Retrieval-Augmented Generation for Generative Artificial Intelligence in Medicine

Generative artificial intelligence (AI) has brought revolutionary innovations in various fields, including medicine. However, it also exhibits limitations. In response, retrieval-augmented generation (RAG) provides a potential solution, enabling models to generate more accurate contents by leveraging the retrieval of external knowledge. With the rapid advancement of generative AI, RAG can pave the way for connecting this transformative technology with medical applications and is expected to bring innovations in equity, reliability, and personalization to health care.

A tutorial on fairness in machine learning in healthcare

$\textbf{OBJECTIVE}$: Ensuring that machine learning (ML) algorithms are safe and effective within all patient groups, and do not disadvantage particular patients, is essential to clinical decision making and preventing the reinforcement of existing healthcare inequities. The objective of this tutorial is to introduce the medical informatics community to the common notions of fairness within ML, focusing on clinical applications and implementation in practice. $\textbf{TARGET AUDIENCE}$: As gaps in fairness arise in a variety of healthcare applications, this tutorial is designed to provide an understanding of fairness, without assuming prior knowledge, to researchers and clinicians who make use of modern clinical data. $\textbf{SCOPE}$: We describe the fundamental concepts and methods used to define fairness in ML, including an overview of why models in healthcare may be unfair, a summary and comparison of the metrics used to quantify fairness, and a discussion of some ongoing research. We illustrate some of the fairness methods introduced through a case study of mortality prediction in a publicly available electronic health record dataset. Finally, we provide a user-friendly R package for comprehensive group fairness evaluation, enabling researchers and clinicians to assess fairness in their own ML work.

Clinical Domain Knowledge-Derived Template Improves Post Hoc AI Explanations in Pneumothorax Classification

Background: Pneumothorax is an acute thoracic disease caused by abnormal air collection between the lungs and chest wall. To address the opaqueness often associated with deep learning (DL) models, explainable artificial intelligence (XAI) methods have been introduced to outline regions related to pneumothorax diagnoses made by DL models. However, these explanations sometimes diverge from actual lesion areas, highlighting the need for further improvement. Method: We propose a template-guided approach to incorporate the clinical knowledge of pneumothorax into model explanations generated by XAI methods, thereby enhancing the quality of these explanations. Utilizing one lesion delineation created by radiologists, our approach first generates a template that represents potential areas of pneumothorax occurrence. This template is then superimposed on model explanations to filter out extraneous explanations that fall outside the template's boundaries. To validate its efficacy, we carried out a comparative analysis of three XAI methods with and without our template guidance when explaining two DL models in two real-world datasets. Results: The proposed approach consistently improved baseline XAI methods across twelve benchmark scenarios built on three XAI methods, two DL models, and two datasets. The average incremental percentages, calculated by the performance improvements over the baseline performance, were 97.8% in Intersection over Union (IoU) and 94.1% in Dice Similarity Coefficient (DSC) when comparing model explanations and ground-truth lesion areas. Conclusions: In the context of pneumothorax diagnoses, we proposed a template-guided approach for improving AI explanations. We anticipate that our template guidance will forge a fresh approach to elucidating AI models by integrating clinical domain expertise.

Developing Federated Time-to-Event Scores Using Heterogeneous Real-World Survival Data

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.

Foundation Model Makes Clustering a Better Initialization for Active Learning

Active learning selects the most informative samples from the unlabeled dataset to annotate in the context of a limited annotation budget. While numerous methods have been proposed for subsequent sample selection based on an initialized model, scant attention has been paid to the indispensable phase of active learning: selecting samples for model initialization. Most of the previous studies resort to random sampling or naive clustering. However, random sampling is prone to fluctuation, and naive clustering suffers from convergence speed, particularly when dealing with high-dimensional data such as imaging data. In this work, we propose to integrate foundation models with clustering methods to select samples for active learning initialization. Foundation models refer to those trained on massive datasets by the self-supervised paradigm and capable of generating informative and compacted embeddings for various downstream tasks. Leveraging these embeddings to replace raw features such as pixel values, clustering quickly converges and identifies better initial samples. For a comprehensive comparison, we included a classic ImageNet-supervised model to acquire embeddings. Experiments on two clinical tasks of image classification and segmentation demonstrated that foundation model-based clustering efficiently pinpointed informative initial samples, leading to models showcasing enhanced performance than the baseline methods. We envisage that this study provides an effective paradigm for future active learning.

Leveraging Anatomical Constraints with Uncertainty for Pneumothorax Segmentation

Pneumothorax is a medical emergency caused by abnormal accumulation of air in the pleural space - the potential space between the lungs and chest wall. On 2D chest radiographs, pneumothorax occurs within the thoracic cavity and outside of the mediastinum and we refer to this area as "lung+ space". While deep learning (DL) has increasingly been utilized to segment pneumothorax lesions in chest radiographs, many existing DL models employ an end-to-end approach. These models directly map chest radiographs to clinician-annotated lesion areas, often neglecting the vital domain knowledge that pneumothorax is inherently location-sensitive. We propose a novel approach that incorporates the lung+ space as a constraint during DL model training for pneumothorax segmentation on 2D chest radiographs. To circumvent the need for additional annotations and to prevent potential label leakage on the target task, our method utilizes external datasets and an auxiliary task of lung segmentation. This approach generates a specific constraint of lung+ space for each chest radiograph. Furthermore, we have incorporated a discriminator to eliminate unreliable constraints caused by the domain shift between the auxiliary and target datasets. Our results demonstrated significant improvements, with average performance gains of 4.6%, 3.6%, and 3.3% regarding Intersection over Union (IoU), Dice Similarity Coefficient (DSC), and Hausdorff Distance (HD). Our research underscores the significance of incorporating medical domain knowledge about the location-specific nature of pneumothorax to enhance DL-based lesion segmentation.

Federated Learning for Clinical Structured Data: A Benchmark Comparison of Engineering and Statistical Approaches

Federated learning (FL) has shown promising potential in safeguarding data privacy in healthcare collaborations. While the term "FL" was originally coined by the engineering community, the statistical field has also explored similar privacy-preserving algorithms. Statistical FL algorithms, however, remain considerably less recognized than their engineering counterparts. Our goal was to bridge the gap by presenting the first comprehensive comparison of FL frameworks from both engineering and statistical domains. We evaluated five FL frameworks using both simulated and real-world data. The results indicate that statistical FL algorithms yield less biased point estimates for model coefficients and offer convenient confidence interval estimations. In contrast, engineering-based methods tend to generate more accurate predictions, sometimes surpassing central pooled and statistical FL models. This study underscores the relative strengths and weaknesses of both types of methods, emphasizing the need for increased awareness and their integration in future FL applications.

LATTE: Label-efficient Incident Phenotyping from Longitudinal Electronic Health Records

Electronic health record (EHR) data are increasingly used to support real-world evidence (RWE) studies. Yet its ability to generate reliable RWE is limited by the lack of readily available precise information on the timing of clinical events such as the onset time of heart failure. We propose a LAbel-efficienT incidenT phEnotyping (LATTE) algorithm to accurately annotate the timing of clinical events from longitudinal EHR data. By leveraging the pre-trained semantic embedding vectors from large-scale EHR data as prior knowledge, LATTE selects predictive EHR features in a concept re-weighting module by mining their relationship to the target event and compresses their information into longitudinal visit embeddings through a visit attention learning network. LATTE employs a recurrent neural network to capture the sequential dependency between the target event and visit embeddings before/after it. To improve label efficiency, LATTE constructs highly informative longitudinal silver-standard labels from large-scale unlabeled patients to perform unsupervised pre-training and semi-supervised joint training. Finally, LATTE enhances cross-site portability via contrastive representation learning. LATTE is evaluated on three analyses: the onset of type-2 diabetes, heart failure, and the onset and relapses of multiple sclerosis. We use various evaluation metrics present in the literature including the $ABC_{gain}$, the proportion of reduction in the area between the observed event indicator and the predicted cumulative incidences in reference to the prediction per incident prevalence. LATTE consistently achieves substantial improvement over benchmark methods such as SAMGEP and RETAIN in all settings.

Federated and distributed learning applications for electronic health records and structured medical data: A scoping review

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.

FedScore: A privacy-preserving framework for federated scoring system development

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.