The influence of microbial colonization on inflammatory versus pro-healing trajectories in combat extremity wounds.

A combination of improved body armor, medical transportation, and treatment has led to the increased survival of warfighters from combat extremity injuries predominantly caused by blasts in modern conflicts. Despite advances, a high rate of complications such as wound infections, wound failure, amputations, and a decreased quality of life exist. To study the molecular underpinnings of wound failure, wound tissue biopsies from combat extremity injuries had RNA extracted and sequenced. Wounds were classified by colonization (colonized vs. non-colonized) and outcome (healed vs. failed) status. Differences in gene expression were investigated between timepoints at a gene level, and longitudinally by multi-gene networks, inferred proportions of immune cells, and expression of healing-related functions. Differences between wound outcomes in colonized wounds were more apparent than in non-colonized wounds. Colonized/healed wounds appeared able to mount an adaptive immune response to infection and progress beyond the inflammatory stage of healing, while colonized/failed wounds did not. Although, both colonized and non-colonized failed wounds showed increasing inferred immune and inflammatory programs, non-colonized/failed wounds progressed beyond the inflammatory stage, suggesting different mechanisms of failure dependent on colonization status. Overall, these data reveal gene expression profile differences in healing wounds that may be utilized to improve clinical treatment paradigms.

Personalized event prediction for Electronic Health Records.

Clinical event sequences consist of hundreds of clinical events that represent records of patient care in time. Developing accurate predictive models of such sequences is of a great importance for supporting a variety of models for interpreting/classifying the current patient condition, or predicting adverse clinical events and outcomes, all aimed to improve patient care. One important challenge of learning predictive models of clinical sequences is their patient-specific variability. Based on underlying clinical conditions, each patient's sequence may consist of different sets of clinical events (observations, lab results, medications, procedures). Hence, simple population-wide models learned from event sequences for many different patients may not accurately predict patient-specific dynamics of event sequences and their differences. To address the problem, we propose and investigate multiple new event sequence prediction models and methods that let us better adjust the prediction for individual patients and their specific conditions. The methods developed in this work pursue refinement of population-wide models to subpopulations, self-adaptation, and a meta-level model switching that is able to adaptively select the model with the best chance to support the immediate prediction. We analyze and test the performance of these models on clinical event sequences of patients in MIMIC-III database.

Hierarchical Active Learning With Qualitative Feedback on Regions.

Learning classification models in practice usually requires numerous labeled data for training. However, instance-based annotation can be inefficient for humans to perform. In this article, we propose and study a new type of human supervision that is fast to perform and useful for model learning. Instead of labeling individual instances, humans provide supervision to data regions, which are subspaces of the input data space, representing subpopulations of data. Since labeling now is performed on a region level, 0/1 labeling becomes imprecise. Thus, we design the region label to be a qualitative assessment of the class proportion, which coarsely preserves the labeling precision but is also easy for humans to do. To identify informative regions for labeling and learning, we further devise a hierarchical active learning process that recursively constructs a region hierarchy. This process is semisupervised in the sense that it is driven by both active learning strategies and human expertise, where humans can provide discriminative features. To evaluate our framework, we conducted extensive experiments on nine datasets as well as a real user study on a survival analysis of colorectal cancer patients. The results have clearly demonstrated the superiority of our region-based active learning framework against many instance-based active learning methods.

Learning EKG Diagnostic Models with Hierarchical Class Label Dependencies.

Electrocardiogram (EKG/ECG) is a key diagnostic tool to assess patient's cardiac condition and is widely used in clinical applications such as patient monitoring, surgery support, and heart medicine research. With recent advances in machine learning (ML) technology there has been a growing interest in the development of models supporting automatic EKG interpretation and diagnosis based on past EKG data. The problem can be modeled as multi-label classification (MLC), where the objective is to learn a function that maps each EKG reading to a vector of diagnostic class labels reflecting the underlying patient condition at different levels of abstraction. In this paper, we propose and investigate an ML model that considers class-label dependency embedded in the hierarchical organization of EKG diagnoses to improve the EKG classification performance. Our model first transforms the EKG signals into a low-dimensional vector, and after that uses the vector to predict different class labels with the help of the conditional tree structured Bayesian network (CTBN) that is able to capture hierarchical dependencies among class variables. We evaluate our model on the publicly available PTB-XL dataset. Our experiments demonstrate that modeling of hierarchical dependencies among class variables improves the diagnostic model performance under multiple classification performance metrics as compared to classification models that predict each class label independently.

Transcriptomic, Proteomic, and Morphologic Characterization of Healing in Volumetric Muscle Loss.

Skeletal muscle has a robust, inherent ability to regenerate in response to injury from acute to chronic. In severe trauma, however, complete regeneration is not possible, resulting in a permanent loss of skeletal muscle tissue referred to as volumetric muscle loss (VML). There are few consistently reliable therapeutic or surgical options to address VML. A major limitation in investigation of possible therapies is the absence of a well-characterized large animal model. In this study, we present results of a comprehensive transcriptomic, proteomic, and morphologic characterization of wound healing following VML in a novel canine model of VML which we compare to a nine-patient cohort of combat-associated VML. The canine model is translationally relevant as it provides both a regional (spatial) and temporal map of the wound healing processes that occur in human VML. Collectively, these data show the spatiotemporal transcriptomic, proteomic, and morphologic properties of canine VML healing as a framework and model system applicable to future studies investigating novel therapies for human VML. Impact Statement The spatiotemporal transcriptomic, proteomic, and morphologic properties of canine volumetric muscle loss (VML) healing is a translational framework and model system applicable to future studies investigating novel therapies for human VML.

Event Outlier Detection in Continuous Time.

Continuous-time event sequences represent discrete events occurring in continuous time. Such sequences arise frequently in real-life. Usually we expect the sequences to follow some regular pattern over time. However, sometimes these patterns may be interrupted by unexpected absence or occurrences of events. Identification of these unexpected cases can be very important as they may point to abnormal situations that need human attention. In this work, we study and develop methods for detecting outliers in continuous-time event sequences, including unexpected absence and unexpected occurrences of events. Since the patterns that event sequences tend to follow may change in different contexts, we develop outlier detection methods based on point processes that can take context information into account. Our methods are based on Bayesian decision theory and hypothesis testing with theoretical guarantees. To test the performance of the methods, we conduct experiments on both synthetic data and real-world clinical data and show the effectiveness of the proposed methods.

Improving Prediction of Low-Prior Clinical Events with Simultaneous General Patient-State Representation Learning.

Low-prior targets are common among many important clinical events, which introduces the challenge of having enough data to support learning of their predictive models. Many prior works have addressed this problem by first building a general patient-state representation model, and then adapting it to a new low-prior prediction target. In this schema, there is potential for the predictive performance to be hindered by the misalignment between the general patient-state model and the target task. To overcome this challenge, we propose a new method that simultaneously optimizes a shared model through multi-task learning of both the low-prior supervised target and general purpose patient-state representation (GPSR). More specifically, our method improves prediction performance of a low-prior task by jointly optimizing a shared model that combines the loss of the target event and a broad range of generic clinical events. We study the approach in the context of Recurrent Neural Networks (RNNs). Through extensive experiments on multiple clinical event targets using MIMIC-III [8] data, we show that the inclusion of general patient-state representation tasks during model training improves the prediction of individual low-prior targets.

Neural Clinical Event Sequence Prediction through Personalized Online Adaptive Learning.

Clinical event sequences consist of thousands of clinical events that represent records of patient care in time. Developing accurate prediction models for such sequences is of a great importance for defining representations of a patient state and for improving patient care. One important challenge of learning a good predictive model of clinical sequences is patient-specific variability. Based on underlying clinical complications, each patient's sequence may consist of different sets of clinical events. However, population-based models learned from such sequences may not accurately predict patient-specific dynamics of event sequences. To address the problem, we develop a new adaptive event sequence prediction framework that learns to adjust its prediction for individual patients through an online model update.

Modeling multivariate clinical event time-series with recurrent temporal mechanisms.

In this work, we propose a novel autoregressive event time-series model that can predict future occurrences of multivariate clinical events. Our model represents multivariate event time-series using different temporal mechanisms aimed to fit different temporal characteristics of the time-series. In particular, information about distant past is modeled through the hidden state space defined by an LSTM-based model, information on recently observed clinical events is modeled through discriminative projections, and information about periodic (repeated) events is modeled using a special recurrent mechanism based on probability distributions of inter-event gaps compiled from past data. We evaluate our proposed model on electronic health record (EHRs) data derived from MIMIC-III dataset. We show that our new model equipped with the above temporal mechanisms leads to improved prediction performance compared to multiple baselines.

Hierarchical Active Learning with Overlapping Regions.

Learning of classification models from real-world data often requires substantial human effort devoted to instance annotation. As this process can be very time-consuming and costly, finding effective ways to reduce the annotation cost becomes critical for building such models. To address this problem we explore a new type of human feedback - region-based feedback. Briefly, a region is defined as a hypercubic subspace of the input data space and represents a subpopulation of data instances; the region's label is a human assessment of the class proportion of the data subpopulation. By using learning from label proportions algorithms one can learn instance-based classifiers from such labeled regions. In general, the key challenge is that there can be infinite many regions one can define and query in a given data space. To minimize the number and complexity of region-based queries, we propose and develop a hierarchical active learning solution that aims at incrementally building a concise hierarchy of regions. Furthermore, to avoid building a possibly class-irrelevant region hierarchy, we further propose to grow multiple different hierarchies in parallel and expand those more informative hierarchies. Through experiments on numerous data sets, we demonstrate that methods using region-based feedback can learn very good classifiers from very few and simple queries, and hence are highly effective in reducing human annotation effort needed for building classification models.

Leveraging Eye Tracking to Prioritize Relevant Medical Record Data: Comparative Machine Learning Study.

BACKGROUND: Electronic medical record (EMR) systems capture large amounts of data per patient and present that data to physicians with little prioritization. Without prioritization, physicians must mentally identify and collate relevant data, an activity that can lead to cognitive overload. To mitigate cognitive overload, a Learning EMR (LEMR) system prioritizes the display of relevant medical record data. Relevant data are those that are pertinent to a context-defined as the combination of the user, clinical task, and patient case. To determine which data are relevant in a specific context, a LEMR system uses supervised machine learning models of physician information-seeking behavior. Since obtaining information-seeking behavior data via manual annotation is slow and expensive, automatic methods for capturing such data are needed. OBJECTIVE: The goal of the research was to propose and evaluate eye tracking as a high-throughput method to automatically acquire physician information-seeking behavior useful for training models for a LEMR system. METHODS: Critical care medicine physicians reviewed intensive care unit patient cases in an EMR interface developed for the study. Participants manually identified patient data that were relevant in the context of a clinical task: preparing a patient summary to present at morning rounds. We used eye tracking to capture each physician's gaze dwell time on each data item (eg, blood glucose measurements). Manual annotations and gaze dwell times were used to define target variables for developing supervised machine learning models of physician information-seeking behavior. We compared the performance of manual selection and gaze-derived models on an independent set of patient cases. RESULTS: A total of 68 pairs of manual selection and gaze-derived machine learning models were developed from training data and evaluated on an independent evaluation data set. A paired Wilcoxon signed-rank test showed similar performance of manual selection and gaze-derived models on area under the receiver operating characteristic curve (P=.40). CONCLUSIONS: We used eye tracking to automatically capture physician information-seeking behavior and used it to train models for a LEMR system. The models that were trained using eye tracking performed like models that were trained using manual annotations. These results support further development of eye tracking as a high-throughput method for training clinical decision support systems that prioritize the display of relevant medical record data.

Modeling physician variability to prioritize relevant medical record information.

OBJECTIVE: Patient information can be retrieved more efficiently in electronic medical record (EMR) systems by using machine learning models that predict which information a physician will seek in a clinical context. However, information-seeking behavior varies across EMR users. To explicitly account for this variability, we derived hierarchical models and compared their performance to nonhierarchical models in identifying relevant patient information in intensive care unit (ICU) cases. MATERIALS AND METHODS: Critical care physicians reviewed ICU patient cases and selected data items relevant for presenting at morning rounds. Using patient EMR data as predictors, we derived hierarchical logistic regression (HLR) and standard logistic regression (LR) models to predict their relevance. RESULTS: In 73 pairs of HLR and LR models, the HLR models achieved an area under the receiver operating characteristic curve of 0.81, 95% confidence interval (CI) [0.80-0.82], which was statistically significantly higher than that of LR models (0.75, 95% CI [0.74-0.76]). Further, the HLR models achieved statistically significantly lower expected calibration error (0.07, 95% CI [0.06-0.08]) than LR models (0.16, 95% CI [0.14-0.17]). DISCUSSION: The physician reviewers demonstrated variability in selecting relevant data. Our results show that HLR models perform significantly better than LR models with respect to both discrimination and calibration. This is likely due to explicitly modeling physician-related variability. CONCLUSION: Hierarchical models can yield better performance when there is physician-related variability as in the case of identifying relevant information in the EMR.

Monitoring ICU Mortality Risk with A Long Short-Term Memory Recurrent Neural Network.

In intensive care units (ICU), mortality prediction is a critical factor not only for effective medical intervention but also for allocation of clinical resources. Structured electronic health records (EHR) contain valuable information for assessing mortality risk in ICU patients, but current mortality prediction models usually require laborious human-engineered features. Furthermore, substantial missing data in EHR is a common problem for both the construction and implementation of a prediction model.Inspired by language-related models, we design a new framework for dynamic monitoring of patients' mortality risk. Our framework uses the bag-of-words representation for all relevant medical events based on most recent history as inputs. By design, it is robust to missing data in EHR and can be easily implemented as an instant scoring system to monitor the medical development of all ICU patients. Specifically, our model uses latent semantic analysis (LSA) to encode the patients' states into low-dimensional embeddings, which are further fed to long short-term memory networks for mortality risk prediction. Our results show that the deep learning based framework performs better than the existing severity scoring system, SAPS-II. We observe that bidirectional long short-term memory demonstrates superior performance, probably due to the successful capture of both forward and backward temporal dependencies.

Active Learning of Multi-class Classification Models from Ordered Class Sets.

In this paper, we study the problem of learning multi-class classification models from a limited set of labeled examples obtained from human annotator. We propose a new machine learning framework that learns multi-class classification models from ordered class sets the annotator may use to express not only her top class choice but also other competing classes still under consideration. Such ordered sets of competing classes are common, for example, in various diagnostic tasks. In this paper, we first develop strategies for learning multi-class classification models from examples associated with ordered class set information. After that we develop an active learning strategy that considers such a feedback. We evaluate the benefit of the framework on multiple datasets. We show that class-order feedback and active learning can reduce the annotation cost both individually and jointly.

Mining compact predictive pattern sets using classification model.

In this paper, we develop a new framework for mining predictive patterns that aims to describe compactly the condition (or class) of interest. Our framework relies on a classification model that considers and combines various predictive pattern candidates and selects only those that are important for improving the overall class prediction performance. We test our approach on data derived from MIMIC-III EHR database, focusing on patterns predictive of sepsis. We show that using our classification approach we can achieve a significant reduction in the number of extracted patterns compared to the state-of-the-art methods based on minimum predictive pattern mining approach, while preserving the overall classification accuracy of the model.

Using machine learning to selectively highlight patient information.

BACKGROUND: Electronic medical record (EMR) systems need functionality that decreases cognitive overload by drawing the clinician's attention to the right data, at the right time. We developed a Learning EMR (LEMR) system that learns statistical models of clinician information-seeking behavior and applies those models to direct the display of data in future patients. We evaluated the performance of the system in identifying relevant patient data in intensive care unit (ICU) patient cases. METHODS: To capture information-seeking behavior, we enlisted critical care medicine physicians who reviewed a set of patient cases and selected data items relevant to the task of presenting at morning rounds. Using patient EMR data as predictors, we built machine learning models to predict their relevancy. We prospectively evaluated the predictions of a set of high performing models. RESULTS: On an independent evaluation data set, 25 models achieved precision of 0.52, 95% CI [0.49, 0.54] and recall of 0.77, 95% CI [0.75, 0.80] in identifying relevant patient data items. For data items missed by the system, the reviewers rated the effect of not seeing those data from no impact to minor impact on patient care in about 82% of the cases. CONCLUSION: Data-driven approaches for adaptively displaying data in EMR systems, like the LEMR system, show promise in using information-seeking behavior of clinicians to identify and highlight relevant patient data.

Recent Context-aware LSTM for Clinical Event Time-series Prediction.

In this work, we propose a novel clinical event time-series model based on the long short-term memory architecture (LSTM) that can predict future event occurrences for a large number of different clinical events. Our model relies on two sources of information to predict future events. One source is derived from the set of recently observed clinical events. The other one is based on the hidden state space defined by the LSTM that aims to abstract past, more distant, patient information that is predictive of future events. We evaluate our proposed model on electronic health record (EHRs) data derived from MIMIC-III dataset. We show that the combination of the two sources of information implemented in our method leads to improved prediction performance compared to the models based on individual sources.

Predicting patient's diagnoses and diagnostic categories from clinical-events in EHR data.

In this paper we develop and study machine learning based models based on latent semantic indexing capable of automatically assigning diagnoses and diagnostic categories to patients based on structured clinical data in their Electronic Health record (EHR). These models can be either used for automatic coding of patient's diagnoses from structured EHR data at the time of discharge, or for supporting dynamic diagnosis and summarization of the patient condition. We study the performance of our diagnostic models on MIMIC-III EHR data.

Hierarchical Active Learning with Proportion Feedback on Regions.

Learning of classification models in practice often relies on human annotation effort in which humans assign class labels to data instances. As this process can be very time-consuming and costly, finding effective ways to reduce the annotation cost becomes critical for building such models. To solve this problem, instead of soliciting instance-based annotation we explore region-based annotation as the feedback. A region is defined as a hyper-cubic subspace of the input feature space and it covers a subpopulation of data instances that fall into this region. Each region is labeled with a number in [0,1] (in binary classification setting), representing a human estimate of the positive (or negative) class proportion in the subpopulation. To learn a classifier from region-based feedback we develop an active learning framework that hierarchically divides the input space into smaller and smaller regions. In each iteration we split the region with the highest potential to improve the classification models. This iterative process allows us to gradually learn more refined classification models from more specific regions with more accurate proportions. Through experiments on numerous datasets we demonstrate that our approach offers a new and promising active learning direction that can outperform existing active learning approaches especially in situations when labeling budget is limited and small.

Region-Based Active Learning with Hierarchical and Adaptive Region Construction.

Learning of classification models in practice often relies on human annotation effort in which humans assign class labels to data instances. As this process can be very time-consuming and costly, finding effective ways to reduce the annotation cost becomes critical for building such models. To solve this problem, instead of soliciting instance-based annotation we explore region-based annotation as the human feedback. A region is defined as a hyper-cubic subspace of the input space X and it covers a subpopulation of data instances that fall into this region. Each region is labeled with a number in [0,1] (in binary classification setting), representing a human estimate of the positive (or negative) class proportion in the subpopulation. To quickly discover pure regions (in terms of class proportion) in the data, we have developed a novel active learning framework that constructs regions in a hierarchical and adaptive way. Hierarchical means that regions are incrementally built into a hierarchical tree, which is done by repeatedly splitting the input space. Adaptive means that our framework can adaptively choose the best heuristic for each of the region splits. Through experiments on numerous datasets we demonstrate that our framework can identify pure regions in very few region queries. Thus our approach is shown to be effective in learning classification models from very limited human feedback.