title: Network meta-analysis combining individual patient and aggregate data from a mixture of study designs with an application to pulmonary arterial hypertension.
abstract: BACKGROUND
  Network meta-analysis (NMA) is a methodology for indirectly comparing, and strengthening direct comparisons of two or more treatments for the management of disease by combining evidence from multiple studies. It is sometimes not possible to perform treatment comparisons as evidence networks restricted to randomized controlled trials (RCTs) may be disconnected. We propose a Bayesian NMA model that allows to include single-arm, before-and-after, observational studies to complete these disconnected networks. We illustrate the method with an indirect comparison of treatments for pulmonary arterial hypertension (PAH).
  
  
  METHODS
  Our method uses a random effects model for placebo improvements to include single-arm observational studies into a general NMA. Building on recent research for binary outcomes, we develop a covariate-adjusted continuous-outcome NMA model that combines individual patient data (IPD) and aggregate data from two-arm RCTs with the single-arm observational studies. We apply this model to a complex comparison of therapies for PAH combining IPD from a phase-III RCT of imatinib as add-on therapy for PAH and aggregate data from RCTs and single-arm observational studies, both identified by a systematic review.
  
  
  RESULTS
  Through the inclusion of observational studies, our method allowed the comparison of imatinib as add-on therapy for PAH with other treatments. This comparison had not been previously possible due to the limited RCT evidence available. However, the credible intervals of our posterior estimates were wide so the overall results were inconclusive. The comparison should be treated as exploratory and should not be used to guide clinical practice.
  
  
  CONCLUSIONS
  Our method for the inclusion of single-arm observational studies allows the performance of indirect comparisons that had previously not been possible due to incomplete networks composed solely of available RCTs. We also built on many recent innovations to enable researchers to use both aggregate data and IPD. This method could be used in similar situations where treatment comparisons have not been possible due to restrictions to RCT evidence and where a mixture of aggregate data and IPD are available.
authors.affiliation: School of Social and Community Medicine, Bristol, UK. howard.thom@bristol.ac.uk.
authors.forename: Howard H Z
authors.initials: HH
authors.lastname: Thom
authors.affiliation: Novartis Pharma AG, Basel, Switzerland. gorana.capkun-niggli@novartis.com.
authors.forename: Gorana
authors.initials: G
authors.lastname: Capkun
authors.affiliation: Novartis Pharma AG, Basel, Switzerland. annamaria.cerulli@novartis.com.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Cerulli
authors.affiliation: Novartis Pharma AG, Basel, Switzerland. richard.nixon@novartis.com.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Nixon
authors.affiliation: National Heart & Lung Institute, Imperial College London, London, UK. l.howard@imperial.ac.uk.
authors.forename: Luke S
authors.initials: LS
authors.lastname: Howard
mesh_terms: D001499:Bayes Theorem; D006801:Humans; D006976:Hypertension, Pulmonary / Q000503:physiopathology / Q000628:therapy*; D015201:Meta-Analysis as Topic; D064887:Observational Studies as Topic; D017063:Outcome Assessment, Health Care / Q000379:methods; D011651:Pulmonary Artery / Q000503:physiopathology; D016032:Randomized Controlled Trials as Topic; D015203:Reproducibility of Results; D012107:Research Design / Q000592:standards*