Objective: To illustrate how to evaluate the need of complex strategies for developing generalizable prediction models in large clustered datasets.

Study Design and Setting: We developed eight Cox regression models to estimate the risk of heart failure using a large population-level dataset. These models differed in the number of predictors, the functional form of the predictor effects (non-linear effects and interaction) and the estimation method (maximum likelihood and penalization). Internal-external cross-validation was used to evaluate the models' generalizability across the included general practices.

Results: Among 871,687 individuals from 225 general practices, 43,987 (5.5%) developed heart failure during a median follow-up time of 5.8 years. For discrimination, the simplest prediction model yielded a good concordance statistic, which was not much improved by adopting complex strategies. Between-practice heterogeneity in discrimination was similar in all models. For calibration, the simplest model performed satisfactorily. Although accounting for non-linear effects and interaction slightly improved the calibration slope, it also led to more heterogeneity in the observed/expected ratio. Similar results were found in a second case study involving patients with stroke.

Conclusion: In large clustered datasets, prediction model studies may adopt internal-external cross-validation to evaluate the generalizability of competing models, and to identify promising modelling strategies.

Non-randomized studies aim to reveal whether or not interventions are effective in real-life clinical practice, and there is a growing interest in including such evidence in the decision-making process. We evaluate existing methodologies and present new approaches to using non-randomized evidence in a network meta-analysis of randomized controlled trials (RCTs) when the aim is to assess relative treatment effects. We first discuss how to assess compatibility between the two types of evidence. We then present and compare an array of alternative methods that allow the inclusion of non-randomized studies in a network meta-analysis of RCTs: the naïve data synthesis, the design-adjusted synthesis, the use of non-randomized evidence as prior information and the use of three-level hierarchical models. We apply some of the methods in two previously published clinical examples comparing percutaneous interventions for the treatment of coronary in-stent restenosis and antipsychotics in patients with schizophrenia. We discuss in depth the advantages and limitations of each method, and we conclude that the inclusion of real-world evidence from non-randomized studies has the potential to corroborate findings from RCTs, increase precision and enhance the decision-making process.