Optimizing the design of invasive placebo interventions in randomized controlled trials.

BACKGROUND: Placebo-controlled trials play an important role in the evaluation of healthcare interventions. However, they can be challenging to design and deliver for invasive interventions, including surgery. In-depth understanding of the component parts of the treatment intervention is needed to ascertain what should, and should not, be delivered as part of the placebo. Assessment of risk to patients and strategies to ensure that the placebo effectively mimics the treatment are also required. To date, no guidance exists for the design of invasive placebo interventions. This study aimed to develop a framework to optimize the design and delivery of invasive placebo interventions in RCTs. METHODS: A preliminary framework was developed using published literature to: expand the scope of an existing typology, which facilitates the deconstruction of invasive interventions; and identify placebo optimization strategies. The framework was refined after consultation with key stakeholders in surgical trials, consensus methodology and medical ethics. RESULTS: The resulting DITTO framework consists of five stages: deconstruct treatment intervention into constituent components and co-interventions; identify critical surgical element(s); take out the critical element(s); think risk, feasibility and role of placebo in the trial when considering remaining components; and optimize placebo to ensure effective blinding of patients and trial personnel. CONCLUSION: DITTO considers invasive placebo composition systematically, accounting for risk, feasibility and placebo optimization. Use of the framework can support the design of high-quality RCTs, which are needed to underpin delivery of healthcare interventions.

ANTECEDENTES: Los ensayos controlados con placebo juegan un papel importante en la evaluación de las intervenciones sanitarias. Sin embargo, pueden ser difíciles de diseñar e implementar en el caso de intervenciones invasivas, incluida la cirugía. Se necesita un conocimiento profundo de los componentes de la intervención terapéutica (para determinar qué se debe y qué no se debe administrar como parte del placebo). También se precisa de una evaluación del riesgo para los pacientes y de las estrategias para garantizar que el placebo imite el tratamiento de forma efectiva. Hasta la fecha no existen guías para el diseño de intervenciones invasivas con placebo. Este estudio tuvo como objetivo desarrollar un marco para optimizar el diseño y la práctica de intervenciones invasivas con placebo dentro en los ensayos clínicos aleatorizados (ECA). MÉTODOS: Utilizando la literatura publicada, se desarrolló un marco preliminar para i) ampliar el alcance de los modelos existentes para facilitar la deconstrucción de las actuaciones invasivas, y ii) identificar estrategias para optimizar el placebo. El marco se perfeccionó tras consultar con partes interesadas ​​en ensayos quirúrgicos, metodología de consenso y ética médica. RESULTADOS: El marco DITTO resultantes consiste en cinco etapas: Etapa 1: deconstrucción de la intervención de tratamiento en sus componentes esenciales y co-intervenciones; Etapa 2: identificar el(los) elemento(s) quirúrgico(s) básico(s); Etapa 3: eliminar el(los) elemento(s) básico(s); Etapa 4: considerar el riesgo, la viabilidad y el papel del placebo en el ensayo al tener en cuenta los demás componentes; y Etapa 5: optimizar el placebo para garantizar el cegamiento efectivo de los pacientes y del personal del ensayo. CONCLUSIÓN: DITTO considera de forma sistemática la naturaleza invasiva del placebo, teniendo en cuenta el riesgo, la viabilidad y la optimización del placebo. El uso de este marco de referencia puede ayudar al diseño de ECAs de alta calidad, necesarios para afianzar la implementación de intervenciones sanitarias.

Inequitable health service use in a Canadian paediatric population: A cross-sectional study of individual- and contextual-level factors.

BACKGROUND: Health service use may be influenced by multilevel predisposing, enabling, and need factors but is equitable when driven by need. The study's objectives were as follows: (a) to investigate residential context's effect on child health service use and (b) to examine inequity of child health service use by testing for effect measure modification of need factors. METHODS: The sample of 1,451 children was from a prenatal cohort recruited from London, Ontario, between 2002 and 2004, with follow-up until children were toddler/preschooler-aged. Individual-level data were linked by residential address to neighbourhood contextual-level data sourced from Statistics Canada. Multilevel logistic regression modelled factors associated with child health service use. Interaction terms were included in the model to test for effect measure modification of need factors by predisposing and enabling factors. RESULTS: Contextual-level factors were not associated with child health service use. Maternal parity and nativity to Canada modified the effect of the need factor, paediatric health condition, on health service use. Health condition's effect was lowest in children of Canadian-born mothers with one child only (OR = 1.58, p = .04) and highest in children of Canadian-born mothers with three or more children (OR = 3.52, p < .01). Further, its effect was higher in children of Canadian-born mothers compared to children of mothers who migrated to Canada; however, odds ratios were not statistically significant for the latter. CONCLUSIONS: Results may inform future investigation of the potential inequity of health service use for subgroups of children whose mothers are of lower parity and not Canadian-born. An understanding of these inequities may inform future healthcare policy and care for paediatric populations.

Maternal, fetal, and placental conditions associated with medically indicated late preterm and early term delivery: a retrospective study.

OBJECTIVE: Our objectives were: (1) to examine the association between maternal, fetal, and placental phenotypes of preterm delivery and medically indicated early delivery of singletons during the late preterm and early term periods; and (2) to identify the specific maternal, fetal, and placental conditions associated with these early deliveries. DESIGN: Retrospective study. SETTING: City of London and Middlesex County, Ontario, Canada. SAMPLE: Singleton live deliveries, at 34-41 weeks of gestation to women in London and Middlesex. METHODS: We obtained data from a city-wide perinatal database (2002-2011; n = 25 699). We used multinomial logistic regression for multivariable analyses. MAIN OUTCOME MEASURE: The outcome was the occurrence of medically indicated late preterm (34-36 weeks of gestation) and early term (37-38 weeks of gestation) delivery, versus delivery at full term (39-41 weeks of gestation). RESULTS: After controlling for confounding factors, all phenotypes were associated with increased odds of medically indicated late preterm and early term delivery. Within the maternal phenotype, chronic maternal medical conditions were associated with increased odds of medically indicated early term delivery (e.g. for gastrointestinal disease, adjusted odds ratio, aOR 1.72, 95% CI 1.47-2.00; for anaemia, aOR 1.40, 95% CI 1.20-1.63), but not late preterm delivery. CONCLUSIONS: The aetiology of medically indicated early delivery close to full term is heterogeneous. Patterns of associations suggest slightly different conditions underlying the late preterm and early term phenotypes, with chronic maternal medical conditions being associated with early term delivery but not with late preterm delivery. These results have implications for the prevention of early delivery as well as the identification of high-risk groups among those born early. TWEETABLE ABSTRACT: The aetiology of medically indicated late preterm and early term delivery is heterogeneous.

Biological determinants of spontaneous late preterm and early term birth: a retrospective cohort study.

OBJECTIVE: Our aim was to examine the association between biological determinants of preterm birth (infection and inflammation, placental ischaemia and other hypoxia, diabetes mellitus, other) and spontaneous late preterm (34-36 weeks) and early term (37-38 weeks) birth. DESIGN: Retrospective cohort study. SETTING: City of London and Middlesex County, Canada. SAMPLE: Singleton live births, delivered at 34-41 weeks to London-Middlesex mothers following spontaneous labour. METHODS: Data were obtained from a city-wide perinatal database on births between 2002 and 2011 (n = 17,678). Multivariable analyses used multinomial logistic regression. MAIN OUTCOME MEASURE: The outcome of interest was the occurrence of late preterm (34-36 weeks) and early term (37-38 weeks) birth, compared with full term birth (39-41 weeks). RESULTS: After controlling for covariates, there were associations between infection and inflammation and late preterm birth (aOR = 2.07, 95% CI 1.65, 2.60); between placental ischaemia and other hypoxia and late preterm (aOR = 2.21, 95% CI 1.88, 2.61) and early term (aOR = 1.25, 95% CI 1.13, 1.39) birth; between diabetes mellitus and late preterm (aOR = 3.89, 95% CI 2.90, 5.21) and early term (aOR = 2.66, 95% CI 2.19, 3.23) birth; and between other biological determinants (polyhydramnios, oligohydramnios) and late preterm (aOR = 2.81, 95% CI 1.70, 4.64) and early term (aOR = 1.89, 95% CI 1.32, 2.70) birth. CONCLUSIONS: Our findings show that delivery following spontaneous labour even close to full term may be a result of pathological processes. Because these biological determinants of preterm birth contribute to an adverse intrauterine environment, they have important implications for fetal and neonatal health.

Cost-effectiveness of ultrasound-guided foam sclerotherapy, endovenous laser ablation or surgery as treatment for primary varicose veins from the randomized CLASS trial.

BACKGROUND: The treatment of patients with varicose veins constitutes a considerable workload and financial burden to the National Health Service. This study aimed to assess the cost-effectiveness of ultrasound-guided foam sclerotherapy (UGFS) and endovenous laser ablation (EVLA) compared with conventional surgery as treatment for primary varicose veins. METHODS: Participant cost and utility data were collected alongside the UK CLASS multicentre randomized clinical trial, which compared EVLA, surgery and UGFS. Regression methods were used to estimate the effects of the alternative treatments on costs to the health service and quality-adjusted life-years (QALYs) at 6 months. A Markov model, incorporating available evidence on clinical recurrence rates, was developed to extrapolate the trial data over a 5-year time horizon. RESULTS: Compared with surgery at 6 months, UGFS and EVLA reduced mean costs to the health service by £655 and £160 respectively. When additional overhead costs associated with theatre use were included, these cost savings increased to £902 and £392 respectively. UGFS produced 0·005 fewer QALYs, whereas EVLA produced 0·011 additional QALYs. Extrapolating to 5 years, EVLA was associated with increased costs and QALYs compared with UGFS (costing £3640 per QALY gained), and generated a cost saving (£206-439) and QALY gain (0·078) compared with surgery. Applying a ceiling willingness-to-pay ratio of £20 000 per QALY gained, EVLA had the highest probability (78·7 per cent) of being cost-effective. CONCLUSION: The results suggest, for patients considered eligible for all three treatment options, that EVLA has the highest probability of being cost-effective at accepted thresholds of willingness to pay per QALY.

Observational study of current use of selective decontamination of the digestive tract in UK critical care units.

BACKGROUND: Evidence supporting selective decontamination of the digestive tract (SDD) is reasonably strong. We set out to determine use in UK critical care units and to compare patient outcomes between units that do and those that do not use SDD. METHODS: A total of 250 UK general critical care units were surveyed. Case mix, outcomes, and lengths of stay for admissions to SDD units (with and without an i.v. component) and non-SDD units were compared using data from the Intensive Care National Audit & Research Centre Case Mix Programme database. RESULTS: A response was received from all the 250 critical care units surveyed. Of these, 13 (5.2%) reported using SDD on some or all admissions, and of these, 3 reported using an i.v. component. Data on 284,690 admissions (April 2008-March 2011) from units reporting to the ICNARC Case Mix Programme (CMP) were included in the analyses. Admissions to SDD (n=196) and non-SDD (n=9) units were a similar case mix with similar infection rates and average lengths of stay in the unit and hospital. There was no difference in risk-adjusted unit or hospital mortality. The rate of unit-acquired infections in blood was significantly lower in SDD units using an i.v. component. CONCLUSIONS: Use of SDD in UK critical care is very low. The rate of unit-acquired infections in blood was significantly lower in SDD units using an i.v. component, but did not translate into a difference in acute hospital mortality or length of stay. There is a need to better understand the barriers to adoption of SDD into clinical practice and such work is underway.

Patient information leaflets for placebo-controlled surgical trials: a review of current practice and recommendations for developers.

INTRODUCTION: Informed consent for participation in an RCT is an important ethical and legal requirement. In placebo surgical trials, further issues are raised, and to date, this has not been explored. Patient information leaflets (PILs) are a core component of the informed consent process. This study aimed to investigate the key content of PILs for recently completed placebo-controlled trials of invasive procedures, including surgery, to highlight areas of good practice, identify gaps in information provision for trials of this type and provide recommendations for practice. METHODS: PILs were sought from trials included in a recent systematic review of placebo-controlled trials of invasive procedures, including surgery. Trial characteristics and data on surgical and placebo interventions under evaluation were extracted. Directed content analysis was applied, informed by published regulatory and good practice guidance on PIL content and existing research on placebo-controlled surgical trials. Results were analysed using descriptive statistics and presented as a narrative summary. RESULTS: Of the 62 eligible RCTs, authors of 59 trials were contactable and 14 PILs were received for analysis. At least 50% of all PILs included content on general trial design. Explanations of how the placebo differs or is similar to the surgical intervention (i.e. fidelity) were reported in 6 (43%) of the included PILs. Over half (57%) of the PILs included information on the potential therapeutic benefits of the surgical intervention. One (7%) included information on potential indirect therapeutic benefits from invasive components of the placebo. Five (36%) presented the known risks of the placebo intervention, whilst 8 (57%) presented information on the known risks of the surgical intervention. A range of terms was used across the PILs to describe the placebo component, including 'control', 'mock' and 'sham'. CONCLUSION: Developers of PILs for placebo-controlled surgical trials should carefully consider the use of language (e.g. sham, mock), be explicit about how the placebo differs (or is similar) to the surgical intervention and provide balanced presentations of potential benefits and risks of the surgical intervention separately from the placebo. Further research is required to determine optimal approaches to design and deliver this information for these trials.

Obesity, hope, and health: findings from the HOPE Works community survey.

According to hope theory, hope is defined as goal-directed thinking in which people perceive that they can find routes to desired goals and the motivation to use those routes. The purpose of this study was to explore relationships between hope and body mass index and hope and self-rated health among women completing a community survey conducted in four rural counties in eastern North Carolina. The survey was administered as part of Hope Works, a participatory, community-led intervention program to improve weight, health and hope among low-income women in rural North Carolina. Survey data from 434 women were analyzed. In multivariate models adjusting for age, race, education and income, higher hope was positively related to self-reported health (OR:0.92; 95% CI: 0.89-0.95) and negatively related to BMI (P < 0.01). These results indicated that women who reported better self-rated health also had higher hope scores and women who were heavier had lower hope scores. While these findings are exploratory, they suggest directions for further research. State-based hope is considered to be a characteristic that is malleable and open to development. Future interventions should examine the importance of hope as a construct to examine in weight loss studies. For example, programs could be designed to increase hope by focusing on goal setting and providing support, information and resources to help women work toward their goals.

Clinical outcomes from a randomised comparison of Microwave Endometrial Ablation with Thermal Balloon endometrial ablation for the treatment of heavy menstrual bleeding.

OBJECTIVE: To compare the clinical outcomes of microwave endometrial ablation and thermal balloon ablation for the treatment of heavy menstrual bleeding. DESIGN: A double blind randomised controlled trial. SETTING: A UK teaching hospital. POPULATION: Three hundred and twenty women requesting endometrial ablation. METHODS: Operative data collection and patient completed postal questionnaires were used to ascertain women's satisfaction with outcome, acceptability of each procedure, changes in menstrual symptoms and health related quality of life and additional treatments received. MAIN OUTCOME MEASURES: Primary outcomes were satisfaction and menstrual scores 1 year. Secondary outcomes were operative differences, acceptability of treatment and changes in health related quality of life. RESULTS: Both technologies achieved high levels of satisfaction (-1%, 95% CI (-11, 9)). Menstrual scores were also similar (4%, 95% CI (-7, 19)) Microwave had a significantly shorter operating time, reduced usage of antiemetics and opiate analgesia, increased discharge by 6 hours and fewer device failures. CONCLUSIONS: Both treatments are acceptable to women, with high levels of satisfaction. Microwave is quicker to perform with faster hospital discharge.

Detection of adverse events in a Scottish hospital using a consensus-based methodology.

OBJECTIVE: To determine, using a consensus based methodology, the rate and nature of adverse events (AEs) among patients admitted to acute medicine, acute surgery and obstetrics in a large teaching hospital in Scotland. METHODS: Retrospective case-note review of 450 medical, nursing and medication records to identify and classify adverse events. For 354 patients whose length of stay was greater than 24 hours, the overall adverse event rate was 7.9% which ranged from 0% in obstetrics, 7.2% in acute medicine to 13% in acute surgery. Among all AEs, 43% were deemed preventable by a consensus group and 59% of the AEs contributed to a proportion of the patients' hospital stay or led to hospital readmission. Whilst nurse identification of adverse events was highly specific (94%), its sensitivity was poor (43%). Only 10% of the identified AEs were identified by the hospital's voluntary reporting system for adverse events. The estimated additional cost of adverse events in terms of bed days was l69,189 which if extrapolated Scotland-wide could cost l297 million per annum. CONCLUSIONS: This study supports the need to continue the traditional retrospective record review to identify adverse events. The current hospital-based reporting of adverse events does not provide a complete measure of adverse events and needs to be complemented by other measures.

Recruitment to randomised trials: strategies for trial enrollment and participation study. The STEPS study.

OBJECTIVES: To identify factors associated with good and poor recruitment to multicentre trials. DATA SOURCES: Part A: database of trials started in or after 1994 and were due to end before 2003 held by the Medical Research Council and Health Technology Assessment Programmes. Part B: interviews with people playing a wide range of roles within four trials that their funders identified as 'exemplars'. Part C: a large multicentre trial (the CRASH trial) of treatment for head injury. REVIEW METHODS: The study used a number of different perspectives ('multiple lenses'), and three components. Part A: an epidemiological review of a cohort of trials. Part B: case studies of trials that appeared to have particularly interesting lessons for recruitment. Part C: a single, in-depth case study to examine the feasibility of applying a business-orientated analytical framework as a reference model in future trials. RESULTS: In the 114 trials found in Part A, less than one-third recruited their original target within the time originally specified, and around one-third had extensions. Factors observed more often in trials that recruited successfully were: having a dedicated trial manager, being a cancer or drug trial, and having interventions only available inside the trial. The most commonly reported strategies to improve recruitment were newsletters and mailshots, but it was not possible to assess whether they were causally linked to changes in recruitment. The analyses in Part B suggested that successful trials were those addressing clinically important questions at a timely point. The investigators were held in high esteem by the interviewees, and the trials were firmly grounded in existing clinical practices, so that the trial processes were not alien to clinical collaborators, and the results could be easily applicable to future practice. The interviewees considered that the needs of patients were well served by participation in the trials. Clinical collaborators particularly appreciated clear delineation of roles, which released them from much of the workload associated with trial participation. There was a strong feeling from interviewees that they were proud to be part of a successful team. This pride fed into further success. Good groundwork and excellent communications across many levels of complex trial structures were considered to be extremely important, including training components for learning about trial interventions and processes, and team building. All four trials had faced recruitment problems, and extra insights into the working of trials were afforded by strategies invoked to address them. The process of the case study in Part C was able to draw attention to a body of research and practice in a different discipline (academic business studies). It generated a reference model derived from a combination of business theory and work within CRASH. This enabled identification of weaker managerial components within CRASH, and initiatives to strengthen them. Although it is not clear, even within CRASH, whether the initiatives that follow from developing and applying the model will be effective in increasing recruitment or other aspects of the success of the trial, the reference model could provide a template, with potential for those managing other trials to use or adapt it, especially at foundation stages. The model derived from this project could also be used as a diagnostic tool if trials have difficulties and hence as a basis for deciding what type of remedial action to take. It may also be useful for auditing the progress of trials, such as during external review. CONCLUSIONS: While not producing sufficiently definitive results to make strong recommendations, the work here suggests that future trials should consider the different needs at different phases in the life of trials, and place greater emphasis on 'conduct' (the process of actually doing trials). This implies learning lessons from successful trialists and trial managers, with better training for issues relating to trial conduct. The complexity of large trials means that unanticipated difficulties are highly likely at some time in every trial. Part B suggested that successful trials were those flexible and robust enough to adapt to unexpected issues. Arguably, the trialists should also expect agility from funders within a proactive approach to monitoring ongoing trials. Further research into different recruitment patterns (including 'failures') may help to clarify whether the patterns seen in the 'exemplar' trials differ or are similar. The reference model from Part C needs to be further considered in other similar and different trials to assess its robustness. These and other strategies aimed at increasing recruitment and making trials more successful need to be formally evaluated for their effectiveness in a range of trials.

Effectiveness of open and arthroscopic rotator cuff repair (UKUFF): a randomised controlled trial.

AIMS: The appropriate management for patients with a degenerative tear of the rotator cuff remains controversial, but operative treatment, particularly arthroscopic surgery, is increasingly being used. Our aim in this paper was to compare the effectiveness of arthroscopic with open repair of the rotator cuff. PATIENTS AND METHODS: A total of 273 patients were recruited to a randomised comparison trial (136 to arthroscopic surgery and 137 to open surgery) from 19 teaching and general hospitals in the United Kingdom. The surgeons used their usual preferred method of repair. The Oxford Shoulder Score (OSS), two years post-operatively, was the primary outcome measure. Imaging of the shoulder was performed at one year after surgery. The trial is registered with Current Controlled Trials, ISRCTN97804283. RESULTS: The mean OSS improved from 26.3 (standard deviation (sd) 8.2) at baseline, to 41.7 (sd 7.9) two years post-operatively for arthroscopic surgery and from 25.0 (sd 8.0) to 41.5 (sd 7.9) for open surgery. Intention-to-treat (ITT) analysis showed no statistical difference between the groups at two years (difference in OSS score -0.76; 95% confidence interval (CI) -2.75 to 1.22; p = 0.452). The confidence interval excluded the pre-determined clinically important difference in the OSS of three points. The rate of re-tear was not significantly different between the two groups (46.4% for arthroscopic and 38.6% for open surgery; 95% CI -6.9 to 25.8; p = 0.256). Healed repairs had the most improved OSS. These findings were the same when analysed per-protocol. CONCLUSION: There is no evidence of difference in effectiveness between open and arthroscopic repair of rotator cuff tears. The rate of re-tear is high in both groups, for all sizes of tear and ages and this adversely affects the outcome. Cite this article: Bone Joint J 2017;99-B:107-15.

Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial.

BACKGROUND: Elderly people who have a fracture are at high risk of another. Vitamin D and calcium supplements are often recommended for fracture prevention. We aimed to assess whether vitamin D3 and calcium, either alone or in combination, were effective in prevention of secondary fractures. METHODS: In a factorial-design trial, 5292 people aged 70 years or older (4481 [85%] of whom were women) who were mobile before developing a low-trauma fracture were randomly assigned 800 IU daily oral vitamin D3, 1000 mg calcium, oral vitamin D3 (800 IU per day) combined with calcium (1000 mg per day), or placebo. Participants who were recruited in 21 UK hospitals were followed up for between 24 months and 62 months. Analysis was by intention-to-treat and the primary outcome was new low-energy fractures. FINDINGS: 698 (13%) of 5292 participants had a new low-trauma fracture, 183 (26%) of which were of the hip. The incidence of new, low-trauma fractures did not differ significantly between participants allocated calcium and those who were not (331 [12.6%] of 2617 vs 367 [13.7%] of 2675; hazard ratio (HR) 0.94 [95% CI 0.81-1.09]); between participants allocated vitamin D3 and those who were not (353 [13.3%] of 2649 vs 345 [13.1%] of 2643; 1.02 [0.88-1.19]); or between those allocated combination treatment and those assigned placebo (165 [12.6%] of 1306 vs 179 [13.4%] of 1332; HR for interaction term 1.01 [0.75-1.36]). The groups did not differ in the incidence of all-new fractures, fractures confirmed by radiography, hip fractures, death, number of falls, or quality of life. By 24 months, 2886 (54.5%) of 5292 were still taking tablets, 451 (8.5%) had died, 58 (1.1%) had withdrawn, and 1897 (35.8%) had stopped taking tablets but were still providing data for at least the main outcomes. Compliance with tablets containing calcium was significantly lower (difference: 9.4% [95% CI 6.6-12.2]), partly because of gastrointestinal symptoms. However, potentially serious adverse events were rare and did not differ between groups. INTERPRETATION: The findings do not support routine oral supplementation with calcium and vitamin D3, either alone or in combination, for the prevention of further fractures in previously mobile elderly people.

Improving the referral process for familial breast cancer genetic counselling: findings of three randomised controlled trials of two interventions.

OBJECTIVES: To evaluate the effectiveness and cost-effectiveness of two complementary interventions, using familial breast cancer as a model condition. The primary care intervention consisted of providing computerised referral guidelines and related education to GPs. The nurse counsellor intervention evaluated genetic nurses as substitutes for specialist geneticists in the initial assessment and management of referred patients. DESIGN: The computerised referral guidelines study was a pragmatic, cluster randomised controlled trial (RCT) with general practices randomised to intervention or control groups. The nurse counsellor intervention was tested in two concurrent RCTs conducted in separate UK health service locations, using predetermined definitions of equivalence. SETTING: The computerised referral guidelines trial took place in general practices in Scotland from November 2000 to June 2001. The nurse counsellor intervention took place in a regional genetics clinic in Scotland, and in two health authorities in Wales served by a single genetics service during 2001. PARTICIPANTS: The computerised referral guidelines study involved GPs and referred patients. Both nurse counsellor intervention trials included women referred for the first time, aged 18 years or over and whose main concern was family history of breast cancer. INTERVENTIONS: The software system was developed with GPs, presenting cancer genetic referral guidelines in a checklist approach. Intervention GPs were invited to postgraduate update education sessions, and both intervention and control practices received paper-based guidelines. The intervention period was November 2000 to June 2001. For the nurse counsellor trial, trial 1 ran outpatient sessions with the same appointment length as the standard service offered by geneticists, but the nurse counsellor saw new patients at the first appointment and referred back to the GP or on to a clinical geneticist according to locally developed protocol, under the supervision of a consultant geneticist. The control intervention was the current service, which comprised an initial and a follow-up appointment with a clinical geneticist. In trial 2, a nurse counsellor ran outpatient sessions with the same appointment length as the new consultant-based cancer genetics service and new patients were seen at the first appointment and referred as in trial 1. The control intervention was a new service, and comprised collection of family history by telephone followed by a consultation with a clinical assistant or a specialist registrar, supervised by a consultant. The intervention was implemented between 1998 and 2001. MAIN OUTCOME MEASURES: In the software system trial, the primary outcome was GPs' confidence in their management of patients with concerns about family history of breast cancer. For the nurse counsellor trial, the primary outcome was patient anxiety, measured using standard scales. RESULTS: In the software system trial, 57 practices (230 GPs) were randomised to the intervention group and 29 (116 GPs) to the control group. No statistically significant differences were detected in GPs' confidence or any other outcomes. Fewer than half of the intervention GPs were aware of the software, and only 22 reported using it in practice. The estimated total cost was GBP3.12 per CD-ROM distributed (2001 prices). For the two arms of the nurse counsellor trial, 289 patients (193 intervention, 96 control) and 297 patients (197 intervention and 100 control) consented, were randomised, returned a baseline questionnaire and attended the clinic for trials 1 and 2 respectively. The analysis in both cases suggested equivalence in all anxiety scores, and no statistically significant differences were detected in other outcomes in either trial. A cost-minimisation analysis suggested that the cost per counselling episode was GBP10.23 lower in intervention arm than in the control arm and GBP10.89 higher in the intervention arm than in the control arm (2001 prices) for trials 1 and 2, respectively. Taking the trials together, the costs were sensitive to the grades of doctors and the time spent in consultant supervision of the nurse counsellor, but they were only slightly affected by the grade of nurse counsellor, the selected discount rate and the lifespan of equipment. CONCLUSIONS: Computer-based systems in the primary care intervention cannot be recommended for widespread use without further evaluation and testing in real practice settings. Genetic nurse counsellors may be a cost-effective alternative to assessment by doctors. This trial does not provide definitive evidence that the general policy of employing genetics nurse counsellors is sound, as it was based on only three individuals. Future evaluations of computer-based decision support systems for primary care must first address their efficacy under ideal conditions, identify barriers to the use of such systems in practice, and provide evidence of the impact of the policy of such systems in routine practice. The nurse counsellor trial should be replicated in other settings to provide reassurance of the generalisability of the intervention and other models of nurse-based assessment, such as in outreach clinics, should be developed and evaluated. The design of future evaluations of professional substitution should also address issues such as the effect of different levels of training and experience of nurse counsellors, and learning effects.

Issues in data monitoring and interim analysis of trials.

OBJECTIVES: To address issues about data monitoring committees (DMCs) for randomised controlled trials (RCTs). DATA SOURCES: Electronic databases. Handsearching of selected books. Personal contacts with experts in the field. REVIEW METHODS: Systematic literature reviews of DMCs and small group processes in decision-making; sample surveys of: reports of RCTs, recently completed and ongoing RCTs and policies of major organisations involved in RCTs; case studies of four DMCs; and interviews with experienced DMC members. All focused on 23 prestated questions. RESULTS: Although still a minority, RCTs increasingly have DMCs. There is wide agreement that nearly all trials need some form of data monitoring. Central to the role of the DMC is monitoring accumulating evidence related to benefit and toxicity; variation in emphasis has been reflected in the plethora of names. DMCs for trials performed for regulatory purposes should be aware of any special requirements and regulatory consequences. Advantages were identified for both larger and smaller DMCs. There is general agreement that a DMC should be independent and multidisciplinary. Consumer and ethicist membership is controversial. The chair is recognised as being particularly influential, and likely to be most effective if he or she is experienced, understands both statistical and clinical issues, and is facilitating in style and impartial. There is no evidence available to judge suggested approaches to training. The review suggested that costs should be covered, but other rewards must be so minimal as to not affect decision-making. It is usual to have a minimum frequency of DMC meetings, with evidence that face-to-face meetings are preferable. It is common to have open sessions and a closed session. A report to a DMC should cover benefits and risks in a balanced way, summarised in an accessible style, avoiding excessive detail, and be as current as possible. Disadvantages of blinded analyses seem to outweigh advantages. Information about comparable studies should be included, although interaction with the DMCs of similar ongoing trials is controversial. A range of formal statistical approaches can be used, although this is only one of a number of considerations. DMCs usually reach decisions by consensus, but other approaches are sometimes used. The general, but not unanimous, view is that DMCs should be advisory rather than executive on the basis that it is the trial organisers who are ultimately responsible for the conduct of the trial. CONCLUSIONS: Some form of data monitoring should be considered for all RCTs, with reasons given where there is no DMC or when any member is not independent. An early DMC meeting is helpful, determining roles and responsibilities; planned operations can be agreed with investigators and sponsors/funders. A template for a DMC charter is suggested. Competing interests should be declared. DMC size (commonly three to eight people) is chosen to optimise performance. Members are usually independent and drawn from appropriate backgrounds, and some, particularly the chair, are experienced. A minimum frequency of meetings is usually agreed, with flexibility for more if needed. The DMC should understand and agree the statistical approach (and guidelines) chosen, with both the DMC statistician and analysis statistician competent to apply the method. A DMC's primary purpose is to ensure that continuing a trial according to its protocol is ethical, taking account of both individual and collective ethics. A broader remit in respect of wider ethical issues is controversial; arguably, these are primarily the responsibility of research ethics committees, trial steering committees and investigators. The DMC should know the range of recommendations or decisions open to it, in advance. A record should be kept describing the key issues discussed and the rationale for decisions taken. Errors are likely to be reduced if a DMC makes a thorough review of the evidence and has a clear understanding of how it should function, there is active participation by all members, differences are resolved through discussion and there is systematic consideration of the various decision options. DMCs should be encouraged to comment on draft final trial reports. These should include information about the data monitoring process and detail the DMC membership. It is recommended that groups responsible for data monitoring be given the standard name 'Data Monitoring Committee' (DMC). Areas for further research include: widening DMC membership beyond clinicians, trialists and statisticians; initiatives to train DMC members; methods of DMC decision-making; 'open' data monitoring; DMCs covering a portfolio of trials rather than single trials; DMC size and membership, incorporating issues of group dynamics; empirical study of the workings of DMCs and their decision-making, and which trials should or should not have a DMC.

Randomized trial of osteoporosis screening. Use of hormone replacement therapy and quality-of-life results.

BACKGROUND: Screening perimenopausal women for low bone density has yet to be tested in a randomized trial. The effect of screening on the use of hormone replacement therapy (HRT) and the subsequent quality of life in these women is unknown. The purpose of this study was to assess the effect of a screening program on HRT use of quality of life. METHODS: A random sample of women aged 45 to 54 years and living within 32 km of Aberdeen, Scotland, was selected from the community health index. Subjects were further randomized to screening or no screening using the design of Zelen. Two years after randomization, a questionnaire follow-up was mailed to both groups to assess HRT use and quality-of-life scores. RESULTS: Use of HRT was higher in the screened group (30% vs 24%; difference, 6%; 95% confidence interval, 1%-11%; P = .02). A multivariate analysis indicated that the odds of using HRT for a screened woman whose measurement for bone mineral density was in the lowest quartile was 2.54 (95% confidence interval, 1.74-3.71) greater than that of an unscreened woman. Screening and subsequent HRT use did not have any detectable effects-positive or adverse-on women's quality of life. CONCLUSION: Screening for low bone density significantly increases the use of HRT in this population but without any immediate adverse or positive effects on quality of life.

Prediction of perimenopausal fractures by bone mineral density and other risk factors.

In a prospective population-based cohort study, we assessed whether bone mineral density (BMD) measurements of perimenopausal women and other risk factors for osteoporosis are predictive of subsequent fracture. Women aged 47-51 years chosen randomly from a population register who underwent a bone density measurement 2 years previously were followed up by questionnaire to assess the 2-year incidence of any self-reported fractures. We found that 44 women, out of 1857 who completed the questionnaire, sustained at least one fracture within a 2-year follow-up period. After adjustment for covariates, the odds ratio of sustaining a fracture was 1.6 (95% confidence interval [CI] 1.16-2.34) for every standard deviation reduction in BMD at the spine, for women with a prior history of fracture the odds ratio of a subsequent fracture was approximately 2 (95% CI 1.31-3.03), a family history of hip fracture (maternal grandmother) carried an odds ratio of 3.7 (95% CI 1.55-8.85), while being postmenopausal or having a hysterectomy resulted in an odds ratio of 1.98 (1.02-3.56). This study has shown that BMD measurements at the hip and spine and other risk factors predict any nonhip and nonspine perimenopausal fractures. Further follow-up is required to assess the predictive performance of BMD measurements and other risk factors for hip and spine fractures.

COL1A1 Sp1 polymorphism predicts perimenopausal and early postmenopausal spinal bone loss.

Genetic factors play an important role in the pathogenesis of osteoporosis but the genes that determine susceptibility to poor bone health are defined incompletely. Previous work has shown that a polymorphism that affects an Spl binding site in the COLIA1 gene is associated with reduced bone mineral density (BMD) and an increased risk of osteoporotic fracture in several populations. Data from cross-sectional studies have indicated that COLIA1 Sp1 alleles also may be associated with increased rates of bone loss with age, but longitudinal studies, which have examined bone loss in relation to COLIA1 genotype, have yielded conflicting results. In this study, we examined the relationship between COLIA1 Sp1 alleles and early postmenopausal bone loss measured by dual-energy X-ray absorptiometry (DXA) in a population-based cohort of 734 Scottish women who were followed up over a 5- to 7-year period. The distribution of genotypes was as expected in a white population with 484 "SS" homozygotes (65.9%); 225 "Ss" heterozygotes (30.7%), and 25 "ss" homozygotes (3.4%). Women taking hormone-replacement therapy (HRT; n = 239) had considerably reduced rates of bone loss at the spine (-0.40 +/- 0.06%/year) and hip (-0.56 +/- 0.06%/year) when compared with non-HRT users (n = 352; spine, -1.36 +/- 0.06%/year; hip, -1.21 +/- 0.05%/year; p < 0.001 for both sites). There was no significant difference in baseline BMD values at the lumbar spine (LS) or femoral neck (FN) between genotypes or in the rates of bone loss between genotypes in HRT users. However, in non-HRT users (n = 352), we found that ss homozygotes (n = 12) lost significantly more bone at the lumbar site than the other genotype groups in which ss = -2.26 +/- 0.31%/year compared with SS = -1.38 +/- 0.07%/year and Ss = -1.22 +/- 0.10%/year (p = 0.004; analysis of variance [ANOVA]) and a similar trend was observed at the FN in which ss = -1.78 +/- 0.19%/year compared with SS = -1.21 +/- 0.06%/year and Ss = -1.16 +/- 0.08%/year (p = 0.06; ANOVA). The differences in spine BMD loss remained significant after correcting for confounding factors. Stepwise multiple regression analysis showed that COLIA1 genotype independently accounted for a further 3.0% of the variation in spine BMD change after age (4.0%), weight (5.0%), and baseline BMD (2.8%). We conclude that women homozygous for the Sp1 polymorphism are at significantly increased risk of excess rates of bone loss at the spine, but this effect may be nullified by the use of HRT.

Dietary influences on bone mass and bone metabolism: further evidence of a positive link between fruit and vegetable consumption and bone health?

BACKGROUND: The role of nutritional influences on bone health remains largely undefined because most studies have focused attention on calcium intake. OBJECTIVE: We reported previously that intakes of nutrients found in abundance in fruit and vegetables are positively associated with bone health. We examined this finding further by considering axial and peripheral bone mass and markers of bone metabolism. DESIGN: This was a cross-sectional study of 62 healthy women aged 45-55 y. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry at the lumbar spine and femoral neck and by peripheral quantitative computed tomography at the ultradistal radial total, trabecular, and cortical sites. Bone resorption was calculated by measuring urinary excretion of pyridinoline and deoxypyridinoline and bone formation by measuring serum osteocalcin. Nutrient intakes were assessed by using a validated food-frequency questionnaire; other lifestyle factors were assessed by additional questions. RESULTS: After present energy intake was controlled for, higher intakes of magnesium, potassium, and alcohol were associated with higher total bone mass by Pearson correlation (P < 0.05 to P < 0.005). Femoral neck BMD was higher in women who had consumed high amounts of fruit in their childhood than in women who had consumed medium or low amounts (P < 0.01). In a regression analysis with age, weight, height, menstrual status, and dietary intake entered into the model, magnesium intake accounted for 12.3% of the variation in pyridinoline excretion and 12% of the variation in deoxypyridinoline excretion. Alcohol and potassium intakes accounted for 18.1% of the variation in total forearm bone mass. CONCLUSION: The BMD results confirm our previous work (but at peripheral bone mass sites), and our findings associating bone resorption with dietary factors provide further evidence of a positive link between fruit and vegetable consumption and bone health.

Correlation between biomarkers of omega-3 fatty acid consumption and questionnaire data in African American and Caucasian United States males with and without prostatic carcinoma.

Results from animal studies suggest that omega-3 fatty acids from marine sources are protective against cancer. To determine whether adipose tissue and erythrocyte membrane fatty acid composition could serve as biomarkers of essential fatty acid consumption in subjects with prostate cancer, we compared fish consumption, which was estimated using a food frequency survey, to the omega-3 fatty acid content of adipose tissue and erythrocyte membranes. The study was conducted using 127 men who had undergone a prostate biopsy. All subjects were recruited from a university hospital urology clinic. African Americans comprised 23% of the subjects, and 70% were diagnosed with prostate cancer. We found a correlation of 0.44 with 95% confidence intervals (CIs) = 0.29-0.57 between reported fish consumption and the omega-3 fatty acid eicosapentaenoic acid composition in erythrocyte membranes and 0.38 with 95% CI = 0.21-0.53 when the dietary survey was compared to eicosapentaenoic acid in adipose tissue. The survey/biomarker correlations in cases were not significantly different from the correlations in controls. The study had 90% power to detect a 0.35 difference between correlations. These results suggest that the presence of prostate cancer does not affect the adipose tissue or erythrocyte membrane biomarkers of fatty acid consumption, and that erythrocyte membranes are as useful as biomarkers as is adipose tissue. Our findings corroborate previous studies that found that tissue biomarkers can reflect past fatty acid consumption and support the use of biomarkers in case-control studies using cancer patients.