Big data in epilepsy: Clinical and research considerations. Report from the Epilepsy Big Data Task Force of the International League Against Epilepsy.

Epilepsy is a heterogeneous condition with disparate etiologies and phenotypic and genotypic characteristics. Clinical and research aspects are accordingly varied, ranging from epidemiological to molecular, spanning clinical trials and outcomes, gene and drug discovery, imaging, electroencephalography, pathology, epilepsy surgery, digital technologies, and numerous others. Epilepsy data are collected in the terabytes and petabytes, pushing the limits of current capabilities. Modern computing firepower and advances in machine and deep learning, pioneered in other diseases, open up exciting possibilities for epilepsy too. However, without carefully designed approaches to acquiring, standardizing, curating, and making available such data, there is a risk of failure. Thus, careful construction of relevant ontologies, with intimate stakeholder inputs, provides the requisite scaffolding for more ambitious big data undertakings, such as an epilepsy data commons. In this review, we assess the clinical and research epilepsy landscapes in the big data arena, current challenges, and future directions, and make the case for a systematic approach to epilepsy big data.

Correlates of quality of life among individuals with epilepsy enrolled in self-management research: From the US Centers for Disease Control and Prevention Managing Epilepsy Well Network.

RATIONALE: Epilepsy is a chronic neurological condition that causes substantial burden on patients and families. Quality of life may be reduced due to the stress of coping with epilepsy. For nearly a decade, the Centers for Disease Control (CDC) Prevention Research Center's Managing Epilepsy Well (MEW) Network has been conducting research on epilepsy self-management to address research and practice gaps. Studies have been conducted by independent centers across the U.S. Recently, the MEW Network sites, collaboratively, began compiling an integrated database to facilitate aggregate secondary analysis of completed and ongoing studies. In this preliminary analysis, correlates of quality of life in people with epilepsy (PWE) were analyzed from pooled baseline data from the MEW Network. METHODS: For this analysis, data originated from 6 epilepsy studies conducted across 4 research sites and comprised 459 PWE. Descriptive comparisons assessed common data elements that included gender, age, ethnicity, race, education, employment, income, seizure frequency, quality of life, and depression. Standardized rating scales were used for quality of life (QOLIE-10) and for depression (Patient Health Questionnaire, PHQ-9). RESULTS: While not all datasets included all common data elements, baseline descriptive analysis found a mean age of 42 (SD 13.22), 289 women (63.0%), 59 African Americans (13.7%), and 58 Hispanics (18.5%). Most, 422 (92.8%), completed at least high school, while 169 (61.7%) were unmarried, divorced/separated, or widowed. Median 30-day seizure frequency was 0.71 (range 0-308). Depression at baseline was common, with a mean PHQ-9 score of 8.32 (SD 6.04); 69 (29.0%) had depression in the mild range (PHQ-9 score 5-9) and 92 (38.7%) had depression in the moderate to severe range (PHQ-9 score >9). Lower baseline quality of life was associated with greater depressive severity (p<.001), more frequent seizures (p<.04) and lower income (p<.05). CONCLUSIONS: The MEW Network Integrated Database offers a unique opportunity for secondary analysis of data from multiple community-based epilepsy research studies. While findings must be tempered by potential sample bias, i.e. a relative under-representation of men and relatively small sample of some racial/ethnic subgroups, results of analyses derived from this first integrated epilepsy self-management database have potential to be useful to the field. Associations between depression severity and lower QOL in PWE are consistent with previous studies derived from clinical samples. Self-management efforts that focus on mental health comorbidity and seizure control may be one way to address modifiable factors that affect quality of life in PWE.

Comparison of common data elements from the Managing Epilepsy Well (MEW) Network integrated database and a well-characterized sample with nonepileptic seizures.

INTRODUCTION: Epilepsy and psychogenic nonepileptic seizures (PNES) are both chronic illnesses characterized by similar and overlapping clinical features. A limited number of studies comparing people with epilepsy (PWE) and patients with PNES that address determinants of health outcomes exist. We conducted an analysis using a well-characterized sample of people with PNES and the Managing Epilepsy Well (MEW) Network integrated data, comparing descriptive data on samples with epilepsy and with documented PNES. Based on the pooled data, we hypothesized that people with PNES would have worse QOL and higher depression severity than PWE. MATERIAL AND METHODS: We used data from the MEW Network integrated database involving select epilepsy self-management studies comprising 182 PWE and 305 individuals with documented PNES from the Rhode Island Hospital Neuropsychiatry and Behavioral Neurology Clinic. We conducted a matched, case-control study assessing descriptive comparisons on 16 common data elements that included gender, age, ethnicity, race, education, employment, income, household composition, relationship status, age at seizure onset, frequency of seizures, seizure type, health status, healthy days, quality of life, and depression. Standardized rating scales for depression and quality of life were used. RESULTS: Median seizure frequency in the last 30days for PWE was 1, compared to 15 for patients with PNES (p<0.05). People with epilepsy had a QOLIE-10 mean score of 3.00 (SD: 0.91) compared to 3.54 (0.88) (p<0.01) for patients with PNES. Depression severity was moderate to severe in 7.7% of PWE compared to 34.1% (p<0.05) of patients with PNES. DISCUSSION: People with epilepsy in selected MEW Network programs are fairly well educated, mostly women, with few minorities and low monthly seizure rates. Those with PNES, however, have higher levels of not working/on disability and had more frequent seizures, higher depression severity, and worse QOL. These differences were present despite demographics that are largely similar in both groups, illustrating that other determinants of illness may influence PNES.

Complex epilepsy phenotype extraction from narrative clinical discharge summaries.

Epilepsy is a common serious neurological disorder with a complex set of possible phenotypes ranging from pathologic abnormalities to variations in electroencephalogram. This paper presents a system called Phenotype Exaction in Epilepsy (PEEP) for extracting complex epilepsy phenotypes and their correlated anatomical locations from clinical discharge summaries, a primary data source for this purpose. PEEP generates candidate phenotype and anatomical location pairs by embedding a named entity recognition method, based on the Epilepsy and Seizure Ontology, into the National Library of Medicine's MetaMap program. Such candidate pairs are further processed using a correlation algorithm. The derived phenotypes and correlated locations have been used for cohort identification with an integrated ontology-driven visual query interface. To evaluate the performance of PEEP, 400 de-identified discharge summaries were used for development and an additional 262 were used as test data. PEEP achieved a micro-averaged precision of 0.924, recall of 0.931, and F1-measure of 0.927 for extracting epilepsy phenotypes. The performance on the extraction of correlated phenotypes and anatomical locations shows a micro-averaged F1-measure of 0.856 (Precision: 0.852, Recall: 0.859). The evaluation demonstrates that PEEP is an effective approach to extracting complex epilepsy phenotypes for cohort identification.

Machine Learning Interpretability Methods to Characterize the Importance of Hematologic Biomarkers in Prognosticating Patients with Suspected Infection.

Early detection of sepsis in patients admitted to the emergency department (ED) is an important clinical objective as early identification and treatment can help reduce morbidity and mortality rate of 20% or higher. Hematologic changes during sepsis-associated organ dysfunction are well established and a new biomarker called Monocyte Distribution Width (MDW) has been recently approved by the US Food and Drug Administration for sepsis. However, MDW, which quantifies monocyte activation in sepsis patients, is not a routinely reported parameter and it requires specialized proprietary laboratory equipment. Further, the relative importance of MDW as compared to other routinely available hematologic parameters and vital signs has not been studied, which makes it difficult for resource constrained hospital systems to make informed decisions in this regard. To address this issue, we analyzed data from a cohort of ED patients (n=10,229) admitted to a large regional safety-net hospital in Cleveland, Ohio with suspected infection who later developed poor outcomes associated with sepsis. We developed a new analytical framework consisting of seven data models and an ensemble of high accuracy machine learning (ML) algorithms (accuracy values ranging from 0.83 to 0.90) for the prediction of outcomes more common in sepsis than uncomplicated infection (3-day intensive care unit stay or death). To characterize the contributions of individual hematologic parameters, we applied the Local Interpretable Model-Agnostic Explanation (LIME) and Shapley Additive Value (SHAP) interpretability methods to the high accuracy ML algorithms. The ML interpretability results were consistent in their findings that the value of MDW is grossly attenuated in the presence of other routinely reported hematologic parameters and vital signs data. Further, this study for the first time shows that complete blood count with differential (CBC-DIFF) together with vital signs data can be used as a substitute for MDW in high accuracy ML algorithms to screen for poor outcomes associated with sepsis.

Large language models for biomedicine: foundations, opportunities, challenges, and best practices.

OBJECTIVES: Generative large language models (LLMs) are a subset of transformers-based neural network architecture models. LLMs have successfully leveraged a combination of an increased number of parameters, improvements in computational efficiency, and large pre-training datasets to perform a wide spectrum of natural language processing (NLP) tasks. Using a few examples (few-shot) or no examples (zero-shot) for prompt-tuning has enabled LLMs to achieve state-of-the-art performance in a broad range of NLP applications. This article by the American Medical Informatics Association (AMIA) NLP Working Group characterizes the opportunities, challenges, and best practices for our community to leverage and advance the integration of LLMs in downstream NLP applications effectively. This can be accomplished through a variety of approaches, including augmented prompting, instruction prompt tuning, and reinforcement learning from human feedback (RLHF). TARGET AUDIENCE: Our focus is on making LLMs accessible to the broader biomedical informatics community, including clinicians and researchers who may be unfamiliar with NLP. Additionally, NLP practitioners may gain insight from the described best practices. SCOPE: We focus on 3 broad categories of NLP tasks, namely natural language understanding, natural language inferencing, and natural language generation. We review the emerging trends in prompt tuning, instruction fine-tuning, and evaluation metrics used for LLMs while drawing attention to several issues that impact biomedical NLP applications, including falsehoods in generated text (confabulation/hallucinations), toxicity, and dataset contamination leading to overfitting. We also review potential approaches to address some of these current challenges in LLMs, such as chain of thought prompting, and the phenomena of emergent capabilities observed in LLMs that can be leveraged to address complex NLP challenge in biomedical applications.

A 360° View for Large Language Models: Early Detection of Amblyopia in Children using Multi-View Eye Movement Recordings.

Amblyopia is a neurodevelopmental visual disorder that affects approximately 3-5% of children globally and it can lead to vision loss if it is not diagnosed and treated early. Traditional diagnostic methods, which rely on subjective assessments and expert interpretation of eye movement recordings presents challenges in resource-limited eye care centers. This study introduces a new approach that integrates the Gemini large language model (LLM) with eye-tracking data to develop a classification tool for diagnosis of patients with amblyopia. The study demonstrates: (1) LLMs can be successfully applied to the analysis of fixation eye movement data to diagnose patients with amblyopia; and (2) Input of medical subject matter expertise, introduced in this study in the form of medical expert augmented generation (MEAG), is an effective adaption of the generic retrieval augmented generation (RAG) approach for medical applications using LLMs. This study introduces a new multi-view prompting framework for ophthalmology applications that incorporates fine granularity feedback from pediatric ophthalmologist together with in-context learning to report an accuracy of 80% in diagnosing patients with amblyopia. In addition to the binary classification task, the classification tool is generalizable to specific subpopulations of amblyopic patients based on severity of amblyopia, type of amblyopia, and with or without nystagmus. The model reports an accuracy of: (1) 83% in classifying patients with moderate or severe amblyopia, (2) 81% in classifying patients with mild or treated amblyopia; and (3) 85% accuracy in classifying patients with nystagmus. To the best of our knowledge, this is the first study that defines a multi-view prompting framework with MEAG to analyze eye tracking data for the diagnosis of amblyopic patients.

MaTiLDA: An Integrated Machine Learning and Topological Data Analysis Platform for Brain Network Dynamics.

Topological data analysis (TDA) combined with machine learning (ML) algorithms is a powerful approach for investigating complex brain interaction patterns in neurological disorders such as epilepsy. However, the use of ML algorithms and TDA for analysis of aberrant brain interactions requires substantial domain knowledge in computing as well as pure mathematics. To lower the threshold for clinical and computational neuroscience researchers to effectively use ML algorithms together with TDA to study neurological disorders, we introduce an integrated web platform called MaTiLDA. MaTiLDA is the first tool that enables users to intuitively use TDA methods together with ML models to characterize interaction patterns derived from neurophysiological signal data such as electroencephalogram (EEG) recorded during routine clinical practice. MaTiLDA features support for TDA methods, such as persistent homology, that enable classification of signal data using ML models to provide insights into complex brain interaction patterns in neurological disorders. We demonstrate the practical use of MaTiLDA by analyzing high-resolution intracranial EEG from refractory epilepsy patients to characterize the distinct phases of seizure propagation to different brain regions. The MaTiLDA platform is available at: https://bmhinformatics.case.edu/nicworkflow/MaTiLDA.

Epilepsy informatics and an ontology-driven infrastructure for large database research and patient care in epilepsy.

The epilepsy community increasingly recognizes the need for a modern classification system that can also be easily integrated with effective informatics tools. The 2010 reports by the United States President's Council of Advisors on Science and Technology (PCAST) identified informatics as a critical resource to improve quality of patient care, drive clinical research, and reduce the cost of health services. An effective informatics infrastructure for epilepsy, which is underpinned by a formal knowledge model or ontology, can leverage an ever increasing amount of multimodal data to improve (1) clinical decision support, (2) access to information for patients and their families, (3) easier data sharing, and (4) accelerate secondary use of clinical data. Modeling the recommendations of the International League Against Epilepsy (ILAE) classification system in the form of an epilepsy domain ontology is essential for consistent use of terminology in a variety of applications, including electronic health records systems and clinical applications. In this review, we discuss the data management issues in epilepsy and explore the benefits of an ontology-driven informatics infrastructure and its role in adoption of a "data-driven" paradigm in epilepsy research.

Machine Learning Interpretability Methods to Characterize Brain Network Dynamics in Epilepsy.

The rapid adoption of machine learning (ML) algorithms in a wide range of biomedical applications has highlighted issues of trust and the lack of understanding regarding the results generated by ML algorithms. Recent studies have focused on developing interpretable ML models and establish guidelines for transparency and ethical use, ensuring the responsible integration of machine learning in healthcare. In this study, we demonstrate the effectiveness of ML interpretability methods to provide important insights into the dynamics of brain network interactions in epilepsy, a serious neurological disorder affecting more than 60 million persons worldwide. Using high-resolution intracranial electroencephalogram (EEG) recordings from a cohort of 16 patients, we developed high accuracy ML models to categorize these brain activity recordings into either seizure or non-seizure classes followed by a more complex task of delineating the different stages of seizure progression to different parts of the brain as a multi-class classification task. We applied three distinct types of interpretability methods to the high-accuracy ML models to gain an understanding of the relative contributions of different categories of brain interaction patterns, including multi-focii interactions, which play an important role in distinguishing between different states of the brain. The results of this study demonstrate for the first time that post-hoc interpretability methods enable us to understand why ML algorithms generate a given set of results and how variations in value of input values affect the accuracy of the ML algorithms. In particular, we show in this study that interpretability methods can be used to identify brain regions and interaction patterns that have a significant impact on seizure events. The results of this study highlight the importance of the integrated implementation of ML algorithms together with interpretability methods in aberrant brain network studies and the wider domain of biomedical research.

NeuroBridge ontology: computable provenance metadata to give the long tail of neuroimaging data a FAIR chance for secondary use.

Background: Despite the efforts of the neuroscience community, there are many published neuroimaging studies with data that are still not findable or accessible. Users face significant challenges in reusing neuroimaging data due to the lack of provenance metadata, such as experimental protocols, study instruments, and details about the study participants, which is also required for interoperability. To implement the FAIR guidelines for neuroimaging data, we have developed an iterative ontology engineering process and used it to create the NeuroBridge ontology. The NeuroBridge ontology is a computable model of provenance terms to implement FAIR principles and together with an international effort to annotate full text articles with ontology terms, the ontology enables users to locate relevant neuroimaging datasets. Methods: Building on our previous work in metadata modeling, and in concert with an initial annotation of a representative corpus, we modeled diagnosis terms (e.g., schizophrenia, alcohol usage disorder), magnetic resonance imaging (MRI) scan types (T1-weighted, task-based, etc.), clinical symptom assessments (PANSS, AUDIT), and a variety of other assessments. We used the feedback of the annotation team to identify missing metadata terms, which were added to the NeuroBridge ontology, and we restructured the ontology to support both the final annotation of the corpus of neuroimaging articles by a second, independent set of annotators, as well as the functionalities of the NeuroBridge search portal for neuroimaging datasets. Results: The NeuroBridge ontology consists of 660 classes with 49 properties with 3,200 axioms. The ontology includes mappings to existing ontologies, enabling the NeuroBridge ontology to be interoperable with other domain specific terminological systems. Using the ontology, we annotated 186 neuroimaging full-text articles describing the participant types, scanning, clinical and cognitive assessments. Conclusion: The NeuroBridge ontology is the first computable metadata model that represents the types of data available in recent neuroimaging studies in schizophrenia and substance use disorders research; it can be extended to include more granular terms as needed. This metadata ontology is expected to form the computational foundation to help both investigators to make their data FAIR compliant and support users to conduct reproducible neuroimaging research.

NeuroBridge: a prototype platform for discovery of the long-tail neuroimaging data.

Introduction: Open science initiatives have enabled sharing of large amounts of already collected data. However, significant gaps remain regarding how to find appropriate data, including underutilized data that exist in the long tail of science. We demonstrate the NeuroBridge prototype and its ability to search PubMed Central full-text papers for information relevant to neuroimaging data collected from schizophrenia and addiction studies. Methods: The NeuroBridge architecture contained the following components: (1) Extensible ontology for modeling study metadata: subject population, imaging techniques, and relevant behavioral, cognitive, or clinical data. Details are described in the companion paper in this special issue; (2) A natural-language based document processor that leveraged pre-trained deep-learning models on a small-sample document corpus to establish efficient representations for each article as a collection of machine-recognized ontological terms; (3) Integrated search using ontology-driven similarity to query PubMed Central and NeuroQuery, which provides fMRI activation maps along with PubMed source articles. Results: The NeuroBridge prototype contains a corpus of 356 papers from 2018 to 2021 describing schizophrenia and addiction neuroimaging studies, of which 186 were annotated with the NeuroBridge ontology. The search portal on the NeuroBridge website https://neurobridges.org/ provides an interactive Query Builder, where the user builds queries by selecting NeuroBridge ontology terms to preserve the ontology tree structure. For each return entry, links to the PubMed abstract as well as to the PMC full-text article, if available, are presented. For each of the returned articles, we provide a list of clinical assessments described in the Section "Methods" of the article. Articles returned from NeuroQuery based on the same search are also presented. Conclusion: The NeuroBridge prototype combines ontology-based search with natural-language text-mining approaches to demonstrate that papers relevant to a user's research question can be identified. The NeuroBridge prototype takes a first step toward identifying potential neuroimaging data described in full-text papers. Toward the overall goal of discovering "enough data of the right kind," ongoing work includes validating the document processor with a larger corpus, extending the ontology to include detailed imaging data, and extracting information regarding data availability from the returned publications and incorporating XNAT-based neuroimaging databases to enhance data accessibility.

From classification to epilepsy ontology and informatics.

The 2010 International League Against Epilepsy (ILAE) classification and terminology commission report proposed a much needed departure from previous classifications to incorporate advances in molecular biology, neuroimaging, and genetics. It proposed an interim classification and defined two key requirements that need to be satisfied. The first is the ability to classify epilepsy in dimensions according to a variety of purposes including clinical research, patient care, and drug discovery. The second is the ability of the classification system to evolve with new discoveries. Multidimensionality and flexibility are crucial to the success of any future classification. In addition, a successful classification system must play a central role in the rapidly growing field of epilepsy informatics. An epilepsy ontology, based on classification, will allow information systems to facilitate data-intensive studies and provide a proven route to meeting the two foregoing key requirements. Epilepsy ontology will be a structured terminology system that accommodates proposed and evolving ILAE classifications, the National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) Common Data Elements, the International Classification of Diseases (ICD) systems and explicitly specifies all known relationships between epilepsy concepts in a proper framework. This will aid evidence-based epilepsy diagnosis, investigation, treatment and research for a diverse community of clinicians and researchers. Benefits range from systematization of electronic patient records to multimodal data repositories for research and training manuals for those involved in epilepsy care. Given the complexity, heterogeneity, and pace of research advances in the epilepsy domain, such an ontology must be collaboratively developed by key stakeholders in the epilepsy community and experts in knowledge engineering and computer science.

Social Service Workers' Use of Social Media to Obtain Client Information: Current Practices and Perspectives on a Potential Informatics Platform.

To gain insight into current use of social-media platforms in human services delivery, we systematically surveyed 172 social-service workers from six agencies in a Midwest US city to gather data about social-media usage among social-service providers, potential challenges and benefits of using social media, and whether a social-media-based informatics platform could be valuable. Quantitative analyses showed that approximately half of participants have used social media to collect client-related information; nearly one-quarter indicated "often" or "nearly daily" use. Adjusting for the effects of worker characteristics, social-media use was associated with the type of agency involved and with increased tenure in social services. Adjusted results also showed that participants' comfort with using the potential application was greater in those agencies substantially involved with investigative/legal work. However, trust in the information collected by the potential application was a stronger, independent predictor of comfort using the tool. Qualitative analyses identified numerous challenges and ethical concerns, and positive and negative aspects of a social-media-based informatics platform. If the platform is to be created, work must be done carefully, fully considering ethical issues rightly raised by social service workers, existing agency policies, and professional standards. Future research should investigate ways to negotiate these complex challenges.

Ontology-based feature engineering in machine learning workflows for heterogeneous epilepsy patient records.

Biomedical ontologies are widely used to harmonize heterogeneous data and integrate large volumes of clinical data from multiple sources. This study analyzed the utility of ontologies beyond their traditional roles, that is, in addressing a challenging and currently underserved field of feature engineering in machine learning workflows. Machine learning workflows are being increasingly used to analyze medical records with heterogeneous phenotypic, genotypic, and related medical terms to improve patient care. We performed a retrospective study using neuropathology reports from the German Neuropathology Reference Center for Epilepsy Surgery at Erlangen, Germany. This cohort included 312 patients who underwent epilepsy surgery and were labeled with one or more diagnoses, including dual pathology, hippocampal sclerosis, malformation of cortical dysplasia, tumor, encephalitis, and gliosis. We modeled the diagnosis terms together with their microscopy, immunohistochemistry, anatomy, etiologies, and imaging findings using the description logic-based Web Ontology Language (OWL) in the Epilepsy and Seizure Ontology (EpSO). Three tree-based machine learning models were used to classify the neuropathology reports into one or more diagnosis classes with and without ontology-based feature engineering. We used five-fold cross validation to avoid overfitting with a fixed number of repetitions while leaving out one subset of data for testing, and we used recall, balanced accuracy, and hamming loss as performance metrics for the multi-label classification task. The epilepsy ontology-based feature engineering approach improved the performance of all the three learning models with an improvement of 35.7%, 54.5%, and 33.3% in logistics regression, random forest, and gradient tree boosting models respectively. The run time performance of all three models improved significantly with ontology-based feature engineering with gradient tree boosting model showing a 93.8% reduction in the time required for training and testing of the model. Although, all three models showed an overall improved performance across the three-performance metrics using ontology-based feature engineering, the rate of improvement was not consistent across all input features. To analyze this variation in performance, we computed feature importance scores and found that microscopy had the highest importance score across the three models, followed by imaging, immunohistochemistry, and anatomy in a decreasing order of importance scores. This study showed that ontologies have an important role in feature engineering to make heterogeneous clinical data accessible to machine learning models and also improve the performance of machine learning models in multilabel multiclass classification tasks.

Enabling Scientific Reproducibility through FAIR Data Management: An ontology-driven deep learning approach in the NeuroBridge Project.

Scientific reproducibility that effectively leverages existing study data is critical to the advancement of research in many disciplines including neuroscience, which uses imaging and electrophysiology modalities as primary endpoints or key dependency in studies. We are developing an integrated search platform called NeuroBridge to enable researchers to search for relevant study datasets that can be used to test a hypothesis or replicate a published finding without having to perform a difficult search from scratch, including contacting individual study authors and locating the site to download the data. In this paper, we describe the development of a metadata ontology based on the World Wide Web Consortium (W3C) PROV specifications to create a corpus of semantically annotated published papers. This annotated corpus was used in a deep learning model to support automated identification of candidate datasets related to neurocognitive assessment of subjects with drug abuse or schizophrenia using neuroimaging. We built on our previous work in the Provenance for Clinical and Health Research (ProvCaRe) project to model metadata information in the NeuroBridge ontology and used this ontology to annotate 51 articles using a Web-based tool called Inception. The Bidirectional Encoder Representations from Transformers (BERT) neural network model, which was trained using the annotated corpus, is used to classify and rank papers relevant to five research hypotheses and the results were evaluated independently by three users for accuracy and recall. Our combined use of the NeuroBridge ontology together with the deep learning model outperforms the existing PubMed Central (PMC) search engine and manifests considerable trainability and transparency compared with typical free-text search. An initial version of the NeuroBridge portal is available at: https://neurobridges.org/.

A unified framework for managing provenance information in translational research.

BACKGROUND: A critical aspect of the NIH Translational Research roadmap, which seeks to accelerate the delivery of "bench-side" discoveries to patient's "bedside," is the management of the provenance metadata that keeps track of the origin and history of data resources as they traverse the path from the bench to the bedside and back. A comprehensive provenance framework is essential for researchers to verify the quality of data, reproduce scientific results published in peer-reviewed literature, validate scientific process, and associate trust value with data and results. Traditional approaches to provenance management have focused on only partial sections of the translational research life cycle and they do not incorporate "domain semantics", which is essential to support domain-specific querying and analysis by scientists. RESULTS: We identify a common set of challenges in managing provenance information across the pre-publication and post-publication phases of data in the translational research lifecycle. We define the semantic provenance framework (SPF), underpinned by the Provenir upper-level provenance ontology, to address these challenges in the four stages of provenance metadata:(a) Provenance collection - during data generation(b) Provenance representation - to support interoperability, reasoning, and incorporate domain semantics(c) Provenance storage and propagation - to allow efficient storage and seamless propagation of provenance as the data is transferred across applications(d) Provenance query - to support queries with increasing complexity over large data size and also support knowledge discovery applicationsWe apply the SPF to two exemplar translational research projects, namely the Semantic Problem Solving Environment for Trypanosoma cruzi (T.cruzi SPSE) and the Biomedical Knowledge Repository (BKR) project, to demonstrate its effectiveness. CONCLUSIONS: The SPF provides a unified framework to effectively manage provenance of translational research data during pre and post-publication phases. This framework is underpinned by an upper-level provenance ontology called Provenir that is extended to create domain-specific provenance ontologies to facilitate provenance interoperability, seamless propagation of provenance, automated querying, and analysis.

Characterizing Brain Network Dynamics using Persistent Homology in Patients with Refractory Epilepsy.

Epilepsy is a common serious neurological disorder that affects more than 65 million persons worldwide and it is characterized by repeated seizures that lead to higher mortality and disabilities with corresponding negative impact on the quality of life of patients. Network science methods that represent brain regions as nodes and the interactions between brain regions as edges have been extensively used in characterizing network changes in neurological disorders. However, the limited ability of graph network models to represent high dimensional brain interactions are being increasingly realized in the computational neuroscience community. In particular, recent advances in algebraic topology research have led to the development of a large number of applications in brain network studies using topological structures. In this paper, we build on a fundamental construct of cliques, which are all-to-all connected nodes with a k-clique in a graph G (V, E), where V is set of nodes and E is set of edges, consisting of k-nodes to characterize the brain network dynamics in epilepsy patients using topological structures. Cliques represent brain regions that are coupled for similar functions or engage in information exchange; therefore, cliques are suitable structures to characterize the dynamics of brain dynamics in neurological disorders. We propose to detect and use clique structures during well-defined clinical events, such as epileptic seizures, to combine non-linear correlation measures in a matrix with identification of geometric structures underlying brain connectivity networks to identify discriminating features that can be used for clinical decision making in epilepsy neurological disorder.

Epilepsy-Connect: An Integrated Knowledgebase for Characterizing Alterations in Consciousness State of Pharmacoresistant Epilepsy Patients.

Alterations in consciousness state are a defining characteristic of focal epileptic seizures. Consequently, understanding the complex changes in neurocognitive networks which underpin seizure-induced alterations in consciousness state is important for advancement in seizure classification. Comprehension of these changes are complicated by a lack of data standardization; however, the use of a common terminological system or ontology in a patient registry minimizes this issue. In this paper, we introduce an integrated knowledgebase called Epilepsy-Connect to improve the understanding of changes in consciousness states during focal seizures of pharmacoresistant epilepsy patients. This registry catalogues over 809 seizures from 70 patients at University Hospital's Epilepsy Center who were undergoing stereotactic electroencephalography (SEEG) monitoring as part of an evaluation for surgical intervention. Although Epilepsy-Connect focuses on consciousness states, it aims to enable users to leverage data from an informatics platform to analyze epilepsy data in a streamlined manner. Epilepsy-Connect is available at https://bmhinformatics.case.edu/Epilepsyconnect/login/.

NeuroIntegrative Connectivity (NIC) Informatics Tool for Brain Functional Connectivity Network Analysis in Cohort Studies.

Objective: Brain functional connectivity measures are often used to study interactions between brain regions in various neurological disorders such as epilepsy. In particular, functional connectivity measures derived from high resolution electrophysiological signal data have been used to characterize epileptic networks in epilepsy patients. However, existing signal data formats as well as computational methods are not suitable for complex multi-step methods used for processing and analyzing signal data across multiple seizure events. To address the significant data management challenges associated with signal data, we have developed a new workflow-based tool called NeuroIntegrative Connectivity (NIC) using the Cloudwave Signal Format (CSF) as a common data abstraction model. Method: The NIC compositional workflow-based tool consists of: (1) Signal data processing component for automated pre- processing and generation of CSF files with semantic annotation using epilepsy domain ontology; and (2) Functional network computation component for deriving functional connectivity metrics from signal data analysis across multiple recording channels. The NIC tool streamlines signal data management using a modular software implementation architecture that supports easy extension with new libraries of signal coupling measures and fast data retrieval using a binary search tree indexing structure called NIC-Index. Result and Conclusion: We evaluated the NIC tool by processing and analyzing signal data for 28 seizure events in two patients with refractory epilepsy. The result shows that certain brain regions have high local measure of connectivity, such as total degree, as compared to other regions during ictal events in both patients. In addition, global connectivity measures, which characterize transitivity and efficiency, increase in value during the initial period of the seizure followed by decrease towards the end of seizure. The NIC tool allows users to efficiently apply several network analysis metrics to study global and local changes in epileptic networks in patient cohort studies.