title: Modelling variable dropout in randomised controlled trials with longitudinal outcomes: application to the MAGNETIC study.
abstract: BACKGROUND
  Clinical trials with longitudinally measured outcomes are often plagued by missing data due to patients withdrawing or dropping out from the trial before completing the measurement schedule. The reasons for dropout are sometimes clearly known and recorded during the trial, but in many instances these reasons are unknown or unclear. Often such reasons for dropout are non-ignorable. However, the standard methods for analysing longitudinal outcome data assume that missingness is non-informative and ignore the reasons for dropout, which could result in a biased comparison between the treatment groups.
  
  
  METHODS
  In this article, as a post hoc analysis, we explore the impact of informative dropout due to competing reasons on the evaluation of treatment effect in the MAGNETIC trial, the largest randomised placebo-controlled study to date comparing the addition of nebulised magnesium sulphate to standard treatment in acute severe asthma in children. We jointly model longitudinal outcome and informative dropout process to incorporate the information regarding the reasons for dropout by treatment group.
  
  
  RESULTS
  The effect of nebulised magnesium sulphate compared with standard treatment is evaluated more accurately using a joint longitudinal-competing risk model by taking account of such complexities. The corresponding estimates indicate that the rate of dropout due to good prognosis is about twice as high in the magnesium group compared with standard treatment.
  
  
  CONCLUSIONS
  We emphasise the importance of identifying reasons for dropout and undertaking an appropriate statistical analysis accounting for such dropout. The joint modelling approach accounting for competing reasons for dropout is proposed as a general approach for evaluating the sensitivity of conclusions to assumptions regarding missing data in clinical trials with longitudinal outcomes.
  
  
  BACKGROUND
  EudraCT number 2007-006227-12 . Registration date 18 Mar 2008.
authors.affiliation: MRC North West Hub for Trials Methodology Research, Department of Biostatistics, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3GA, UK. kdrr@liverpool.ac.uk.
authors.forename: Ruwanthi
authors.initials: R
authors.lastname: Kolamunnage-Dona
authors.affiliation: Department of Child Health, Institute of Molecular and Experimental Medicine, Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XW, UK.|Department of General Paediatrics, Children's Hospital for Wales, Heath Park, Cardiff, CF14 4XW, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Powell
authors.affiliation: MRC North West Hub for Trials Methodology Research, Department of Biostatistics, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3GA, UK.
authors.forename: Paula Ruth
authors.initials: PR
authors.lastname: Williamson
mesh_terms: D000280:Administration, Inhalation; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage*; D001249:Asthma / Q000188:drug therapy*; D015982:Bias; D006801:Humans; D008137:Longitudinal Studies; D008278:Magnesium Sulfate / Q000008:administration & dosage*; D015233:Models, Statistical; D009330:Nebulizers and Vaporizers; D010352:Patient Dropouts / Q000706:statistics & numerical data*; D012107:Research Design / Q000706:statistics & numerical data*; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D018927:Anti-Asthmatic Agents; D008278:Magnesium Sulfate
keywords: Competing risks; Dropout process; Joint modelling; Longitudinal outcome