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Longitudinal mediation in the PACE randomised clinical trial of rehabilitative treatments for chronic fatigue syndrome: modelling and design considerations
Goldsmith et al. Trials
Longitudinal mediation in the PACE randomised clinical trial of rehabilitative treatments for chronic fatigue syndrome: modelling and design considerations
Kimberley Goldsmith 2 3
Trudie Chalder 2 3
Peter White 1 2
Michael Sharpe 0 2
Andrew Pickles 2 3
0 Psychological Medicine Research, Department of Psychiatry, University of Oxford , Oxford , UK
1 Centre for Psychiatry, Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine, Queen Mary University , London , UK
2 Authors' details
3 Institute of Psychiatry, Psychology & Neuroscience, King's College London , London , UK
Background Clinical trials require large monetary and time commitments and should provide information on both whether and how treatments work. Treatment mechanisms can be studied using mediation analysis, allowing refinement of treatments. Mediation studies often use only single contemporaneous measures of mediator and outcome limiting the conclusions that can be drawn. Longitudinally measured mediators and outcomes, such as those in the Pacing, Graded Activity, and Cognitive Behaviour Therapy: A Randomised Evaluation trial (PACE, ISRCTN 54285094) allow for more realistic estimates of mediated effects.
Methods
Autoregressive models accounting for measurement error
were used to study treatment effect mediation of
cognitive behaviour therapy (CBT) and graded exercise therapy
(GET) in PACE. Fear avoidance and physical function
were used as example mediator and outcome; these were
measured at baseline and three times post-randomisation
as part of the trial design. Model fit criteria, Wald tests
and comparisons of parameter estimates were used.
Results
Longitudinal SEM were more flexible and gave what were
likely more plausible estimates of mediated effects.
Constancy of mediator - outcome effects over time and
across treatment groups increased precision. For CBT and
GET, 46% and 53% of the overall effect were mediated
through fear avoidance.
Conclusions
Trials should be designed to include multiple
measurements of mediators and outcomes so that more realistic
mediation models can be used. Longitudinal models
may have more power to detect mediated effects.
Approximately half of the effect of each of CBT and
GET were on physical function was mediated through
reducing avoidance of fearful situations. (...truncated)