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Abstract Background Breast imaging clinics in the United States (U.S.) are increasingly implementing breast cancer risk assessment (BCRA) to align with evolving guideline recommendations but with limited uptake of risk-reduction care. Effectively communicating risk information to women is central to implementation efforts, but remains understudied in the U.S. This study aims to characterize, and identify factors associated with women’s interest in and preferences for breast cancer risk communication. Methods This is a cross-sectional survey study of U.S. women presenting for a mammogram between January and March of 2021 at a large, tertiary breast imaging clinic. Survey items assessed women’s interest in knowing their risk and preferences for risk communication if considered to be at high risk in hypothetical situations. Multivariable logistic regression modeling assessed factors associated with women’s interest in knowing their personal risk and preferences for details around exact risk estimates. Results Among 1119 women, 72.7% were interested in knowing their breast cancer risk. If at high risk, 77% preferred to receive their exact risk estimate and preferred verbal (52.9% phone/47% in-person) vs. written (26.5% online/19.5% letter) communications. Adjusted regression analyses found that those with a primary family history of breast cancer were significantly more interested in knowing their risk (OR 1.5, 95% CI 1.0, 2.1, p = 0.04), while those categorized as “more than one race or other” were significantly less interested in knowing their risk (OR 0.4, 95% CI 0.2, 0.9, p = 0.02). Women 60 + years of age were significantly less likely to prefer exact estimates of their risk (OR 0.6, 95% CI 0.5, 0.98, p

Abstract Current risk scores using clinical risk factors for predicting ischemic heart disease (IHD) events—the leading cause of global mortality—have known limitations and may be improved by imaging biomarkers. While body composition (BC) imaging biomarkers derived from abdominopelvic computed tomography (CT) correlate with IHD risk, they are impractical to measure manually. Here, in a retrospective cohort of 8139 contrast-enhanced abdominopelvic CT examinations undergoing up to 5 years of follow-up, we developed multimodal opportunistic risk assessment models for IHD by automatically extracting BC features from abdominal CT images and integrating these with features from each patient’s electronic medical record (EMR). Our predictive methods match and, in some cases, outperform clinical risk scores currently used in IHD risk assessment. We provide clinical interpretability of our model using a new method of determining tissue-level contributions from CT along with weightings of EMR features contributing to IHD risk. We conclude that such a multimodal approach, which automatically integrates BC biomarkers and EMR data, can enhance IHD risk assessment and aid primary prevention efforts for IHD. To further promote research, we release the Opportunistic L3 Ischemic heart disease (OL3I) dataset, the first public multimodal dataset for opportunistic CT prediction of IHD.

BackgroundArtificial intelligence (AI) and machine learning (ML) are poised to have a substantial impact in the health care space. While a plethora of web-based resources exist to teach programming skills and ML model development, there are few introductory curricula specifically tailored to medical students without a background in data science or programming. Programs that do exist are often restricted to a specific specialty. ObjectiveWe hypothesized that a 1-month elective for fourth-year medical students, composed of high-quality existing web-based resources and a project-based structure, would empower students to learn about the impact of AI and ML in their chosen specialty and begin contributing to innovation in their field of interest. This study aims to evaluate the success of this elective in improving self-reported confidence scores in AI and ML. The authors also share our curriculum with other educators who may be interested in its adoption. MethodsThis elective was offered in 2 tracks: technical (for students who were already competent programmers) and nontechnical (with no technical prerequisites, focusing on building a conceptual understanding of AI and ML). Students established a conceptual foundation of knowledge using curated web-based resources and relevant research papers, and were then tasked with completing 3 projects in their chosen specialty: a data set analysis, a literature review, and an AI project proposal. The project-based nature of the elective was designed to be self-guided and flexible to each student’s interest area and career goals. Students’ success was measured by self-reported confidence in AI and ML skills in pre and postsurveys. Qualitative feedback on students’ experiences was also collected. ResultsThis web-based, self-directed elective was offered on a pass-or-fail basis each month to fourth-year students at Emory University School of Medicine beginning in May 2021. As of June 2022, a total of 19 students had successfully completed the elective, representing a wide range of chosen specialties: diagnostic radiology (n=3), general surgery (n=1), internal medicine (n=5), neurology (n=2), obstetrics and gynecology (n=1), ophthalmology (n=1), orthopedic surgery (n=1), otolaryngology (n=2), pathology (n=2), and pediatrics (n=1). Students’ self-reported confidence scores for AI and ML rose by 66% after this 1-month elective. In qualitative surveys, students overwhelmingly reported enthusiasm and satisfaction with the course and commented that the self-direction and flexibility and the project-based design of the course were essential. ConclusionsCourse participants were successful in diving deep into applications of AI in their widely-ranging specialties, produced substantial project deliverables, and generally reported satisfaction with their elective experience. The authors are hopeful that a brief, 1-month investment in AI and ML education during medical school will empower this next generation of physicians to pave the way for AI and ML innovation in health care.

Objective: To identify prognostically distinct phenotype clusters in transcatheter edge-to-edge repair (TEER) patients based on topological data analysis (TDA), which was never used to assess the heterogeneous TEER population. Patients and Methods: Patients who underwent TEER (June 2014-September 2020) at Mayo Clinic sites were identified from the institutional database. Thirteen variables were used for TDA. The topological network graph was created using the Python Scikit-TDA Kepler-Mapper package (v. 2.0.1), and clustering was performed at the graph level with Louvain’s modularity method. Kaplan-Meier survival analysis was used to assess the all-cause mortality of each cluster. Result: A total of 389 consecutive patients were included in the final analysis, and 2 major clusters were identified. The mean age was 80.3 ± 8.7 years; 256 (65.8%) were male. Fifty-five (14.5%) patients died during the mean follow-up duration (185 days). Kaplan-Meier analysis showed significant survival differences among the 2 clusters (hazard ratio, 2.70; 95% CI, 1.50-4.87; P=.0005). Cluster 1 (n=227) had moderate or increased residual mitral regurgitation (cluster 0 vs cluster 1: 19.4% vs 41.9%; P

Abstract This work presents an on-chip analog-to-information conversion technique that utilizes analog hyper-dimensional computing based on reservoir-computing paradigm to process electrocardiograph (ECG) signals locally in-sensor and reduce radio frequency transmission by more than three orders-of-magnitude. Instead of transmitting the naturally sparse ECG signal or extracted features, the on-chip analog-to-information converter analyzes the ECG signal through a nonlinear reservoir kernel followed by an artificial neural network, and transmits the prediction results. The proposed technique is demonstrated for detection of sepsis onset and achieves state-of-the-art accuracy and energy efficiency while reducing sensor power by $$159\times $$ 159 × with test-chips prototyped in 65 nm CMOS.

IntroductionTo date, most mammography-related AI models have been trained using either film or digital mammogram datasets with little overlap. We investigated whether or not combining film and digital mammography during training will help or hinder modern models designed for use on digital mammograms.MethodsTo this end, a total of six binary classifiers were trained for comparison. The first three classifiers were trained using images only from Emory Breast Imaging Dataset (EMBED) using ResNet50, ResNet101, and ResNet152 architectures. The next three classifiers were trained using images from EMBED, Curated Breast Imaging Subset of Digital Database for Screening Mammography (CBIS-DDSM), and Digital Database for Screening Mammography (DDSM) datasets. All six models were tested only on digital mammograms from EMBED.ResultsThe results showed that performance degradation to the customized ResNet models was statistically significant overall when EMBED dataset was augmented with CBIS-DDSM/DDSM. While the performance degradation was observed in all racial subgroups, some races are subject to more severe performance drop as compared to other races.DiscussionThe degradation may potentially be due to ( 1) a mismatch in features between film-based and digital mammograms ( 2) a mismatch in pathologic and radiological information. In conclusion, use of both film and digital mammography during training may hinder modern models designed for breast cancer screening. Caution is required when combining film-based and digital mammograms or when utilizing pathologic and radiological information simultaneously.

Abstract The objective of this work is to develop a fusion artificial intelligence (AI) model that combines patient electronic medical record (EMR) and physiological sensor data to accurately predict early risk of sepsis. The fusion AI model has two components—an on-chip AI model that continuously analyzes patient electrocardiogram (ECG) data and a cloud AI model that combines EMR and prediction scores from on-chip AI model to predict fusion sepsis onset score. The on-chip AI model is designed using analog circuits for sepsis prediction with high energy efficiency for integration with resource constrained wearable device. Combination of EMR and sensor physiological data improves prediction performance compared to EMR or physiological data alone, and the late fusion model has an accuracy of 93% in predicting sepsis 4 h before onset. The key differentiation of this work over existing sepsis prediction literature is the use of single modality patient vital (ECG) and simple demographic information, instead of comprehensive laboratory test results and multiple vital signs. Such simple configuration and high accuracy makes our solution favorable for real-time, at-home use for self-monitoring.

Abstract Background Transfer learning is a common practice in image classification with deep learning where the available data is often limited for training a complex model with millions of parameters. However, transferring language models requires special attention since cross-domain vocabularies (e.g. between two different modalities MR and US) do not always overlap as the pixel intensity range overlaps mostly for images. Method We present a concept of similar domain adaptation where we transfer inter-institutional language models (context-dependent and context-independent) between two different modalities (ultrasound and MRI) to capture liver abnormalities. Results We use MR and US screening exam reports for hepatocellular carcinoma as the use-case and apply the transfer language space strategy to automatically label imaging exams with and without structured template with > 0.9 average f1-score. Conclusion We conclude that transfer learning along with fine-tuning the discriminative model is often more effective for performing shared targeted tasks than the training for a language space from scratch.

Chest radiography (CXR) is the most frequently performed radiological test worldwide because of its wide availability, non-invasive nature, and low cost. The ability of CXR to diagnose cardiovascular diseases, give insight into cardiac function, and predict cardiovascular events is often underutilized, not clearly understood, and affected by inter- and intra-observer variability. Therefore, more sophisticated tests are generally needed to assess cardiovascular diseases. Considering the sustained increase in the incidence of cardiovascular diseases, it is critical to find accessible, fast, and reproducible tests to help diagnose these frequent conditions. The expanded focus on the application of artificial intelligence (AI) with respect to diagnostic cardiovascular imaging has also been applied to CXR, with several publications suggesting that AI models can be trained to detect cardiovascular conditions by identifying features in the CXR. Multiple models have been developed to predict mortality, cardiovascular morphology and function, coronary artery disease, valvular heart diseases, aortic diseases, arrhythmias, pulmonary hypertension, and heart failure. The available evidence demonstrates that the use of AI-based tools applied to CXR for the diagnosis of cardiovascular conditions and prognostication has the potential to transform clinical care. AI-analyzed CXRs could be utilized in the future as a complimentary, easy-to-apply technology to improve diagnosis and risk stratification for cardiovascular diseases. Such advances will likely help better target more advanced investigations, which may reduce the burden of testing in some cases, as well as better identify higher-risk patients who would benefit from earlier, dedicated, and comprehensive cardiovascular evaluation.

Abstract The strain on healthcare resources brought forth by the recent COVID-19 pandemic has highlighted the need for efficient resource planning and allocation through the prediction of future consumption. Machine learning can predict resource utilization such as the need for hospitalization based on past medical data stored in electronic medical records (EMR). We conducted this study on 3194 patients (46% male with mean age 56.7 (±16.8), 56% African American, 7% Hispanic) flagged as COVID-19 positive cases in 12 centers under Emory Healthcare network from February 2020 to September 2020, to assess whether a COVID-19 positive patient’s need for hospitalization can be predicted at the time of RT-PCR test using the EMR data prior to the test. Five main modalities of EMR, i.e., demographics, medication, past medical procedures, comorbidities, and laboratory results, were used as features for predictive modeling, both individually and fused together using late, middle, and early fusion. Models were evaluated in terms of precision, recall, F1-score (within 95% confidence interval). The early fusion model is the most effective predictor with 84% overall F1-score [CI 82.1–86.1]. The predictive performance of the model drops by 6 % when using recent clinical data while omitting the long-term medical history. Feature importance analysis indicates that history of cardiovascular disease, emergency room visits in the past year prior to testing, and demographic factors are predictive of the disease trajectory. We conclude that fusion modeling using medical history and current treatment data can forecast the need for hospitalization for patients infected with COVID-19 at the time of the RT-PCR test.

Abstract Efficient prediction of cancer recurrence in advance may help to recruit high risk breast cancer patients for clinical trial on-time and can guide a proper treatment plan. Several machine learning approaches have been developed for recurrence prediction in previous studies, but most of them use only structured electronic health records and only a small training dataset, with limited success in clinical application. While free-text clinic notes may offer the greatest nuance and detail about a patient’s clinical status, they are largely excluded in previous predictive models due to the increase in processing complexity and need for a complex modeling framework. In this study, we developed a weak-supervision framework for breast cancer recurrence prediction in which we trained a deep learning model on a large sample of free-text clinic notes by utilizing a combination of manually curated labels and NLP-generated non-perfect recurrence labels. The model was trained jointly on manually curated data from 670 patients and NLP-curated data of 8062 patients. It was validated on manually annotated data from 224 patients with recurrence and achieved 0.94 AUROC. This weak supervision approach allowed us to learn from a larger dataset using imperfect labels and ultimately provided greater accuracy compared to a smaller hand-curated dataset, with less manual effort invested in curation.

Aims:Increased left ventricular (LV) wall thickness is frequently encountered in transthoracic echocardiography (TTE). While accurate and early diagnosis is clinically important, given the differences in available therapeutic options and prognosis, an extensive workup is often required to establish the diagnosis. We propose the first echo-based, automated deep learning model with a fusion architecture to facilitate the evaluation and diagnosis of increased left ventricular (LV) wall thickness. Methods and Results: Patients with an established diagnosis of increased LV wall thickness (hypertrophic cardiomyopathy (HCM), cardiac amyloidosis (CA), and hypertensive heart disease (HTN)/others) between 1/2015 and 11/2019 at Mayo Clinic Arizona were identified. The cohort was divided into 80%/10%/10% for training, validation, and testing sets, respectively. Six baseline TTE views were used to optimize a pre-trained InceptionResnetV2 model. Each model output was used to train a meta-learner under a fusion architecture. Model performance was assessed by multiclass area under the receiver operating characteristic curve (AUROC). A total of 586 patients were used for the final analysis (194 HCM, 201 CA, and 191 HTN/others). The mean age was 55.0 years, and 57.8% were male. Among the individual view-dependent models, the apical 4-chamber model had the best performance (AUROC: HCM: 0.94, CA: 0.73, and HTN/other: 0.87). The final fusion model outperformed all the view-dependent models (AUROC: HCM: 0.93, CA: 0.90, and HTN/other: 0.92). Conclusion: The echo-based InceptionResnetV2 fusion model can accurately classify the main etiologies of increased LV wall thickness and can facilitate the process of diagnosis and workup.

Echocardiography is an integral part of the diagnosis and management of cardiovascular disease. The use and application of artificial intelligence (AI) is a rapidly expanding field in medicine to improve consistency and reduce interobserver variability. AI can be successfully applied to echocardiography in addressing variance during image acquisition and interpretation. Furthermore, AI and machine learning can aid in the diagnosis and management of cardiovascular disease. In the realm of echocardiography, accurate interpretation is largely dependent on the subjective knowledge of the operator. Echocardiography is burdened by the high dependence on the level of experience of the operator, to a greater extent than other imaging modalities like computed tomography, nuclear imaging, and magnetic resonance imaging. AI technologies offer new opportunities for echocardiography to produce accurate, automated, and more consistent interpretations. This review discusses machine learning as a subfield within AI in relation to image interpretation and how machine learning can improve the diagnostic performance of echocardiography. This review also explores the published literature outlining the value of AI and its potential to improve patient care.

Abstract Recent advancements in deep learning have led to a resurgence of medical imaging and Electronic Medical Record (EMR) models for a variety of applications, including clinical decision support, automated workflow triage, clinical prediction and more. However, very few models have been developed to integrate both clinical and imaging data, despite that in routine practice clinicians rely on EMR to provide context in medical imaging interpretation. In this study, we developed and compared different multimodal fusion model architectures that are capable of utilizing both pixel data from volumetric Computed Tomography Pulmonary Angiography scans and clinical patient data from the EMR to automatically classify Pulmonary Embolism (PE) cases. The best performing multimodality model is a late fusion model that achieves an AUROC of 0.947 [95% CI: 0.946–0.948] on the entire held-out test set, outperforming imaging-only and EMR-only single modality models.

Abstract Advancements in deep learning techniques carry the potential to make significant contributions to healthcare, particularly in fields that utilize medical imaging for diagnosis, prognosis, and treatment decisions. The current state-of-the-art deep learning models for radiology applications consider only pixel-value information without data informing clinical context. Yet in practice, pertinent and accurate non-imaging data based on the clinical history and laboratory data enable physicians to interpret imaging findings in the appropriate clinical context, leading to a higher diagnostic accuracy, informative clinical decision making, and improved patient outcomes. To achieve a similar goal using deep learning, medical imaging pixel-based models must also achieve the capability to process contextual data from electronic health records (EHR) in addition to pixel data. In this paper, we describe different data fusion techniques that can be applied to combine medical imaging with EHR, and systematically review medical data fusion literature published between 2012 and 2020. We conducted a systematic search on PubMed and Scopus for original research articles leveraging deep learning for fusion of multimodality data. In total, we screened 985 studies and extracted data from 17 papers. By means of this systematic review, we present current knowledge, summarize important results and provide implementation guidelines to serve as a reference for researchers interested in the application of multimodal fusion in medical imaging.

Abstract Pulmonary embolism (PE) is a life-threatening clinical problem and computed tomography pulmonary angiography (CTPA) is the gold standard for diagnosis. Prompt diagnosis and immediate treatment are critical to avoid high morbidity and mortality rates, yet PE remains among the diagnoses most frequently missed or delayed. In this study, we developed a deep learning model—PENet, to automatically detect PE on volumetric CTPA scans as an end-to-end solution for this purpose. The PENet is a 77-layer 3D convolutional neural network (CNN) pretrained on the Kinetics-600 dataset and fine-tuned on a retrospective CTPA dataset collected from a single academic institution. The PENet model performance was evaluated in detecting PE on data from two different institutions: one as a hold-out dataset from the same institution as the training data and a second collected from an external institution to evaluate model generalizability to an unrelated population dataset. PENet achieved an AUROC of 0.84 [0.82–0.87] on detecting PE on the hold out internal test set and 0.85 [0.81–0.88] on external dataset. PENet also outperformed current state-of-the-art 3D CNN models. The results represent successful application of an end-to-end 3D CNN model for the complex task of PE diagnosis without requiring computationally intensive and time consuming preprocessing and demonstrates sustained performance on data from an external institution. Our model could be applied as a triage tool to automatically identify clinically important PEs allowing for prioritization for diagnostic radiology interpretation and improved care pathways via more efficient diagnosis.

Despite successes on the Sustainable Development Goals for access to improved water sources and sanitation, many low and middle-income countries (LMICs) continue to struggle with high rates of diarrheal disease. In Guatemala, 98% of water sources are estimated to have E. coli contamination. This project moves toward a novel low-cost approach to bridge the gap between the microbiologic identification of E. coli and the vast impact that this pathogen has on human health within marginalized communities using co-designed community-based tools, low-cost technology, and AI. An agile co-design process was followed with water quality stakeholders, community staff, and local graphic design artists to develop a community water quality education mobile app. A series of alpha- and beta-testers completed interactive demonstration, feedback, and in-depth interview sessions. A microbiology lab in Guatemala developed and piloted field protocols with lay community workers to collect and process water samples. A preliminary artificial intelligence (AI) algorithm was developed to detect the presence of E. coli in images generated from community-derived water samples. The mobile app emerged as a pictorial and audio-driven community-facing tool. The field protocol for water sampling and testing was successfully implemented by lay community workers. Feedback from the community workers indicated both desire and ability to conduct the water sampling and testing protocol under field conditions. However, images derived from the low-cost $2 microscope in field conditions were not of a suitable quality for AI object detection of E. coli, and additional low-cost technologies are being considered. The preliminary AI object detection algorithm from lab-derived images performed at 94% accuracy in identifying E. coli in comparison to the Chromocult gold-standard.

Background: Population-based state cancer registries are an authoritative source for cancer statistics in the United States. They routinely collect a variety of data, including patient demographics, primary tumor site, stage at diagnosis, first course of treatment, and survival, on every cancer case that is reported across all U.S. states and territories. The goal of our project is to enrich NCI’s Surveillance, Epidemiology, and End Results (SEER) registry data with high-quality population-based biospecimen data in the form of digital pathology, machine-learning-based classifications, and quantitative histopathology imaging feature sets (referred to here as Pathomics features). Materials and methods: As part of the project, the underlying informatics infrastructure was designed, tested, and implemented through close collaboration with several participating SEER registries to ensure consistency with registry processes, computational scalability, and ability to support creation of population cohorts that span multiple sites. Utilizing computational imaging algorithms and methods to both generate indices and search for matches makes it possible to reduce inter- and intra-observer inconsistencies and to improve the objectivity with which large image repositories are interrogated. Results: Our team has created and continues to expand a well-curated repository of high-quality digitized pathology images corresponding to subjects whose data are routinely collected by the collaborating registries. Our team has systematically deployed and tested key, visual analytic methods to facilitate automated creation of population cohorts for epidemiological studies and tools to support visualization of feature clusters and evaluation of whole-slide images. As part of these efforts, we are developing and optimizing advanced search and matching algorithms to facilitate automated, content-based retrieval of digitized specimens based on their underlying image features and staining characteristics. Conclusion: To meet the challenges of this project, we established the analytic pipelines, methods, and workflows to support the expansion and management of a growing repository of high-quality digitized pathology and information-rich, population cohorts containing objective imaging and clinical attributes to facilitate studies that seek to discriminate among different subtypes of disease, stratify patient populations, and perform comparisons of tumor characteristics within and across patient cohorts. We have also successfully developed a suite of tools based on a deep-learning method to perform quantitative characterizations of tumor regions, assess infiltrating lymphocyte distributions, and generate objective nuclear feature measurements. As part of these efforts, our team has implemented reliable methods that enable investigators to systematically search through large repositories to automatically retrieve digitized pathology specimens and correlated clinical data based on their computational signatures.

Pathology reports primarily consist of unstructured free text and thus the clinical information contained in the reports is not trivial to access or query. Multiple natural language processing (NLP) techniques have been proposed to automate the coding of pathology reports via text classification. In this systematic review, we follow the guidelines proposed by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA; Page et al., 2020: BMJ.) to identify the NLP systems for classifying pathology reports published between the years of 2010 and 2021. Based on our search criteria, a total of 3445 records were retrieved, and 25 articles met the final review criteria. We benchmarked the systems based on methodology, complexity of the prediction task and core types of NLP models: i) Rule-based and Intelligent systems, ii) statistical machine learning, and iii) deep learning. While certain tasks are well addressed by these models, many others have limitations and remain as open challenges, such as, extraction of many cancer characteristics (size, shape, type of cancer, others) from pathology reports. We investigated the final set of papers (25) and addressed their potential as well as their limitations. We hope that this systematic review helps researchers prioritize the development of innovated approaches to tackle the current limitations and help the advancement of cancer research.

Abstract Introduction A learning health system (LHS) must improve care in ways that are meaningful to patients, integrating patient‐centered outcomes (PCOs) into core infrastructure. PCOs are common following cancer treatment, such as urinary incontinence (UI) following prostatectomy. However, PCOs are not systematically recorded because they can only be described by the patient, are subjective and captured as unstructured text in the electronic health record (EHR). Therefore, PCOs pose significant challenges for phenotyping patients. Here, we present a natural language processing (NLP) approach for phenotyping patients with UI to classify their disease into severity subtypes, which can increase opportunities to provide precision‐based therapy and promote a value‐based delivery system. Methods Patients undergoing prostate cancer treatment from 2008 to 2018 were identified at an academic medical center. Using a hybrid NLP pipeline that combines rule‐based and deep learning methodologies, we classified positive UI cases as mild, moderate, and severe by mining clinical notes. Results The rule‐based model accurately classified UI into disease severity categories (accuracy: 0.86), which outperformed the deep learning model (accuracy: 0.73). In the deep learning model, the recall rates for mild and moderate group were higher than the precision rate (0.78 and 0.79, respectively). A hybrid model that combined both methods did not improve the accuracy of the rule‐based model but did outperform the deep learning model (accuracy: 0.75). Conclusion Phenotyping patients based on indication and severity of PCOs is essential to advance a patient centered LHS. EHRs contain valuable information on PCOs and by using NLP methods, it is feasible to accurately and efficiently phenotype PCO severity. Phenotyping must extend beyond the identification of disease to provide classification of disease severity that can be used to guide treatment and inform shared decision‐making. Our methods demonstrate a path to a patient centered LHS that could advance precision medicine.

Abstract Background Pathogenesis of inflammatory diseases can be tracked by studying the causality relationships among the factors contributing to its development. We could, for instance, hypothesize on the connections of the pathogenesis outcomes to the observed conditions. And to prove such causal hypotheses we would need to have the full understanding of the causal relationships, and we would have to provide all the necessary evidences to support our claims. In practice, however, we might not possess all the background knowledge on the causality relationships, and we might be unable to collect all the evidence to prove our hypotheses. Results In this work we propose a methodology for the translation of biological knowledge on causality relationships of biological processes and their effects on conditions to a computational framework for hypothesis testing. The methodology consists of two main points: hypothesis graph construction from the formalization of the background knowledge on causality relationships, and confidence measurement in a causality hypothesis as a normalized weighted path computation in the hypothesis graph. In this framework, we can simulate collection of evidences and assess confidence in a causality hypothesis by measuring it proportionally to the amount of available knowledge and collected evidences. Conclusions We evaluate our methodology on a hypothesis graph that represents both contributing factors which may cause cartilage degradation and the factors which might be caused by the cartilage degradation during osteoarthritis. Hypothesis graph construction has proven to be robust to the addition of potentially contradictory information on the simultaneously positive and negative effects. The obtained confidence measures for the specific causality hypotheses have been validated by our domain experts, and, correspond closely to their subjective assessments of confidences in investigated hypotheses. Overall, our methodology for a shared hypothesis testing framework exhibits important properties that researchers will find useful in literature review for their experimental studies, planning and prioritizing evidence collection acquisition procedures, and testing their hypotheses with different depths of knowledge on causal dependencies of biological processes and their effects on the observed conditions.

Widely-prescribed prodrug opioids (e.g., hydrocodone) require conversion by liver enzyme CYP-2D6 to exert their analgesic effects. The most commonly prescribed antidepressant, selective serotonin reuptake inhibitors (SSRIs), inhibits CYP-2D6 activity and therefore may reduce the effectiveness of prodrug opioids. We used a machine learning approach to identify patients prescribed a combination of SSRIs and prodrug opioids postoperatively and to examine the effect of this combination on postoperative pain control. Using EHR data from an academic medical center, we identified patients receiving surgery over a 9-year period. We developed and validated natural language processing (NLP) algorithms to extract depression-related information (diagnosis, SSRI use, symptoms) from structured and unstructured data elements. The primary outcome was the difference between preoperative pain score and postoperative pain at discharge, 3-week and 8-week time points. We developed computational models to predict the increase or decrease in the postoperative pain across the 3 time points by using the patient's EHR data (e.g. medications, vitals, demographics) captured before surgery. We evaluate the generalizability of the model using 10-fold cross-validation method where the holdout test method is repeated 10 times and mean area-under-the-curve (AUC) is considered as evaluation metrics for the prediction performance. We identified 4,306 surgical patients with symptoms of depression. A total of 14.1% were prescribed both an SSRI and a prodrug opioid, 29.4% were prescribed an SSRI and a non-prodrug opioid, 18.6% were prescribed a prodrug opioid but were not on SSRIs, and 37.5% were prescribed a non-prodrug opioid but were not on SSRIs. Our NLP algorithm identified depression with a F1 score of 0.95 against manual annotation of 300 randomly sampled clinical notes. On average, patients receiving prodrug opioids had lower average pain scores (p0.05). The machine learning algorithm accurately predicted the increase or decrease of the discharge, 3-week and 8-week follow-up pain scores when compared to the pre-operative pain score using 10-fold cross validation (mean area under the receiver operating characteristic curve 0.87, 0.81, and 0.69, respectively). Preoperative pain, surgery type, and opioid tolerance were the strongest predictors of postoperative pain control. We provide the first direct clinical evidence that the known ability of SSRIs to inhibit prodrug opioid effectiveness is associated with worse pain control among depressed patients. Current prescribing patterns indicate that prescribers may not account for this interaction when choosing an opioid. The study results imply that prescribers might instead choose direct acting opioids (e.g. oxycodone or morphine) in depressed patients on SSRIs.

Datasets displaying temporal dependencies abound in science and engineering applications, with Markov models representing a simplified and popular view of the temporal dependence structure. In this paper, we consider Bayesian settings that place prior distributions over the parameters of the transition kernel of a Markov model, and seek to characterize the resulting, typically intractable, posterior distributions. We present a Probably Approximately Correct (PAC)-Bayesian analysis of variational Bayes (VB) approximations to tempered Bayesian posterior distributions, bounding the model risk of the VB approximations. Tempered posteriors are known to be robust to model misspecification, and their variational approximations do not suffer the usual problems of over confident approximations. Our results tie the risk bounds to the mixing and ergodic properties of the Markov data generating model. We illustrate the PAC-Bayes bounds through a number of example Markov models, and also consider the situation where the Markov model is misspecified.

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