EpiCare: A Reinforcement Learning Benchmark for Dynamic Treatment Regimes.

Introduction Reinforcement learning formalizes the concept of learning from interactions.1 Broadly, reinforcement learning focuses on a setting in which an agent (decision maker) sequentially interacts with an environment that is partially unknown to them. At each stage, the agent takes an action and receives a reward. The objective of the agent is to maximize rewards accumulated in the long run. There are many situations in health care where decisions are made sequentially for which reinforcement learning approaches could prove useful for decision making. Throughout this article, we consider treatment prescription as an archetypical example to connect reinforcement learning concepts to a health care setting. In this setting, the care provider, the prescribed treatment, and the patients can be viewed as the agent, the action, and the environment, respectively, as depicted in Figure 1.Figure 1: Sequential treatment of AKI or CKD complications modeled as a reinforcement learning problem.Background In this section, with the objective of making reinforcement learning literature more accessible to a clinical audience, we briefly introduce related fundamental concepts and approaches. We refer the interested reader to Sutton and Barto1 for a comprehensive introduction to reinforcement learning. Markov Decision Processes Markov decision processes (MDPs) are a formalism of the sequential decision-making problem that has been central to the theoretical and practical advancements of reinforcement learning. In each stage of an MDP, the agent observes the state of the environment and takes an action, which, in turn, results in a change of the state. This change of state is assumed to be probabilistic with the next state being determined only by the preceding state, the chosen action, and the transition probability. The agent also receives a reward that is a function of the taken action, the preceding state, and the subsequent state. In an MDP, the objective of the agent is to maximize the return defined as the reward accumulated over a time horizon. In some applications, it is common to consider the horizon to be infinite, in which case the future rewards are discounted by a factor smaller than one. The selection of action by the agent on the basis of the observed state is known as the policy. More formally, a policy is a probabilistic mapping from states to each possible action. Because the policy and the reward are a function of the state, it is critical to estimate the utility of being in a certain state. More specifically, the value function is defined as the expected return starting from a given state under the chosen policy. Under this formalism, the objective of the agent is to find the optimal policy that maximizes the value function for all states. Reinforcement Learning Methods Action-value methods are a class of reinforcement learning methods in which the actions are chosen on the basis of the estimation of their long-term value. A prominent example of an action-value method is Q-learning in which the agent iteratively takes actions with the highest estimated values and updates the action-state value function on the basis of new observations. Policy gradient methods are another class of reinforcement learning methods that seek to optimize the policy directly instead of choosing actions on the basis of their respective estimated value. Such methods could be advantageous in health care applications that entail a large number of possible actions, e.g., when recommending a wide range of drug dosages or treatment options. Clinical Applications Reinforcement learning frameworks and methods are broadly applicable to clinical settings in which decisions are made sequentially. A prominent clinical application of reinforcement learning is for treatment recommendation, which has been studied across a variety of diseases and treatments including radiation and chemotherapy for cancer, brain stimulation for epilepsy, and treatment strategies for sepsis.2–5 In such treatment recommendation settings, a policy is commonly known as a dynamic treatment regime. There are various other clinical applications of reinforcement learning including diagnosis, medical imaging, and decision support tools (see refs. 2–5 and the references therein). Reinforcement Learning in Nephrology Although there have been recent applications of machine learning in nephrology,6,7 to the best of the authors' knowledge, the application of reinforcement learning to nephrology has been primarily limited to optimizing the erythropoietin dosage in hemodialysis patients.8,9 However, there are other settings where reinforcement learning has the potential to improve patient care in nephrology. For example, reinforcement learning methods can be adopted in the treatment of the complications of AKI or CKD (Figure 1). In this problem, the state models the conditions of the patient (e.g., vital signs, laboratory test results including urine and blood tests, and urine output measurements). The action refers to the treatment options (e.g., the dosage of medications such as sodium polystyrene sulfonate, and hemodialysis). The reward models the improvement in patient conditions. Similarly, reinforcement learning can help automate and optimize the dosage of immunosuppressive drugs in kidney transplants. Challenges and Opportunities Despite the success of reinforcement learning in several simplified clinical settings, their large-scale application to patient care faces several open challenges. The complexity of human biology complicates modeling clinical decision making as a reinforcement learning problem. The state space in such settings is often enormous, which could make a purely computational approach infeasible. Moreover, modeling all potential objectives a priori as a reward function may not be feasible. To overcome these challenges and realize the potential of reinforcement learning, clinical insight can play a pivotal role. More specifically, restricting the state space to only include highly relevant clinical variables could greatly reduce the computational complexity. Furthermore, using inverse reinforcement learning,2 relevant reward functions can be learned from retrospective studies assuming the optimality of clinical decisions. Another critical challenge is addressing moral and ethical concerns. It is imperative to ensure that reinforcement learning methods do not cause harm to the patient. To this end, there exists a need for a thorough validation of such methods before their use in patient care. Hence, there is a need to go beyond retrospective studies that have been used for the proof of concept of most existing reinforcement learning methods in health care applications.2,3 The lessons learned from the success of reinforcement learning in other application areas (e.g., self-driving cars) can help navigate the path to realizing its potential in health care. Accessible open-source simulation environments that enable researchers to compare various approaches are essential to the field of reinforcement learning. OpenAI Gym is currently the leading toolkit containing a wide range of simulated environments, e.g., surgical robotics.10 The development of high-quality and reliable simulation environments for nephrology and other health care applications can facilitate the development and validation of reinforcement learning methods beyond limited retrospective studies. The adoption of methods validated in such simulation environments in actual clinical settings will require clinicians' oversight. Similar to how self-driving cars require a human driver to ensure collision avoidance, clinicians' oversight is critical to ensure the safety of the patients, especially in the early stages of the adoption of reinforcement learning methods. The data from clinicians' decisions (e.g., overruling the automated treatment recommendation) can be used to improve the reliability of autonomous systems over time and reduce the burden of clinicians' oversight.

Recent developments in discovering dynamic treatment regimes (DTRs) have heightened the importance of deep reinforcement learning (DRL) which are used to recover the doctor’s treatment policies. However, existing DRL-based methods expose the following limitations: 1) supervised methods based on behavior cloning suffer from compounding errors; 2) the self-defined reward signals in reinforcement learning models are either too sparse or need clinical guidance; 3) only positive trajectories (e.g. survived patients) are considered in current imitation learning models, with negative trajectories (e.g. deceased patients) been largely ignored, which are examples of what not to do and could help the learned policy avoid repeating mistakes. To address these limitations, in this paper, we propose the adversarial cooperative imitation learning model, ACIL, to deduce the optimal dynamic treatment regimes that mimics the positive trajectories while differs from the negative trajectories. Specifically, two discriminators are used to help achieve this goal: an adversarial discriminator is designed to minimize the discrepancies between the trajectories generated from the policy and the positive trajectories, and a cooperative discriminator is used to distinguish the negative trajectories from the positive and generated trajectories. The reward signals from the discriminators are utilized to refine the policy for dynamic treatment regimes. Experiments on the publicly real-world medical data demonstrate that ACIL improves the likelihood of patient survival and provides better dynamic treatment regimes with the exploitation of information from both positive and negative trajectories.

Ambiguous Dynamic Treatment Regimes: A Reinforcement Learning Approach

While optimal dynamic treatment regimes (DTRs) can be estimated without specification of a predictive model, a model-based approach, combined with dynamic programming and Monte Carlo integration, enables direct probabilistic comparisons between the outcomes under the optimal DTR and alternative (dynamic or static) treatment regimes. The Bayesian predictive approach also circumvents problems related to frequentist estimators under the nonregular estimation problem. However, the model-based approach is susceptible to misspecification, in particular of the "null-paradox" type, which is due to the model parameters not having a direct causal interpretation in the presence of latent individual-level characteristics. Because it is reasonable to insist on correct inferences under the null of no difference between the alternative treatment regimes, we discuss how to achieve this through a "null-robust" reparametrization of the problem in a longitudinal setting. Since we argue that causal inference can be entirely understood as posterior predictive inference in a hypothetical population without covariate imbalances, we also discuss how controlling for confounding through inverse probability of treatment weighting can be justified and incorporated in the Bayesian setting.

Reinforcement learning (RL), a promising framework for data-driven decision making in an uncertain environment, has successfully been applied in many real-world operation and control problems. However, the application of RL in a large-scale decentralized multi-agent environment remains a challenging problem due to the partial observability and limited communications between agents. In this paper, we develop a model-based kernel RL approach and a model-free deep RL approach for learning a decentralized, shared policy among homogeneous agents. By leveraging the strengths of both these methods, we further propose a novel deep ensemble multi-agent reinforcement learning (MARL) method that efficiently learns to arbitrate between the decisions of the local kernel-based RL model and the wider-reaching deep RL model. We validate the proposed deep ensemble method on a highly challenging real-world air traffic control problem, where the goal is to provide effective guidance to aircraft to avoid air traffic congestion, conflicting situations, and to improve arrival timeliness, by dynamically recommending adjustments of aircraft speeds in real-time. Extensive empirical results from an open-source air traffic management simulation model, developed by Eurocontrol and built on a real-world data set including thousands of aircrafts, demonstrate that our proposed deep ensemble MARL method significantly outperforms three state-of-the-art benchmark approaches.

Precision medicine requires individualized treatment regime for subjects with different clinical characteristics. Machine learning methods have witnessed rapid progress in recent years, which can be employed to make individualized treatment regime in clinical practice. The idea of reinforcement learning method is to take action in response to the changing environment. In clinical medicine, this idea can be used to assign optimal regime to patients with distinct characteristics. In the field of statistics, reinforcement learning has been widely investigated, aiming to identify an optimal dynamic treatment regime (DTR). Q-learning is among the earliest methods to identify optimal DTR, which fits linear outcome models in a recursive manner. The advantage is its easy interpretation and can be performed in most statistical software. However, it suffers from the risk of misspecification of the linear model. More recently, some other methods not so heavily depend on model specification have been developed such as inverse probability weighted estimator and augmented inverse probability weighted estimator. This review introduces the basic ideas of these methods and shows how to perform the learning algorithm within R environment.

Appropriate analysis of observational data is our best chance to obtain answers to many questions that involve dynamic treatment regimes. This paper describes a simple method to compare dynamic treatment regimes by artificially censoring subjects and then using inverse probability weighting (IPW) to adjust for any selection bias introduced by the artificial censoring. The basic strategy can be summarized in four steps: 1) define two regimes of interest, 2) artificially censor individuals when they stop following one of the regimes of interest, 3) estimate inverse probability weights to adjust for the potential selection bias introduced by censoring in the previous step, 4) compare the survival of the uncensored individuals under each regime of interest by fitting an inverse probability weighted Cox proportional hazards model with the dichotomous regime indicator and the baseline confounders as covariates. In the absence of model misspecification, the method is valid provided data are available on all time-varying and baseline joint predictors of survival and regime discontinuation. We present an application of the method to compare the AIDS-free survival under two dynamic treatment regimes in a large prospective study of HIV-infected patients. The paper concludes by discussing the relative advantages and disadvantages of censoring/IPW versus g-estimation of nested structural models to compare dynamic regimes.

Reinforcement Learning (RL) is a successful and established Artificial Intelligence (AI) method, particularly with recent groundbreaking progress in Deep Reinforcement Learning (DRL). Reinforcement learning is very well suited for sequential decision-making tasks, wherein a learned agent learns an optimal policy after many interactions with an environment. The present paper examines the application of reinforcement learning for automating screening of literature in academic research, particularly in the fields of computer science and e-learning. Keyword filtering techniques, while predominantly applied, are found to be inflexible as well as unable to capture the dynamic nature of research themes. To overcome such constraints, we present a Deep Q-Network (DQN)-based reinforcement learning model that combines reinforcement learning with the Semantic Scholar API to enhance research paper classification based on dynamically acquired decision rules. The proposed reinforcement learning model was trained and tested with a dataset of 8,934 research papers, accessed by systematic searching. The agent filtered and picked 11 effective papers depending on improved selection criteria like publication date, keyword relevance, and scholarly topic provided. The model iteratively optimizes the decision-making process through reward-based learning and therefore maximizes categorization accuracy over time. Test experiments demonstrate utilization of RL-based suggested framework yields classification accuracy at 91.5%, recall at 86.3%, and precision at 89.7%. A comparison test demonstrates that the approach performs 12.5% better on recall and 9.8% better on accuracy compared to traditional keyword-filtering methods. The finding confirms the power of the model in minimizing false positives and false negatives for screening literature, hence proving the scalability and adaptability of reinforcement learning in managing high academic data. This work offers a scalable, cognitive approach to conducting systematic reviews of literature through the application of reinforcement learning to programmatically execute work in academic research. The work shows the promise of reinforcement learning to further enhance research methodology, make literature reviews more effective, and facilitate more knowledgeable decision-making in fast-changing scientific disciplines. Further research will be focused on incorporating hybrid AI models with multi-agent systems of reinforcement learning for responsiveness and classification enhancements.

BackgroundDecision support systems based on reinforcement learning (RL) have been implemented to facilitate the delivery of personalized care. This paper aimed to provide a comprehensive review of RL applications in the critical care setting.ObjectiveThis review aimed to survey the literature on RL applications for clinical decision support in critical care and to provide insight into the challenges of applying various RL models.MethodsWe performed an extensive search of the following databases: PubMed, Google Scholar, Institute of Electrical and Electronics Engineers (IEEE), ScienceDirect, Web of Science, Medical Literature Analysis and Retrieval System Online (MEDLINE), and Excerpta Medica Database (EMBASE). Studies published over the past 10 years (2010-2019) that have applied RL for critical care were included.ResultsWe included 21 papers and found that RL has been used to optimize the choice of medications, drug dosing, and timing of interventions and to target personalized laboratory values. We further compared and contrasted the design of the RL models and the evaluation metrics for each application.ConclusionsRL has great potential for enhancing decision making in critical care. Challenges regarding RL system design, evaluation metrics, and model choice exist. More importantly, further work is required to validate RL in authentic clinical environments.

Sequential, multiple assignment, randomized trials (SMARTs) compare sequences of treatment decision rules called dynamic treatment regimes (DTRs). In particular, the Adaptive Treatment for Alcohol and Cocaine Dependence (ENGAGE) SMART aimed to determine the best DTRs for patients with a substance use disorder. While many authors have focused on a single pairwise comparison, addressing the main goal involves comparisons of >2 DTRs. For complex comparisons, there is a paucity of methods for binary outcomes. We fill this gap by extending the multiple comparisons with the best (MCB) methodology to the Bayesian binary outcome setting. The set of best is constructed based on simultaneous credible intervals. A substantial challenge for power analysis is the correlation between outcome estimators for distinct DTRs embedded in SMARTs due to overlapping subjects. We address this using Robins' G-computation formula to take a weighted average of parameter draws obtained via simulation from the parameter posteriors. We use non-informative priors and work with the exact distribution of parameters avoiding unnecessary normality assumptions and specification of the correlation matrix of DTR outcome summary statistics. We conduct simulation studies for both the construction of a set of optimal DTRs using the Bayesian MCB procedure and the sample size calculation for two common SMART designs. We illustrate our method on the ENGAGE SMART. The R package SMARTbayesR for power calculations is freely available on the Comprehensive R Archive Network (CRAN) repository. An RShiny app is available at https://wilart.shinyapps.io/shinysmartbayesr/.

Despite intense efforts in basic and clinical research, an individualized ventilation strategy for critically ill patients remains a major challenge. Recently, dynamic treatment regime (DTR) with reinforcement learning (RL) on electronic health records (EHR) has attracted interest from both the healthcare industry and machine learning research community. However, most learned DTR policies might be biased due to the existence of confounders. Although some treatment actions non-survivors received may be helpful, if confounders cause the mortality, the training of RL models guided by long-term outcomes (e.g., 90-day mortality) would punish those treatment actions causing the learned DTR policies to be suboptimal. In this study, we develop a new deconfounding actor-critic network (DAC) to learn optimal DTR policies for patients. To alleviate confounding issues, we incorporate a patient resampling module and a confounding balance module into our actor-critic framework. To avoid punishing the effective treatment actions non-survivors received, we design a short-term reward to capture patients' immediate health state changes. Combining short-term with long-term rewards could further improve the model performance. Moreover, we introduce a policy adaptation method to successfully transfer the learned model to new-source small-scale datasets. The experimental results on one semi-synthetic and two different real-world datasets show the proposed model outperforms the state-of-the-art models. The proposed model provides individualized treatment decisions for mechanical ventilation that could improve patient outcomes.

This Guide to Statistics and Methods provides an overview of using observational data and reinforcement learning strategies to develop dynamic treatment regimes for patients who are critically ill.

Experimental research such as cell cultures and carbon nanotube (CNT) growth are largely governed by following predefined execution protocols with fine-tuned control of parameters. There are promising opportunities to apply reinforcement learning (RL), an established learning technique in the area of artificial intelligence, in order to automate CNT growth process and accelerate related scientific breakthroughs in material discovery. Although there are benefits in RL-based exploration and exploitation methodologies, there are also challenges in developing relevant learning policies in experimental settings relating to CNT growth. In this paper, we present a novel data-driven RL approach for assisting experimental CNT growth. Our approach focuses on developing an RL model to learn from simulation-based images and characteristics of temporal CNT growth, considering various growth parameters. Our RL model learns from CNT growth variation in a simulation-based environment where critical control parameters, such as density, growth rate, tube radius, tube stiffness, and Van der Waals forces, are used. Our RL model enables CNT growth automation in order to explore of a wider range of growth conditions, and improve reproducibility. The ultimate goal of our RL model is to achieve desired CNT growth by dynamically controlling growth parameters throughout a sequence of experiments. We evaluate the effectiveness of our RL approach by measuring the improvement in the maximum compressive strength of a carbon nanotube ‘with’ and ‘without’ the RL model. Our results show the effectiveness of course correction recommended by our RL approach when controlling the parameters of angular deviation and rate of growth of carbon nanotubes, when compared against non-regulated CNT growth.

The steep rise in reinforcement learning (RL) in various applications in energy as well as the penetration of home automation in recent years are the motivation for this article. It surveys the use of RL in various home energy management system (HEMS) applications. There is a focus on deep neural network (DNN) models in RL. The article provides an overview of reinforcement learning. This is followed with discussions on state-of-the-art methods for value, policy, and actor–critic methods in deep reinforcement learning (DRL). In order to make the published literature in reinforcement learning more accessible to the HEMS community, verbal descriptions are accompanied with explanatory figures as well as mathematical expressions using standard machine learning terminology. Next, a detailed survey of how reinforcement learning is used in different HEMS domains is described. The survey also considers what kind of reinforcement learning algorithms are used in each HEMS application. It suggests that research in this direction is still in its infancy. Lastly, the article proposes four performance metrics to evaluate RL methods.

Data quality is a critical aspect of data analytics since it directly influences the accuracy and effectiveness of insights and predictions generated from data. Artificial Intelligence (AI) schemes have grown in the existing era of technological advancement, which provides innovative exposure to healthcare applications. Reinforcement Learning (RL) is a subfield and an influential Machine Learning (ML) model aimed at optimizing decision-making by association with dynamic environments. In healthcare applications, RL can modify conduct strategies, enhance source application, and improve patient investigation history by using various data modalities. The worth of the data quality regulates how effective RL is in healthcare applications. In healthcare, the model predictions have a direct impact on patient's lives, and poor data quality often leads to wrong evaluations that expose patient safety and treatment quality. Biases in data quality have also presented a challenging influence on the RL model's effectiveness and accuracy. RL models have enormous potential in healthcare; however, various strategic limitations prevent their widespread acceptance and deployment. The implementation of RL in healthcare faces serious issues, mostly around data quality, bias, and tactical difficulties. This study delivers a broad survey of these challenges, emphasizing how imbalanced, imperfect, and biased data can affect the generalizability and performance of RL models. We critically assessed the sources of data bias, comprising demographic imbalances and irregularities in electronic health records (EHRs), and their impact on RL algorithms. This survey aims to present a detailed study of the complex circumstances relating to data quality, data biases, and strategic barriers in RL models deploying in healthcare applications. However, the main contribution of the proposed study is that it provides a systematic review of these challenges and delivers a roadmap for future work intended to refine the consistency, fairness, and scalability of RL in healthcare sectors.