The algorithm journey map: a tangible approach to implementing AI solutions in healthcare.

When integrating AI tools in healthcare settings, complex interactions between technologies and primary users are not always fully understood or visible. This deficient and ambiguous understanding hampers attempts by healthcare organizations to adopt AI/ML, and it also creates new challenges for researchers to identify opportunities for simplifying adoption and developing best practices for the use of AI-based solutions. Our study fills this gap by documenting the process of designing, building, and maintaining an AI solution called SepsisWatch at Duke University Health System. We conducted 20 interviews with the team of engineers and scientists that led the multi-year effort to build the tool, integrate it into practice, and maintain the solution. This "Algorithm Journey Map" enumerates all social and technical activities throughout the AI solution's procurement, development, integration, and full lifecycle management. In addition to mapping the "who?" and "what?" of the adoption of the AI tool, we also show several 'lessons learned' throughout the algorithm journey maps including modeling assumptions, stakeholder inclusion, and organizational structure. In doing so, we identify generalizable insights about how to recognize and navigate barriers to AI/ML adoption in healthcare settings. We expect that this effort will further the development of best practices for operationalizing and sustaining ethical principles-in algorithmic systems.

Development and Validation of a Natural Language Processing Model to Identify Low-Risk Pulmonary Embolism in Real Time to Facilitate Safe Outpatient Management.

STUDY OBJECTIVE: This study aimed to (1) develop and validate a natural language processing model to identify the presence of pulmonary embolism (PE) based on real-time radiology reports and (2) identify low-risk PE patients based on previously validated risk stratification scores using variables extracted from the electronic health record at the time of diagnosis. The combination of these approaches yielded an natural language processing-based clinical decision support tool that can identify patients presenting to the emergency department (ED) with low-risk PE as candidates for outpatient management. METHODS: Data were curated from all patients who received a PE-protocol computed tomography pulmonary angiogram (PE-CTPA) imaging study in the ED of a 3-hospital academic health system between June 1, 2018 and December 31, 2020 (n=12,183). The "preliminary" radiology reports from these imaging studies made available to ED clinicians at the time of diagnosis were adjudicated as positive or negative for PE by the clinical team. The reports were then divided into development, internal validation, and temporal validation cohorts in order to train, test, and validate an natural language processing model that could identify the presence of PE based on unstructured text. For risk stratification, patient- and encounter-level data elements were curated from the electronic health record and used to compute a real-time simplified pulmonary embolism severity (sPESI) score at the time of diagnosis. Chart abstraction was performed on all low-risk PE patients admitted for inpatient management. RESULTS: When applied to the internal validation and temporal validation cohorts, the natural language processing model identified the presence of PE from radiology reports with an area under the receiver operating characteristic curve of 0.99, sensitivity of 0.86 to 0.87, and specificity of 0.99. Across cohorts, 10.5% of PE-CTPA studies were positive for PE, of which 22.2% were classified as low-risk by the sPESI score. Of all low-risk PE patients, 74.3% were admitted for inpatient management. CONCLUSION: This study demonstrates that a natural language processing-based model utilizing real-time radiology reports can accurately identify patients with PE. Further, this model, used in combination with a validated risk stratification score (sPESI), provides a clinical decision support tool that accurately identifies patients in the ED with low-risk PE as candidates for outpatient management.

Implementation of a Prospective Index-Cluster Sampling Strategy for the Detection of Presymptomatic Viral Respiratory Infection in Undergraduate Students.

Background: Index-cluster studies may help characterize the spread of communicable infections in the presymptomatic state. We describe a prospective index-cluster sampling strategy (ICSS) to detect presymptomatic respiratory viral illness and its implementation in a college population. Methods: We enrolled an annual cohort of first-year undergraduates who completed daily electronic symptom diaries to identify index cases (ICs) with respiratory illness. Investigators then selected 5-10 potentially exposed, asymptomatic close contacts (CCs) who were geographically co-located to follow for infections. Symptoms and nasopharyngeal samples were collected for 5 days. Logistic regression model-based predictions for proportions of self-reported illness were compared graphically for the whole cohort sampling group and the CC group. Results: We enrolled 1379 participants between 2009 and 2015, including 288 ICs and 882 CCs. The median number of CCs per IC was 6 (interquartile range, 3-8). Among the 882 CCs, 111 (13%) developed acute respiratory illnesses. Viral etiology testing in 246 ICs (85%) and 719 CCs (82%) identified a pathogen in 57% of ICs and 15% of CCs. Among those with detectable virus, rhinovirus was the most common (IC: 18%; CC: 6%) followed by coxsackievirus/echovirus (IC: 11%; CC: 4%). Among 106 CCs with a detected virus, only 18% had the same virus as their associated IC. Graphically, CCs did not have a higher frequency of self-reported illness relative to the whole cohort sampling group. Conclusions: Establishing clusters by geographic proximity did not enrich for cases of viral transmission, suggesting that ICSS may be a less effective strategy to detect spread of respiratory infection.

Development and Temporal Validation of a Machine Learning Model to Predict Clinical Deterioration.

OBJECTIVES: Early warning scores detecting clinical deterioration in pediatric inpatients have wide-ranging performance and use a limited number of clinical features. This study developed a machine learning model leveraging multiple static and dynamic clinical features from the electronic health record to predict the composite outcome of unplanned transfer to the ICU within 24 hours and inpatient mortality within 48 hours in hospitalized children. METHODS: Using a retrospective development cohort of 17 630 encounters across 10 388 patients, 2 machine learning models (light gradient boosting machine [LGBM] and random forest) were trained on 542 features and compared with our institutional Pediatric Early Warning Score (I-PEWS). RESULTS: The LGBM model significantly outperformed I-PEWS based on receiver operating characteristic curve (AUROC) for the composite outcome of ICU transfer or mortality for both internal validation and temporal validation cohorts (AUROC 0.785 95% confidence interval [0.780-0.791] vs 0.708 [0.701-0.715] for temporal validation) as well as lead-time before deterioration events (median 11 hours vs 3 hours; P = .004). However, LGBM performance as evaluated by precision recall curve was lesser in the temporal validation cohort with associated decreased positive predictive value (6% vs 29%) and increased number needed to evaluate (17 vs 3) compared with I-PEWS. CONCLUSIONS: Our electronic health record based machine learning model demonstrated improved AUROC and lead-time in predicting clinical deterioration in pediatric inpatients 24 to 48 hours in advance compared with I-PEWS. Further work is needed to optimize model positive predictive value to allow for integration into clinical practice.

Preliminary results of a clinical research and innovation scholarship to prepare medical students to lead innovations in health care.

There is consensus amongst national organizations to integrate health innovation and augmented intelligence (AI) into medical education. However, there is scant evidence to guide policymakers and medical educators working to revise curricula. This study presents academic, operational, and domain understanding outcomes for the first three cohorts of participants in a clinical research and innovation scholarship program.

Development and Validation of Machine Learning Models to Predict Admission From Emergency Department to Inpatient and Intensive Care Units.

STUDY OBJECTIVE: This study aimed to develop and validate 2 machine learning models that use historical and current-visit patient data from electronic health records to predict the probability of patient admission to either an inpatient unit or ICU at each hour (up to 24 hours) of an emergency department (ED) encounter. The secondary goal was to provide a framework for the operational implementation of these machine learning models. METHODS: Data were curated from 468,167 adult patient encounters in 3 EDs (1 academic and 2 community-based EDs) of a large academic health system from August 1, 2015, to October 31, 2018. The models were validated using encounter data from January 1, 2019, to December 31, 2019. An operational user dashboard was developed, and the models were run on real-time encounter data. RESULTS: For the intermediate admission model, the area under the receiver operating characteristic curve was 0.873 and the area under the precision-recall curve was 0.636. For the ICU admission model, the area under the receiver operating characteristic curve was 0.951 and the area under the precision-recall curve was 0.461. The models had similar performance in both the academic- and community-based settings as well as across the 2019 and real-time encounter data. CONCLUSION: Machine learning models were developed to accurately make predictions regarding the probability of inpatient or ICU admission throughout the entire duration of a patient's encounter in ED and not just at the time of triage. These models remained accurate for a patient cohort beyond the time period of the initial training data and were integrated to run on live electronic health record data, with similar performance.

Impact of diagnosis code grouping method on clinical prediction model performance: A multi-site retrospective observational study.

OBJECTIVE: The primary purpose of this work is to systematically assess the performance trade-offs on clinical prediction tasks of four diagnosis code groupings: AHRQ-Elixhauser, Single-level CCS, truncated ICD-9-CM codes, and raw ICD-9-CM codes. MATERIALS AND METHODS: We used two distinct datasets from different geographic regions and patient populations and train models for three prediction tasks: 1-year mortality following an ICU stay, 30-day mortality following surgery, and 30-day complication following surgery. We run multiple commonly-used binary classification models including penalized logistic regression, random forest, and gradient boosted trees. Model performance is evaluated using the Area Under the Receiver Operating Characteristic (AUROC) and the Area Under the Precision-Recall Curve (AUCPR). RESULTS: Single-level CCS, truncated codes, and raw codes significantly outperformed AHRQ-Elixhauser ICD grouping when predicting 30-day postoperative complication and one-year mortality after ICU admission. The performance across groupings was more similar in the 30-day postoperative mortality prediction task. DISCUSSION: Single-level CCS groupings represent aggregations of raw codes into meaningful clinical concepts and consistently balance interoperability between ICD-9-CM and ICD-10-CM while maintaining strong model performance as measured by AUROC and AUCPR. Key limitations include experimentation across two datasets and three prediction tasks, which although were well labeled and sufficiently prevalent, do not encompass all modeling tasks and outcomes. CONCLUSION: Single-level CCS groupings may serve as a good baseline for future models that incorporate diagnosis codes as features in clinical prediction tasks. Code and a compute environment summary are provided along with the analyses to enable reproducibility and to support future research.

A blood-based host gene expression assay for early detection of respiratory viral infection: an index-cluster prospective cohort study.

BACKGROUND: Early and accurate identification of individuals with viral infections is crucial for clinical management and public health interventions. We aimed to assess the ability of transcriptomic biomarkers to identify naturally acquired respiratory viral infection before typical symptoms are present. METHODS: In this index-cluster study, we prospectively recruited a cohort of undergraduate students (aged 18-25 years) at Duke University (Durham, NC, USA) over a period of 5 academic years. To identify index cases, we monitored students for the entire academic year, for the presence and severity of eight symptoms of respiratory tract infection using a daily web-based survey, with symptoms rated on a scale of 0-4. Index cases were defined as individuals who reported a 6-point increase in cumulative daily symptom score. Suspected index cases were visited by study staff to confirm the presence of reported symptoms of illness and to collect biospecimen samples. We then identified clusters of close contacts of index cases (ie, individuals who lived in close proximity to index cases, close friends, and partners) who were presumed to be at increased risk of developing symptomatic respiratory tract infection while under observation. We monitored each close contact for 5 days for symptoms and viral shedding and measured transcriptomic responses at each timepoint each day using a blood-based 36-gene RT-PCR assay. FINDINGS: Between Sept 1, 2009, and April 10, 2015, we enrolled 1465 participants. Of 264 index cases with respiratory tract infection symptoms, 150 (57%) had a viral cause confirmed by RT-PCR. Of their 555 close contacts, 106 (19%) developed symptomatic respiratory tract infection with a proven viral cause during the observation window, of whom 60 (57%) had the same virus as their associated index case. Nine viruses were detected in total. The transcriptomic assay accurately predicted viral infection at the time of maximum symptom severity (mean area under the receiver operating characteristic curve [AUROC] 0·94 [95% CI 0·92-0·96]), as well as at 1 day (0·87 [95% CI 0·84-0·90]), 2 days (0·85 [0·82-0·88]), and 3 days (0·74 [0·71-0·77]) before peak illness, when symptoms were minimal or absent and 22 (62%) of 35 individuals, 25 (69%) of 36 individuals, and 24 (82%) of 29 individuals, respectively, had no detectable viral shedding. INTERPRETATION: Transcriptional biomarkers accurately predict and diagnose infection across diverse viral causes and stages of disease and thus might prove useful for guiding the administration of early effective therapy, quarantine decisions, and other clinical and public health interventions in the setting of endemic and pandemic infectious diseases. FUNDING: US Defense Advanced Research Projects Agency.

Predicting Hospital Utilization and Inpatient Mortality of Patients Tested for COVID-19.

Using structured elements from Electronic Health Records (EHR), we seek to: i) build predictive models to stratify patients tested for COVID-19 by their likelihood for hospitalization, ICU admission, mechanical ventilation and inpatient mortality, and ii) identify the most important EHR-based features driving the predictions. We leveraged EHR data from the Duke University Health System tested for COVID-19 or hospitalized between March 11, 2020 and August 24, 2020, to build models to predict hospital admissions within 4 weeks. Models were also created for ICU admissions, need for mechanical ventilation and mortality following admission. Models were developed on a cohort of 86,355 patients with 112,392 outpatient COVID-19 tests or any-cause hospital admissions between March 11, 2020 and June 4, 2020. The four models considered resulted in AUROC=0.838 (CI: 0.832-0.844) and AP=0.272 (CI: 0.260-0.287) for hospital admissions, AUROC=0.847 (CI: 0.839-855) and AP=0.585 (CI: 0.565-0.603) for ICU admissions, AUROC=0.858 (CI: 0.846-0.871) and AP=0.434 (CI: 0.403-0.467) for mechanical ventilation, and AUROC=0.0.856 (CI: 0.842-0.872) and AP=0.243 (CI: 0.205-0.282) for inpatient mortality. Patient history abstracted from the EHR has the potential for being used to stratify patients tested for COVID-19 in terms of utilization and mortality. The dominant EHR features for hospital admissions and inpatient outcomes are different. For the former, age, social indicators and previous utilization are the most important predictive features. For the latter, age and physiological summaries (pulse and blood pressure) are the main drivers.

Machine learning for early detection of sepsis: an internal and temporal validation study.

OBJECTIVE: Determine if deep learning detects sepsis earlier and more accurately than other models. To evaluate model performance using implementation-oriented metrics that simulate clinical practice. MATERIALS AND METHODS: We trained internally and temporally validated a deep learning model (multi-output Gaussian process and recurrent neural network [MGP-RNN]) to detect sepsis using encounters from adult hospitalized patients at a large tertiary academic center. Sepsis was defined as the presence of 2 or more systemic inflammatory response syndrome (SIRS) criteria, a blood culture order, and at least one element of end-organ failure. The training dataset included demographics, comorbidities, vital signs, medication administrations, and labs from October 1, 2014 to December 1, 2015, while the temporal validation dataset was from March 1, 2018 to August 31, 2018. Comparisons were made to 3 machine learning methods, random forest (RF), Cox regression (CR), and penalized logistic regression (PLR), and 3 clinical scores used to detect sepsis, SIRS, quick Sequential Organ Failure Assessment (qSOFA), and National Early Warning Score (NEWS). Traditional discrimination statistics such as the C-statistic as well as metrics aligned with operational implementation were assessed. RESULTS: The training set and internal validation included 42 979 encounters, while the temporal validation set included 39 786 encounters. The C-statistic for predicting sepsis within 4 h of onset was 0.88 for the MGP-RNN compared to 0.836 for RF, 0.849 for CR, 0.822 for PLR, 0.756 for SIRS, 0.619 for NEWS, and 0.481 for qSOFA. MGP-RNN detected sepsis a median of 5 h in advance. Temporal validation assessment continued to show the MGP-RNN outperform all 7 clinical risk score and machine learning comparisons. CONCLUSIONS: We developed and validated a novel deep learning model to detect sepsis. Using our data elements and feature set, our modeling approach outperformed other machine learning methods and clinical scores.

Real-World Integration of a Sepsis Deep Learning Technology Into Routine Clinical Care: Implementation Study.

BACKGROUND: Successful integrations of machine learning into routine clinical care are exceedingly rare, and barriers to its adoption are poorly characterized in the literature. OBJECTIVE: This study aims to report a quality improvement effort to integrate a deep learning sepsis detection and management platform, Sepsis Watch, into routine clinical care. METHODS: In 2016, a multidisciplinary team consisting of statisticians, data scientists, data engineers, and clinicians was assembled by the leadership of an academic health system to radically improve the detection and treatment of sepsis. This report of the quality improvement effort follows the learning health system framework to describe the problem assessment, design, development, implementation, and evaluation plan of Sepsis Watch. RESULTS: Sepsis Watch was successfully integrated into routine clinical care and reshaped how local machine learning projects are executed. Frontline clinical staff were highly engaged in the design and development of the workflow, machine learning model, and application. Novel machine learning methods were developed to detect sepsis early, and implementation of the model required robust infrastructure. Significant investment was required to align stakeholders, develop trusting relationships, define roles and responsibilities, and to train frontline staff, leading to the establishment of 3 partnerships with internal and external research groups to evaluate Sepsis Watch. CONCLUSIONS: Machine learning models are commonly developed to enhance clinical decision making, but successful integrations of machine learning into routine clinical care are rare. Although there is no playbook for integrating deep learning into clinical care, learnings from the Sepsis Watch integration can inform efforts to develop machine learning technologies at other health care delivery systems.

Correction: Developing a common framework for evaluating the implementation of genomic medicine interventions in clinical care: the IGNITE Network's Common Measures Working Group.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Prospective and External Evaluation of a Machine Learning Model to Predict In-Hospital Mortality of Adults at Time of Admission.

Importance: The ability to accurately predict in-hospital mortality for patients at the time of admission could improve clinical and operational decision-making and outcomes. Few of the machine learning models that have been developed to predict in-hospital death are both broadly applicable to all adult patients across a health system and readily implementable. Similarly, few have been implemented, and none have been evaluated prospectively and externally validated. Objectives: To prospectively and externally validate a machine learning model that predicts in-hospital mortality for all adult patients at the time of hospital admission and to design the model using commonly available electronic health record data and accessible computational methods. Design, Setting, and Participants: In this prognostic study, electronic health record data from a total of 43 180 hospitalizations representing 31 003 unique adult patients admitted to a quaternary academic hospital (hospital A) from October 1, 2014, to December 31, 2015, formed a training and validation cohort. The model was further validated in additional cohorts spanning from March 1, 2018, to August 31, 2018, using 16 122 hospitalizations representing 13 094 unique adult patients admitted to hospital A, 6586 hospitalizations representing 5613 unique adult patients admitted to hospital B, and 4086 hospitalizations representing 3428 unique adult patients admitted to hospital C. The model was integrated into the production electronic health record system and prospectively validated on a cohort of 5273 hospitalizations representing 4525 unique adult patients admitted to hospital A between February 14, 2019, and April 15, 2019. Main Outcomes and Measures: The main outcome was in-hospital mortality. Model performance was quantified using the area under the receiver operating characteristic curve and area under the precision recall curve. Results: A total of 75 247 hospital admissions (median [interquartile range] patient age, 59.5 [29.0] years; 45.9% involving male patients) were included in the study. The in-hospital mortality rates for the training validation; retrospective validations at hospitals A, B, and C; and prospective validation cohorts were 3.0%, 2.7%, 1.8%, 2.1%, and 1.6%, respectively. The area under the receiver operating characteristic curves were 0.87 (95% CI, 0.83-0.89), 0.85 (95% CI, 0.83-0.87), 0.89 (95% CI, 0.86-0.92), 0.84 (95% CI, 0.80-0.89), and 0.86 (95% CI, 0.83-0.90), respectively. The area under the precision recall curves were 0.29 (95% CI, 0.25-0.37), 0.17 (95% CI, 0.13-0.22), 0.22 (95% CI, 0.14-0.31), 0.13 (95% CI, 0.08-0.21), and 0.14 (95% CI, 0.09-0.21), respectively. Conclusions and Relevance: Prospective and multisite retrospective evaluations of a machine learning model demonstrated good discrimination of in-hospital mortality for adult patients at the time of admission. The data elements, methods, and patient selection make the model implementable at a system level.

Assessing Quality of Surgical Real-World Data from an Automated Electronic Health Record Pipeline.

BACKGROUND: Significant analysis errors can be caused by nonvalidated data quality of electronic health records data. To determine surgical data fitness, a framework of foundational and study-specific data analyses was adapted and assessed using conformance, completeness, and plausibility analyses. STUDY DESIGN: Electronic health records-derived data from a cohort of 241,695 patients undergoing 412,182 procedures from October 1, 2014 to August 31, 2018 at 3 hospital sites was evaluated. Data quality analyses tested CPT codes, medication administrations, vital signs, provider notes, labs, orders, diagnosis codes, medication lists, and encounters. RESULTS: Foundational checks showed that all encounters had procedures within the inclusion period, all admission dates occurred before discharge dates, and race was missing for 1% of patients. All procedures had associated CPT codes, 69% had recorded blood pressure, pulse, temperature, respiration rate, and oxygen saturation. After curation, all medication matched RxNorm medication naming standards, 84% of procedures had current outpatient medication lists, and 15% of procedures had missing procedure notes. Study-specific checks temporally validated CPT codes, intraoperative medication doses were in conventional units, and of the 13,500 patients who received blood pressure medication intraoperatively, 93% had a systolic blood pressure >140 mmHg. All procedure notes were completed within less than 30 days of the procedure and 93% of patients after total knee arthroplasty had postoperative physical therapy notes. All patients with postoperative troponin-T lab values ≥0.10 ng/mL had more than 1 ECG with relevant diagnoses. Postoperative opioid prescription decreased by 8.8% and nonopioid use increased by 8.8%. CONCLUSIONS: High levels of conformance, completeness, and clinical plausability demonstrate higher quality of real-world data fitness and low levels demonstrate less-fit-for-use data.

Machine Learning in Health Care: A Critical Appraisal of Challenges and Opportunities.

Examples of fully integrated machine learning models that drive clinical care are rare. Despite major advances in the development of methodologies that outperform clinical experts and growing prominence of machine learning in mainstream medical literature, major challenges remain. At Duke Health, we are in our fourth year developing, piloting, and implementing machine learning technologies in clinical care. To advance the translation of machine learning into clinical care, health system leaders must address barriers to progress and make strategic investments necessary to bring health care into a new digital age. Machine learning can improve clinical workflows in subtle ways that are distinct from how statistics has shaped medicine. However, most machine learning research occurs in siloes, and there are important, unresolved questions about how to retrain and validate models post-deployment. Academic medical centers that cultivate and value transdisciplinary collaboration are ideally suited to integrate machine learning in clinical care. Along with fostering collaborative environments, health system leaders must invest in developing new capabilities within the workforce and technology infrastructure beyond standard electronic health records. Now is the opportunity to break down barriers and achieve scalable growth in the number of high-impact collaborations between clinical researchers and machine learning experts to transform clinical care.

Unsupervised Analysis of Transcriptomics in Bacterial Sepsis Across Multiple Datasets Reveals Three Robust Clusters.

OBJECTIVES: To find and validate generalizable sepsis subtypes using data-driven clustering. DESIGN: We used advanced informatics techniques to pool data from 14 bacterial sepsis transcriptomic datasets from eight different countries (n = 700). SETTING: Retrospective analysis. SUBJECTS: Persons admitted to the hospital with bacterial sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A unified clustering analysis across 14 discovery datasets revealed three subtypes, which, based on functional analysis, we termed "Inflammopathic, Adaptive, and Coagulopathic." We then validated these subtypes in nine independent datasets from five different countries (n = 600). In both discovery and validation data, the Adaptive subtype is associated with a lower clinical severity and lower mortality rate, and the Coagulopathic subtype is associated with higher mortality and clinical coagulopathy. Further, these clusters are statistically associated with clusters derived by others in independent single sepsis cohorts. CONCLUSIONS: The three sepsis subtypes may represent a unifying framework for understanding the molecular heterogeneity of the sepsis syndrome. Further study could potentially enable a precision medicine approach of matching novel immunomodulatory therapies with septic patients most likely to benefit.

A community approach to mortality prediction in sepsis via gene expression analysis.

Improved risk stratification and prognosis prediction in sepsis is a critical unmet need. Clinical severity scores and available assays such as blood lactate reflect global illness severity with suboptimal performance, and do not specifically reveal the underlying dysregulation of sepsis. Here, we present prognostic models for 30-day mortality generated independently by three scientific groups by using 12 discovery cohorts containing transcriptomic data collected from primarily community-onset sepsis patients. Predictive performance is validated in five cohorts of community-onset sepsis patients in which the models show summary AUROCs ranging from 0.765-0.89. Similar performance is observed in four cohorts of hospital-acquired sepsis. Combining the new gene-expression-based prognostic models with prior clinical severity scores leads to significant improvement in prediction of 30-day mortality as measured via AUROC and net reclassification improvement index These models provide an opportunity to develop molecular bedside tests that may improve risk stratification and mortality prediction in patients with sepsis.

A miRNA Host Response Signature Accurately Discriminates Acute Respiratory Infection Etiologies.

Background: Acute respiratory infections (ARIs) are the leading indication for antibacterial prescriptions despite a viral etiology in the majority of cases. The lack of available diagnostics to discriminate viral and bacterial etiologies contributes to this discordance. Recent efforts have focused on the host response as a source for novel diagnostic targets although none have explored the ability of host-derived microRNAs (miRNA) to discriminate between these etiologies. Methods: In this study, we compared host-derived miRNAs and mRNAs from human H3N2 influenza challenge subjects to those from patients with Streptococcus pneumoniae pneumonia. Sparse logistic regression models were used to generate miRNA signatures diagnostic of ARI etiologies. Generalized linear modeling of mRNAs to identify differentially expressed (DE) genes allowed analysis of potential miRNA:mRNA relationships. High likelihood miRNA:mRNA interactions were examined using binding target prediction and negative correlation to further explore potential changes in pathway regulation in response to infection. Results: The resultant miRNA signatures were highly accurate in discriminating ARI etiologies. Mean accuracy was 100% [88.8-100; 95% Confidence Interval (CI)] in discriminating the healthy state from S. pneumoniae pneumonia and 91.3% (72.0-98.9; 95% CI) in discriminating S. pneumoniae pneumonia from influenza infection. Subsequent differential mRNA gene expression analysis revealed alterations in regulatory networks consistent with known biology including immune cell activation and host response to viral infection. Negative correlation network analysis of miRNA:mRNA interactions revealed connections to pathways with known immunobiology such as interferon regulation and MAP kinase signaling. Conclusion: We have developed novel human host-response miRNA signatures for bacterial and viral ARI etiologies. miRNA host response signatures reveal accurate discrimination between S. pneumoniae pneumonia and influenza etiologies for ARI and integrated analyses of the host-pathogen interface are consistent with expected biology. These results highlight the differential miRNA host response to bacterial and viral etiologies of ARI, offering new opportunities to distinguish these entities.

Developing a common framework for evaluating the implementation of genomic medicine interventions in clinical care: the IGNITE Network's Common Measures Working Group.

PurposeImplementation research provides a structure for evaluating the clinical integration of genomic medicine interventions. This paper describes the Implementing Genomics in Practice (IGNITE) Network's efforts to promote (i) a broader understanding of genomic medicine implementation research and (ii) the sharing of knowledge generated in the network.MethodsTo facilitate this goal, the IGNITE Network Common Measures Working Group (CMG) members adopted the Consolidated Framework for Implementation Research (CFIR) to guide its approach to identifying constructs and measures relevant to evaluating genomic medicine as a whole, standardizing data collection across projects, and combining data in a centralized resource for cross-network analyses.ResultsCMG identified 10 high-priority CFIR constructs as important for genomic medicine. Of those, eight did not have standardized measurement instruments. Therefore, we developed four survey tools to address this gap. In addition, we identified seven high-priority constructs related to patients, families, and communities that did not map to CFIR constructs. Both sets of constructs were combined to create a draft genomic medicine implementation model.ConclusionWe developed processes to identify constructs deemed valuable for genomic medicine implementation and codified them in a model. These resources are freely available to facilitate knowledge generation and sharing across the field.