title: Investigation of continuous effect modifiers in a meta-analysis on higher versus lower PEEP in patients requiring mechanical ventilation--protocol of the ICEM study.
abstract: BACKGROUND
  Categorizing an inherently continuous predictor in prognostic analyses raises several critical methodological issues: dependence of the statistical significance on the number and position of the chosen cut-point(s), loss of statistical power, and faulty interpretation of the results if a non-linear association is incorrectly assumed to be linear. This also applies to a therapeutic context where investigators of randomized clinical trials (RCTs) are interested in interactions between treatment assignment and one or more continuous predictors.
  
  
  METHODS
  Our goal is to apply the multivariable fractional polynomial interaction (MFPI) approach to investigate interactions between continuous patient baseline variables and the allocated treatment in an individual patient data meta-analysis of three RCTs (N = 2,299) from the intensive care field. For each study, MFPI will provide a continuous treatment effect function. Functions from each of the three studies will be averaged by a novel meta-analysis approach for functions. We will plot treatment effect functions separately for each study and also the averaged function. The averaged function with a related confidence interval will provide a suitable basis to assess whether a continuous patient characteristic modifies the treatment comparison and may be relevant for clinical decision-making. The compared interventions will be a higher or lower positive end-expiratory pressure (PEEP) ventilation strategy in patients requiring mechanical ventilation. The continuous baseline variables body mass index, PaO2/FiO2, respiratory compliance, and oxygenation index will be the investigated potential effect modifiers. Clinical outcomes for this analysis will be in-hospital mortality, time to death, time to unassisted breathing, and pneumothorax.
  
  
  CONCLUSIONS
  This project will be the first meta-analysis to combine continuous treatment effect functions derived by the MFPI procedure separately in each of several RCTs. Such an approach requires individual patient data (IPD). They are available from an earlier IPD meta-analysis using different methods for analysis. This new analysis strategy allows assessing whether treatment effects interact with continuous baseline patient characteristics and avoids categorization-based subgroup analyses. These interaction analyses of the present study will be exploratory in nature. However, they may help to foster future research using the MFPI approach to improve interaction analyses of continuous predictors in RCTs and IPD meta-analyses. This study is registered in PROSPERO (CRD42012003129).
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kasenda
authors.affiliation: Department of Medical Biometry and Medical Informatics, University Medical Center Freiburg, Freiburg, Germany. wfs@imbi.uni-freiburg.de.
authors.forename: Willi
authors.initials: W
authors.lastname: Sauerbrei
authors.forename: Patrick
authors.initials: P
authors.lastname: Royston
authors.forename: Matthias
authors.initials: M
authors.lastname: Briel
mesh_terms: D006801:Humans; D017052:Hospital Mortality; D011175:Positive-Pressure Respiration / Q000009:adverse effects / Q000379:methods / Q000401:mortality; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome; D015201:Meta-Analysis as Topic