Reinforcement Learning (RL) is emerging as tool for tackling complex control and decision-making problems. However, in high-risk environments such as healthcare, manufacturing, automotive or aerospace, it is often challenging to bridge the gap between an apparently optimal policy learnt by an agent and its real-world deployment, due to the uncertainties and risk associated with it. Broadly speaking RL agents face two kinds of uncertainty, 1. aleatoric uncertainty, which reflects randomness or noise in the dynamics of the world, and 2. epistemic uncertainty, which reflects the bounded knowledge of the agent due to model limitations and finite amount of information/data the agent has acquired about the world. These two types of uncertainty carry fundamentally different implications for the evaluation of performance and the level of risk or trust. Yet these aleatoric and epistemic uncertainties are generally confounded as standard and even distributional RL is agnostic to this difference. Here we propose how a distributional approach (UA-DQN) can be recast to render uncertainties by decomposing the net effects of each uncertainty. We demonstrate the operation of this method in grid world examples to build intuition and then show a proof of concept application for an RL agent operating as a clinical decision support system in critical care

Health-related data is noisy and stochastic in implying the true physiological states of patients, limiting information contained in single-moment observations for sequential clinical decision making. We model patient-clinician interactions as partially observable Markov decision processes (POMDPs) and optimize sequential treatment based on belief states inferred from history sequence. To facilitate inference, we build a variational generative model and boost state representation with a recurrent neural network (RNN), incorporating an auxiliary loss from sequence auto-encoding. Meanwhile, we optimize a continuous policy of drug levels with an actor-critic method where policy gradients are obtained from a stablized off-policy estimate of advantage function, with the value of belief state backed up by parallel best-first suffix trees. We exploit our methodology in optimizing dosages of vasopressor and intravenous fluid for sepsis patients using a retrospective intensive care dataset and evaluate the learned policy with off-policy policy evaluation (OPPE). The results demonstrate that modelling as POMDPs yields better performance than MDPs, and that incorporating heuristic search improves sample efficiency.

In this document, we explore in more detail our published work (Komorowski, Celi, Badawi, Gordon, & Faisal, 2018) for the benefit of the AI in Healthcare research community. In the above paper, we developed the AI Clinician system, which demonstrated how reinforcement learning could be used to make useful recommendations towards optimal treatment decisions from intensive care data. Since publication a number of authors have reviewed our work (e.g. Given the difference of our framework to previous work, the fact that we are bridging two very different academic communities (intensive care and machine learning) and that our work has impact on a number of other areas with more traditional computer-based approaches (biosignal processing and control, biomedical engineering), we are providing here additional details on our recent publication. We acknowledge the online comments by Jeter et al (https://arxiv.org/abs/1902.03271). The sections of the present document are structured so as to address some of their questions. For clarity, we label figures from our main Nature Medicine publication as "M", figures from Jeter et al.'s arXiv paper as "J" and figures from our response here as "R". Jeter et al. state "the only possible response we can afford is a more aggressive and open dialogue".

Sepsis is the leading cause of mortality in the ICU. It is challenging to manage because individual patients respond differently to treatment. Thus, tailoring treatment to the individual patient is essential for the best outcomes. In this paper, we take steps toward this goal by applying a mixture-of-experts framework to personalize sepsis treatment. The mixture model selectively alternates between neighbor-based (kernel) and deep reinforcement learning (DRL) experts depending on patient's current history. On a large retrospective cohort, this mixture-based approach outperforms physician, kernel only, and DRL-only experts.

We study the problem of off-policy policy evaluation (OPPE) in RL. In contrast to prior work, we consider how to estimate both the individual policy value and average policy value accurately. We draw inspiration from recent work in causal reasoning, and propose a new finite sample generalization error bound for value estimates from MDP models. Using this upper bound as an objective, we develop a learning algorithm of an MDP model with a balanced representation, and show that our approach can yield substantially lower MSE in common synthetic benchmarks and a HIV treatment simulation domain.

We study the problem of off-policy policy evaluation (OPPE) in RL. In contrast to prior work, we consider how to estimate both the individual policy value and average policy value accurately. We draw inspiration from recent work in causal reasoning, and propose a new finite sample generalization error bound for value estimates from MDP models. Using this upper bound as an objective, we develop a learning algorithm of an MDP model with a balanced representation, and show that our approach can yield substantially lower MSE in common synthetic benchmarks and a HIV treatment simulation domain.

Sepsis is a dangerous condition that is a leading cause of patient mortality. Treating sepsis is highly challenging, because individual patients respond very differently to medical interventions and there is no universally agreed-upon treatment for sepsis. In this work, we explore the use of continuous state-space model-based reinforcement learning (RL) to discover high-quality treatment policies for sepsis patients. Our quantitative evaluation reveals that by blending the treatment strategy discovered with RL with what clinicians follow, we can obtain improved policies, potentially allowing for better medical treatment for sepsis.

In this work, we consider the problem of estimating a behaviour policy for use in Off-Policy Policy Evaluation (OPE) when the true behaviour policy is unknown. Via a series of empirical studies, we demonstrate how accurate OPE is strongly dependent on the calibration of estimated behaviour policy models: how precisely the behaviour policy is estimated from data. We show how powerful parametric models such as neural networks can result in highly uncalibrated behaviour policy models on a real-world medical dataset, and illustrate how a simple, non-parametric, k-nearest neighbours model produces better calibrated behaviour policy estimates and can be used to obtain superior importance sampling-based OPE estimates.

Much attention has been devoted recently to the development of machine learning algorithms with the goal of improving treatment policies in healthcare. Reinforcement learning (RL) is a sub-field within machine learning that is concerned with learning how to make sequences of decisions so as to optimize long-term effects. Already, RL algorithms have been proposed to identify decision-making strategies for mechanical ventilation, sepsis management and treatment of schizophrenia. However, before implementing treatment policies learned by black-box algorithms in high-stakes clinical decision problems, special care must be taken in the evaluation of these policies. In this document, our goal is to expose some of the subtleties associated with evaluating RL algorithms in healthcare. We aim to provide a conceptual starting point for clinical and computational researchers to ask the right questions when designing and evaluating algorithms for new ways of treating patients. In the following, we describe how choices about how to summarize a history, variance of statistical estimators, and confounders in more ad-hoc measures can result in unreliable, even misleading estimates of the quality of a treatment policy. We also provide suggestions for mitigating these effects---for while there is much promise for mining observational health data to uncover better treatment policies, evaluation must be performed thoughtfully.

Off-policy reinforcement learning enables near-optimal policy from suboptimal experience, thereby provisions opportunity for artificial intelligence applications in healthcare. Previous works have mainly framed patient-clinician interactions as Markov decision processes, while true physiological states are not necessarily fully observable from clinical data. We capture this situation with partially observable Markov decision process, in which an agent optimises its actions in a belief represented as a distribution of patient states inferred from individual history trajectories. A Gaussian mixture model is fitted for the observed data. Moreover, we take into account the fact that nuance in pharmaceutical dosage could presumably result in significantly different effect by modelling a continuous policy through a Gaussian approximator directly in the policy space, i.e. the actor. To address the challenge of infinite number of possible belief states which renders exact value iteration intractable, we evaluate and plan for only every encountered belief, through heuristic search tree by tightly maintaining lower and upper bounds of the true value of belief. We further resort to function approximations to update value bounds estimation, i.e. the critic, so that the tree search can be improved through more compact bounds at the fringe nodes that will be back-propagated to the root. Both actor and critic parameters are learned via gradient-based approaches. Our proposed policy trained from real intensive care unit data is capable of dictating dosing on vasopressors and intravenous fluids for sepsis patients that lead to the best patient outcomes.