Age-matched dendritic cell subpopulations reference values in childhood.

Dendritic cells (DCs) are the most potent antigen-presenting cells and are the key link between the innate and adaptive immune response. Only a few reports with study populations of up to 50 individuals have been published with age-based reference values for DC subpopulations in healthy children. Therefore, we aimed to establish reference ranges in a larger study population of 100 healthy children, which allowed age-matched subgroups. Most previous studies were performed using a dual-platform approach. In this study, a single-platform approach in a lyse no-wash procedure was used. DC subpopulations were defined as follows: CD45(+) CD85k(+) HLA-DR(+) CD14(-) CD16(-) CD33(+) cells as myeloid DCs (mDCs) and CD45(+) CD85k(+) HLA-DR(+) CD14(-) CD16(-) CD123(+) cells as plasmacytoid DCs (pDCs). Reference ranges were established using a semi-parametric regression of age-matched absolute and relative DC counts. We found a significant decline with increasing age in the medians of mDCs (P = 0.0003) and pDCs per µl peripheral blood (PB) (P = 0.004) and in the 50%, 90% and 95% reference ranges. We also identified significantly lower absolute cell counts of mDCs per µl PB in girls than in boys for all age groups (P = 0.0015). Due to the larger paediatric study population and single-platform approach, this study may give a more precise overview of the normal age-matched development of DC subpopulations and may provide a basis for analyzing abnormal DC counts in different illnesses or therapies such as post stem cell transplantation.

Modelling bounded health scores with censored skew-normal distributions.

Health care interventions that use quality of life or health scores often provide data which are skewed and bounded. The scores are typically formed by adding up numerical responses to a number of questions. Different questions might have different weights, but the scores will be bounded, and are often scaled to the range 0-100. If improvement in health over time is measured, scores will tend to cluster near the 'healthy' or 'good' boundary as time progresses, leading to a skew distribution. Further, some patients will drop-out as time progresses, hence the scores reflect a selected population.We fit models based on the skew-normal distribution to data from a randomized controlled trial of treatments for sprained ankles, in which scores were recorded at baseline and at 1, 3 and 9 months after injury. We consider the extent to which skewness in the data can be explained by clustering at the boundary via a comparison between a censored normal and a censored skew-normal model.As this analysis is based on the complete data only, a formula for the bias of the treatment effects due to informative drop-out is given. This allows us to assess under what conditions the conclusions drawn from the complete data might be either reinforced or reversed, when the informative drop-out process is taken into account.

Fetal growth and birthweight standards as screening tools: methods for evaluating performance.

OBJECTIVE: To discuss different methods for evaluating fetal growth and population-based birthweight standards relevant to different uses: either in antenatal care or in epidemiology. DESIGN: Population-based cohort study. SETTING: Routinely collected data in Scotland. POPULATION: A total of 540,849 singletons born after 24 weeks between 1980 and 2003. METHODS: The performance of a fetal growth standard and a population-based birthweight standard are compared in two ways. First, we consider the accuracy of estimated risks of stillbirth at any point during the remaining pregnancy, a measure that is relevant in antenatal care. Second, the rates of stillbirth at each gestation, which are measures relevant in epidemiology, are compared with the actual rates. MAIN OUTCOME MEASURES: Standard measures of screening and diagnostic performance: sensitivity, specificity, and positive and negative predictive values. RESULTS: In clinical care, the evidence points towards using fetal growth standards: sensitivity at term is about 30%, increasing to 43% for preterm births (24-31 weeks of gestation), compared with about 29% across all ages under the birthweight standard. Positive predictive values are about 1% across gestations. For epidemiology, the evidence is not so clear-cut: preterm, the population birthweight standard has higher sensitivity and specificity, but this is not the case in the full-term weeks. CONCLUSIONS: The performance of fetal growth and birthweight standards should be evaluated in different ways, depending on whether they are intended for use in antenatal care or in epidemiological investigations.

Mechanical supports for acute, severe ankle sprain: a pragmatic, multicentre, randomised controlled trial.

BACKGROUND: Severe ankle sprains are a common presentation in emergency departments in the UK. We aimed to assess the effectiveness of three different mechanical supports (Aircast brace, Bledsoe boot, or 10-day below-knee cast) compared with that of a double-layer tubular compression bandage in promoting recovery after severe ankle sprains. METHODS: We did a pragmatic, multicentre randomised trial with blinded assessment of outcome. 584 participants with severe ankle sprain were recruited between April, 2003, and July, 2005, from eight emergency departments across the UK. Participants were provided with a mechanical support within the first 3 days of attendance by a trained health-care professional, and given advice on reducing swelling and pain. Functional outcomes were measured over 9 months. The primary outcome was quality of ankle function at 3 months, measured using the Foot and Ankle Score; analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN37807450. RESULTS: Patients who received the below-knee cast had a more rapid recovery than those given the tubular compression bandage. We noted clinically important benefits at 3 months in quality of ankle function with the cast compared with tubular compression bandage (mean difference 9%; 95% CI 2.4-15.0), as well as in pain, symptoms, and activity. The mean difference in quality of ankle function between Aircast brace and tubular compression bandage was 8%; 95% CI 1.8-14.2, but there were little differences for pain, symptoms, and activity. Bledsoe boots offered no benefit over tubular compression bandage, which was the least effective treatment throughout the recovery period. There were no significant differences between tubular compression bandage and the other treatments at 9 months. Side-effects were rare with no discernible differences between treatments. Reported events (all treatments combined) were cellulitis (two cases), pulmonary embolus (two cases), and deep-vein thrombosis (three cases). INTERPRETATION: A short period of immobilisation in a below-knee cast or Aircast results in faster recovery than if the patient is only given tubular compression bandage. We recommend below-knee casts because they show the widest range of benefit. FUNDING: National Co-ordinating Centre for Health Technology Assessment.

Meta-regression with partial information on summary trial or patient characteristics.

We present a model for meta-regression in the presence of missing information on some of the study level covariates, obtaining inferences using Bayesian methods. In practice, when confronted with missing covariate data in a meta-regression, it is common to carry out a complete case or available case analysis. We propose to use the full observed data, modelling the joint density as a factorization of a meta-regression model and a conditional factorization of the density for the covariates. With the inclusion of several covariates, inter-relations between these covariates are modelled. Under this joint likelihood-based approach, it is shown that the lesser assumption of the covariates being Missing At Random is imposed, instead of the more usual Missing Completely At Random (MCAR) assumption. The model is easily programmable in WinBUGS, and we examine, through the analysis of two real data sets, sensitivity and robustness of results to the MCAR assumption.

Reporting and analysis of open-label extension studies of anti-epileptic drugs.

PURPOSE: Open-label extension studies, or follow-on randomised controlled trials (FORCTs) are widely believed to be prone to patient selection biases which may inflate effect estimates. This study investigates the reporting and analysis of efficacy outcomes in FORCTs and critically evaluates the associated underlying assumptions. We propose an alternative method of analysis, in line with that recommended in the analysis of RCTs, the intention to treat (ITT) approach, in which it is assumed that all patients who discontinue treatment are non-responders. METHODS: A systematic review of FORCTs and randomised controlled trials (RCT) of topiramate, levetiracetam and gabapentin as adjuvant therapy in refractory adult epilepsy was conducted. Sample sizes and numbers of responders, along with reported outcomes were extracted. To evaluate the feasibility of the assumptions underlying the various methods of analysis, the most common causes of discontinuation were evaluated. For each FORCT, we compared the reported outcome to the proposed ITT analysis. RESULTS: The 10 FORCT reports identified all excluded from the analysis patients who dropped out of the RCT. Adverse events or inefficacy were the main reasons for treatment discontinuation. Analysis based on the ITT method, led to smaller effect estimates than those reported. For example, a FORCT of levetiracetam reported a responder rate of 43%, which reduced to 28% under an ITT analysis, comparable to an ITT analysis outcome of 26% for the parent RCT. CONCLUSIONS: FORCTs can provide important information about long-term efficacy and tolerability of newer therapies. However, current reporting methods are likely to be misleading as outcomes are reported for the subset of patients continuing with treatment at the end of the FORCT. Since the majority of patients who discontinue treatment do so for reasons associated with inefficacy, an analysis based on the ITT approach more closely reflects the outcomes of the patients.

Overwhelming heterogeneity in systematic reviews of observational anti-epileptic studies.

PURPOSE: Observational studies may provide important information on the long-term effects of treatments for epilepsy, but systematic reviews of observational studies may be more prone to heterogeneity and biases. These issues were investigated in a systematic review of non-randomised add-on anti-epileptic drug studies. METHODS: Searches of MEDLINE (1966-2006), EMBASE (1974-2006), CINAHL (1982-2006), the Cochrane database of systematic reviews, the Cochrane Controlled Trials register, the DARE database and hand-searching congress proceedings were conducted. Randomised controlled trials, follow-on randomised controlled trials and prospective and retrospective cohort studies of gabapentin, topiramate, or levetiracetam as add-on therapy in adults (>12 years old) were identified. Outcomes were 50% responders and proportion seizure free. RESULTS: Thirty-eight non-randomised gabapentin studies, 82 topiramate and 84 levetiracetam studies were identified. There was marked heterogeneity of effect estimates from observational studies which prohibited the pooling of estimates in random effects models. Median effect estimates were larger and more varied for observational studies than randomised placebo-controlled trials (RCTs). For example, the median value (10th and 90th percentile) for 50% responders for gabapentin was 36% (15 and 71%) compared to 23% (19 and 38%) for gabapentin RCTs. Patient and study covariates in meta-regression models could not explain the vast heterogeneity. Publication bias was evident and a sensitivity analysis, allowing for the effects of publication bias, showed that effect estimates could increase by up to 6% for seizure freedom rates. DISCUSSION: Reports of observational anti-epileptic studies give limited information on patient selection and characteristics. Systematic reviews of observational studies are prone to significant heterogeneity and bias which cannot adequately be explained by reported study characteristics. Reporting standards for observational studies of anti-epileptic drugs could be improved by following guidelines for reporting non-randomised studies of interventions.

Outcome selection bias in meta-analysis.

Publication bias has been previously identified as a threat to the validity of a meta-analysis. Recently, new evidence has documented an additional threat to validity, the selective reporting of trial outcomes within published studies. Several diseases have several possible measures of outcome. Some articles might report only a selection of those outcomes, perhaps those with statistically significant results. In this article, we review this problem while addressing the questions: what is within-study selective reporting? how common is it? why is it done? how can it mislead? how can it be detected?, and finally, what is the solution? We recommend that both publication bias and selective reporting should be routinely investigated in systematic reviews.

Clinical and cost effectiveness of mechanical support for severe ankle sprains: design of a randomised controlled trial in the emergency department [ISRCTN 37807450].

BACKGROUND: The optimal management for severe sprains (Grades II and III) of the lateral ligament complex of the ankle is unclear. The aims of this randomised controlled trial are to estimate (1) the clinical effectiveness of three methods of providing mechanical support to the ankle (below knee cast, Aircast brace and Bledsoe boot) in comparison to Tubigrip, and (2) to compare the cost of each strategy, including subsequent health care costs. METHODS/DESIGN: Six hundred and fifty people with a diagnosis of severe sprain are being identified through emergency departments. The study has been designed to complement routine practice in the emergency setting. Outcomes are recovery of mobility (primary outcome) and usual activity, residual symptoms and need for further medical, rehabilitation or surgical treatment. Parallel economic and qualitative studies are being conducted to aid interpretation of the results and to evaluate the cost-effectiveness of the interventions. DISCUSSION: This paper highlights the design, methods and operational aspects of a clinical trial of acute injury management in the emergency department.

Dendritic cell reconstitution is associated with relapse-free survival and acute GVHD severity in children after allogeneic stem cell transplantation.

DCs are potent APCs and key regulators of innate and adaptive immunity. After allo-SCT, their reconstitution in the peripheral blood (PB) to levels similar to those in healthy individuals tends to be slow. We investigate the age- and sex-dependant immune reconstitution of myeloid (mDC) and plasmacytoid DC (pDC) in the PB of 45 children with leukaemia or myelodysplastic syndrome (aged 1-17 years, median 10) after allo-SCT with regard to relapse, acute GVHD (aGVHD) and relapse-free survival. Low pDC/µL PB up to day 60 post SCT are associated with higher incidence of moderate or severe aGVHD (P=0.035), whereas high pDC/µL PB up to day 60 are associated with higher risk of relapse (P<0.001). The time-trend of DCs/µL PB for days 0-200 is a significant predictor of relapse-free survival for both mDCs (P<0.001) and pDCs (P=0.020). Jointly modelling DC reconstitution and complications improves on these simple criteria. Compared with BM, PBSC transplants tend to show slower mDC/pDC reconstitution (P=0.001, 0.031, respectively), but have no direct effect on relapse-free survival. These results suggest an important role for both mDCs and pDCs in the reconstituting immune system. The inclusion of mDCs and pDCs may improve existing models for complication prediction following allo-SCT.

Issues in methodological research: perspectives from researchers and commissioners.

OBJECTIVES: (1) Methodological research has few well-defined tools and processes analogous to those available for reviews and data collection in substantive health technology assessment. (2) This project was set up to obtain researchers' and others' views on the innovative projects on research methodology under the NHS Health Technology Assessment Programme and the usefulness of the research. (3) The study was intended to span both epistemological and management issues. (4) The following issues were explored: (a) the degree to which researchers would feel constrained by the "Cochrane" approach to systematic reviews when undertaking reviews of a methodological nature; (b) whether methodological projects may require exceptional design and management arrangements, in view of their novelty, subjectivity and complexity; (c) whether researchers would seek out other methods, in addition to undertaking reviews of argument, as a means of extending their understanding of methodological issues (there may be three categories of research methods in methodology: reviews of methodological argument, studies that use the literature as a source of data, and research that collects new primary data); (d) whether the Methodology Programme overall can be considered a "success". METHODS: (1) Telephone interviews were carried out on researchers (one senior and one junior per project), resulting in 35 interviews from 19 of the 20 target projects. (2) A qualitative postal survey was sent to 12 people who had played a key role in the development of the Methodology Programme; replies were received from six of them. (3) Analysis was undertaken of the hit rates for 29 projects on the NCCHTA website by the end of February and the end of May 1999, comparing those concerned with methodology (n = 10) and those concerned with other issues (n = 19). RESULTS: UNDERTAKING METHODOLOGICAL RESEARCH: VIEWS OF RESEARCHERS: This section summarises the views of 35 researchers who were interviewed by telephone. RESULTS: UNDERTAKING METHODOLOGICAL RESEARCH: VIEWS OF RESEARCHERS: (THE NATURE OF METHODOLOGICAL REVIEWS): (1) There was a reluctance among researchers to use the term "systematic review" in the methodological context. (2) Practical problems in undertaking methodological reviews were found at every stage of the research process. (a) In the initial search stage, preplanned strategies were difficult to maintain, owing to the need to respond to the problems of too few or too many references. (b) At the analysis stage, most studies were not formally weighted, but there was implicit weighting in researchers' views of their merits or relevance. (c) It was often only at the synthesis stage that researchers could see clearly what their study was able to do; iteration was frequently necessary at this point. (d) It was difficult to form simple conclusions and recommendations beyond summaries of what was known in the field. (e) Dissemination activities were most often directed to other health service researchers, with some attention to NHS policy makers and research commissioners. RESULTS: UNDERTAKING METHODOLOGICAL RESEARCH: VIEWS OF RESEARCHERS (THE NEED FOR FLEXIBILITY): (1) Few researchers had amended their topic or methods once their research was under way, although some had made minor changes to their original plan, generally to refine the topic to fit the time or data available. (2) Changing a topic was seen as inappropriate unless checked with funders, but changes in research methods were viewed as reasonable because questions might be refined in the light of information gained or early thinking. RESULTS: UNDERTAKING METHODOLOGICAL RESEARCH: VIEWS OF RESEARCHERS (THE QUESTION OF BIAS): (1) Few researchers considered that this kind of research could be undertaken or presented in a wholly unbiased way because of the need to assess the research studied. (2) Objectivity was nonetheless seen as something that researchers should strive towards. Efforts to do so included presenting data clearly, separating findings from discussion, covering all points of view, setting out their own assumptions and values, and testing their ideas on others known to have differing views. (3) The formal peer-review process was not seen to have made a difference here, primarily because of the stage at which referees become involved. RESULTS: UNDERTAKING METHODOLOGICAL RESEARCH: VIEWS OF RESEARCHERS (PROJECT MANAGEMENT--TIMING AND TIME MANAGEMENT): (1) A majority of projects were completed within 3 months of their due date. Those studies completed roughly on time were considered to have efficient junior researchers and good project management, including clear deadlines for different stages of the research. (2) Some studies had severe problems of time management. Too much time tended to be spent on collecting and reading the literature and the writing stage was not always well planned. Referees' comments were also slow in coming. (ABSTRACT TRUNCATED)

Implications of socio-cultural contexts for the ethics of clinical trials.

BACKGROUND: Health technology assesment (HTA) requires scientifically rigorous experimentation involving patients as subjects. HTA itself is required so that treatment given to patients will be both effective and efficient; this requirement is itself ethical in nature. At the same time it is essential that the methods used in HTA are ethically sound. Most healthcare researchers agree that the most effective and soundest method for assessing treatments is the randomised controlled trial (RCT). However, some researchers believe that the RCT is unethical, either in essence, or for use in some forms of medical research and HTA. Furthermore, many patients seem unable to understand the principles and purposes of the RCT, a factor which is highly detrimental for the validity of informed consent. Informed consent is the key to the ethics of medical research, both in most theories and in all codes of research conduct. Many RCTs therefore risk being unethical in practice, even if ethical in principle. AIM OF REPORT: To survey the main objections to the RCT and its alternatives. To assess the philosophical and methodological basis of these objections, and of the methods recommended for addressing them. To identify areas where objections are founded in social or cultural factors normally overlooked in ethical argument about the RCT methodology. To identify alternative arguments or methods which might resolve ethical conflicts in this area. HOW THE RESEARCH WAS CONDUCTED: The methods used were adapted from systematic reviews in medicine. Systematic searches of Medline, Psychlit and Sociofile CD-ROM databases; hand-searches of the major journals in general medicine and surgery, medical ethics and philosophy; and searches of books were carried out. The literature survey was restricted to articles published or abstracted in English. A database of the most relevant and useful materials was compiled, and is accessible on the Internet (http://www.liv.ac.uk/sdthomps/page1.html). RESEARCH FINDINGS: UNDERSTANDING RCTS AND THEIR ALTERNATIVES: There is some evidence of difficulty in understanding the aims and methods of RCTs, and some disquiet about elements of the RCT methodologies. These objections are well known and much discussed, and concern the use of placebo, the continuation of trials after significant differentials in benefit or harm are apparent, and randomisation. CULTURAL OR RELIGIOUS OBJECTIONS: There was an absence of evidence of cultural or religious objections to randomisation, placebo or other kinds of controlled prospective trials. This most likely reflects an absence of research rather than absence of objections. (ABSTRACT TRUNCATED)

Levetiracetam, oxcarbazepine, remacemide and zonisamide for drug resistant localization-related epilepsy: a systematic review.

OBJECTIVE: To undertake a systematic review and meta-analysis of placebo controlled add-on trials of levetiracetam, oxcarbazepine, remacemide and zonisamide for patients with drug resistant localization related epilepsy. METHODS: We searched Medline, The Cochrane Library and contacted the relevant pharmaceutical companies. Outcomes were 50% or greater reduction in seizure frequency and treatment withdrawal for any reason. Data were synthesised in a meta-analysis. The effect of dose was explored in regression models for levetiracetam and remacemide. RESULTS: We found four trials (1023 patients) of levetiracetam, two (961) of oxcarbazepine, two (388) of remacemide and three (499) of zonisamide. Ignoring dose, the relative risks (95% CI) for a 50% response were 3.78 (2.62-5.44), 2.51 (1.88-3.33), 1.59 (0.91-2.97) and 2.46 (1.61-3.79), respectively. There was evidence for increasing effect with increasing dose for levetiracetam, oxcarbazepine and remacemide. The relative risks for treatment withdrawal were 1.21 (0.88-1.66), 1.72 (1.35-2.18), 1.90 (1.00-3.60) and 1.64 (1.02-2.62), respectively. CONCLUSIONS: These data suggest a useful effect for levetiracetam, oxcarbazepine and zonisamide. Levetiracetam has the more favourable 'responder-withdrawal ratio' followed by zonisamide and oxcarbazepine.

Magnocellular visual function and children's single word reading.

Recent research has shown that reading disabled children find it unusually difficult to detect flickering or moving visual stimuli, consistent with impaired processing in the magnocellular visual stream. Yet, it remains controversial to suggest that reduced visual sensitivity of this kind might affect children's reading. Here we suggest that when children read, impaired magnocellular function may degrade information about where letters are positioned with respect to each other, leading to reading errors which contain sounds not represented in the printed word. We call these orthographically inconsistent nonsense errors "letter" errors. To test this idea we assessed magnocellular function in a sample of 58 unselected children by using a coherent motion detection task. We then gave these children a single word reading task and found that their "letter" errors were best explained by independent contributions from motion detection (i.e., magnocellular function) and phonological awareness (assessed by a spoonerism task). This result held even when chronological age, reading ability, and IQ were controlled for. These findings suggest that impaired magnocellular visual function, as well as phonological deficits may affect how children read.

Differential effects of preterm birth and small gestational age on cognitive and motor development.

AIMS: To determine the differential effects of preterm birth and being small for gestational age on the cognitive and motor ability of the child. METHODS: A longitudinal cohort of all infants of gestational age < or = 32 weeks born to mothers resident in the counties of Cheshire and Merseyside in 1980-1 was studied. The children were assessed at the age of 8 to 9 years using the Wechsler Intelligence Scale for Children, the Neale analysis of reading ability, and the Stott-Moyes-Henderson test of motor impairment. Adequacy of fetal growth was determined by the birthweight ratio--that is, the ratio of the observed birthweight to the expected birthweight for a given gestational age. Children with clinically diagnosed motor, learning or sensory disabilities were excluded. Information on social variables was obtained by a questionnaire completed by the parents. Of the 182 children, 158 were assessed. RESULTS: IQ was positively correlated with birthweight ratio but not with birthweight or gestational age. Motor ability was associated with birthweight, gestational age, and birthweight ratio. Reading comprehension was associated with birthweight ratio, but reading rate and accuracy were best explained by social variables and sex. IQ remained associated with birthweight ratio, after adjusting for maternal education, housing status, and number of social service benefits received. Reading ability was related to these social variables but motor ability was not. CONCLUSIONS: The effects of SGA and preterm birth differed: SGA was associated with cognitive ability, as measured by IQ and reading comprehension; motor ability was additionally associated with preterm birth. Reading rate and accuracy were not associated with SGA or preterm birth but were socially determined.

Energy and nitrogen balance and changes in midupper-arm circumference with multiple organ failure.

Energy intake and energy expenditure, nitrogen intake, and urinary nitrogen excretion (or urea production rates) were measured in 35 intravenously fed patients with multiple organ failure over the course of their illness to determine to what extent nutrient requirements were met despite fluid retention. Energy and nitrogen balance were related to serial measurements of midupper-arm circumference (MAC). The target feeding regimen of 176 kJ (42 kcal)/kg fat-free mass (FFM) was achieved in only three patients and the target of 0.24 g N/kg FFM in only four. Two patterns of change in MAC were noted: a steady decrease with time and no change with time. Serial muscle biopsy data indicated that all the patients were wasting away; the maintenance of MAC in the group with no change over time was due to fluid retention. Abnormal losses were not measured, but energy and nitrogen balance in the group in which arm circumference decreased had no apparent effect on the rate of wasting.

The long-term stability in whole blood of 14 commonly-requested hormone analytes.

Concentrations of 14 commonly-requested plasma hormones were measured in octuplicate in each of six subjects to determine their stability when unseparated from red cells for periods up to 1 week. Most of the analytes were stable when stored in this way and although statistically significant changes were recorded, in the great majority of cases the changes seen would have no bearing on the clinical interpretation of the result. In the light of these findings, we would confidently report results of analyses for these hormones in plasma that had remained in contact with red cells at ambient temperature for long periods of time.

Ethics of medical research in developing countries: the role of international codes of conduct.

Many statisticians work with informal codes of ethics, and are probably unaware of the existence or content of rules which have been drawn up to govern statistical practice. Medical statisticians will be aware of codes of conduct for medical research, and most codes of professional ethics have some dependence on evidence. Statisticians, therefore, have a valuable contribution to make to debates on ethics which concern scientific soundness, data and perceptions of risk. A lively debate on the revision of the widely respected Declaration of Helsinki, to reflect issues arising from research in developing countries, particularly HIV research, centres on questions of study design, data analysis and assessment of risk. Collectively owned multiprofessional work requires each of the various professions to take responsibility for the conduct of the research, and the impact that it might have. Statisticians share important responsibilities in maintaining ethical medical research in all countries.