BACKGROUND: Validating new algorithms, such as methods to disentangle intrinsic treatment risk from risk associated with experiential learning of novel treatments, often requires knowing the ground truth for data characteristics under investigation. Since the ground truth is inaccessible in real world data, simulation studies using synthetic datasets that mimic complex clinical environments are essential. We describe and evaluate a generalizable framework for injecting hierarchical learning effects within a robust data generation process that incorporates the magnitude of intrinsic risk and accounts for known critical elements in clinical data relationships. METHODS: We present a multi-step data generating process with customizable options and flexible modules to support a variety of simulation requirements. Synthetic patients with nonlinear and correlated features are assigned to provider and institution case series. The probability of treatment and outcome assignment are associated with patient features based on user definitions. Risk due to experiential learning by providers and/or institutions when novel treatments are introduced is injected at various speeds and magnitudes. To further reflect real-world complexity, users can request missing values and omitted variables. We illustrate an implementation of our method in a case study using MIMIC-III data for reference patient feature distributions. RESULTS: Realized data characteristics in the simulated data reflected specified values. Apparent deviations in treatment effects and feature distributions, though not statistically significant, were most common in small datasets (n < 3000) and attributable to random noise and variability in estimating realized values in small samples. When learning effects were specified, synthetic datasets exhibited changes in the probability of an adverse outcomes as cases accrued for the treatment group impacted by learning and stable probabilities as cases accrued for the treatment group not affected by learning. CONCLUSIONS: Our framework extends clinical data simulation techniques beyond generation of patient features to incorporate hierarchical learning effects. This enables the complex simulation studies required to develop and rigorously test algorithms developed to disentangle treatment safety signals from the effects of experiential learning. By supporting such efforts, this work can help identify training opportunities, avoid unwarranted restriction of access to medical advances, and hasten treatment improvements.

Non-randomised studies of the effects of interventions are critical to many areas of healthcare evaluation, but their results may be biased. It is therefore important to understand and appraise their strengths and weaknesses. We developed ROBINS-I (“Risk Of Bias In Non-randomised Studies - of Interventions”), a new tool for evaluating risk of bias in estimates of the comparative effectiveness (harm or benefit) of interventions from studies that did not use randomisation to allocate units (individuals or clusters of individuals) to comparison groups. The tool will be particularly useful to those undertaking systematic reviews that include non-randomised studies.