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Case Examples: Contamination Example 1: Participants who share the same provider in a trial comparing different weight-loss strategies may meet each other in the waiting room and communicate about their respective strategies, or the provider might not be able to adapt to coaching differently depending on the randomization. Some participants in each group might even adopt elements of both strategies, and neither group would demonstrate the impact of its intended strategy.
Randomization at the provider level, with each provider coaching only one of the strategies, would reduce the risk of contamination. Example 2: A trial evaluating a campaign designed to reduce nosocomial infections by encouraging better staff handwashing practices might include posters in each of the rooms.
Below are various examples of trials that have been conducted for these reasons:. The intervention is implemented at the cluster level or it is logistically easier or more ethical to administer to groups of individuals.
The Lancet Global Health. A cleaner burning biomass-fuelled cookstove intervention to prevent pneumonia in children under 5 years old in rural Malawi the Cooking and Pneumonia Study : a cluster randomised controlled trial. The Lancet. Assessing the effectiveness of enhanced psychological care for patients with depressive symptoms attending cardiac rehabilitation compared with treatment as usual CADENCE : study protocol for a pilot cluster randomised controlled trial.
Effects of water quality, sanitation, handwashing, and nutritional interventions on diarrhoea and child growth in rural Bangladesh: a cluster randomised controlled trial. Ethical issues in the design and conduct of cluster randomised controlled trials.
To avoid issues of contamination, e. Toward Causal Inference With Interference. Journal of the American Statistical Association.
Haber M. Estimation of the direct and indirect effects of vaccination. Statistics in Medicine. Design of a group-randomized Streptococcus pneumoniae vaccine trial. Controlled clinical trials. Efficacy and effectiveness of an rVSV-vectored vaccine expressing Ebola surface glycoprotein: interim results from the Guinea ring vaccination cluster-randomised trial. Village-Integrated Eye Worker trial VIEW : rationale and design of a cluster-randomised trial to prevent corneal ulcers in resource-limited settings.
BMJ Open. In comparison to trials in which individual randomisation is used, outcomes from individuals in the same cluster will tend to be more similar to each other than a random sample for the whole group and this must be accounted for in both the design and analysis of CRTs.
The intracluster correlation ICC is a measure of the between-cluster variation. It can also be thought of as a measure of the homogeneity of individuals within a cluster. The experimental group wore the short wave UVA-blocking sunscreen daily, and the control group wore the long wave UVA-blocking sunscreen daily. After one year, the general health of the skin was measured in both groups and statistically analyzed. The preventive effect of the nordic hamstring exercise on hamstring injuries in amateur soccer players: a randomized controlled trial.
The American Journal of Sports Medicine, 43 6 , Natour, J. Pilates improves pain, function and quality of life in patients with chronic low back pain: a randomized controlled trial. Clinical Rehabilitation, 29 1 , When the groups that have been randomly selected from a population do not know whether they are in the control group or the experimental group. Being able to show that an independent variable directly causes the dependent variable.
The various colors of the individuals in each cluster light red, medium red, dark red identify the various age groups. Matching in cluster-randomized studies: In the matching process, the maximally homogeneous cluster pairs are divided randomly between the intervention and control arms of the study with regard to the predefined participant characteristics in this example: age.
Stratification in cluster-randomized studies: In stratified randomization, care homes from a region are randomly selected from the whole set of care homes in that region and divided equally between the two study arms.
Each stratum is homogeneous with regard to relevant characteristics, but the strata may differ very widely from one another. Clusters for the intervention and control arms are chosen randomly to form equally sized blocks in each stratum.
The number of strata should be kept low so that balanced blocks result. This requirement often stands in opposition to the frequent need for randomization to take account of a large number of variables by differentiation of cluster and individual level. For example, stratification in a geographic region with four values and two funding bodies would involve division of the clusters into eight strata.
Such a strategy can lead to underoccupation of individual cells. The minimization method represents a compromise between balance and true randomization. The aim is to make the arms of the trial as homogeneous as possible. In the case of a small number of clusters this balance runs against the principle of randomness and may lead to an increased risk of selection bias. In minimization the number of covariables for stratification is limited, so that the variables that are considered can also be modeled when it comes to analysis.
Clusters are deterministically assigned to an intervention or the control group according to relevant variables. In this way observable confounders can be balanced between the study arms.
Another approach is covariable-restricted randomization, in which clusters are allotted to the study arms in equal numbers according to the distribution of relevant basic variables 19 — For constant variables one takes account of aggregated data such as mean values within clusters or strata.
Data from the basic data acquisition stage must already be available at the time of randomization. A randomization scheme is selected randomly from among those that result in balanced study arms with regard to predefined relevant properties and exposures. Because the final randomization scheme is selected from the group of all theoretically possible schemes see the equation for the number of possible randomization schemes in Box 2 , randomness of assignment to intervention or control is largely preserved.
The evaluation of CRT takes place on at least two levels, namely the cluster level and the individual patient level. In the multi-level models the statistical model is expanded by adding a random component for the variation of the clusters 21 , This takes account of the ICC resulting from the design.
A lucid account of how to carry out a multi-level analysis is provided by Ansmann et al. The use of CRT has increased steeply in the past 15 years. The provision for the influence of clustering in the individual phases of the study from case number calculation through randomization to analysis should be described.
The reporting of CRT in medical research currently displays major deficits. Therefore, it is very important that authors plan their studies in accordance with the expanded CONSORT guidelines or, for example, the stepped wedge design The first step in planning a study is to decide whether it can be performed with individual randomization or whether a CRT is necessary.
An acceptable reason for carrying out a CRT is that the intervention is being performed in clusters and there would be a risk of contamination in an individually randomized trial. Alternative study types for organizational interventions are the stepped wedge and crossover designs, in which the clusters are included in analysis both as intervention and as control entities.
The planning and conduct of CRT presents special challenges differing from the requirements for individually randomized trials. The clustering must be retained at all stages, from case number planning through analysis techniques to reporting. Study conduct also involves specific challenges, e.
Whether conclusions should be drawn at the individual patient level or at cluster level is determined by the choice of design and analysis technique 5. To increase analytical precision, strict inclusion and exclusion criteria have to be defined.
It is always important to consider the benefit of an intervention not only at cluster level but also at the level of individual patients, e. When planning a study, the study-specific ICC can be estimated on the basis of a baseline survey.
Moreover, stratification variables that are already relevant can be identified. It is often argued that the conduct of CRT is associated with less administrative effort, e. On the other hand, the consent of the study participants must be obtained at two levels, because although the intervention is carried out at cluster level, when it comes to analysis there are frequently interesting parameters at the individual level. For large communities, it may be logistically challenging or even impossible to obtain informed consent for all individual study participants 5 , However, this should not necessarily be viewed as a limitation of ethical requirements, provided there is sufficient justification The level at which consent is necessary depends on the intervention, on the study-specific data protection regulations, and on the specific requirements of the ethics committee involved.
In some situations it may be justified to go ahead in the absence of informed consent, for instance if the intervention only tangentially affects individual persons.
An example is the introduction of new rules regarding hygiene, which does not require the agreement of all patients. Cluster-randomized trials CRT are frequently used when interventions are to be carried out at the level of whole groups rather than single individuals.
As a result of cluster formation, persons within a group often have more characteristics in common than persons in different groups. The so-called intracluster correlation coefficient should be reported as measure of similarity of individuals between and within clusters. The results of CRT can be distorted by recruitment bias, baseline imbalance, loss of clusters, and incorrect analysis. Blinding of the participants and study personnel in a CRT is frequently not feasible.
This may result in differing motivation and thus become a source of recruitment bias. If at all possible, therefore, recruitment of study participants should be complete before randomization. In CRT where the study staff are not blinded, the outcome parameters should be documented by an external person.
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