Novel echocardiographic pixel intensity quantification method for differentiating transthyretin cardiac amyloidosis from light chain cardiac amyloidosis and other phenocopies.

AIMS: Differentiating cardiac amyloidosis (CA) subtypes is important considering the significantly different therapies for transthyretin (ATTR)-CA and light chain (AL)-CA. Therefore, an echocardiographic method to distinguish ATTR-CA from AL-CA would provide significant value. We assessed a novel echocardiographic pixel intensity method to quantify myocardial calcification to differentiate ATTR-CA from phenocopies of CA and from AL-CA, specifically. METHODS AND RESULTS: 167 patients with ATTR-CA (n=53), AL-CA (n=32), hypertrophic cardiomyopathy (n=37), and advanced chronic kidney disease (n=45) were retrospectively evaluated. The septal reflectivity ratio (SRR) was measured as the average pixel intensity of the visible anterior septal wall divided by the average pixel intensity of the visible posterior lateral wall. SRR and other myocardial strain-based echocardiographic measures were evaluated with receiver operator characteristic analysis to evaluate accuracy in distinguishing ATTR-CA from AL-CA and other forms of left ventricular hypertrophy. Mean septal reflectivity ratio (SRR) was significantly higher in the ATTR-CA cohort compared to the other cohorts (p <0.001). SRR demonstrated the largest AUC (0.91, p<0.0001) for distinguishing ATTR from all other cohorts and specifically for distinguishing ATTR-CA from AL-CA (AUC=0.90, p<0.0001, specificity 96%, sensitivity 63%). There was excellent inter- and intra-operator reproducibility with an ICC of 0.91 (p <0.001) and 0.89 (p <0.001), respectively. CONCLUSION: The SRR is a reproducible and robust parameter for differentiating ATTR-CA from other phenocopies of CA and specifically ATTR-CA from AL-CA.

Integrative analysis of functional genomic screening and clinical data identifies a protective role for spironolactone in severe COVID-19.

We demonstrate that integrative analysis of CRISPR screening datasets enables network-based prioritization of prescription drugs modulating viral entry in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by developing a network-based approach called Rapid proXimity Guidance for Repurposing Investigational Drugs (RxGRID). We use our results to guide a propensity-score-matched, retrospective cohort study of 64,349 COVID-19 patients, showing that a top candidate drug, spironolactone, is associated with improved clinical prognosis, measured by intensive care unit (ICU) admission and mechanical ventilation rates. Finally, we show that spironolactone exerts a dose-dependent inhibitory effect on viral entry in human lung epithelial cells. Our RxGRID method presents a computational framework, implemented as an open-source software package, enabling genomics researchers to identify drugs likely to modulate a molecular phenotype of interest based on high-throughput screening data. Our results, derived from this method and supported by experimental and clinical analysis, add additional supporting evidence for a potential protective role of the potassium-sparing diuretic spironolactone in severe COVID-19.

Transportability of bacterial infection prediction models for critically ill patients.

OBJECTIVE: Bacterial infections (BIs) are common, costly, and potentially life-threatening in critically ill patients. Patients with suspected BIs may require empiric multidrug antibiotic regimens and therefore potentially be exposed to prolonged and unnecessary antibiotics. We previously developed a BI risk model to augment practices and help shorten the duration of unnecessary antibiotics to improve patient outcomes. Here, we have performed a transportability assessment of this BI risk model in 2 tertiary intensive care unit (ICU) settings and a community ICU setting. We additionally explored how simple multisite learning techniques impacted model transportability. METHODS: Patients suspected of having a community-acquired BI were identified in 3 datasets: Medical Information Mart for Intensive Care III (MIMIC), Northwestern Medicine Tertiary (NM-T) ICUs, and NM "community-based" ICUs. ICU encounters from MIMIC and NM-T datasets were split into 70/30 train and test sets. Models developed on training data were evaluated against the NM-T and MIMIC test sets, as well as NM community validation data. RESULTS: During internal validations, models achieved AUROCs of 0.78 (MIMIC) and 0.81 (NM-T) and were well calibrated. In the external community ICU validation, the NM-T model had robust transportability (AUROC 0.81) while the MIMIC model transported less favorably (AUROC 0.74), likely due to case-mix differences. Multisite learning provided no significant discrimination benefit in internal validation studies but offered more stability during transport across all evaluation datasets. DISCUSSION: These results suggest that our BI risk models maintain predictive utility when transported to external cohorts. CONCLUSION: Our findings highlight the importance of performing external model validation on myriad clinically relevant populations prior to implementation.

Comparison of Dynamic Knee Contact Mechanics with T2 Imaging in Different Ages of Healthy Participants.

Aging is a known risk factor for Osteoarthritis (OA), however, relations between cartilage composition and aging remain largely unknown in understanding human OA. T2 imaging provides an approach to assess cartilage composition. Whether these T2 relaxation times in the joint contact region change with time during gait remain unexplored. The study purpose was to demonstrate a methodology for linking dynamic joint contact mechanics to cartilage composition as measured by T2 relaxometry. T2 relaxation times for unloaded cartilage were measured in a 3T General Electric magnetic resonance (MR) scanner in this preliminary study. High-speed biplanar video-radiography (HSBV) was captured for five 20-30-year-old and five 50-60-year-old participants with asymptomatic knees. By mapping the T2 cartilages to the dynamic contact regions, T2 values were averaged over the contact area at each measurement within the gait cycle. T2 values demonstrated a functional relationship across the gait cycle. There were no statistically significant differences between 20- and 30-year-old and 50-60-year-old participant T2 values at first force peak of the gait cycle in the medial femur (p = 1.00, U = 12) or in the medial tibia (p = 0.31, U = 7). In the medial and lateral femur in swing phase, the joint moved from a region of high T2 values at 75% of gait to a minimum at 85-95% of swing. The lateral femur and tibia demonstrated similar patterns to the medial compartments but were less pronounced. This research advances understanding of the linkage between cartilage contact and cartilage composition. The change from a high T2 value at ~ 75% of gait to a lower value near the initiation of terminal swing (90% gait) indicates that there are changes to T2 averages corresponding to changes in the contact region across the gait cycle. No differences were found between age groups for healthy participants. These preliminary findings provide interesting insights into the cartilage composition corresponding to dynamic cyclic motion and inform mechanisms of osteoarthritis.

Patterns of diverse and changing sentiments towards COVID-19 vaccines: a sentiment analysis study integrating 11 million tweets and surveillance data across over 180 countries.

OBJECTIVES: Vaccines are crucial components of pandemic responses. Over 12 billion coronavirus disease 2019 (COVID-19) vaccines were administered at the time of writing. However, public perceptions of vaccines have been complex. We integrated social media and surveillance data to unravel the evolving perceptions of COVID-19 vaccines. MATERIALS AND METHODS: Applying human-in-the-loop deep learning models, we analyzed sentiments towards COVID-19 vaccines in 11 211 672 tweets of 2 203 681 users from 2020 to 2022. The diverse sentiment patterns were juxtaposed against user demographics, public health surveillance data of over 180 countries, and worldwide event timelines. A subanalysis was performed targeting the subpopulation of pregnant people. Additional feature analyses based on user-generated content suggested possible sources of vaccine hesitancy. RESULTS: Our trained deep learning model demonstrated performances comparable to educated humans, yielding an accuracy of 0.92 in sentiment analysis against our manually curated dataset. Albeit fluctuations, sentiments were found more positive over time, followed by a subsequence upswing in population-level vaccine uptake. Distinguishable patterns were revealed among subgroups stratified by demographic variables. Encouraging news or events were detected surrounding positive sentiments crests. Sentiments in pregnancy-related tweets demonstrated a lagged pattern compared with the general population, with delayed vaccine uptake trends. Feature analysis detected hesitancies stemmed from clinical trial logics, risks and complications, and urgency of scientific evidence. DISCUSSION: Integrating social media and public health surveillance data, we associated the sentiments at individual level with observed populational-level vaccination patterns. By unraveling the distinctive patterns across subpopulations, the findings provided evidence-based strategies for improving vaccine promotion during pandemics.

Multimodal machine learning in precision health: A scoping review.

Machine learning is frequently being leveraged to tackle problems in the health sector including utilization for clinical decision-support. Its use has historically been focused on single modal data. Attempts to improve prediction and mimic the multimodal nature of clinical expert decision-making has been met in the biomedical field of machine learning by fusing disparate data. This review was conducted to summarize the current studies in this field and identify topics ripe for future research. We conducted this review in accordance with the PRISMA extension for Scoping Reviews to characterize multi-modal data fusion in health. Search strings were established and used in databases: PubMed, Google Scholar, and IEEEXplore from 2011 to 2021. A final set of 128 articles were included in the analysis. The most common health areas utilizing multi-modal methods were neurology and oncology. Early fusion was the most common data merging strategy. Notably, there was an improvement in predictive performance when using data fusion. Lacking from the papers were clear clinical deployment strategies, FDA-approval, and analysis of how using multimodal approaches from diverse sub-populations may improve biases and healthcare disparities. These findings provide a summary on multimodal data fusion as applied to health diagnosis/prognosis problems. Few papers compared the outputs of a multimodal approach with a unimodal prediction. However, those that did achieved an average increase of 6.4% in predictive accuracy. Multi-modal machine learning, while more robust in its estimations over unimodal methods, has drawbacks in its scalability and the time-consuming nature of information concatenation.

PsmPy: A Package for Retrospective Cohort Matching in Python.

Propensity score matching (PSM) is a technique used in retrospective investigation of cohort matching as an alternative approach to the prospective matching that is typically used by a randomized control trial (RCT). The process of selecting untreated cases that are the best match to the treated cases is the focus of this research. We created a PSM package for the python environment, termed PsmPy, to carry out this task. The PsmPy package debuted and proposed here is based on a logistic regression logit score where a match is selected using k-nearest neighbors (k-NN). Additional plotting and arguments are available to the user and are also described. To benchmark our method, we compared it with the existing R package, MatchIt, and evaluated our covariates' residual effect sizes with respect to the treatment condition before and after matching. Using a Mann-Whitney statistical test, we showed that our method significantly outperformed MatchIt in cohort matching (U=49, p<0.0001) when comparing residual effect sizes of the covariates. The PsmPy demonstrated a 10-fold average improvement in residual effect sizes amongst covariates when compared with the package MatchIt, suggesting that it is a viable alternative for use in propensity matching studies.

Semi-Supervised Segmentation of Renal Pathology: An Alternative to Manual Segmentation and Input to Deep Learning Training.

Kidney biopsy interpretation is the gold standard for the diagnosis and prognosis for kidney disease. Pathognomonic diagnosis hinges on the correct assessment of different structures within a biopsy that is manually visualized and interpreted by a renal pathologist. This laborious undertaking has spurred attempts to automate the process, offloading the consumption of temporal resources. Segmentation of kidney structures, specifically, the glomeruli, tubules, and interstitium, is a precursory step for disease classification problems. Translating renal disease decision making into a deep learning model for diagnostic and prognostic classification also relies on adequate segmentation of structures within the kidney biopsy. This study showcases a semi-automated segmentation technique where the user defines starting points for glomeruli in kidney biopsy images of both healthy normal and diabetic kidney disease stained with Nile Red that are subsequently partitioned into four areas: background, glomeruli, tubules and interstitium. Five of 30 biopsies that were segmented using the semi-automated method were randomly selected and the regions of interest were compared to the manual segmentation of the same images. Dice Similarity Coefficients (DSC) between the methods showed excellent agreement; Healthy (glomeruli: 0.92, tubules: 0.86, intersititium: 0.78) and diabetic nephropathy: (glomeruli: 0.94, tubules: 0.80, intersititium: 0.80). To our knowledge this is the first semi-automated segmentation algorithm performed with human renal biopsies stained with Nile Red. Utility of this methodology includes further image processing within structures across disease states based on biological morphological structures. It can also be used as input into a deep learning network to train semantic segmentation and input into a deep learning algorithm for classification of disease states.

fMRI-Informed EEG for brain mapping of imagined lower limb movement: Feasibility of a brain computer interface.

BACKGROUND: EEG and fMRI have contributed greatly to our understanding of brain activity and its link to behaviors by helping to identify both when and where the activity occurs. This is particularly important in the development of brain-computer interfaces (BCIs), where feed forward systems gather data from imagined brain activity and then send that information to an effector. The purpose of this study was to develop and evaluate a computational approach that enables an accurate mapping of spatial brain activity (fMRI) in relation to the temporal receptors (EEG electrodes) associated with imagined lower limb movement. NEW METHOD: EEG and fMRI data from 16 healthy, male participants while imagining lower limb movement were used for this purpose. A combined analysis of fMRI data and EEG electrode locations was developed to identify EEG electrodes with a high likelihood of capturing imagined lower limb movement originating from various clusters of brain activity. This novel feature selection tool was used to develop an artificial neural network model to classify right and left lower limb movement. RESULTS: Results showed that left versus right lower limb imagined movement could be classified with 66.5% accuracy using this approach. Comparison with existing methods: Adopting a purely data-driven approach for feature selection to use in the right/left classification task resulted in the same accuracy (66.6%) but with reduced interpretability. CONCLUSIONS: The developed fMRI-informed EEG approach could pave the way towards improved brain computer interfaces for lower limb movement while also being applicable to other systems where fMRI could be helpful to inform EEG acquisition and processing.

Digital public health surveillance: a systematic scoping review.

The ubiquitous and openly accessible information produced by the public on the Internet has sparked an increasing interest in developing digital public health surveillance (DPHS) systems. We conducted a systematic scoping review in accordance with the PRISMA extension for scoping reviews to consolidate and characterize the existing research on DPHS and identify areas for further research. We used Natural Language Processing and content analysis to define the search strings and searched Global Health, Web of Science, PubMed, and Google Scholar from 2005 to January 2020 for peer-reviewed articles on DPHS, with extensive hand searching. Seven hundred fifty-five articles were included in this review. The studies were from 54 countries and utilized 26 digital platforms to study 208 sub-categories of 49 categories associated with 16 public health surveillance (PHS) themes. Most studies were conducted by researchers from the United States (56%, 426) and dominated by communicable diseases-related topics (25%, 187), followed by behavioural risk factors (17%, 131). While this review discusses the potentials of using Internet-based data as an affordable and instantaneous resource for DPHS, it highlights the paucity of longitudinal studies and the methodological and inherent practical limitations underpinning the successful implementation of a DPHS system. Little work studied Internet users' demographics when developing DPHS systems, and 39% (291) of studies did not stratify their results by geographic region. A clear methodology by which the results of DPHS can be linked to public health action has yet to be established, as only six (0.8%) studies deployed their system into a PHS context.

Item response theory as a feature selection and interpretation tool in the context of machine learning.

Optimizing the number and utility of features to use in a classification analysis has been the subject of many research studies. Most current models use end-classifications as part of the feature reduction process, leading to circularity in the methodology. The approach demonstrated in the present research uses item response theory (IRT) to select features independent of the end-classification results without the biased accuracies that this circularity engenders. Dichotomous and polytomous IRT models were used to analyze 30 histological breast cancer features from 569 patients using the Wisconsin Diagnostic Breast Cancer data set. Based on their characteristics, three features were selected for use in a machine learning classifier. For comparison purposes, two machine learning-based feature selection protocols were run-recursive feature elimination (RFE) and ridge regression-and the three features selected from these analyses were also used in the subsequent learning classifier. Classification results demonstrated that all three selection processes performed comparably. The non-biased nature of the IRT protocol and information provided about the specific characteristics of the features as to why they are of use in classification help to shed light on understanding which attributes of features make them suitable for use in a machine learning context.

EEG differentiates left and right imagined Lower Limb movement.

BACKGROUND: Identifying which EEG signals distinguish left from right leg movements in imagined lower limb movement is crucial to building an effective and efficient brain-computer interface (BCI). Past findings on this issue have been mixed, partly due to the difficulty in collecting and isolating the relevant information. The purpose of this study was to contribute to this new and important literature. RESEARCH QUESTION: Can left versus right imagined stepping be differentiated using the alpha, beta, and gamma frequencies of EEG data at four electrodes (C1, C2, PO3, and PO4)? METHODS: An experiment was conducted with a sample of 16 healthy male participants. They imagined left and right lower limb movements across 60 trials at two time periods separated by one week. Participants were fitted with a 64-electrode headcap, lay supine on a specially designed device and then completed the imagined task while observing a customized computer-generated image of a human walking to signify the left and right steps, respectively. RESULTS: Findings showed that eight of the twelve frequency bands from 4 EEG electrodes were significant in differentiating imagined left from right lower limb movement. Using these data points, a neural network analysis resulted in an overall participant average test classification accuracy of left versus right movements at 63 %. SIGNIFICANCE: Our study provides support for using the alpha, beta and gamma frequency bands at the sensorimotor areas (C1 and C2 electrodes) and incorporating information from the parietal/occipital lobes (PO3 and PO4 electrodes) for focused, real-time EEG signal processing to assist in creating a BCI for those with lower limb compromised mobility.

Evaluation of Machine Learning-based Patient Outcome Prediction Using Patient-specific Difficulty and Discrimination Indices.

Given the extensive use of machine learning in patient outcome prediction, and the understanding that the challenging nature of predictions in this field may considerably modify the performance of predictive models, research in this area requires some forms of context-sensitive performance metrics. The area under the receiver operating characteristic curve (AUC), precision, recall, specificity, and F1 are widely used measures of performance for patient outcome prediction. These metrics have several merits: they are easy to interpret and do not need any subjective input from the user. However, they weight all samples equally and do not adequately reflect the ability of predictive models in classifying difficult samples. In this paper, we propose the Difficulty Weight Adjustment (DWA) algorithm, a simple method that incorporates the difficulty level of samples when evaluating predictive models. Using a large dataset of 139,367 unique ICU admissions within the eICU Collaborative Research Database (eICU-CRD), we show that the classification difficulty and the discrimination ability of samples are critical aspects that need to be considered when comparing machine learning models that predict patient outcomes.

Novel Feature Selection for Artificial Intelligence Using Item Response Theory for Mortality Prediction.

Feature selection is a critical component in supervised machine learning classification analyses. Extraneous features introduce noise and inefficiencies into the system leading to a need for feature reduction techniques. Many feature reduction models use the end-classification results in the feature reduction process, committing a circular error. Item Response Theory (IRT) examines the characteristics of features independent of the end-classification results, and provides high levels of information regarding feature utility. A two-parameter dichotomous IRT model was used to analyze 18 features from an intensive care unit data set with 2520 cases. The classification results showed that the features selected via IRT were comparable to that using more traditional machine learning approaches. Strengths and limitations of the IRT selection protocol are discussed.

Using Item Response Theory for Explainable Machine Learning in Predicting Mortality in the Intensive Care Unit: Case-Based Approach.

BACKGROUND: Supervised machine learning (ML) is being featured in the health care literature with study results frequently reported using metrics such as accuracy, sensitivity, specificity, recall, or F1 score. Although each metric provides a different perspective on the performance, they remain to be overall measures for the whole sample, discounting the uniqueness of each case or patient. Intuitively, we know that all cases are not equal, but the present evaluative approaches do not take case difficulty into account. OBJECTIVE: A more case-based, comprehensive approach is warranted to assess supervised ML outcomes and forms the rationale for this study. This study aims to demonstrate how the item response theory (IRT) can be used to stratify the data based on how difficult each case is to classify, independent of the outcome measure of interest (eg, accuracy). This stratification allows the evaluation of ML classifiers to take the form of a distribution rather than a single scalar value. METHODS: Two large, public intensive care unit data sets, Medical Information Mart for Intensive Care III and electronic intensive care unit, were used to showcase this method in predicting mortality. For each data set, a balanced sample (n=8078 and n=21,940, respectively) and an imbalanced sample (n=12,117 and n=32,910, respectively) were drawn. A 2-parameter logistic model was used to provide scores for each case. Several ML algorithms were used in the demonstration to classify cases based on their health-related features: logistic regression, linear discriminant analysis, K-nearest neighbors, decision tree, naive Bayes, and a neural network. Generalized linear mixed model analyses were used to assess the effects of case difficulty strata, ML algorithm, and the interaction between them in predicting accuracy. RESULTS: The results showed significant effects (P<.001) for case difficulty strata, ML algorithm, and their interaction in predicting accuracy and illustrated that all classifiers performed better with easier-to-classify cases and that overall the neural network performed best. Significant interactions suggest that cases that fall in the most arduous strata should be handled by logistic regression, linear discriminant analysis, decision tree, or neural network but not by naive Bayes or K-nearest neighbors. Conventional metrics for ML classification have been reported for methodological comparison. CONCLUSIONS: This demonstration shows that using the IRT is a viable method for understanding the data that are provided to ML algorithms, independent of outcome measures, and highlights how well classifiers differentiate cases of varying difficulty. This method explains which features are indicative of healthy states and why. It enables end users to tailor the classifier that is appropriate to the difficulty level of the patient for personalized medicine.

Differentiating the Brain's involvement in Executed and Imagined Stepping using fMRI.

The purpose of this study was to extend the extant literature regarding brain areas that are activated during executed and imagined lower limb movement. Past research suggests that stepping, as a cyclical movement, should activate the motor control areas of the brain that integrates smooth movements with spinal cord nerves. The neuronal activity needed to imagine that same activity is likely to recruit additional sensory-motor areas that provide initiation and inhibition signals, making this task take on a neuronal activity pattern that is more similar to discrete movements. To assess this research question, 16 participants took part in the current study where they executed and imagined stepping, with movement at the hip, knee, and ankle joints, while viewing a computer-generated image of a human walking. A block design with a total of 10 blocks for rest and task for each condition was used. Rest blocks lasted 18 seconds, followed by an 18-second display of the visual stimulus. Results showed that in the executed condition, areas of the brain that are most prominently associated with sensory-motor activity were activated. In the imagined condition areas of the brain associated with movement control, inhibition of movement, and the integration of sensory input and motor output (parietal and occipital) were also activated. These findings contribute to the literature identifying brain areas that are activated in lower limb locomotion.

Imaging limitations in evaluating blunt cardiac trauma: A case report.

A 20-year old male presented with life-threatening polytrauma secondary to a motor vehicle accident. He had sustained injuries to the chest, including blunt cardiac trauma. On a short-term follow-up imaging, it was determined the patient had an injury to the main pulmonary artery and possible pericardial rupture. Given these imaging findings, he was taken to the operating room for emergent surgical intervention. Surgery revealed intracardiac injury; however, the pulmonary artery was intact. This case report is significant for the following two learning points: (a) The potential limitations of computed tomography when assessing intrathoracic injury, and (b) unique constellation of injuries secondary to trauma.

Macrophages Promote Wound-Induced Hair Follicle Regeneration in a CX3CR1- and TGF-ß1-Dependent Manner.

Hair follicle stem cells are regulated by intrafollicular and extrafollicular niche signals. Appropriate hair follicle regeneration relies on the coordinated release and integration of these signals. How immune cells, particularly cutaneous macrophages, influence the hair follicle stem cell niche and regeneration is not well understood. We took advantage of wound-induced hair growth (WIHG) to explore the relationship between wound macrophages and hair follicle regeneration. First, we showed that WIHG is dependent on CD11b+F4/80+ macrophages at 7-11 days after injury. Next, using CX3CR1gfp/+:CCR2rfp/+ mice to capture the dynamic spectrum of macrophage phenotypes during wound healing, we showed that wound macrophages transition from a CX3CR1lo/med to a CX3CR1hi phenotype at the onset of WIHG. Finally, WIHG is abolished in mice deficient for CX3CR1, delayed with pharmacological inhibition of transforming growth factor-ß receptor type 1, and rescued with exogenous transforming growth factor-ß1. Overall, we propose a model in which transforming growth factor-ß1 and CX3CR1 are critical for recruiting and maintaining the CCR2+CX3CR1hiLy6CloTNFα+ macrophages critical for stimulating WIHG.