Arden Syntax on FHIR.

Arden Syntax, a medical knowledge representation and processing language for clinical decision support tasks supervised by Health Level Seven International (HL7), was extended with HL7's Fast Healthcare Interoperability Resources (FHIR) constructs to allow standardized data access. The new version, Arden Syntax version 3.0, was successfully balloted as part of the audited, consensus-based, iterative HL7 standards development process.

Computer clinical decision support that automates personalized clinical care: a challenging but needed healthcare delivery strategy.

How to deliver best care in various clinical settings remains a vexing problem. All pertinent healthcare-related questions have not, cannot, and will not be addressable with costly time- and resource-consuming controlled clinical trials. At present, evidence-based guidelines can address only a small fraction of the types of care that clinicians deliver. Furthermore, underserved areas rarely can access state-of-the-art evidence-based guidelines in real-time, and often lack the wherewithal to implement advanced guidelines. Care providers in such settings frequently do not have sufficient training to undertake advanced guideline implementation. Nevertheless, in advanced modern healthcare delivery environments, use of eActions (validated clinical decision support systems) could help overcome the cognitive limitations of overburdened clinicians. Widespread use of eActions will require surmounting current healthcare technical and cultural barriers and installing clinical evidence/data curation systems. The authors expect that increased numbers of evidence-based guidelines will result from future comparative effectiveness clinical research carried out during routine healthcare delivery within learning healthcare systems.

Categorizing metadata to help mobilize computable biomedical knowledge.

INTRODUCTION: Computable biomedical knowledge artifacts (CBKs) are digital objects conveying biomedical knowledge in machine-interpretable structures. As more CBKs are produced and their complexity increases, the value obtained from sharing CBKs grows. Mobilizing CBKs and sharing them widely can only be achieved if the CBKs are findable, accessible, interoperable, reusable, and trustable (FAIR+T). To help mobilize CBKs, we describe our efforts to outline metadata categories to make CBKs FAIR+T. METHODS: We examined the literature regarding metadata with the potential to make digital artifacts FAIR+T. We also examined metadata available online today for actual CBKs of 12 different types. With iterative refinement, we came to a consensus on key categories of metadata that, when taken together, can make CBKs FAIR+T. We use subject-predicate-object triples to more clearly differentiate metadata categories. RESULTS: We defined 13 categories of CBK metadata most relevant to making CBKs FAIR+T. Eleven of these categories (type, domain, purpose, identification, location, CBK-to-CBK relationships, technical, authorization and rights management, provenance, evidential basis, and evidence from use metadata) are evident today where CBKs are stored online. Two additional categories (preservation and integrity metadata) were not evident in our examples. We provide a research agenda to guide further study and development of these and other metadata categories. CONCLUSION: A wide variety of metadata elements in various categories is needed to make CBKs FAIR+T. More work is needed to develop a common framework for CBK metadata that can make CBKs FAIR+T for all stakeholders.

CheXED: Comparison of a Deep Learning Model to a Clinical Decision Support System for Pneumonia in the Emergency Department.

PURPOSE: Patients with pneumonia often present to the emergency department (ED) and require prompt diagnosis and treatment. Clinical decision support systems for the diagnosis and management of pneumonia are commonly utilized in EDs to improve patient care. The purpose of this study is to investigate whether a deep learning model for detecting radiographic pneumonia and pleural effusions can improve functionality of a clinical decision support system (CDSS) for pneumonia management (ePNa) operating in 20 EDs. MATERIALS AND METHODS: In this retrospective cohort study, a dataset of 7434 prior chest radiographic studies from 6551 ED patients was used to develop and validate a deep learning model to identify radiographic pneumonia, pleural effusions, and evidence of multilobar pneumonia. Model performance was evaluated against 3 radiologists' adjudicated interpretation and compared with performance of the natural language processing of radiology reports used by ePNa. RESULTS: The deep learning model achieved an area under the receiver operating characteristic curve of 0.833 (95% confidence interval [CI]: 0.795, 0.868) for detecting radiographic pneumonia, 0.939 (95% CI: 0.911, 0.962) for detecting pleural effusions and 0.847 (95% CI: 0.800, 0.890) for identifying multilobar pneumonia. On all 3 tasks, the model achieved higher agreement with the adjudicated radiologist interpretation compared with ePNa. CONCLUSIONS: A deep learning model demonstrated higher agreement with radiologists than the ePNa CDSS in detecting radiographic pneumonia and related findings. Incorporating deep learning models into pneumonia CDSS could enhance diagnostic performance and improve pneumonia management.

Optimization of sepsis therapy based on patient-specific digital precision diagnostics using next generation sequencing (DigiSep-Trial)-study protocol for a randomized, controlled, interventional, open-label, multicenter trial.

BACKGROUND: Sepsis is triggered by an infection and represents one of the greatest challenges of modern intensive care medicine. With regard to a targeted antimicrobial treatment strategy, the earliest possible pathogen detection is of crucial importance. Until now, culture-based detection methods represent the diagnostic gold standard, although they are characterized by numerous limitations. Culture-independent molecular diagnostic procedures represent a promising alternative. In particular, the plasmatic detection of circulating, cell-free DNA by next-generation sequencing (NGS) has shown to be suitable for identifying disease-causing pathogens in patients with bloodstream infections. METHODS: The DigiSep-Trial is a randomized, controlled, interventional, open-label, multicenter trial characterizing the effect of the combination of NGS-based digital precision diagnostics with standard-of-care microbiological analyses compared to solely standard-of-care microbiological analyses in the clinical picture of sepsis/septic shock. Additional anti-infective expert consultations are provided for both study groups. In 410 patients (n = 205 per arm) with sepsis/septic shock, the study examines whether the so-called DOOR-RADAR (Desirability of Outcome Ranking/Response Adjusted for Duration of Antibiotic Risk) score (representing a combined endpoint including the criteria (1) intensive/intermediate care unit length of stay, (2) consumption of antibiotics, (3) mortality, and (4) acute kidney injury (AKI)) can be improved by an additional NGS-based diagnostic concept. We also aim to investigate the cost-effectiveness of this new diagnostic procedure. It is postulated that intensive/intermediate care unit length of stay, mortality rate, incidence of AKI, the duration of antimicrobial therapy as well as the costs caused by complications and outpatient aftercare can be reduced. Moreover, a significant improvement in patient's quality of life is expected. DISCUSSION: The authors´ previous work suggests that NGS-based diagnostics have a higher specificity and sensitivity compared to standard-of-care microbiological analyses for detecting bloodstream infections. In combination with the here presented DigiSep-Trial, this work provides the optimal basis to establish a new NGS-driven concept as part of the national standard based on the best possible evidence. TRIAL REGISTRATIONS: DRKS-ID DRKS00022782 . Registered on August 25, 2020 ClinicalTrials.gov NCT04571801 . Registered October 1, 2020.

Electronic pulmonary embolism clinical decision support and effect on yield of computerized tomographic pulmonary angiography: ePE-A pragmatic prospective cohort study.

OBJECTIVE: Multiple professional societies recommend pre-test probability (PTP) assessment prior to imaging in the evaluation of patients with suspected pulmonary embolism (PE), however, PTP testing remains uncommon, with imaging occurring frequently and rates of confirmed PE remaining low. The goal of this study was to assess the impact of a clinical decision support tool embedded into the electronic health record to improve the diagnostic yield of computerized tomography pulmonary angiography (CTPA) in suspected patients with PE in the emergency department (ED). METHODS: Between July 24, 2014 and December 31, 2016, 4 hospitals from a healthcare system embedded an optional electronic clinical decision support system to assist in the diagnosis of pulmonary embolism (ePE). This system employs the Pulmonary Embolism Rule-out Criteria (PERC) and revised Geneva Score (RGS) in series prior to CT imaging. We compared the diagnostic yield of CTPA) among patients for whom the physician opted to use ePE versus the diagnostic yield of CTPA when ePE was not used. RESULTS: During the 2.5-year study period, 37,288 adult patients were eligible and included for study evaluation. Of eligible patients, 1949 of 37,288 (5.2%) were enrolled by activation of the tool. A total of 16,526 CTPAs were performed system-wide. When ePE was not engaged, CTPA was positive for PE in 1556 of 15,546 scans for a positive yield of 10.0%. When ePE was used, CTPA identified PE in 211 of 980 scans (21.5% yield) (P < 0.001). CONCLUSIONS: ePE significantly increased the diagnostic yield of CTPA without missing 30-day clinically overt PE.

Contemporary clinical decision support standards using Health Level Seven International Fast Healthcare Interoperability Resources.

OBJECTIVE: To facilitate the development of standards-based clinical decision support (CDS) systems, we review the current set of CDS standards that are based on Health Level Seven International Fast Healthcare Interoperability Resources (FHIR). Widespread adoption of these standards may help reduce healthcare variability, improve healthcare quality, and improve patient safety. TARGET AUDIENCE: This tutorial is designed for the broad informatics community, some of whom may be unfamiliar with the current, FHIR-based CDS standards. SCOPE: This tutorial covers the following standards: Arden Syntax (using FHIR as the data model), Clinical Quality Language, FHIR Clinical Reasoning, SMART on FHIR, and CDS Hooks. Detailed descriptions and selected examples are provided.

Enabling a learning healthcare system with automated computer protocols that produce replicable and personalized clinician actions.

Clinical decision-making is based on knowledge, expertise, and authority, with clinicians approving almost every intervention-the starting point for delivery of "All the right care, but only the right care," an unachieved healthcare quality improvement goal. Unaided clinicians suffer from human cognitive limitations and biases when decisions are based only on their training, expertise, and experience. Electronic health records (EHRs) could improve healthcare with robust decision-support tools that reduce unwarranted variation of clinician decisions and actions. Current EHRs, focused on results review, documentation, and accounting, are awkward, time-consuming, and contribute to clinician stress and burnout. Decision-support tools could reduce clinician burden and enable replicable clinician decisions and actions that personalize patient care. Most current clinical decision-support tools or aids lack detail and neither reduce burden nor enable replicable actions. Clinicians must provide subjective interpretation and missing logic, thus introducing personal biases and mindless, unwarranted, variation from evidence-based practice. Replicability occurs when different clinicians, with the same patient information and context, come to the same decision and action. We propose a feasible subset of therapeutic decision-support tools based on credible clinical outcome evidence: computer protocols leading to replicable clinician actions (eActions). eActions enable different clinicians to make consistent decisions and actions when faced with the same patient input data. eActions embrace good everyday decision-making informed by evidence, experience, EHR data, and individual patient status. eActions can reduce unwarranted variation, increase quality of clinical care and research, reduce EHR noise, and could enable a learning healthcare system.

The design and evaluation of a Bayesian system for detecting and characterizing outbreaks of influenza.

The prediction and characterization of outbreaks of infectious diseases such as influenza remains an open and important problem. This paper describes a framework for detecting and characterizing outbreaks of influenza and the results of testing it on data from ten outbreaks collected from two locations over five years. We model outbreaks with compartment models and explicitly model non-influenza influenza-like illnesses.

CDS in a Learning Health Care System: Identifying Physicians' Reasons for Rejection of Best-Practice Recommendations in Pneumonia through Computerized Clinical Decision Support.

BACKGROUND: Local implementation of guidelines for pneumonia care is strongly recommended, but the context of care that affects implementation is poorly understood. In a learning health care system, computerized clinical decision support (CDS) provides an opportunity to both improve and track practice, providing insights into the implementation process. OBJECTIVES: This article examines physician interactions with a CDS to identify reasons for rejection of guideline recommendations. METHODS: We implemented a multicenter bedside CDS for the emergency department management of pneumonia that integrated patient data with guideline-based recommendations. We examined the frequency of adoption versus rejection of recommendations for site-of-care and antibiotic selection. We analyzed free-text responses provided by physicians explaining their clinical reasoning for rejection, using concept mapping and thematic analysis. RESULTS: Among 1,722 patient episodes, physicians rejected recommendations to send a patient home in 24%, leaving text in 53%; reasons for rejection of the recommendations included additional or alternative diagnoses beyond pneumonia, and comorbidities or signs of physiologic derangement contributing to risk of outpatient failure that were not processed by the CDS. Physicians rejected broad-spectrum antibiotic recommendations in 10%, leaving text in 76%; differences in pathogen risk assessment, additional patient information, concern about antibiotic properties, and admitting physician preferences were given as reasons for rejection. CONCLUSION: While adoption of CDS recommendations for pneumonia was high, physicians rejecting recommendations frequently provided feedback, reporting alternative diagnoses, additional individual patient characteristics, and provider preferences as major reasons for rejection. CDS that collects user feedback is feasible and can contribute to a learning health system.

Implementation of Real-Time Electronic Clinical Decision Support for Emergency Department Patients with Pneumonia Across a Healthcare System.

A real-time electronic CDS for pneumonia (ePNa) identifies possible pneumonia patients, measures severity and antimicrobial resistance risk, and then recommends disposition, antibiotics, and microbiology studies. Use is voluntary, and clinicians may modify treatment recommendations. ePNa was associated with lower mortality in emergency department (ED) patients versus usual care (Annals EM 66:511). We adapted ePNa for the Cerner EHR, and implemented it across Intermountain Healthcare EDs (Utah, USA) throughout 2018. We introduced ePNa through didactic, interactive presentations to ED clinicians; follow-up visits identified barriers and facilitators to use. Email reminded clinicians and answered questions. Hospital admitting clinicians encouraged ePNa use to smooth care transitions. Audit-and-feedback measured utilization, showing variations from best practice when ePNa and associated electronic order sets were not used. Use was initially low, but gradually increased especially at larger hospitals. A user-friendly interface, frequent reminders, audit-and- feedback, a user survey, a nurse educator, and local physician champions are additive towards implementation success.

Discovery of N-arylpyrroles as agonists of GPR120 for the treatment of type II diabetes.

The discovery of a novel series of N-arylpyrroles as agonists of GPR120 (FFAR4) is discussed. One lead compound is a potent GPR120 agonist, has good selectivity for related receptor GPR40 (FFAR1), has acceptable PK properties, and is active in 2 models of Type 2 Diabetes in mice.

Evolution of the Arden Syntax: Key Technical Issues from the Standards Development Organization Perspective.

BACKGROUND: The initial version of the Arden Syntax for Medical Logic Systems was created to facilitate explicit representation of medical logic in a form that could be easily composed and interpreted by clinical experts in order to facilitate clinical decision support (CDS). Because of demand from knowledge engineers and programmers to improve functionality related to complex use cases, the Arden Syntax evolved to include features typical of general programming languages but that were specialized to meet the needs of the clinical decision support environment, including integration into a clinical information system architecture. METHOD: Review of the design history and evolution of the Arden Syntax by workers who participated in this evolution from the perspective of the standards development organization (SDO). RESULTS: In order to meet user needs, a variety of features were successively incorporated in Arden Syntax. These can be grouped in several classes of change, including control flow, data structures, operators and external links. These changes included expansion of operators to manipulate lists and strings; a formalism for structured output; iteration constructs; user-defined objects and operators to manipulate them; features to support international use and output in different natural languages; additional control features; fuzzy logic formalisms; and mapping of the entire syntax to XML. The history and rationale of this evolution are summarized. CONCLUSION: In response to user demand and to reflect its growing role in clinical decision support, the Arden Syntax has evolved to include a number of powerful features. These depart somewhat from the original vision of the syntax as simple and easily understandable but from the SDO perspective increase the utility of this standard for implementation of CDS. Backwards compatibility has been maintained, allowing continued support of the earlier, simpler decision support models.

Promoting national and international standards to build interoperable clinical applications.

During the last decade, software supporting healthcare delivery has proliferated. This software can be divided into electronic medical record (EHR) systems and applications that treat EHRs as platforms. These collect, manage, and interpret medical data, thereby adding value to associated EHRs. To reduce the burden of developing for multiple EHR platforms, a group of standards has evolved that allow software written for one vendor's EHR to be introduced into settings supported by other vendors. The Health Services Platform Consortium (HSPC) is a collaborative effort to advocate for standards that will make healthcare applications truly interoperable. In this document, we discuss the approach adopted by the consortium and the standards central to this approach. We discriminate between interoperability standards that support the plug-and-play transfer of applications from one vendor's EHR to another and knowledge portability standards that allow knowledge artifacts used in one software environment to be introduced effectively in others.

Enhancing a Commercial EMR with an Open, Standards-Based Publish-Subscribe Infrastructure.

Intermountain Healthcare has designed and implemented a publish-subscribe (PubSub) infrastructure to support essential event processing workflows across our organization. A recent implementation of a commercial EMR highlighted the need to provide this capability on top of the EMR to support external applications and services that require access to triggering events within the EMR. A description of the PubSub architecture is presented. Use cases for health information exchange, public health reporting, and pulmonary embolism diagnosis that utilize PubSub are described, along with benefits of using the paradigm. Besides providing support for these external applications, the PubSub infrastructure allows additional event handling functionality not available in the commercial EMR. The open, standards-based nature of the design should allow other organizations to implement the system in their information systems environment.

Discovery of an Isothiazole-Based Phenylpropanoic Acid GPR120 Agonist as a Development Candidate for Type 2 Diabetes.

We have discovered a novel series of isothiazole-based phenylpropanoic acids as GPR120 agonists. Extensive structure-activity relationship studies led to the discovery of a potent GPR120 agonist 4x, which displayed good EC50 values in both calcium and ß-arrestin assays. It also presented good pharmaceutical properties and a favorable PK profile. Moreover, it demonstrated in vivo antidiabetic activity in C57BL/6 DIO mice. Studies in WT and knockout DIO mice showed that it improved glucose handling during an OGTT via GPR120. Overall, 4x possessed promising antidiabetic effect and good safety profile to be a development candidate.

A Bayesian system to detect and characterize overlapping outbreaks.

Outbreaks of infectious diseases such as influenza are a significant threat to human health. Because there are different strains of influenza which can cause independent outbreaks, and influenza can affect demographic groups at different rates and times, there is a need to recognize and characterize multiple outbreaks of influenza. This paper describes a Bayesian system that uses data from emergency department patient care reports to create epidemiological models of overlapping outbreaks of influenza. Clinical findings are extracted from patient care reports using natural language processing. These findings are analyzed by a case detection system to create disease likelihoods that are passed to a multiple outbreak detection system. We evaluated the system using real and simulated outbreaks. The results show that this approach can recognize and characterize overlapping outbreaks of influenza. We describe several extensions that appear promising.

Automating Construction of Machine Learning Models With Clinical Big Data: Proposal Rationale and Methods.

BACKGROUND: To improve health outcomes and cut health care costs, we often need to conduct prediction/classification using large clinical datasets (aka, clinical big data), for example, to identify high-risk patients for preventive interventions. Machine learning has been proposed as a key technology for doing this. Machine learning has won most data science competitions and could support many clinical activities, yet only 15% of hospitals use it for even limited purposes. Despite familiarity with data, health care researchers often lack machine learning expertise to directly use clinical big data, creating a hurdle in realizing value from their data. Health care researchers can work with data scientists with deep machine learning knowledge, but it takes time and effort for both parties to communicate effectively. Facing a shortage in the United States of data scientists and hiring competition from companies with deep pockets, health care systems have difficulty recruiting data scientists. Building and generalizing a machine learning model often requires hundreds to thousands of manual iterations by data scientists to select the following: (1) hyper-parameter values and complex algorithms that greatly affect model accuracy and (2) operators and periods for temporally aggregating clinical attributes (eg, whether a patient's weight kept rising in the past year). This process becomes infeasible with limited budgets. OBJECTIVE: This study's goal is to enable health care researchers to directly use clinical big data, make machine learning feasible with limited budgets and data scientist resources, and realize value from data. METHODS: This study will allow us to achieve the following: (1) finish developing the new software, Automated Machine Learning (Auto-ML), to automate model selection for machine learning with clinical big data and validate Auto-ML on seven benchmark modeling problems of clinical importance; (2) apply Auto-ML and novel methodology to two new modeling problems crucial for care management allocation and pilot one model with care managers; and (3) perform simulations to estimate the impact of adopting Auto-ML on US patient outcomes. RESULTS: We are currently writing Auto-ML's design document. We intend to finish our study by around the year 2022. CONCLUSIONS: Auto-ML will generalize to various clinical prediction/classification problems. With minimal help from data scientists, health care researchers can use Auto-ML to quickly build high-quality models. This will boost wider use of machine learning in health care and improve patient outcomes.