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Abstract ObjectivesEpileptiform activity (EA) worsens outcomes in patients with acute brain injuries (e.g., aneurysmal subarachnoid hemorrhage [aSAH]). Randomized trials (RCTs) assessing anti-seizure interventions are needed. Due to scant drug efficacy data and ethical reservations with placebo utilization, RCTs are lacking or hindered by design constraints. We used a pharmacological model-guided simulator to design and determine feasibility of RCTs evaluating EA treatment. MethodsIn a single-center cohort of adults (age >18) with aSAH and EA, we employed a mechanistic pharmacokinetic-pharmacodynamic framework to model treatment response using observational data. We subsequently simulated RCTs for levetiracetam and propofol, each with three treatment arms mirroring clinical practice and an additional placebo arm. Using our framework we simulated EA trajectories across treatment arms. We predicted discharge modified Rankin Scale as a function of baseline covariates, EA burden, and drug doses using a double machine learning model learned from observational data. Differences in outcomes across arms were used to estimate the required sample size. ResultsSample sizes ranged from 500 for levetiracetam 7 mg/kg vs placebo, to >4000 for levetiracetam 15 vs. 7 mg/kg to achieve 80% power (5% type I error). For propofol 1mg/kg/hr vs. placebo 1200 participants were needed. Simulations comparing propofol at varying doses did not reach 80% power even at samples >1200. InterpretationOur simulations using drug efficacy show sample sizes are infeasible, even for potentially unethical placebo-control trials. We highlight the strength of simulations with observational data to inform the null hypotheses and assess feasibility of future trials of EA treatment. 

Causal inference is at the heart of empirical research in natu- ral and social sciences and is critical for scientific discovery and informed decision making. The gold standard in causal inference is performing randomized controlled trials; unfortu- nately these are not always feasible due to ethical, legal, or cost constraints. As an alternative, methodologies for causal inference from observational data have been developed in sta- tistical studies and social sciences. However, existing meth- ods critically rely on restrictive assumptions such as the study population consisting of homogeneous elements that can be represented in a single flat table, where each row is referred to as a unit. In contrast, in many real-world set- tings, the study domain naturally consists of heterogeneous elements with complex relational structure, where the data is naturally represented in multiple related tables. In this paper, we present a formal framework for causal inference from such relational data. We propose a declarative language called CaRL for capturing causal background knowledge and assumptions, and specifying causal queries using simple Datalog-like rules. CaRL provides a foundation for infer- ring causality and reasoning about the effect of complex interventions in relational domains. We present an extensive experimental evaluation on real relational data to illustrate the applicability of CaRL in social sciences and healthcare.