title: Meta-regression models to address heterogeneity and inconsistency in network meta-analysis of survival outcomes.
abstract: BACKGROUND
  Recently, network meta-analysis of survival data with a multidimensional treatment effect was introduced. With these models the hazard ratio is not assumed to be constant over time, thereby reducing the possibility of violating transitivity in indirect comparisons. However, bias is still present if there are systematic differences in treatment effect modifiers across comparisons.
  
  
  METHODS
  In this paper we present multidimensional network meta-analysis models for time-to-event data that are extended with covariates to explain heterogeneity and adjust for confounding bias in the synthesis of evidence networks of randomized controlled trials. The impact of a covariate on the treatment effect can be assumed to be treatment specific or constant for all treatments compared.
  
  
  RESULTS
  An illustrative example analysis is presented for a network of randomized controlled trials evaluating different interventions for advanced melanoma. Incorporating a covariate related to the study date resulted in different estimates for the hazard ratios over time than an analysis without this covariate, indicating the importance of adjusting for changes in contextual factors over time.
  
  
  CONCLUSIONS
  Adding treatment-by-covariate interactions to multidimensional network meta-analysis models for published survival curves can be worthwhile to explain systematic differences across comparisons, thereby reducing inconsistencies and bias. An additional advantage is that heterogeneity in treatment effects can be explored.
authors.affiliation: MAPI Consultancy, Boston, MA 02114, USA. jjansen@mapigroup.com
authors.forename: Jeroen P
authors.initials: JP
authors.lastname: Jansen
authors.forename: Shannon
authors.initials: S
authors.lastname: Cope
mesh_terms: D015987:Effect Modifier, Epidemiologic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008545:Melanoma / Q000401:mortality / Q000556:secondary / Q000628:therapy; D015233:Models, Statistical; D009367:Neoplasm Staging / Q000401:mortality; D016571:Neural Networks, Computer; D016032:Randomized Controlled Trials as Topic / Q000592:standards / Q000706:statistics & numerical data*; D012044:Regression Analysis; D015203:Reproducibility of Results; D015996:Survival Rate; D013997:Time Factors; D016896:Treatment Outcome