title: Evaluation and validation of social and psychological markers in randomised trials of complex interventions in mental health: a methodological research programme.
abstract: BACKGROUND
  The development of the capability and capacity to evaluate the outcomes of trials of complex interventions is a key priority of the National Institute for Health Research (NIHR) and the Medical Research Council (MRC). The evaluation of complex treatment programmes for mental illness (e.g. cognitive-behavioural therapy for depression or psychosis) not only is a vital component of this research in its own right but also provides a well-established model for the evaluation of complex interventions in other clinical areas. In the context of efficacy and mechanism evaluation (EME) there is a particular need for robust methods for making valid causal inference in explanatory analyses of the mechanisms of treatment-induced change in clinical outcomes in randomised clinical trials.
  
  
  OBJECTIVE
  The key objective was to produce statistical methods to enable trial investigators to make valid causal inferences about the mechanisms of treatment-induced change in these clinical outcomes. The primary objective of this report is to disseminate this methodology, aiming specifically at trial practitioners.
  
  
  METHODS
  The three components of the research were (1) the extension of instrumental variable (IV) methods to latent growth curve models and growth mixture models for repeated-measures data; (2) the development of designs and regression methods for parallel trials; and (3) the evaluation of the sensitivity/robustness of findings to the assumptions necessary for model identifiability. We illustrate our methods with applications from psychological and psychosocial intervention trials, keeping the technical details to a minimum, leaving the reporting of the more theoretical and mathematically demanding results for publication in appropriate specialist journals.
  
  
  RESULTS
  We show how to estimate treatment effects and introduce methods for EME. We explain the use of IV methods and principal stratification to evaluate the role of putative treatment effect mediators and therapeutic process measures. These results are extended to the analysis of longitudinal data structures. We consider the design of EME trials. We focus on designs to create convincing IVs, bearing in mind assumptions needed to attain model identifiability. A key area of application that has become apparent during this work is the potential role of treatment moderators (predictive markers) in the evaluation of treatment effect mechanisms for personalised therapies (stratified medicine). We consider the role of targeted therapies and multiarm trials and the use of parallel trials to help elucidate the evaluation of mediators working in parallel.
  
  
  CONCLUSIONS
  In order to demonstrate both efficacy and mechanism, it is necessary to (1) demonstrate a treatment effect on the primary (clinical) outcome, (2) demonstrate a treatment effect on the putative mediator (mechanism) and (3) demonstrate a causal effect from the mediator to the outcome. Appropriate regression models should be applied for (3) or alternative IV procedures, which account for unmeasured confounding, provided that a valid instrument can be identified. Stratified medicine may provide a setting where such instruments can be designed into the trial. This work could be extended by considering improved trial designs, sample size considerations and measurement properties.
  
  
  BACKGROUND
  The project presents independent research funded under the MRC-NIHR Methodology Research Programme (grant reference G0900678).
authors.affiliation: Centre for Biostatistics, Institute of Population Health, University of Manchester and Manchester Academic Health Science Centre, Manchester, UK.|Medical Research Council North West Hub for Trials Methodology Research, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: Dunn
authors.affiliation: Centre for Biostatistics, Institute of Population Health, University of Manchester and Manchester Academic Health Science Centre, Manchester, UK.|Medical Research Council North West Hub for Trials Methodology Research, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Emsley
authors.affiliation: Centre for Biostatistics, Institute of Population Health, University of Manchester and Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Hanhua
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Biostatistics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Sabine
authors.initials: S
authors.lastname: Landau
authors.affiliation: Institute of Brain, Behaviour and Mental Health, University of Manchester and Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Green
authors.affiliation: Medical Research Council Biostatistics Unit, University of Cambridge, Cambridge, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: White
authors.affiliation: Department of Biostatistics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Pickles
mesh_terms: D015415:Biomarkers; D003627:Data Interpretation, Statistical; D006801:Humans; D001523:Mental Disorders / Q000523:psychology / Q000628:therapy*; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D012044:Regression Analysis; D012107:Research Design; D013673:Technology Assessment, Biomedical
chemical_list: D015415:Biomarkers