Bibhas Chakraborty

Mingxuan Liu, Siqi Li, Han Yuan et al.

Objective: The proper handling of missing values is critical to delivering reliable estimates and decisions, especially in high-stakes fields such as clinical research. The increasing diversity and complexity of data have led many researchers to develop deep learning (DL)-based imputation techniques. We conducted a systematic review to evaluate the use of these techniques, with a particular focus on data types, aiming to assist healthcare researchers from various disciplines in dealing with missing values. Methods: We searched five databases (MEDLINE, Web of Science, Embase, CINAHL, and Scopus) for articles published prior to August 2021 that applied DL-based models to imputation. We assessed selected publications from four perspectives: health data types, model backbone (i.e., main architecture), imputation strategies, and comparison with non-DL-based methods. Based on data types, we created an evidence map to illustrate the adoption of DL models. Results: We included 64 articles, of which tabular static (26.6%, 17/64) and temporal data (37.5%, 24/64) were the most frequently investigated. We found that model backbone(s) differed among data types as well as the imputation strategy. The "integrated" strategy, that is, the imputation task being solved concurrently with downstream tasks, was popular for tabular temporal (50%, 12/24) and multi-modal data (71.4%, 5/7), but limited for other data types. Moreover, DL-based imputation methods yielded better imputation accuracy in most studies, compared with non-DL-based methods. Conclusion: DL-based imputation models can be customized based on data type, addressing the corresponding missing patterns, and its associated "integrated" strategy can enhance the efficacy of imputation, especially in scenarios where data is complex. Future research may focus on the portability and fairness of DL-based models for healthcare data imputation.

Siqi Li, Pinyan Liu, Gustavo G. Nascimento et al.

Federated learning (FL) has gained popularity in clinical research in recent years to facilitate privacy-preserving collaboration. Structured data, one of the most prevalent forms of clinical data, has experienced significant growth in volume concurrently, notably with the widespread adoption of electronic health records in clinical practice. This review examines FL applications on structured medical data, identifies contemporary limitations and discusses potential innovations. We searched five databases, SCOPUS, MEDLINE, Web of Science, Embase, and CINAHL, to identify articles that applied FL to structured medical data and reported results following the PRISMA guidelines. Each selected publication was evaluated from three primary perspectives, including data quality, modeling strategies, and FL frameworks. Out of the 1160 papers screened, 34 met the inclusion criteria, with each article consisting of one or more studies that used FL to handle structured clinical/medical data. Of these, 24 utilized data acquired from electronic health records, with clinical predictions and association studies being the most common clinical research tasks that FL was applied to. Only one article exclusively explored the vertical FL setting, while the remaining 33 explored the horizontal FL setting, with only 14 discussing comparisons between single-site (local) and FL (global) analysis. The existing FL applications on structured medical data lack sufficient evaluations of clinically meaningful benefits, particularly when compared to single-site analyses. Therefore, it is crucial for future FL applications to prioritize clinical motivations and develop designs and methodologies that can effectively support and aid clinical practice and research.

Siqi Li, Yilin Ning, Marcus Eng Hock Ong et al.

We propose FedScore, a privacy-preserving federated learning framework for scoring system generation across multiple sites to facilitate cross-institutional collaborations. The FedScore framework includes five modules: federated variable ranking, federated variable transformation, federated score derivation, federated model selection and federated model evaluation. To illustrate usage and assess FedScore's performance, we built a hypothetical global scoring system for mortality prediction within 30 days after a visit to an emergency department using 10 simulated sites divided from a tertiary hospital in Singapore. We employed a pre-existing score generator to construct 10 local scoring systems independently at each site and we also developed a scoring system using centralized data for comparison. We compared the acquired FedScore model's performance with that of other scoring models using the receiver operating characteristic (ROC) analysis. The FedScore model achieved an average area under the curve (AUC) value of 0.763 across all sites, with a standard deviation (SD) of 0.020. We also calculated the average AUC values and SDs for each local model, and the FedScore model showed promising accuracy and stability with a high average AUC value which was closest to the one of the pooled model and SD which was lower than that of most local models. This study demonstrates that FedScore is a privacy-preserving scoring system generator with potentially good generalizability.

Nina Deliu, Joseph Jay Williams, Bibhas Chakraborty

In recent years, reinforcement learning (RL) has acquired a prominent position in health-related sequential decision-making problems, gaining traction as a valuable tool for delivering adaptive interventions (AIs). However, in part due to a poor synergy between the methodological and the applied communities, its real-life application is still limited and its potential is still to be realized. To address this gap, our work provides the first unified technical survey on RL methods, complemented with case studies, for constructing various types of AIs in healthcare. In particular, using the common methodological umbrella of RL, we bridge two seemingly different AI domains, dynamic treatment regimes and just-in-time adaptive interventions in mobile health, highlighting similarities and differences between them and discussing the implications of using RL. Open problems and considerations for future research directions are outlined. Finally, we leverage our experience in designing case studies in both areas to showcase the significant collaborative opportunities between statistical, RL, and healthcare researchers in advancing AIs.

Yan Shuo Tan, Kenyon Ng, Ruizhe Deng et al.

Thompson sampling is a widely used strategy for contextual bandits: at each round, it samples a reward function from a Bayesian posterior and acts greedily under that sample. Prior-data fitted networks (PFNs), such as TabPFN v2+ and TabICL v2, are attractive candidates for this purpose because they approximate Bayesian posterior predictive distributions in a single forward pass. However, PFNs predict noisy future rewards, while Thompson sampling requires uncertainty over the latent mean reward function. We propose PFN-TS, a Thompson sampling algorithm that converts PFN posterior predictives into mean-reward samples using a subsampled predictive central limit theorem. The method estimates posterior variance from a geometric grid of $O(\log n)$ dataset prefixes rather than the full $O(n)$ predictive sequence used in previous predictive-sequence approaches, and reuses TabICL's cached representations across rounds. We prove consistency of the subsampled variance estimator and give a Bayesian regret bound that decomposes PFN-TS regret into exact posterior-sampling regret under the PFN prior plus approximation terms. Empirically, PFN-TS achieves the best average rank across nonlinear synthetic and OpenML classification-to-bandit benchmarks, remains competitive on linear and BART-generated rewards, and attains the highest estimated policy value in an offline mobile-health evaluation. Code is available at https://anonymous.4open.science/r/PFN_TS-36ED/.

Rui Yang, Huitao Li, Weihao Xuan et al.

Despite continuous advances in medical technology, the global distribution of health care resources remains uneven. The development of large language models (LLMs) has transformed the landscape of medicine and holds promise for improving health care quality and expanding access to medical information globally. However, existing LLMs are primarily trained on high-resource languages, limiting their applicability in global medical scenarios. To address this gap, we constructed GlobMed, a large multilingual medical dataset, containing over 500,000 entries spanning 12 languages, including four low-resource languages. Building on this, we established GlobMed-Bench, which systematically assesses 56 state-of-the-art proprietary and open-weight LLMs across multiple multilingual medical tasks, revealing significant performance disparities across languages, particularly for low-resource languages. Additionally, we introduced GlobMed-LLMs, a suite of multilingual medical LLMs trained on GlobMed, with parameters ranging from 1.7B to 8B. GlobMed-LLMs achieved an average performance improvement of over 40% relative to baseline models, with a more than threefold increase in performance on low-resource languages. Together, these resources provide an important foundation for advancing the equitable development and application of LLMs globally, enabling broader language communities to benefit from technological advances.

Xueqing Liu, Nina Deliu, Tanujit Chakraborty et al.

Mobile health (mHealth) interventions often aim to improve distal outcomes, such as clinical conditions, by optimizing proximal outcomes through just-in-time adaptive interventions. Contextual bandits provide a suitable framework for customizing such interventions according to individual time-varying contexts. However, unique challenges, such as modeling count outcomes within bandit frameworks, have hindered the widespread application of contextual bandits to mHealth studies. The current work addresses this challenge by leveraging count data models into online decision-making approaches. Specifically, we combine four common offline count data models (Poisson, negative binomial, zero-inflated Poisson, and zero-inflated negative binomial regressions) with Thompson sampling, a popular contextual bandit algorithm. The proposed algorithms are motivated by and evaluated on a real dataset from the Drink Less trial, where they are shown to improve user engagement with the mHealth platform. The proposed methods are further evaluated on simulated data, achieving improvement in maximizing cumulative proximal outcomes over existing algorithms. Theoretical results on regret bounds are also derived. The countts R package provides an implementation of our approach.

Nina Deliu, Bibhas Chakraborty

Precision health, increasingly supported by digital technologies, is a domain of research that broadens the paradigm of precision medicine, advancing everyday healthcare. This vision goes hand in hand with the groundbreaking advent of artificial intelligence (AI), which is reshaping the way we diagnose, treat, and monitor both clinical subjects and the general population. AI tools powered by machine learning have shown considerable improvements in a variety of healthcare domains. In particular, reinforcement learning (RL) holds great promise for sequential and dynamic problems such as dynamic treatment regimes and just-in-time adaptive interventions in digital health. In this work, we discuss the opportunity offered by AI, more specifically RL, to current trends in healthcare, providing a methodological survey of RL methods in the context of precision and digital health. Focusing on the area of adaptive interventions, we expand the methodological survey with illustrative case studies that used RL in real practice. This invited article has undergone anonymous review and is intended as a book chapter for the volume "Frontiers of Statistics and Data Science" edited by Subhashis Ghoshal and Anindya Roy for the International Indian Statistical Association Series on Statistics and Data Science, published by Springer. It covers the material from a short course titled "Artificial Intelligence in Precision and Digital Health" taught by the author Bibhas Chakraborty at the IISA 2022 Conference, December 26-30 2022, at the Indian Institute of Science, Bengaluru.

Yang Yang, Kathryn Pollak, Bibhas Chakraborty et al.

Objective: Electronic health record (EHR) phenotyping often relies on noisy proxy labels, which undermine the reliability of downstream risk prediction. Active learning can reduce annotation costs, but most rely on fixed heuristics and do not ensure that phenotype refinement improves prediction performance. Our goal was to develop a framework that directly uses downstream prediction performance as feedback to guide phenotype correction and sample selection under constrained labeling budgets. Materials and Methods: We propose Reinforcement-Enhanced Label-Efficient Active Phenotyping (RELEAP), a reinforcement learning-based active learning framework. RELEAP adaptively integrates multiple querying strategies and, unlike prior methods, updates its policy based on feedback from downstream models. We evaluated RELEAP on a de-identified Duke University Health System (DUHS) cohort (2014-2024) for incident lung cancer risk prediction, using logistic regression and penalized Cox survival models. Performance was benchmarked against noisy-label baselines and single-strategy active learning. Results: RELEAP consistently outperformed all baselines. Logistic AUC increased from 0.774 to 0.805 and survival C-index from 0.718 to 0.752. Using downstream performance as feedback, RELEAP produced smoother and more stable gains than heuristic methods under the same labeling budget. Discussion: By linking phenotype refinement to prediction outcomes, RELEAP learns which samples most improve downstream discrimination and calibration, offering a more principled alternative to fixed active learning rules. Conclusion: RELEAP optimizes phenotype correction through downstream feedback, offering a scalable, label-efficient paradigm that reduces manual chart review and enhances the reliability of EHR-based risk prediction.

Feng Xie, Jun Zhou, Jin Wee Lee et al.

The demand for emergency department (ED) services is increasing across the globe, particularly during the current COVID-19 pandemic. Clinical triage and risk assessment have become increasingly challenging due to the shortage of medical resources and the strain on hospital infrastructure caused by the pandemic. As a result of the widespread use of electronic health records (EHRs), we now have access to a vast amount of clinical data, which allows us to develop predictive models and decision support systems to address these challenges. To date, however, there are no widely accepted benchmark ED triage prediction models based on large-scale public EHR data. An open-source benchmarking platform would streamline research workflows by eliminating cumbersome data preprocessing, and facilitate comparisons among different studies and methodologies. In this paper, based on the Medical Information Mart for Intensive Care IV Emergency Department (MIMIC-IV-ED) database, we developed a publicly available benchmark suite for ED triage predictive models and created a benchmark dataset that contains over 400,000 ED visits from 2011 to 2019. We introduced three ED-based outcomes (hospitalization, critical outcomes, and 72-hour ED reattendance) and implemented a variety of popular methodologies, ranging from machine learning methods to clinical scoring systems. We evaluated and compared the performance of these methods against benchmark tasks. Our codes are open-source, allowing anyone with MIMIC-IV-ED data access to perform the same steps in data processing, benchmark model building, and experiments. This study provides future researchers with insights, suggestions, and protocols for managing raw data and developing risk triaging tools for emergency care.

Mingxuan Liu, Yilin Ning, Yuhe Ke et al.

The escalating integration of machine learning in high-stakes fields such as healthcare raises substantial concerns about model fairness. We propose an interpretable framework - Fairness-Aware Interpretable Modeling (FAIM), to improve model fairness without compromising performance, featuring an interactive interface to identify a "fairer" model from a set of high-performing models and promoting the integration of data-driven evidence and clinical expertise to enhance contextualized fairness. We demonstrated FAIM's value in reducing sex and race biases by predicting hospital admission with two real-world databases, MIMIC-IV-ED and SGH-ED. We show that for both datasets, FAIM models not only exhibited satisfactory discriminatory performance but also significantly mitigated biases as measured by well-established fairness metrics, outperforming commonly used bias-mitigation methods. Our approach demonstrates the feasibility of improving fairness without sacrificing performance and provides an a modeling mode that invites domain experts to engage, fostering a multidisciplinary effort toward tailored AI fairness.

Siqi Li, Yuqing Shang, Ziwen Wang et al.

Survival analysis serves as a fundamental component in numerous healthcare applications, where the determination of the time to specific events (such as the onset of a certain disease or death) for patients is crucial for clinical decision-making. Scoring systems are widely used for swift and efficient risk prediction. However, existing methods for constructing survival scores presume that data originates from a single source, posing privacy challenges in collaborations with multiple data owners. We propose a novel framework for building federated scoring systems for multi-site survival outcomes, ensuring both privacy and communication efficiency. We applied our approach to sites with heterogeneous survival data originating from emergency departments in Singapore and the United States. Additionally, we independently developed local scores at each site. In testing datasets from each participant site, our proposed federated scoring system consistently outperformed all local models, evidenced by higher integrated area under the receiver operating characteristic curve (iAUC) values, with a maximum improvement of 11.6%. Additionally, the federated score's time-dependent AUC(t) values showed advantages over local scores, exhibiting narrower confidence intervals (CIs) across most time points. The model developed through our proposed method exhibits effective performance on each local site, signifying noteworthy implications for healthcare research. Sites participating in our proposed federated scoring model training gained benefits by acquiring survival models with enhanced prediction accuracy and efficiency. This study demonstrates the effectiveness of our privacy-preserving federated survival score generation framework and its applicability to real-world heterogeneous survival data.

Shraddha M. Naik, Tanujit Chakraborty, Madhurima Panja et al.

Real-world datasets often exhibit imbalanced data distribution, where certain class levels are severely underrepresented. In such cases, traditional pattern classifiers have shown a bias towards the majority class, impeding accurate predictions for the minority class. This paper introduces an imbalanced data-oriented classifier using probabilistic neural networks (PNN) with a skew-normal kernel function to address this major challenge. PNN is known for providing probabilistic outputs, enabling quantification of prediction confidence, interpretability, and the ability to handle limited data. By leveraging the skew-normal distribution, which offers increased flexibility, particularly for imbalanced and non-symmetric data, our proposed Skew-Probabilistic Neural Networks (SkewPNN) can better represent underlying class densities. Hyperparameter fine-tuning is imperative to optimize the performance of the proposed approach on imbalanced datasets. To this end, we employ a population-based heuristic algorithm, the Bat optimization algorithm, to explore the hyperparameter space effectively. We also prove the statistical consistency of the density estimates, suggesting that the true distribution will be approached smoothly as the sample size increases. Theoretical analysis of the computational complexity of the proposed SkewPNN and BA-SkewPNN is also provided. Numerical simulations have been conducted on different synthetic datasets, comparing various benchmark-imbalanced learners. Real-data analysis on several datasets shows that SkewPNN and BA-SkewPNN substantially outperform most state-of-the-art machine-learning methods for both balanced and imbalanced datasets (binary and multi-class categories) in most experimental settings.

Seyed Ehsan Saffari, Yilin Ning, Xie Feng et al.

Background: Risk prediction models are useful tools in clinical decision-making which help with risk stratification and resource allocations and may lead to a better health care for patients. AutoScore is a machine learning-based automatic clinical score generator for binary outcomes. This study aims to expand the AutoScore framework to provide a tool for interpretable risk prediction for ordinal outcomes. Methods: The AutoScore-Ordinal framework is generated using the same 6 modules of the original AutoScore algorithm including variable ranking, variable transformation, score derivation (from proportional odds models), model selection, score fine-tuning, and model evaluation. To illustrate the AutoScore-Ordinal performance, the method was conducted on electronic health records data from the emergency department at Singapore General Hospital over 2008 to 2017. The model was trained on 70% of the data, validated on 10% and tested on the remaining 20%. Results: This study included 445,989 inpatient cases, where the distribution of the ordinal outcome was 80.7% alive without 30-day readmission, 12.5% alive with 30-day readmission, and 6.8% died inpatient or by day 30 post discharge. Two point-based risk prediction models were developed using two sets of 8 predictor variables identified by the flexible variable selection procedure. The two models indicated reasonably good performance measured by mean area under the receiver operating characteristic curve (0.785 and 0.793) and generalized c-index (0.737 and 0.760), which were comparable to alternative models. Conclusion: AutoScore-Ordinal provides an automated and easy-to-use framework for development and validation of risk prediction models for ordinal outcomes, which can systematically identify potential predictors from high-dimensional data.

Yilin Ning, Siqi Li, Marcus Eng Hock Ong et al.

Risk scores are widely used for clinical decision making and commonly generated from logistic regression models. Machine-learning-based methods may work well for identifying important predictors, but such 'black box' variable selection limits interpretability, and variable importance evaluated from a single model can be biased. We propose a robust and interpretable variable selection approach using the recently developed Shapley variable importance cloud (ShapleyVIC) that accounts for variability across models. Our approach evaluates and visualizes overall variable contributions for in-depth inference and transparent variable selection, and filters out non-significant contributors to simplify model building steps. We derive an ensemble variable ranking from variable contributions, which is easily integrated with an automated and modularized risk score generator, AutoScore, for convenient implementation. In a study of early death or unplanned readmission, ShapleyVIC selected 6 of 41 candidate variables to create a well-performing model, which had similar performance to a 16-variable model from machine-learning-based ranking.

Yilin Ning, Marcus Eng Hock Ong, Bibhas Chakraborty et al.

Interpretable machine learning has been focusing on explaining final models that optimize performance. The current state-of-the-art is the Shapley additive explanations (SHAP) that locally explains variable impact on individual predictions, and it is recently extended for a global assessment across the dataset. Recently, Dong and Rudin proposed to extend the investigation to models from the same class as the final model that are "good enough", and identified a previous overclaim of variable importance based on a single model. However, this method does not directly integrate with existing Shapley-based interpretations. We close this gap by proposing a Shapley variable importance cloud that pools information across good models to avoid biased assessments in SHAP analyses of final models, and communicate the findings via novel visualizations. We demonstrate the additional insights gain compared to conventional explanations and Dong and Rudin's method using criminal justice and electronic medical records data.

Feng Xie, Han Yuan, Yilin Ning et al.

Objective: Temporal electronic health records (EHRs) can be a wealth of information for secondary uses, such as clinical events prediction or chronic disease management. However, challenges exist for temporal data representation. We therefore sought to identify these challenges and evaluate novel methodologies for addressing them through a systematic examination of deep learning solutions. Methods: We searched five databases (PubMed, EMBASE, the Institute of Electrical and Electronics Engineers [IEEE] Xplore Digital Library, the Association for Computing Machinery [ACM] digital library, and Web of Science) complemented with hand-searching in several prestigious computer science conference proceedings. We sought articles that reported deep learning methodologies on temporal data representation in structured EHR data from January 1, 2010, to August 30, 2020. We summarized and analyzed the selected articles from three perspectives: nature of time series, methodology, and model implementation. Results: We included 98 articles related to temporal data representation using deep learning. Four major challenges were identified, including data irregularity, data heterogeneity, data sparsity, and model opacity. We then studied how deep learning techniques were applied to address these challenges. Finally, we discuss some open challenges arising from deep learning. Conclusion: Temporal EHR data present several major challenges for clinical prediction modeling and data utilization. To some extent, current deep learning solutions can address these challenges. Future studies can consider designing comprehensive and integrated solutions. Moreover, researchers should incorporate additional clinical domain knowledge into study designs and enhance the interpretability of the model to facilitate its implementation in clinical practice.

Han Yuan, Feng Xie, Marcus Eng Hock Ong et al.

Background: Medical decision-making impacts both individual and public health. Clinical scores are commonly used among a wide variety of decision-making models for determining the degree of disease deterioration at the bedside. AutoScore was proposed as a useful clinical score generator based on machine learning and a generalized linear model. Its current framework, however, still leaves room for improvement when addressing unbalanced data of rare events. Methods: Using machine intelligence approaches, we developed AutoScore-Imbalance, which comprises three components: training dataset optimization, sample weight optimization, and adjusted AutoScore. All scoring models were evaluated on the basis of their area under the curve (AUC) in the receiver operating characteristic analysis and balanced accuracy (i.e., mean value of sensitivity and specificity). By utilizing a publicly accessible dataset from Beth Israel Deaconess Medical Center, we assessed the proposed model and baseline approaches in the prediction of inpatient mortality. Results: AutoScore-Imbalance outperformed baselines in terms of AUC and balanced accuracy. The nine-variable AutoScore-Imbalance sub-model achieved the highest AUC of 0.786 (0.732-0.839) while the eleven-variable original AutoScore obtained an AUC of 0.723 (0.663-0.783), and the logistic regression with 21 variables obtained an AUC of 0.743 (0.685-0.800). The AutoScore-Imbalance sub-model (using down-sampling algorithm) yielded an AUC of 0. 0.771 (0.718-0.823) with only five variables, demonstrating a good balance between performance and variable sparsity. Conclusions: The AutoScore-Imbalance tool has the potential to be applied to highly unbalanced datasets to gain further insight into rare medical events and to facilitate real-world clinical decision-making.

Palash Ghosh, Xinru Wang, Trikay Nalamada et al.

A dynamic treatment regimen (DTR) is a set of decision rules to personalize treatments for an individual using their medical history. The Q-learning-based Q-shared algorithm has been used to develop DTRs that involve decision rules shared across multiple stages of intervention. We show that the existing Q-shared algorithm can suffer from non-convergence due to the use of linear models in the Q-learning setup, and identify the condition under which Q-shared fails. We develop a penalized Q-shared algorithm that not only converges in settings that violate the condition, but can outperform the original Q-shared algorithm even when the condition is satisfied. We give evidence for the proposed method in a real-world application and several synthetic simulations.

Feng Xie, Yilin Ning, Han Yuan et al.

Scoring systems are highly interpretable and widely used to evaluate time-to-event outcomes in healthcare research. However, existing time-to-event scores are predominantly created ad-hoc using a few manually selected variables based on clinician's knowledge, suggesting an unmet need for a robust and efficient generic score-generating method. AutoScore was previously developed as an interpretable machine learning score generator, integrated both machine learning and point-based scores in the strong discriminability and accessibility. We have further extended it to time-to-event data and developed AutoScore-Survival, for automatically generating time-to-event scores with right-censored survival data. Random survival forest provides an efficient solution for selecting variables, and Cox regression was used for score weighting. We illustrated our method in a real-life study of 90-day mortality of patients in intensive care units and compared its performance with survival models (i.e., Cox) and the random survival forest. The AutoScore-Survival-derived scoring model was more parsimonious than survival models built using traditional variable selection methods (e.g., penalized likelihood approach and stepwise variable selection), and its performance was comparable to survival models using the same set of variables. Although AutoScore-Survival achieved a comparable integrated area under the curve of 0.782 (95% CI: 0.767-0.794), the integer-valued time-to-event scores generated are favorable in clinical applications because they are easier to compute and interpret. Our proposed AutoScore-Survival provides an automated, robust and easy-to-use machine learning-based clinical score generator to studies of time-to-event outcomes. It provides a systematic guideline to facilitate the future development of time-to-event scores for clinical applications.