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Marion Campbell Profile picture
@MarionKCampbell
Apr 17 • 11 tweets • 5 min read Twitter logo Read on Twitter
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This week some of my discussions have centred on #ClusterTrials. Cluster trials involve the randomisation of intact units (wards, hospitals, GP practices etc) rather than individuals. They have a number of key elements that must be accounted for 1/11
#MethodologyMonday
There are very good reasons for cluster/group randomisation eg when evaluating interventions like clinical guidelines or educational interventions which apply at practice/hospital level; or when there is potential of contamination of the intervention across trial groups 2/11
However, cluster randomisation has some major impacts for design & analysis primarily because observations within a cluster are not independent (outcomes are likely to be more similar within a cluster) 3/11
This intra-cluster correlation - measured by the intracluster correlation coefficient (ICC) - needs to be accounted for or trial results will appear more “significant” than they actually are. 4/11
Sample size needs to be inflated to account for this clustering. In its simplest form a std sample size needs to be inflated by a multiplier - the design effect - which accounts for the cluster size and the ICC 5/11
academic.oup.com/ije/article/44… Image
Estimates of the ICC are needed. There are published estimates to help for different fields. Some are given below 6/11

Implementation research: journals.sagepub.com/doi/abs/10.119…
Primary care: jclinepi.com/article/S0895-…
Schools: jclinepi.com/article/S0895-…
Consent can also be different in cluster trials as many interventions are not targeting patients directly. Some cluster trials therefore seek a waiver of consent. The Ottawa statement on cluster trials is a great read on consent & ethical issues 7/11
journals.plos.org/plosmedicine/a… Image
Selection bias can be an issue in cluster trials as usually treatment allocation is known ahead of patient recruitment. Awareness of allocation can lead to biased recruitment in the different arms of the trial. It is important to mitigate against this 8/11
bmcmedresmethodol.biomedcentral.com/articles/10.11… Image
Process evaluations also need to think about the extra dimension added by the clustering. Aileen Grant et al discuss some of the issues which arise in the following paper 9/11
trialsjournal.biomedcentral.com/articles/10.11… Image
Analysis also needs cluster-tailored methods to ensure the results are adjusted to account for the ICC and don’t over amplify the significance of the results. 10/11
trialsjournal.biomedcentral.com/articles/10.11… Image
There are now neat variants on the cluster design including the cluster-crossover design (CRXO) which is a particularly efficient design in this space 11/11

bmj.com/content/371/bm… Image

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More from @MarionKCampbell

Marion Campbell Profile picture
Apr 3
The first step in a clinical trial is deciding the #ResearchQuestion. Knowing which question is most important to focus on may not be clear cut. An interesting paper was recently published which developed a tool to rank the importance of research questions 1/7
#MethodologyMonday
This tool was developed for the musculo-skeletal field (ANZMUSC-RQIT), but the concepts are highly likely to be transferable to other fields 2/7
journals.plos.org/plosone/articl…
The tool identified 5 domains to be ranked:1) extent of stakeholder consensus, 2) social burden of health condition, 3) patient burden of health condition, 4) anticipated effectiveness of proposed intervention, and 5) extent to which health equity is addressed by the research 3/7
Read 7 tweets
Marion Campbell Profile picture
Mar 27
There was an interesting paper this week on different stakeholders understanding of the concept of #equipoise. Equipoise is an essential concept in clinical trials but is often not well understood 1/8
#MethodologyMonday
For it to be ethical to randomise in a trial, it is important that there is uncertainty which treatment is best 2/8
Originally uncertainty (equipoise) had to be at the level of the individual clinician but was refined to uncertainty at the professional community level by Freedman in the 1980s 3/8
nejm.org/doi/full/10.10…
Read 8 tweets
Marion Campbell Profile picture
Mar 20
The #FactorialTrial design is one of the very original efficient trial designs yet its potential often remains underused 1/7
#MethodologyMonday
In a #FactorialTrial you can evaluate the effectiveness of more than one treatment simultaneously and for the same sample size requirements as doing a single trial 2/7
bmcmedresmethodol.biomedcentral.com/articles/10.11…
For a factorial trial of say 2 treatments, patients are allocated to 1 of 4 groups: Gp1 receives both treatments A and B; Gp2 receives only A; Gp3 receives only B; and Gp4 receives neither A nor B (the control) 3/7
cambridge.org/core/services/…
Read 7 tweets
Marion Campbell Profile picture
Mar 13
A clinical trial design that is often misunderstood is the #NonInferiority clinical trial design. 1/8
#MethodologyMonday
Mostly we set up trials to test if a new treatment is better than another (ie we test for superiority) but in a #NonInferiority design we wish to test if a treatment is not unacceptably worse than a comparator. 2/8
The main reasons why we might look for non-inferiority is when an alternative treatment is say much cheaper, or has fewer side effects … but we would only wish to use it if the benefits of the standard treatment are not significantly compromised. 3/8
onlinelibrary.wiley.com/doi/full/10.10…
Read 8 tweets
Marion Campbell Profile picture
Mar 6
Having spent the last couple of weeks discussing composite & surrogate outcomes, I was reminded this week of the importance of thoughtful planning on the choice of outcomes in the first place 1/6
#MethodologyMonday
In particular I was reminded of the fundamental work of #Donabedian to conceptualise what is important to measure to assess quality of (and improvement in) health care. Although developed decades ago, it remains just as relevant today 2/6
jamanetwork.com/journals/jama/…
When we seek to assess the impact of a new intervention on care, the Donabedian model suggests there are 3 elements that may be impacted - the #structure the #process and the #outcome of care 3/6
Read 6 tweets
Marion Campbell Profile picture
Feb 27
Last week I discussed composite endpoints and how while they can be useful, they can also be fraught with difficulty. The same descriptors could equally be applied to #SurrogateOutcomes in clinical trials 1/9
#MethodologyMonday
A #SurrogateOutcome is a substitute measure (eg blood pressure) that one might use to stand in for the real outcome of interest (eg stroke) when the real outcomes of interest may take a very long time to measure - to allow trials to be completed more quickly & efficiently 2/9
Surrogate outcomes can take many forms and may be histological, physiological, radiological etc … biomarkers that predict events 3/9
Read 9 tweets

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