Controls (n = 1083) were randomly selected from the Aberdeen Maternity Neonatal Databank, matched by year of birth. Exposure data were obtained from the Aberdeen Maternity Neonatal Databank. Conditional logistic regression was used to evaluate the association between various maternal and neonatal factors and the risk of type 1 diabetes. RESULTS: There was no evidence of statistically significant associations between type 1 diabetes and maternal age, maternal body mass index, previous abortions, pre-eclampsia, amniocentesis, maternal deprivation, use of syntocinon, mode of delivery, antepartum haemorrhage, baby's sex, gestational age at birth, birth order, birth weight, jaundice, phototherapy, breast feeding, admission to neonatal unit and Apgar score (P > 0.05). A significantly decreased risk of type 1 diabetes was observed in children whose mothers smoked at the booking appointment compared to those whose mothers did not, with an adjusted OR of 0.67, 95% CI (0.46, 0.99). CONCLUSIONS: This case-control study found limited evidence of a reduced risk of the development of type 1 diabetes in children whose mothers smoked, compared to children whose mothers did not. No evidence was found of a significant association between other maternal and neonatal factors and childhood type 1 diabetes.

Surgery for tubal infertility.

BACKGROUND: Tubal surgery is a widely accepted treatment for tubal infertility. Estimated livebirth rates after surgery range from 9% for women with severe tubal disease to 69% for those with mild disease, however, its effectiveness has not been rigorously evaluated in comparison with other treatments such as in vitro fertilisation (IVF) and expectant management (no treatment). Livebirth rates have not been adequately assessed in relation to the severity of tubal damage. It is important to determine the effectiveness of surgery against other treatment options in women with tubal infertility because of concerns about adverse outcomes, intra-operative complications and the costs associated with tubal surgery. OBJECTIVES: The aim of this review was to determine whether surgery improves the probability of livebirth compared with expectant management or IVF in the context of tubal infertility (regardless of grade of severity). SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders and Subfertility Group's trials register (searched August 2007), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue, 2007), MEDLINE (1970 to August 2007), EMBASE (1985 to August 2007) and reference lists of articles. We also handsearched relevant conference proceedings and contacted researchers in the field. SELECTION CRITERIA: Only randomised controlled trials were considered eligible, with livebirth rate per woman as the primary outcome of interest. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility and quality of trials. MAIN RESULTS: No suitable randomised controlled trials were identified. AUTHORS' CONCLUSIONS: Any effect of tubal surgery relative to expectant management and IVF in terms of livebirth rates for women with tubal infertility remains unknown. Large trials with adequate power are warranted to establish the effectiveness of surgery in these women. Future trials should not only report livebirth rates per woman, but also compare adverse effects and costs of the treatments as outcomes. Factors that have a major effect on these outcomes, such as fertility treatment, female partner's age, duration of infertility, and previous pregnancy history should be considered. Livebirth rates in relation to the severity of tubal damage, and different techniques used for tubal repair including microsurgery and laparoscopic methods should also be reported.

Trends in semen parameters in the northeast of Scotland.

The data on trends in semen quality are conflicting and sensitive to geographical variations. Although previous British surveys on semen quality indicate a decline, the northeast of Scotland has never been included in these surveys. This is an area with low out migration rates where andrology services for a population of 500 000 are centralized within a single laboratory, thus providing a unique opportunity to study population-based trends in semen quality over time. We investigated trends in semen parameters between 1994-2005, in a cohort of 4832 men attending for routine semen analysis at the Aberdeen Fertility Centre who had a sperm density of greater than 20 million per mL. The main outcome measures were trends in sperm density, sperm motility and motile density in the first semen sample. Linear regression and time series analysis were used to examine trends over time in the semen parameters. The mean and standard deviation (SD) age of all men (n=5204) in the study was 34(6) years. The median (inter quartile range) for sperm density and motile density for the study population were 61 (40-91) million/mL and 99 (47-181) million. The mean (SD) sperm motility was 49 (19)%. Among 4832 men (with sperm count >20 million per mL), data adjusted for age and period of abstinence showed a decreasing trend for sperm density over time, R2=0.45 (P=.017). There was no such trend in sperm motility and motile density. However, this trend has to be interpreted with caution due to fluctuations in semen parameters, population bias and the retrospective nature of the analysis.

Recruitment issues when primary care population clusters are used in randomised controlled clinical trials: climbing mountains or pushing boulders uphill?

Cluster randomised controlled trials for health promotion, education, public health or organisational change interventions are becoming increasingly common to inform evidence-based policy. However, there is little published methodological evidence on recruitment strategies for primary care population clusters. In this paper, we discuss how choosing which population cluster to randomise can impact on the practicalities of recruitment in primary care. We describe strategies developed through our experiences of recruiting primary care organisations to participate in a national randomised controlled trial of a policy to provide community breastfeeding groups for pregnant and breastfeeding mothers, the BIG (Breastfeeding in Groups) trial. We propose an iterative qualitative approach to recruitment; collecting data generated through the recruitment process, identifying themes and using the constant comparative method of analysis. This can assist in developing successful recruitment strategies and contrasts with the standardised approach commonly used when recruiting individuals to participate in randomised controlled trials. Recruiting primary care population clusters to participate in trials is currently an uphill battle in Britain. It is a complex process, which can benefit from applying qualitative methods to inform trial design and recruitment strategy. Recruitment could be facilitated if health service managers were committed to supporting peer reviewed, funded and ethics committee approved research at national level.

Age-dependent differences in presentation, risk factor profile, and outcome of suspected acute coronary syndrome.

OBJECTIVES: To compare the presenting complaint, risk factors, and outcome of suspected acute coronary syndrome (ACS) in those aged 65 and older with those of a younger cohort. DESIGN: Prospective observational cohort study. SETTING: A typical Scottish district general hospital covering a population of 150,000. PARTICIPANTS: Patients presenting with suspected ACS (N=869) over a 6-month period. MEASUREMENTS: Main presenting complaint and major risk factors including electrocardiogram (ECG) changes. Primary outcome measures were percutaneous coronary intervention, recurrent myocardial infarction, and death at 3-month follow-up. RESULTS: Four hundred seventy-seven (55%) were aged 65 and older. Older patients were less likely to present with chest pain and more likely to present with breathlessness or collapse. They had fewer major risk factors for heart disease. There was a higher proportion with ischemic ECG changes, elevated troponin, and major acute coronary events at follow-up. Older patients were less likely to be accepted for angiography even though they were more likely than the younger cohort to have significant coronary artery disease when angiography was performed (chi-square test, P<.01 for all above). CONCLUSION: Older patients with suspected ACS were more likely to present atypically and have worse outcomes than their younger counterparts, despite having fewer major risk factors. The results highlight the importance of age as a predictor of adverse outcome and suggest that clinicians need to ensure equitable access to angiography for older patients.