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We present a neural network framework for learning a survival model to predict a time-to-event outcome while simultaneously learning a topic model that reveals feature relationships. In particular, we model each subject as a distribution over "topics", where a topic could, for instance, correspond to an age group, a disorder, or a disease. The presence of a topic in a subject means that specific clinical features are more likely to appear for the subject. Topics encode information about related features and are learned in a supervised manner to predict a time-to-event outcome. Our framework supports combining many different topic and survival models; training the resulting joint survival-topic model readily scales to large datasets using standard neural net optimizers with minibatch gradient descent. For example, a special case is to combine LDA with a Cox model, in which case a subject's distribution over topics serves as the input feature vector to the Cox model. We explain how to address practical implementation issues that arise when applying these neural survival-supervised topic models to clinical data, including how to visualize results to assist clinical interpretation. We study the effectiveness of our proposed framework on seven clinical datasets on predicting time until death as well as hospital ICU length of stay, where we find that neural survival-supervised topic models achieve competitive accuracy with existing approaches while yielding interpretable clinical topics that explain feature relationships. Our code is available at: https://github.com/georgehc/survival-topics., Competing Interests: Declaration of competing interest All authors have participated in (a) conception and design, or analysis and interpretation of the data; (b) drafting the article or revising it critically for important intellectual content; and (c) approval of the final version. This manuscript has not been submitted to, nor is under review at, another journal or other publishing venue. The authors have no affiliation with any organization with a direct or indirect financial interest in the subject matter discussed in the manuscript, (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Reliable extraction of temporal relations from clinical notes is a growing need in many clinical research domains. Our work introduces typed markers to the task of clinical temporal relation extraction. We demonstrate that the addition of medical entity information to clinical text as tags with context sentences then input to a transformer-based architecture can outperform more complex systems requiring feature engineering and temporal reasoning. We propose several strategies of typed marker creation that incorporate entity type information at different granularities, with extensive experiments to test their effectiveness. Our system establishes the best result on I2B2, a clinical benchmark dataset for temporal relation extraction, with a F1 at 83.5% that provides a substantial 3.3% improvement over the previous best system.

With COVID-19 now pervasive, identification of high-risk individuals is crucial. Using data from a major healthcare provider in Southwestern Pennsylvania, we develop survival models predicting severe COVID-19 progression. In this endeavor, we face a tradeoff between more accurate models relying on many features and less accurate models relying on a few features aligned with clinician intuition. Complicating matters, many EHR features tend to be under-coded degrading the accuracy of smaller models. In this study we develop two sets of high-performance risk scores: (i) an unconstrained model built from all available features; and (ii) a pipeline that learns a small set of clinical concepts before training a risk predictor. Learned concepts boost performance over the corresponding features (C-index 0.858 vs. 0.844) and demonstrate improvements over (i) when evaluated out-of-sample (subsequent time periods). Our models outperform previous works (C-index 0.844-0.872 vs. 0.598-0.810)., (©2022 AMIA - All rights reserved.)

We consider the problem of predicting how the likelihood of an outcome of interest for a patient changes over time as we observe more of the patient's data. To solve this problem, we propose a supervised contrastive learning framework that learns an embedding representation for each time step of a patient time series. Our framework learns the embedding space to have the following properties: (1) nearby points in the embedding space have similar predicted class probabilities, (2) adjacent time steps of the same time series map to nearby points in the embedding space, and (3) time steps with very different raw feature vectors map to far apart regions of the embedding space. To achieve property (3), we employ a nearest neighbor pairing mechanism in the raw feature space. This mechanism also serves as an alternative to "data augmentation", a key ingredient of contrastive learning, which lacks a standard procedure that is adequately realistic for clinical tabular data, to our knowledge. We demonstrate that our approach outperforms state-of-the-art baselines in predicting mortality of septic patients (MIMIC-III dataset) and tracking progression of cognitive impairment (ADNI dataset). Our method also consistently recovers the correct synthetic dataset embedding structure across experiments, a feat not achieved by baselines. Our ablation experiments show the pivotal role of our nearest neighbor pairing.

Background: Little is known about whether machine-learning algorithms developed to predict opioid overdose using earlier years and from a single state will perform as well when applied to other populations. We aimed to develop a machine-learning algorithm to predict 3-month risk of opioid overdose using Pennsylvania Medicaid data and externally validated it in two data sources (ie, later years of Pennsylvania Medicaid data and data from a different state)., Methods: This prognostic modelling study developed and validated a machine-learning algorithm to predict overdose in Medicaid beneficiaries with one or more opioid prescription in Pennsylvania and Arizona, USA. To predict risk of hospital or emergency department visits for overdose in the subsequent 3 months, we measured 284 potential predictors from pharmaceutical and health-care encounter claims data in 3-month periods, starting 3 months before the first opioid prescription and continuing until loss to follow-up or study end. We developed and internally validated a gradient-boosting machine algorithm to predict overdose using 2013-16 Pennsylvania Medicaid data (n=639 693). We externally validated the model using (1) 2017-18 Pennsylvania Medicaid data (n=318 585) and (2) 2015-17 Arizona Medicaid data (n=391 959). We reported several prediction performance metrics (eg, C-statistic, positive predictive value). Beneficiaries were stratified into risk-score subgroups to support clinical use., Findings: A total of 8641 (1·35%) 2013-16 Pennsylvania Medicaid beneficiaries, 2705 (0·85%) 2017-18 Pennsylvania Medicaid beneficiaries, and 2410 (0·61%) 2015-17 Arizona beneficiaries had one or more overdose during the study period. C-statistics for the algorithm predicting 3-month overdoses developed from the 2013-16 Pennsylvania training dataset and validated on the 2013-16 Pennsylvania internal validation dataset, 2017-18 Pennsylvania external validation dataset, and 2015-17 Arizona external validation dataset were 0·841 (95% CI 0·835-0·847), 0·828 (0·822-0·834), and 0·817 (0·807-0·826), respectively. In external validation datasets, 71 361 (22·4%) of 318 585 2017-18 Pennsylvania beneficiaries were in high-risk subgroups (positive predictive value of 0·38-4·08%; capturing 73% of overdoses in the subsequent 3 months) and 40 041 (10%) of 391 959 2015-17 Arizona beneficiaries were in high-risk subgroups (positive predictive value of 0·19-1·97%; capturing 55% of overdoses). Lower risk subgroups in both validation datasets had few individuals (≤0·2%) with an overdose., Interpretation: A machine-learning algorithm predicting opioid overdose derived from Pennsylvania Medicaid data performed well in external validation with more recent Pennsylvania data and with Arizona Medicaid data. The algorithm might be valuable for overdose risk prediction and stratification in Medicaid beneficiaries., Funding: National Institute of Health, National Institute on Drug Abuse, National Institute on Aging., Competing Interests: Declaration of interests W-HL-C and WFG are named as inventors in one preliminary patent (U1195.70174US00) filing from the University of Florida and University of Pittsburgh for use of the machine learning algorithm for opioid risk prediction in Medicare described in this Article. W-HL-C , WFG, DLW, and C-YC are recipients of a grant from the National Institute on Aging (NIA; R21 AG060308). W-HL-C , WFG , JMD, AJG, GC, JLH, CCK, DCM, QY, JW, and HHZ are recipients of a grant from the US National Institute on Drug Abuse (NIDA; R01DA044985). W-HL-C declares grants from the Richard King Mellon Foundation–University of Pittsburgh, University of Florida Clinical and Translational Science Institute, the US National Institute of Mental Health (1R03MH114503-01 and R01MH121907), Pharmaceutical Research and Manufacturers of America Foundation, NIDA (1R01DA050676-01A1 and R01DA044985), Veterans Affairs (VA) Merit 1 (I01HX002191-01A2), and Merck, Sharp & Dohme and Bristol Myers Squibb. CKK declares grants from Lilly, Pfizer, GSK, Cumberland Pharmaceuticals, AbbVie, and EMD Serono; consultant fees from EMD Serono, Express Scripts, and Regeneron; an advisory board role with EMD Serono, Thusane, Regeneron, Taiwan Lipisome Company, Amzell, LG Chem, and Novartis; payment or honoraria from Focus Communications and PRIME Education; and being on the Data and Safety Monitoring Committee for Kolon Tissue Gene and on the board of directors for the International Chinese Osteoarthritis Research Society. WFG declares grant or contract to his institution from Richard King Mellon Foundation. JMD declares salary support from the Pennsylvania Department of Human Services, Richard King Mellon Foundation, and the US National Institute of Health (NIH)–NIDA (R01DA048019). AJG declares grants or contracts from NIH and the VA; royalties from UpToDate; and other financial and non-financial interests from American Society of Addiction Medicine, Association for Multidisciplinary Education and Research in Substance Use and Addiction, and the International Society of Addiction Journal Editors. JCW declares grants or contracts from Allegheny Health Network, Carnegie Mellon University, and University of Pittsburgh Medical Center; payment or honoraria from St Jude's; and receipt of equipment, materials, or other services from Amazon Web Services and Azure. DLW declares grant funding from Merck, Sharp & Dohme, and NIH–NIDA (1R01DA050676-01A1). All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Spelling correction is a particularly important problem in clinical natural language processing because of the abundant occurrence of misspellings in medical records. However, the scarcity of labeled datasets in a clinical context makes it hard to build a machine learning system for such clinical spelling correction. In this work, we present a probabilistic model of correcting misspellings based on a simple conditional independence assumption, which leads to a modular decomposition into a language model and a corruption model. With a deep character-level language model trained on a large clinical corpus, and a simple edit-based corruption model, we can build a spelling correction model with small or no real data. Experimental results show that our model significantly outperforms baselines on two healthcare spelling correction datasets.

Since the COVID-19 pandemic began, the United States's case fatality rate (CFR) has plummeted. Using national and Florida data, we unpack the drop in CFR between April and December 2020, accounting for such confounders as expanded testing, age distribution shift, and detection-to-death lags. Guided by the insight that treatment improvements in this period should correspond to decreases in hospitalization fatality rate (HFR), and using a block-bootstrapping procedure to quantify uncertainty, we find that although treatment improvements do not follow the same trajectory in Florida and nationally (with Florida undergoing a comparatively severe second peak), by December, significant improvements are observed both in Florida and nationally (at least 17% and 55% respectively). These estimates paint a more realistic picture of improvements than the drop in aggregate CFR (70.8%-91.1%). We publish a website where users can apply our analyses to selected demographics, regions, and dates of interest., (©2021 AMIA - All rights reserved.)

The COVID-19 pandemic presented enormous data challenges in the United States. Policy makers, epidemiological modelers, and health researchers all require up-to-date data on the pandemic and relevant public behavior, ideally at fine spatial and temporal resolution. The COVIDcast API is our attempt to fill this need: Operational since April 2020, it provides open access to both traditional public health surveillance signals (cases, deaths, and hospitalizations) and many auxiliary indicators of COVID-19 activity, such as signals extracted from deidentified medical claims data, massive online surveys, cell phone mobility data, and internet search trends. These are available at a fine geographic resolution (mostly at the county level) and are updated daily. The COVIDcast API also tracks all revisions to historical data, allowing modelers to account for the frequent revisions and backfill that are common for many public health data sources. All of the data are available in a common format through the API and accompanying R and Python software packages. This paper describes the data sources and signals, and provides examples demonstrating that the auxiliary signals in the COVIDcast API present information relevant to tracking COVID activity, augmenting traditional public health reporting and empowering research and decision-making., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Background: Survivors of opioid overdose have substantially increased mortality risk, although this risk is not evenly distributed across individuals. No study has focused on predicting an individual's risk of death after a nonfatal opioid overdose., Objective: To predict risk of death after a nonfatal opioid overdose., Design and Participants: This retrospective cohort study included 9686 Pennsylvania Medicaid beneficiaries with an emergency department or inpatient claim for nonfatal opioid overdose in 2014-2016. The index date was the first overdose claim during this period., Exposures, Main Outcome, and Measures: Predictor candidates were measured in the 180 days before the index overdose. Primary outcome was 180-day all-cause mortality. Using a gradient boosting machine model, we classified beneficiaries into six subgroups according to their risk of mortality (< 25th percentile of the risk score, 25th to < 50th, 50th to < 75th, 75th to < 90th, 90th to < 98th, ≥ 98th). We then measured receipt of medication for opioid use disorder (OUD), risk mitigation interventions (e.g., prescriptions for naloxone), and prescription opioids filled in the 180 days after the index overdose, by risk subgroup., Key Results: Of eligible beneficiaries, 347 (3.6%) died within 180 days after the index overdose. The C-statistic of the mortality prediction model was 0.71. In the highest risk subgroup, the observed 180-day mortality rate was 20.3%, while in the lowest risk subgroup, it was 1.5%. Medication for OUD and risk mitigation interventions after overdose were more commonly seen in lower risk groups, while opioid prescriptions were more likely to be used in higher risk groups (both p trends < .001)., Conclusions: A risk prediction model performed well for classifying mortality risk after a nonfatal opioid overdose. This prediction score can identify high-risk subgroups to target interventions to improve outcomes among overdose survivors.

Objective: To develop and validate a machine-learning algorithm to improve prediction of incident OUD diagnosis among Medicare beneficiaries with ≥1 opioid prescriptions., Methods: This prognostic study included 361,527 fee-for-service Medicare beneficiaries, without cancer, filling ≥1 opioid prescriptions from 2011-2016. We randomly divided beneficiaries into training, testing, and validation samples. We measured 269 potential predictors including socio-demographics, health status, patterns of opioid use, and provider-level and regional-level factors in 3-month periods, starting from three months before initiating opioids until development of OUD, loss of follow-up or end of 2016. The primary outcome was a recorded OUD diagnosis or initiating methadone or buprenorphine for OUD as proxy of incident OUD. We applied elastic net, random forests, gradient boosting machine, and deep neural network to predict OUD in the subsequent three months. We assessed prediction performance using C-statistics and other metrics (e.g., number needed to evaluate to identify an individual with OUD [NNE]). Beneficiaries were stratified into subgroups by risk-score decile., Results: The training (n = 120,474), testing (n = 120,556), and validation (n = 120,497) samples had similar characteristics (age ≥65 years = 81.1%; female = 61.3%; white = 83.5%; with disability eligibility = 25.5%; 1.5% had incident OUD). In the validation sample, the four approaches had similar prediction performances (C-statistic ranged from 0.874 to 0.882); elastic net required the fewest predictors (n = 48). Using the elastic net algorithm, individuals in the top decile of risk (15.8% [n = 19,047] of validation cohort) had a positive predictive value of 0.96%, negative predictive value of 99.7%, and NNE of 104. Nearly 70% of individuals with incident OUD were in the top two deciles (n = 37,078), having highest incident OUD (36 to 301 per 10,000 beneficiaries). Individuals in the bottom eight deciles (n = 83,419) had minimal incident OUD (3 to 28 per 10,000)., Conclusions: Machine-learning algorithms improve risk prediction and risk stratification of incident OUD in Medicare beneficiaries., Competing Interests: We have read the journal's policy and the authors of this manuscript have the following competing interests: Dr. Kwoh has received honoraria from AbbVie and EMD Serono and has provided consulting services for Astellas, Thusane, and Novartis, EMD Serono and Express Scripts. I confirm that this does not alter our adherence to PLOS ONE policies on sharing data and materials.

We consider the task of producing a useful clustering of healthcare providers from their clinical action signature- their drug, procedure, and billing codes. Because high-dimensional sparse count vectors are challenging to cluster, we develop a novel autoencoder framework to address this task. Our solution creates a low-dimensional embedded representation of the high-dimensional space that preserves angular relationships and assigns examples to clusters while optimizing the quality of this clustering. Our method is able to find a better clustering than under a two-step alternative, e.g., projected K means/medoids, where a representation is learned and then clustering is applied to the representation. We demonstrate our method's characteristics through quantitative and qualitative analysis of real and simulated data, including in several real-world healthcare case studies. Finally, we develop a tool to enhance exploratory analysis of providers based on their clinical behaviors., (©2019 AMIA - All rights reserved.)

Importance: Current approaches to identifying individuals at high risk for opioid overdose target many patients who are not truly at high risk., Objective: To develop and validate a machine-learning algorithm to predict opioid overdose risk among Medicare beneficiaries with at least 1 opioid prescription., Design, Setting, and Participants: A prognostic study was conducted between September 1, 2017, and December 31, 2018. Participants (n = 560 057) included fee-for-service Medicare beneficiaries without cancer who filled 1 or more opioid prescriptions from January 1, 2011, to December 31, 2015. Beneficiaries were randomly and equally divided into training, testing, and validation samples., Exposures: Potential predictors (n = 268), including sociodemographics, health status, patterns of opioid use, and practitioner-level and regional-level factors, were measured in 3-month windows, starting 3 months before initiating opioids until loss of follow-up or the end of observation., Main Outcomes and Measures: Opioid overdose episodes from inpatient and emergency department claims were identified. Multivariate logistic regression (MLR), least absolute shrinkage and selection operator-type regression (LASSO), random forest (RF), gradient boosting machine (GBM), and deep neural network (DNN) were applied to predict overdose risk in the subsequent 3 months after initiation of treatment with prescription opioids. Prediction performance was assessed using the C statistic and other metrics (eg, sensitivity, specificity, and number needed to evaluate [NNE] to identify one overdose). The Youden index was used to identify the optimized threshold of predicted score that balanced sensitivity and specificity., Results: Beneficiaries in the training (n = 186 686), testing (n = 186 685), and validation (n = 186 686) samples had similar characteristics (mean [SD] age of 68.0 [14.5] years, and approximately 63% were female, 82% were white, 35% had disabilities, 41% were dual eligible, and 0.60% had at least 1 overdose episode). In the validation sample, the DNN (C statistic = 0.91; 95% CI, 0.88-0.93) and GBM (C statistic = 0.90; 95% CI, 0.87-0.94) algorithms outperformed the LASSO (C statistic = 0.84; 95% CI, 0.80-0.89), RF (C statistic = 0.80; 95% CI, 0.75-0.84), and MLR (C statistic = 0.75; 95% CI, 0.69-0.80) methods for predicting opioid overdose. At the optimized sensitivity and specificity, DNN had a sensitivity of 92.3%, specificity of 75.7%, NNE of 542, positive predictive value of 0.18%, and negative predictive value of 99.9%. The DNN classified patients into low-risk (76.2% [142 180] of the cohort), medium-risk (18.6% [34 579] of the cohort), and high-risk (5.2% [9747] of the cohort) subgroups, with only 1 in 10 000 in the low-risk subgroup having an overdose episode. More than 90% of overdose episodes occurred in the high-risk and medium-risk subgroups, although positive predictive values were low, given the rare overdose outcome., Conclusions and Relevance: Machine-learning algorithms appear to perform well for risk prediction and stratification of opioid overdose, especially in identifying low-risk subgroups that have minimal risk of overdose.

Learning temporal dependencies between variables over continuous time is an important and challenging task. Continuous-time Bayesian networks effectively model such processes but are limited by the number of conditional intensity matrices, which grows exponentially in the number of parents per variable. We develop a partition-based representation using regression trees and forests whose parameter spaces grow linearly in the number of node splits. Using a multiplicative assumption we show how to update the forest likelihood in closed form, producing efficient model updates. Our results show multiplicative forests can be learned from few temporal trajectories with large gains in performance and scalability.

Systemic administration of chemotherapeutic agents results in indiscriminate drug distribution and severe toxicity. Here we report a technology potentially overcoming these shortcomings through encapsulation and cancer cell-specific targeting of chemotherapeutics in bacterially derived 400 nm minicells. We discovered that minicells can be packaged with therapeutically significant concentrations of chemotherapeutics of differing charge, hydrophobicity, and solubility. Targeting of minicells via bispecific antibodies to receptors on cancer cell membranes results in endocytosis, intracellular degradation, and drug release. This affects highly significant tumor growth inhibition and regression in mouse xenografts and case studies of lymphoma in dogs despite administration of minute amounts of drug and antibody; a factor critical for limiting systemic toxicity that should allow the use of complex regimens of combination chemotherapy.

Background: Geocoding methods vary among spatial epidemiology studies. Errors in the geocoding process and differential match rates may reduce study validity. We compared two geocoding methods using 8,157 Washington State addresses. The multi-stage geocoding method implemented by the state health department used a sequence of local and national reference files. The single-stage method used a single national reference file. For each address geocoded by both methods, we measured the distance between the locations assigned by each method. Area-level characteristics were collected from census data, and modeled as predictors of the discordance between geocoded address coordinates., Results: The multi-stage method had a higher match rate than the single-stage method: 99% versus 95%. Of 7,686 addresses were geocoded by both methods, 96% were geocoded to the same census tract by both methods and 98% were geocoded to locations within 1 km of each other by the two methods. The distance between geocoded coordinates for the same address was higher in sparsely populated and low poverty areas, and counties with local reference files., Conclusion: The multi-stage geocoding method had a higher match rate than the single-stage method. An examination of differences in the location assigned to the same address suggested that study results may be most sensitive to the choice of geocoding method in sparsely populated or low-poverty areas.