Background: Previous studies suggest that hemodiafiltration reduces mortality compared to hemodialysis in patients with end-stage kidney disease (ESKD), but controversy surrounding its benefits remain and it is unclear to what extent individual patients benefit from hemodiafiltration. This study aimed to develop and validate a treatment effect prediction model to determine which patients would benefit most from hemodiafiltration compared to hemodialysis in terms of all-cause mortality.

Methods: Individual participant data from four randomized controlled trials comparing hemodiafiltration with hemodialysis on mortality were used to derive a Royston-Parmar model for prediction of absolute treatment effect of hemodiafiltration based on pre-specified patient and disease characteristics. Validation of the model was performed using internal-external cross validation.

Results: The median predicted survival benefit was 44 (Q1-Q3: 44-46) days for every year of treatment with hemodiafiltration compared to hemodialysis. The median survival benefit with hemodiafiltration ranged from 2 to 48 months. Patients who benefited most from hemodiafiltration were younger, less likely to have diabetes or a cardiovascular history and had higher serum creatinine and albumin levels. Internal-external cross validation showed adequate discrimination and calibration.

Conclusion: Although overall mortality is reduced by hemodiafiltration compared to hemodialysis in ESKD patients, the absolute survival benefit can vary greatly between individuals. Our results indicate that the effects of hemodiafiltration on survival can be predicted using a combination of readily available patient and disease characteristics, which could guide shared decision-making.

Meta-analysis of randomized controlled trials is generally considered the most reliable source of estimates of relative treatment effects. However, in the last few years, there has been interest in using non-randomized studies to complement evidence from randomized controlled trials. Several meta-analytical models have been proposed to this end. Such models mainly focussed on estimating the average relative effects of interventions. In real-life clinical practice, when deciding on how to treat a patient, it might be of great interest to have personalized predictions of absolute outcomes under several available treatment options. This paper describes a general framework for developing models that combine individual patient data from randomized controlled trials and non-randomized study when aiming to predict outcomes for a set of competing medical interventions applied in real-world clinical settings. We also discuss methods for measuring the models' performance to identify the optimal model to use in each setting. We focus on the case of continuous outcomes and illustrate our methods using a data set from rheumatoid arthritis, comprising patient-level data from three randomized controlled trials and two registries from Switzerland and Britain.

As real world evidence on drug efficacy involves non-randomised studies, statistical methods adjusting for confounding are needed. In this context, prognostic score (PGS) analysis has recently been proposed as a method for causal inference. It aims to restore balance across the different treatment groups by identifying subjects with a similar prognosis for a given reference exposure ('control'). This requires the development of a multivariable prognostic model in the control arm of the study sample, which is then extrapolated to the different treatment arms. Unfortunately, large cohorts for developing prognostic models are not always available. Prognostic models are therefore subject to a dilemma between overfitting and parsimony; the latter being prone to a violation of the assumption of no unmeasured confounders when important covariates are ignored. Although it is possible to limit overfitting by using penalization strategies, an alternative approach is to adopt evidence synthesis. Aggregating previously published prognostic models may improve the generalizability of PGS, while taking account of a large set of covariates - even when limited individual participant data are available. In this article, we extend a method for prediction model aggregation to PGS analysis in non- randomised studies. We conduct extensive simulations to assess the validity of model aggregation, compared with other methods of PGS analysis for estimating marginal treatment effects. We show that aggregating existing PGS into a 'meta-score' is robust to misspecification, even when elementary scores wrongfully omit confounders or focus on different outcomes. We illustrate our methods in a setting of treatments for asthma.

In non-randomised studies, inferring causal effects requires appropriate methods for addressing confounding bias. Although it is common to adopt propensity score analysis to this purpose, prognostic score analysis has recently been proposed as an alternative strategy. Whilst both approaches were originally introduced to estimate causal effects for binary interventions, the theory of propensity score has since been extended to the case of general treatment regimes. Indeed, many treatments are not assigned in a binary fashion, and require a certain extent of dosing. Hence, researchers may often be interested in estimating treatment effects across multiple exposures. To the best of our knowledge, the prognostic score analysis has not been yet generalised to this case. In this article, we describe the theory of prognostic scores for causal inference with general treatment regimes. Our methods can be applied to compare multiple treatments using non-randomised data, a topic of great relevance in contemporary evaluations of clinical interventions. We propose estimators for the average treatment effects in different populations of interest, the validity of which is assessed through a series of simulations. Finally, we present an illustrative case in which we estimate the effect of the delay to Aspirin administration on a composite outcome of death or dependence at 6 months in stroke patients.