PRECIS研究进展

随机对照试验(RCT)可分为评估效力的解释性试验和评估临床效果的实用性临床试验(PCT)。PCT反映了临床实际条件下的干预效应,具有一定的外推性,但其内部真实性相对较差。与此相反,解释性试验是在理想条件下进行,其内部真实性较好,而外推性较差。但在RCT实际设计中,PCT和解释性试验并不是截然分离的两个极端,有许多RCT同时兼有两种设计的属性。PRECIS通过评价RCT设计的解释和实用两方面,指导如何实行干预和试验设计,使RCT在内部和外部真实性之间达到平衡。目前国内对PRECIS介绍甚少,更未见应用的报道,基于此以下介绍PRECIS基本原理、特点及应用,以期为临床试验设计提供参考。     

再论观察与实验：大数据现实世界研究不能取代随机对照试验

传统上,流行病学多以干预划分观察和实验,干预研究等于实验研究,还认为干预研究的科学性高于观察性研究。在一般科学实验里,干预指人为施加的改变自然状况的措施。干预并不一定是有益的,也并不一定是研究者当下施加的,研究者、受试者或第三者目前或过去施加的措施都可以形成"有效的"干预。例如,由研究者、受试者和第三者通过某种方法致使视神经损伤,都可以形成有效改变视神经正常功能的干预,研究者可以由此观察到视神经和视力的关系。以此推论,由受试者自己过去施加的不良干预（如吸烟）也属于干预,那么研究吸烟和肺癌的观察性队列研究就等同于实验研究了。由此看来,干预本身并不足以有效地区分观察和实验。如果认为实验的科学性高于观察,那么在干预的基础上,只能从科学性上（即设计特征）区分观察和实验。在评估医学干预效果的临床试验中,随机分组是在传统认为的观察研究基础上引入的最重要的偏倚控制措施,应该是区分观察和实验的核心属性。如果一定要把人群研究分成观察和实验,随机对照试验才是真正的实验研究,非随机分组形成的干预研究属于试验,但不是实验。基于大数据的现实世界研究,如果没有随机分组,不能构成实验,也不能成为对干预效果的最终检验。大数据现实世界研究不能取代随机对照试验,这是本文希望传达的最重要的信息。     

Pragmatic vs. explanatory: an adaptation of the PRECIS tool helps to judge the applicability of systematic reviews for daily practice

Objective

The Pragmatic-Explanatory Continuum Indicator Summary (PRECIS) tool was designed to classify randomized clinical trials (RCT) as being more pragmatic or explanatory. We modified the PRECIS tool (called PRECIS-Review tool [PR-tool]) to grade individual trials and systematic reviews of trials. This should help policy makers, clinicians, researchers, and guideline developers to judge the applicability of individual trials and systematic reviews.

Study Design and Setting

To illustrate the usefulness and applicability of the PR-tool, we applied it to two systematic reviews. Each included RCT was scored on the 10 PRECIS domains on a scale of 1-5. After this scoring, a 10-domain average for each individual trial and for the systematic review a single domain average and an overall average was calculated.

Results

One review was more pragmatic with an average score of 3.7 (range, 2.9-4.6) on our PR-tool, whereas the other review was more explanatory with an average score of 1.9 (range, 1.1-3.3). The results also suggest that the included studies within each systematic review were rather uniform in their approach, although some domains seemed more prone to heterogeneity.

Conclusion

The PR-tool provides a useful estimate that gives insight by estimating quantitatively how pragmatic each RCT in the review is, which methodological domains are pragmatic or explanatory, and how pragmatic the review is.     

On choosing the number of interim analyses in clinical trials

Small but important therapeutic effects of new treatments can be most efficiently detected through the study of large randomized prospective series of patients. Such large scale clinical trials are nowadays commonplace. The alternative is years of polemic and debate surrounding several trials each too small to detect plausible differences with any certainty. Such trials produce equivocal and contradictory results, which could be predicted from power calculations based upon sensible pre-trial estimates of treatment differences. Unfortunately such calculations often lead to sample sizes of several thousands. It is not surprising that investigators tend to be over-optimistic in their estimation of treatment effects (which are necessarily uncertain) especially when the sample size requirements are so stark. In this paper a method is outlined for incorporating into the sample size calculations the uncertainty of the estimate made at the design stage of a clinical trial. In particular a formal scheme is described for deciding how many interim analyses should be performed to satisfy ethical and pragmatic requirements of large clinical trial design. Although the argument will be ‘Bayesian’, the criteria for assessment and comparison will be strictly of a Neyman-Pearson (i.e. significance testing) kind.     

临床真实世界研究中的实验性研究设计

真实世界研究作为解释性随机对照试验在医疗实践中评价干预措施效果的进一步验证和补充已成为医疗卫生领域关注的焦点。但是也存在错误将真实世界研究等同于观察性研究,认为真实世界研究不能实施人为干预,更不能采取随机化。实际上,真实世界研究的基本设计既可以是观察性的,也可以是实验性的。其中真实世界研究的实验性研究设计主要是指实用性随机对照试验和基于注册登记研究的随机对照试验,也可采用非随机对照、自适应设计等其他研究设计方案。     

维生素D治疗妊娠期糖尿病的系统综述

目的 评价维生素D治疗妊娠期糖尿病的疗效。方法 计算机检索Embase、Medline、Cochrane图书馆、中国期刊全文数据库、中国生物医学文献数据库,收集以VD为干预措施治疗妊娠期糖尿病的随机对照试验,由2位研究者独立筛选符合纳入标准的试验、评估文献质量、提取数据并进行Meta分析和敏感性分析。结果 共5项RCT,285例妊娠期糖尿病患者符合纳入标准。Meta分析结果显示,干预组较对照组的血清25-羟维生素D3水平高[MD = 25.97,95% CI = （12.37,39.57）],空腹胰岛素水平低[MD = -3.18,95% CI = (-3.32,-3.05)],稳态模式评估法的胰岛素抵抗指数低[MD = -1.07,95% CI = (-1.80,-0.24)],以上差异均具有统计学意义;但2组空腹血糖水平无统计学差异。结论 维生素D可能通过改善患者的胰岛素抵抗而治疗妊娠期糖尿病,但由于缺乏高质量的随机对照试验证据支持,尚不能做出最后结论,还需进行更多高质量的随机对照试验进一步验证。     

Attitudes to evidence in acupuncture: an interview study

The use of complementary and alternative medicine is increasing in the Western world. However, there is no clear evidence of effect of alternative therapies. Moreover, there is no consensus between practitioners and researchers as to the right way of assessing the efficacy of alternative therapies. To investigate practitioners?? perspective on evidence and ways of assessing efficacy twelve in-depth interviews were conducted in Denmark with acupuncturists, including physicians practising acupuncture, acupuncturists with a health-related background, and acupuncturists without a health-related background. Two themes predominated the study, first, the interviewees?? general reflections on how it is possible to establish knowledge about an effect of acupuncture; and second the interviewees?? reflections on the use of randomized controlled trials in acupuncture, including obstacles and alternatives to conducting randomized controlled trials. Further, two conceptions of what constitutes evidence were identified: a biomedical conception and an experience-based conception. Most interviewees were sceptical about the use of randomized controlled trials in acupuncture. Two reasons, especially, were given for this scepticism. First, practical and instrumental reasons concerning the specific elements of the randomized controlled trial or relating to limited resources; and second, value-based reasons are concerning the nature of acupuncture. However, the interviewees were really opposed only to a certain kind of randomized controlled trial, the so-called explanatory trial. They would actually welcome a pragmatic trial. The study gives valuable insight into an under explored field and provide a platform for further investigation, and a better informed discussion of the subject.     

Economic evaluation of factorial randomised controlled trials: challenges,methods and recommendations

Increasing numbers of economic evaluations are conducted alongside randomised controlled trials. Such studies include factorial trials, which randomise patients to different levels of two or more factors and can therefore evaluate the effect of multiple treatments alone and in combination. Factorial trials can provide increased statistical power or assess interactions between treatments, but raise additional challenges for trial‐based economic evaluations: interactions may occur more commonly for costs and quality‐adjusted life‐years (QALYs) than for clinical endpoints; economic endpoints raise challenges for transformation and regression analysis; and both factors must be considered simultaneously to assess which treatment combination represents best value for money. This article aims to examine issues associated with factorial trials that include assessment of costs and/or cost‐effectiveness, describe the methods that can be used to analyse such studies and make recommendations for health economists, statisticians and trialists. A hypothetical worked example is used to illustrate the challenges and demonstrate ways in which economic evaluations of factorial trials may be conducted, and how these methods affect the results and conclusions. Ignoring interactions introduces bias that could result in adopting a treatment that does not make best use of healthcare resources, while considering all interactions avoids bias but reduces statistical power. We also introduce the concept of the opportunity cost of ignoring interactions as a measure of the bias introduced by not taking account of all interactions. We conclude by offering recommendations for planning, analysing and reporting economic evaluations based on factorial trials, taking increased analysis costs into account. © 2017 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.     

Meta-analysis adjusting for compliance: the example of screening for breast cancer.

Randomized controlled trials are usually analysed by the group to which the patient was randomized, i.e. by "intention-to-treat", regardless of the degree of compliance. However, the "explanatory" effect, i.e. the effect that would occur if we had 100% compliance, is often of interest. This "explanatory" effect is diluted by poor compliance, and hence meta-analyses should ideally avoid both the heterogeneity of effect due to variation in compliance rates among studies, and the undeserved weight given to trials with poor compliance. Newcombe's deattenuation method, which adjusts estimates for the degree of compliance, is extended and applied to a meta-analysis of the five reported randomized controlled trials of mammographic screening. Compliance with screening varied across studies: from 61 to 93% assigned to screening had one or more mammograms. The adjusted estimate of the reduction in breast cancer mortality at 9 years follow-up is 0.37 (95% confidence interval: 0.21, 0.49).     

Physical exercise, weight gain, and perinatal outcomes in overweight and obese pregnant women: a systematic review of clinical trials

This study aimed to evaluate the effects of exercise on weight gain and perinatal outcomes among overweight and obese pregnant women, through a systematic review in MEDLINE/PubMed, EMBASE, LILACS, and SciELO. We included ten clinical trials that evaluated the effectiveness of exercise with or without combined diet in the control of gestational weight gain. Three studies were randomized, and methodological quality was assessed using the CONSORT 2010 Checklist, but none met all the criteria. Four studies showed weight gain differences between groups. The majority (60%) of studies showed no differences in perinatal outcomes (mode of delivery, gestational age at birth, birth weight). In conclusion, few studies confirmed the positive effect of exercise in controlling weight gain during pregnancy, thus requiring more research in this direction. Regarding perinatal outcomes, mild to moderate exercise does not appear to be decisive for perinatal outcomes, and is safe for pregnant women with overweight and obesity.     

A systematic review of the effects of calcium supplementation on body weight

Animal studies and epidemiological studies have suggested that Ca supplementation (with Ca supplements or dairy products) may be associated with weight loss in human adults. We aimed to assess whether any association was present by reviewing relevant randomized controlled trials in human subjects. The study was a systematic review and subsequent meta-analysis of randomized controlled trials that used Ca supplementation as an intervention in persons 18 or more years of age, and that reported body weight as a final outcome. A total of thirteen randomized controlled trials were included in the meta-analysis. There was no association between the increased consumption of either Ca supplements or dairy products and weight loss after adjusting for differences in baseline weights between the control and intervention groups (P=0.19 and 0.85, respectively). We therefore concluded that Ca supplementation has no statistically significant association with a reduction in body weight.     

Should meta-analyses of interventions include observational studies in addition to randomized controlled trials? A critical examination of underlying principles

Some authors argue that systematic reviews and meta-analyses of intervention studies should include only randomized controlled trials because the randomized controlled trial is a more valid study design for causal inference compared with the observational study design. However, a review of the principal elements underlying this claim (randomization removes the chance of confounding, and the double-blind process minimizes biases caused by the placebo effect) suggests that both classes of study designs have strengths and weaknesses, and including information from observational studies may improve the inference based on only randomized controlled trials. Furthermore, a review of empirical studies suggests that meta-analyses based on observational studies generally produce estimates of effect similar to those from meta-analyses based on randomized controlled trials. The authors found that the advantages of including both observational studies and randomized studies in a meta-analysis could outweigh the disadvantages in many situations and that observational studies should not be excluded a priori.     

What do community-based dengue control programmes achieve? A systematic review of published evaluations

Owing to increased epidemic activity and difficulties in controlling the insect vector, dengue has become a major public health problem in many parts of the tropics. The objective of this review is to analyse evidence regarding the achievements of community-based dengue control programmes. Medline, EMBASE, WHOLIS and the Cochrane Database of Systematic Reviews were searched (all to March 2005) to identify potentially relevant articles using keywords such as 'Aedes', 'dengue', 'breeding habits', 'housing' and 'community intervention'. According to the evaluation criteria recommended by the Cochrane Effective Practice and Organisation of Care Review Group, only studies that met the inclusion criteria of randomised controlled trials (RCT), controlled clinical trials (CCT), controlled before and after trials (CBA) or interrupted time series (ITS) were included. Eleven of 1091 studies met the inclusion criteria. Of these, two were RCTs, six were CBAs and three were ITS. The selected studies varied widely with respect to target groups, intervention procedures and outcome measurements. Six studies combined community participation programmes with dengue control tools. Methodological weaknesses were found in all studies: only two papers reported confidence intervals (95% CI); five studies reported P-values; two studies recognised the importance of water container productivity as a measure for vector density; in no study was cluster randomisation attempted; and in no study were costs and sustainability assessed. Evidence that community-based dengue control programmes alone and in combination with other control activities can enhance the effectiveness of dengue control programmes is weak.     

A simple and valid tool distinguished efficacy from effectiveness studies

OBJECTIVE: To propose and test a simple instrument based on seven criteria of study design to distinguish effectiveness (pragmatic) from efficacy (explanatory) trials. STUDY DESIGN: Currently no validated definition of effectiveness studies exists. We asked the directors of 12 Evidence-based Practice Centers to select six studies each: four that they considered to be examples of effectiveness trials and two considered efficacy studies. We then applied our proposed criteria to test the construct validity using the selected studies as if they had been identified by a gold standard. RESULTS: Based on the rationale to identify effectiveness studies reliably with minimal false positives (i.e., a high specificity), a cutoff of six criteria produced the most desirable balance between sensitivity and specificity. This setting produced a specificity of 0.83 and a sensitivity of 0.72. CONCLUSION: When applied in a standardized manner, our proposed criteria can provide a valid and simple tool to distinguish effectiveness from efficacy studies. The applicability of systematic reviews can improve when analysts place more emphasis on the generalizability of included studies. In addition, clinicians can also use our criteria to determine the external validity of individual studies, given an appropriate population of interest.     

Evaluating therapy in cerebral palsy

Summary The optimal design for most clinical trials of treatment is the randomized controlled group trial. This methodology is not, however, uniformly applicable or appropriate. The evaluation of physiotherapy in the management of cerebral palsy in childhood is a good example of treatment for which modification of this trial design is needed. Some of the problems with eight studies in this field published between 1960 and 1993 are reviewed here and an alternative approach proposed. A representative series of single case studies with individual goal setting and a validated outcome measurement, using randomized treatment, would overcome many of the disadvantages of published studies at a greatly reduced cost. The results would enable more effective group trials to be mounted in due course to evaluate the probable impact of providing treatment to a defined population of subjects.     

A pragmatic–explanatory continuum indicator summary (PRECIS): a tool to help trial designers

ObjectiveTo propose a tool to assist trialists in making design decisions that are consistent with their trial's stated purpose.Study Design and SettingRandomized trials have been broadly categorized as either having a pragmatic or explanatory attitude. Pragmatic trials seek to answer the question, “Does this intervention work under usual conditions?,” whereas explanatory trials are focused on the question, “Can this intervention work under ideal conditions?” Design decisions make a trial more (or less) pragmatic or explanatory, but no tool currently exists to help researchers make the best decisions possible in accordance with their trial's primary goal. During the course of two international meetings, participants with experience in clinical care, research commissioning, health care financing, trial methodology, and reporting defined and refined aspects of trial design that distinguish pragmatic attitudes from explanatory.ResultsWe have developed a tool (called PRECIS) with 10 key domains and which identifies criteria to help researchers determine how pragmatic or explanatory their trial is. The assessment is summarized graphically.ConclusionWe believe that PRECIS is a useful first step toward a tool that can help trialists to ensure that their design decisions are consistent with the stated purpose of the trial.     

Effectiveness of interventions in preventing injuries in agriculture--a systematic review and meta-analysis

OBJECTIVES: This study reviewed the effectiveness of interventions in preventing occupational injuries among workers in agriculture. METHODS: Randomized controlled trials, controlled before-after studies, and interrupted time-series studies assessing interventions aimed at preventing injuries among workers in agriculture were considered. MEDLINE and five other databases were searched up to June 2006. Two authors independently assessed the eligibility of studies and the methodological quality of the ones included. Randomized controlled trials were combined in a meta-analysis. Interrupted time-series studies were reanalyzed to assess the immediate and progressive effect on injuries. RESULTS: Five randomized controlled trials and three interrupted time-series studies met the inclusion criteria. Six studies evaluated educational interventions and financial incentives, and two studies evaluated the effect of legislation. Three randomized controlled trials on educational interventions with 4670 adult participants did not indicate any injury-reducing effect, with a rate ratio of 1.02 (95% confidence interval 0.87-1.20), nor did two randomized controlled trials among children (6895 participants). Financial incentives decreased the injury level immediately after the intervention in one interrupted time-series study. Banning endosulfan pesticide in Sri Lanka led to a significant decrease in the trend of poisonings over time. Legislation requiring rollover protective structures on all tractors in Sweden did not produce a reduction in injuries, but the same requirement for new tractors was associated with a decrease in fatal injuries. CONCLUSIONS: The reviewed studies provided no evidence that educational interventions are effective in decreasing injury rates among agricultural workers. Financial incentives may be a better means of reducing injury rates. Banning highly toxic pesticides may be effective. Legislation on safety devices on tractors yielded contradictory results.     

Form follows function: pragmatic controlled trials (PCTs) have to answer different questions and require different designs than randomized controlled trials (RCTs)

Aim

Rising concern for demonstrated real world comparative effectiveness has heightened interest in “pragmatic trials” design. Pragmatic trials investigate whether the efficacy, presumed or found in explanatory trials under ideal conditions, can also be detected under real world conditions, i.e. effectiveness. It is also recognized that ‘real world’ effects which are usually addressed in public health research gain growing interest in confirming the ‘road capability’ of results obtained under ideal study conditions. This paper demonstrates that studies under ideal or real world conditions use different methods, generate different information and cannot replace each other.

Subjects and methods

The PCT design meets four requirements of public health and of effectiveness research. It includes all individuals who presented with the selected condition. It classifies the included individuals according to baseline risks. It enables plausibility controls. Finally, it compares the outcomes resulting from specified and not-specified interventions or treatments.

Proposal

We propose a pragmatic controlled trial (PCT) design in which patient preference and other co-factors crucial in determining the actual effectiveness of interventional options will not be neutralized by concealed randomization and blinding. This design is applicable to record the selected interventions and generated outcomes in day-to-day health care and is capable of incorporating preference and other participative factors into assessment of effectiveness.

Conclusions

The PCT design is useful for public health research, e.g. the effectiveness of interventions to change smoking habits or to prevent death from breast cancer, as well as for comparative effectiveness research where it will supplement the traditional randomized controlled trial (RCT).