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Automatic subphenotyping from electronic health records (EHRs)provides numerous opportunities to understand diseases with unique subgroups and enhance personalized medicine for patients. However, existing machine learning algorithms either focus on specific diseases for better interpretability or produce coarse-grained phenotype topics without considering nuanced disease patterns. In this study, we propose a guided topic model, MixEHR-Nest, to infer sub-phenotype topics from thousands of disease using multi-modal EHR data. Specifically, MixEHR-Nest detects multiple subtopics from each phenotype topic, whose prior is guided by the expert-curated phenotype concepts such as Phenotype Codes (PheCodes) or Clinical Classification Software (CCS) codes. We evaluated MixEHR-Nest on two EHR datasets: (1) the MIMIC-III dataset consisting of over 38 thousand patients from intensive care unit (ICU) from Beth Israel Deaconess Medical Center (BIDMC) in Boston, USA; (2) the healthcare administrative database PopHR, comprising 1.3 million patients from Montreal, Canada. Experimental results demonstrate that MixEHR-Nest can identify subphenotypes with distinct patterns within each phenotype, which are predictive for disease progression and severity. Consequently, MixEHR-Nest distinguishes between type 1 and type 2 diabetes by inferring subphenotypes using CCS codes, which do not differentiate these two subtype concepts. Additionally, MixEHR-Nest not only improved the prediction accuracy of short-term mortality of ICU patients and initial insulin treatment in diabetic patients but also revealed the contributions of subphenotypes. For longitudinal analysis, MixEHR-Nest identified subphenotypes of distinct age prevalence under the same phenotypes, such as asthma, leukemia, epilepsy, and depression. The MixEHR-Nest software is available at GitHub: https://github.com/li-lab-mcgill/MixEHR-Nest.

In many domains, such as healthcare, time-series data is often irregularly sampled with varying intervals between observations. This poses challenges for classical time-series models that require equally spaced data. To address this, we propose a novel time-series Transformer called Trajectory Generative Pre-trained Transformer (TrajGPT). TrajGPT employs a novel Selective Recurrent Attention (SRA) mechanism, which utilizes a data-dependent decay to adaptively filter out irrelevant past information based on contexts. By interpreting TrajGPT as discretized ordinary differential equations (ODEs), it effectively captures the underlying continuous dynamics and enables time-specific inference for forecasting arbitrary target timesteps. Experimental results demonstrate that TrajGPT excels in trajectory forecasting, drug usage prediction, and phenotype classification without requiring task-specific fine-tuning. By evolving the learned continuous dynamics, TrajGPT can interpolate and extrapolate disease risk trajectories from partially-observed time series. The visualization of predicted health trajectories shows that TrajGPT forecasts unseen diseases based on the history of clinically relevant phenotypes (i.e., contexts)., Comment: 9 pages

Learning time-series representations for discriminative tasks, such as classification and regression, has been a long-standing challenge in the healthcare domain. Current pre-training methods are limited in either unidirectional next-token prediction or randomly masked token prediction. We propose a novel architecture called Bidirectional Timely Generative Pre-trained Transformer (BiTimelyGPT), which pre-trains on biosignals and longitudinal clinical records by both next-token and previous-token prediction in alternating transformer layers. This pre-training task preserves original distribution and data shapes of the time-series. Additionally, the full-rank forward and backward attention matrices exhibit more expressive representation capabilities. Using biosignals and longitudinal clinical records, BiTimelyGPT demonstrates superior performance in predicting neurological functionality, disease diagnosis, and physiological signs. By visualizing the attention heatmap, we observe that the pre-trained BiTimelyGPT can identify discriminative segments from biosignal time-series sequences, even more so after fine-tuning on the task.

Large-scale pre-trained models (PTMs) such as BERT and GPT have recently achieved great success in Natural Language Processing and Computer Vision domains. However, the development of PTMs on healthcare time-series data is lagging behind.This underscores the limitations of the existing transformer-based architectures, particularly their scalability to handle large-scale time series and ability to capture long-term temporal dependencies. In this study, we present Timely Generative Pre-trained Transformer (TimelyGPT). TimelyGPT employs an extrapolatable position (xPos) embedding to encode trend and periodic patterns into time-series representations. It also integrates recurrent attention and temporal convolution modules to effectively capture global-local temporal dependencies. We evaluated TimelyGPT on two large-scale healthcare time series datasets corresponding to continuous biosignals and irregularly-sampled time series, respectively. Our experiments show that during pre-training, TimelyGPT excels in learning time-series representations from continuously monitored biosignals and irregularly-sampled time series data commonly observed in longitudinal electronic health records (EHRs). In forecasting continuous biosignals, TimelyGPT achieves accurate extrapolation up to 6,000 timesteps of body temperature during the sleep stage transition, given a short look-up window (i.e., prompt) containing only 2,000 timesteps. For irregularly-sampled time series, TimelyGPT with a proposed time-specific inference demonstrates high top recall scores in predicting future diagnoses using early diagnostic records, effectively handling irregular intervals between clinical records. Together, we envision TimelyGPT to be useful in a broad spectrum of health domains, including long-term patient health state forecasting and patient risk trajectory prediction., Comment: 17 pages

Infectious disease outbreaks continue to pose a significant threat to human health and well-being. To improve disease surveillance and understanding of disease spread, several surveillance systems have been developed to monitor daily news alerts and social media. However, existing systems lack thorough epidemiological analysis in relation to corresponding alerts or news, largely due to the scarcity of well-annotated reports data. To address this gap, we introduce the Biomedical Alert News Dataset (BAND), which includes 1,508 samples from existing reported news articles, open emails, and alerts, as well as 30 epidemiology-related questions. These questions necessitate the model's expert reasoning abilities, thereby offering valuable insights into the outbreak of the disease. The BAND dataset brings new challenges to the NLP world, requiring better disguise capability of the content and the ability to infer important information. We provide several benchmark tasks, including Named Entity Recognition (NER), Question Answering (QA), and Event Extraction (EE), to show how existing models are capable of handling these tasks in the epidemiology domain. To the best of our knowledge, the BAND corpus is the largest corpus of well-annotated biomedical outbreak alert news with elaborately designed questions, making it a valuable resource for epidemiologists and NLP researchers alike.

We propose a multivariate GARCH model for non-stationary health time series by modifying the variance of the observations of the standard state space model. The proposed model provides an intuitive way of dealing with heteroskedastic data using the conditional nature of state space models. We follow the Bayesian paradigm to perform the inference procedure. In particular, we use Markov chain Monte Carlo methods to obtain samples from the resultant posterior distribution. Due to the natural temporal correlation structure induced on model parameters, we use the forward filtering backward sampling algorithm to efficiently obtain samples from the posterior distribution. The proposed model also handles missing data in a fully Bayesian fashion. We validate our model on synthetic data, and then use it to analyze a data set obtained from an intensive care unit in a Montreal hospital. We further show that our proposed models offer better performance, in terms of WAIC, than standard state space models. The proposed model provides a new way to model multivariate heteroskedastic non-stationary time series data and the simplicity in applying the WAIC allows us to compare competing models.

Recurrent COVID-19 outbreaks have placed immense strain on the hospital system in Quebec. We develop a Bayesian three-state coupled Markov switching model to analyze COVID-19 outbreaks across Quebec based on admissions in the 30 largest hospitals. Within each catchment area, we assume the existence of three states for the disease: absence, a new state meant to account for many zeroes in some of the smaller areas, endemic and outbreak. Then we assume the disease switches between the three states in each area through a series of coupled nonhomogeneous hidden Markov chains. Unlike previous approaches, the transition probabilities may depend on covariates and the occurrence of outbreaks in neighboring areas, to account for geographical outbreak spread. Additionally, to prevent rapid switching between endemic and outbreak periods we introduce clone states into the model which enforce minimum endemic and outbreak durations. We make some interesting findings, such as that mobility in retail and recreation venues had a positive association with the development and persistence of new COVID-19 outbreaks in Quebec. Based on model comparison our contributions show promise in improving state estimation retrospectively and in real-time, especially when there are smaller areas and highly spatially synchronized outbreaks. Furthermore, our approach offers new and interesting epidemiological interpretations, such as being able to estimate the effect of covariates on disease extinction., Comment: The accepted version in The Annals of Applied Statistics

The rapid growth of electronic health record (EHR) datasets opens up promising opportunities to understand human diseases in a systematic way. However, effective extraction of clinical knowledge from the EHR data has been hindered by its sparsity and noisy information. We present KG-ETM, an end-to-end knowledge graph-based multimodal embedded topic model. KG-ETM distills latent disease topics from EHR data by learning the embedding from the medical knowledge graphs. We applied KG-ETM to a large-scale EHR dataset consisting of over 1 million patients. We evaluated its performance based on EHR reconstruction and drug imputation. KG-ETM demonstrated superior performance over the alternative methods on both tasks. Moreover, our model learned clinically meaningful graph-informed embedding of the EHR codes. In additional, our model is also able to discover interpretable and accurate patient representations for patient stratification and drug recommendations.

Motivation: Electronic health record (EHR) data provides a new venue to elucidate disease comorbidities and latent phenotypes for precision medicine. To fully exploit its potential, a realistic data generative process of the EHR data needs to be modelled. We present MixEHR-S to jointly infer specialist-disease topics from the EHR data. As the key contribution, we model the specialist assignments and ICD-coded diagnoses as the latent topics based on patient's underlying disease topic mixture in a novel unified supervised hierarchical Bayesian topic model. For efficient inference, we developed a closed-form collapsed variational inference algorithm to learn the model distributions of MixEHR-S. We applied MixEHR-S to two independent large-scale EHR databases in Quebec with three targeted applications: (1) Congenital Heart Disease (CHD) diagnostic prediction among 154,775 patients; (2) Chronic obstructive pulmonary disease (COPD) diagnostic prediction among 73,791 patients; (3) future insulin treatment prediction among 78,712 patients diagnosed with diabetes as a mean to assess the disease exacerbation. In all three applications, MixEHR-S conferred clinically meaningful latent topics among the most predictive latent topics and achieved superior target prediction accuracy compared to the existing methods, providing opportunities for prioritizing high-risk patients for healthcare services. MixEHR-S source code and scripts of the experiments are freely available at https://github.com/li-lab-mcgill/mixehrS

The rapid global spread of COVID-19 has led to an unprecedented demand for effective methods to mitigate the spread of the disease, and various digital contact tracing (DCT) methods have emerged as a component of the solution. In order to make informed public health choices, there is a need for tools which allow evaluation and comparison of DCT methods. We introduce an agent-based compartmental simulator we call COVI-AgentSim, integrating detailed consideration of virology, disease progression, social contact networks, and mobility patterns, based on parameters derived from empirical research. We verify by comparing to real data that COVI-AgentSim is able to reproduce realistic COVID-19 spread dynamics, and perform a sensitivity analysis to verify that the relative performance of contact tracing methods are consistent across a range of settings. We use COVI-AgentSim to perform cost-benefit analyses comparing no DCT to: 1) standard binary contact tracing (BCT) that assigns binary recommendations based on binary test results; and 2) a rule-based method for feature-based contact tracing (FCT) that assigns a graded level of recommendation based on diverse individual features. We find all DCT methods consistently reduce the spread of the disease, and that the advantage of FCT over BCT is maintained over a wide range of adoption rates. Feature-based methods of contact tracing avert more disability-adjusted life years (DALYs) per socioeconomic cost (measured by productive hours lost). Our results suggest any DCT method can help save lives, support re-opening of economies, and prevent second-wave outbreaks, and that FCT methods are a promising direction for enriching BCT using self-reported symptoms, yielding earlier warning signals and a significantly reduced spread of the virus per socioeconomic cost.

The COVID-19 pandemic has spread rapidly worldwide, overwhelming manual contact tracing in many countries and resulting in widespread lockdowns for emergency containment. Large-scale digital contact tracing (DCT) has emerged as a potential solution to resume economic and social activity while minimizing spread of the virus. Various DCT methods have been proposed, each making trade-offs between privacy, mobility restrictions, and public health. The most common approach, binary contact tracing (BCT), models infection as a binary event, informed only by an individual's test results, with corresponding binary recommendations that either all or none of the individual's contacts quarantine. BCT ignores the inherent uncertainty in contacts and the infection process, which could be used to tailor messaging to high-risk individuals, and prompt proactive testing or earlier warnings. It also does not make use of observations such as symptoms or pre-existing medical conditions, which could be used to make more accurate infectiousness predictions. In this paper, we use a recently-proposed COVID-19 epidemiological simulator to develop and test methods that can be deployed to a smartphone to locally and proactively predict an individual's infectiousness (risk of infecting others) based on their contact history and other information, while respecting strong privacy constraints. Predictions are used to provide personalized recommendations to the individual via an app, as well as to send anonymized messages to the individual's contacts, who use this information to better predict their own infectiousness, an approach we call proactive contact tracing (PCT). We find a deep-learning based PCT method which improves over BCT for equivalent average mobility, suggesting PCT could help in safe re-opening and second-wave prevention.

The purpose of this paper is to describe and analyze the development of a knowledge-based infrastructure to support MSP decision-making processes. The paper emerged from a study to define specifications for a knowledge-based infrastructure to provide decision support for community-level MSPs in the Canadian province of Quebec. As part of the study, a process assessment was conducted to understand the needs of communities as they collect, organize, and analyze data to make decisions about their priorities. The result of this process is a portrait, which is an epidemiological profile of health and nutrition in their community. Portraits inform strategic planning and development of interventions and are used to assess the impact of interventions. Our key findings indicate ambiguities and disagreement among MSP decision-makers regarding causal relationships between actions and outcomes, and the relevant data needed for making decisions. MSP decision-makers expressed a desire for easy-to-use tools that facilitate the collection, organization, synthesis, and analysis of data, to enable decision-making in a timely manner. Findings inform conceptual modeling and ontological analysis to capture the domain knowledge and specify relationships between actions and outcomes. This modeling and analysis provide the foundation for an ontology, encoded using OWL 2 Web Ontology Language. The ontology is developed to provide semantic support for the MSP process, defining objectives, strategies, actions, indicators, and data sources. In the future, software interacting with the ontology can facilitate interactive browsing by decision-makers in the MSP in the form of concepts, instances, relationships, and axioms. Our ontology also facilitates the integration and interpretation of community data and can help in managing semantic interoperability between different knowledge sources.

We develop clustering procedures for longitudinal trajectories based on a continuous-time hidden Markov model (CTHMM) and a generalized linear observation model. Specifically in this paper, we carry out finite and infinite mixture model-based clustering for a CTHMM and achieve inference using Markov chain Monte Carlo (MCMC). For a finite mixture model with prior on the number of components, we implement reversible-jump MCMC to facilitate the trans-dimensional move between different number of clusters. For a Dirichlet process mixture model, we utilize restricted Gibbs sampling split-merge proposals to expedite the MCMC algorithm. We employ proposed algorithms to the simulated data as well as a real data example, and the results demonstrate the desired performance of the new sampler.

Modeling disease progression in healthcare administrative databases is complicated by the fact that patients are observed only at irregular intervals when they seek healthcare services. In a longitudinal cohort of 76,888 patients with chronic obstructive pulmonary disease (COPD), we used a continuous-time hidden Markov model with a generalized linear model to model healthcare utilization events. We found that the fitted model provides interpretable results suitable for summarization and hypothesis generation., Comment: Machine Learning for Health (ML4H) Workshop at NeurIPS 2018 arXiv:1811.07216