Deep Learning for Echo Analysis, Tracking, and Evaluation of Mitral Regurgitation (DELINEATE-MR).

BACKGROUND: Artificial intelligence, particularly deep learning (DL), has immense potential to improve the interpretation of transthoracic echocardiography (TTE). Mitral regurgitation (MR) is the most common valvular heart disease and presents unique challenges for DL, including the integration of multiple video-level assessments into a final study-level classification. METHODS: A novel DL system was developed to intake complete TTEs, identify color MR Doppler videos, and determine MR severity on a 4-step ordinal scale (none/trace, mild, moderate, and severe) using the reading cardiologist as a reference standard. This DL system was tested in internal and external test sets with performance assessed by agreement with the reading cardiologist, weighted κ, and area under the receiver-operating characteristic curve for binary classification of both moderate or greater and severe MR. In addition to the primary 4-step model, a 6-step MR assessment model was studied with the addition of the intermediate MR classes of mild-moderate and moderate-severe with performance assessed by both exact agreement and ±1 step agreement with the clinical MR interpretation. RESULTS: A total of 61 689 TTEs were split into train (n=43 811), validation (n=8891), and internal test (n=8987) sets with an additional external test set of 8208 TTEs. The model had high performance in MR classification in internal (exact accuracy, 82%; κ=0.84; area under the receiver-operating characteristic curve, 0.98 for moderate/severe MR) and external test sets (exact accuracy, 79%; κ=0.80; area under the receiver-operating characteristic curve, 0.98 for moderate or greater MR). Most (63% internal and 66% external) misclassification disagreements were between none/trace and mild MR. MR classification accuracy was slightly higher using multiple TTE views (accuracy, 82%) than with only apical 4-chamber views (accuracy, 80%). In subset analyses, the model was accurate in the classification of both primary and secondary MR with slightly lower performance in cases of eccentric MR. In the analysis of the 6-step classification system, the exact accuracy was 80% and 76% with a ±1 step agreement of 99% and 98% in the internal and external test set, respectively. CONCLUSIONS: This end-to-end DL system can intake entire echocardiogram studies to accurately classify MR severity and may be useful in helping clinicians refine MR assessments.

An ECG-based machine learning model for predicting new-onset atrial fibrillation is superior to age and clinical features in identifying patients at high stroke risk.

BACKGROUND: Several large trials have employed age or clinical features to select patients for atrial fibrillation (AF) screening to reduce strokes. We hypothesized that a machine learning (ML) model trained to predict AF risk from 12­lead electrocardiogram (ECG) would be more efficient than criteria based on clinical variables in indicating a population for AF screening to potentially prevent AF-related stroke. METHODS: We retrospectively included all patients with clinical encounters in Geisinger without a prior history of AF. Incidence of AF within 1 year and AF-related strokes within 3 years of the encounter were identified. AF-related stroke was defined as a stroke where AF was diagnosed at the time of stroke or within a year after the stroke. The efficiency of five methods was evaluated for selecting a cohort for AF screening. The methods were selected from four clinical trials (mSToPS, GUARD-AF, SCREEN-AF and STROKESTOP) and the ECG-based ML model. We simulated patient selection for the five methods between the years 2011 and 2014 and evaluated outcomes for 1 year intervals between 2012 and 2015, resulting in a total of twenty 1-year periods. Patients were considered eligible if they met the criteria before the start of the given 1-year period or within that period. The primary outcomes were numbers needed to screen (NNS) for AF and AF-associated stroke. RESULTS: The clinical trial models indicated large proportions of the population with a prior ECG for AF screening (up to 31%), coinciding with NNS ranging from 14 to 18 for AF and 249-359 for AF-associated stroke. At comparable sensitivity, the ECG ML model indicated a modest number of patients for screening (14%) and had the highest efficiency in NNS for AF (7.3; up to 60% reduction) and AF-associated stroke (223; up to 38% reduction). CONCLUSIONS: An ECG-based ML risk prediction model is more efficient than contemporary AF-screening criteria based on age alone or age and clinical features at indicating a population for AF screening to potentially prevent AF-related strokes.

Generalizability and quality control of deep learning-based 2D echocardiography segmentation models in a large clinical dataset.

Use of machine learning (ML) for automated annotation of heart structures from echocardiographic videos is an active research area, but understanding of comparative, generalizable performance among models is lacking. This study aimed to (1) assess the generalizability of five state-of-the-art ML-based echocardiography segmentation models within a large Geisinger clinical dataset, and (2) test the hypothesis that a quality control (QC) method based on segmentation uncertainty can further improve segmentation results. Five models were applied to 47,431 echocardiography studies that were independent from any training samples. Chamber volume and mass from model segmentations were compared to clinically-reported values. The median absolute errors (MAE) in left ventricular (LV) volumes and ejection fraction exhibited by all five models were comparable to reported inter-observer errors (IOE). MAE for left atrial volume and LV mass were similarly favorable to respective IOE for models trained for those tasks. A single model consistently exhibited the lowest MAE in all five clinically-reported measures. We leveraged the tenfold cross-validation training scheme of this best-performing model to quantify segmentation uncertainty. We observed that removing segmentations with high uncertainty from 14 to 71% studies reduced volume/mass MAE by 6-10%. The addition of convexity filters improved specificity, efficiently removing < 10% studies with large MAE (16-40%). In conclusion, five previously published echocardiography segmentation models generalized to a large, independent clinical dataset-segmenting one or multiple cardiac structures with overall accuracy comparable to manual analyses-with variable performance. Convexity-reinforced uncertainty QC efficiently improved segmentation performance and may further facilitate the translation of such models.

Analysis of rare genetic variation underlying cardiometabolic diseases and traits among 200,000 individuals in the UK Biobank.

Cardiometabolic diseases are the leading cause of death worldwide. Despite a known genetic component, our understanding of these diseases remains incomplete. Here, we analyzed the contribution of rare variants to 57 diseases and 26 cardiometabolic traits, using data from 200,337 UK Biobank participants with whole-exome sequencing. We identified 57 gene-based associations, with broad replication of novel signals in Geisinger MyCode. There was a striking risk associated with mutations in known Mendelian disease genes, including MYBPC3, LDLR, GCK, PKD1 and TTN. Many genes showed independent convergence of rare and common variant evidence, including an association between GIGYF1 and type 2 diabetes. We identified several large effect associations for height and 18 unique genes associated with blood lipid or glucose levels. Finally, we found that between 1.0% and 2.4% of participants carried rare potentially pathogenic variants for cardiometabolic disorders. These findings may facilitate studies aimed at therapeutics and screening of these common disorders.

Deep-learning-assisted analysis of echocardiographic videos improves predictions of all-cause mortality.

Machine learning promises to assist physicians with predictions of mortality and of other future clinical events by learning complex patterns from historical data, such as longitudinal electronic health records. Here we show that a convolutional neural network trained on raw pixel data in 812,278 echocardiographic videos from 34,362 individuals provides superior predictions of one-year all-cause mortality. The model's predictions outperformed the widely used pooled cohort equations, the Seattle Heart Failure score (measured in an independent dataset of 2,404 patients with heart failure who underwent 3,384 echocardiograms), and a machine learning model involving 58 human-derived variables from echocardiograms and 100 clinical variables derived from electronic health records. We also show that cardiologists assisted by the model substantially improved the sensitivity of their predictions of one-year all-cause mortality by 13% while maintaining prediction specificity. Large unstructured datasets may enable deep learning to improve a wide range of clinical prediction models.

Deep Neural Networks Can Predict New-Onset Atrial Fibrillation From the 12-Lead ECG and Help Identify Those at Risk of Atrial Fibrillation-Related Stroke.

BACKGROUND: Atrial fibrillation (AF) is associated with substantial morbidity, especially when it goes undetected. If new-onset AF could be predicted, targeted screening could be used to find it early. We hypothesized that a deep neural network could predict new-onset AF from the resting 12-lead ECG and that this prediction may help identify those at risk of AF-related stroke. METHODS: We used 1.6 M resting 12-lead digital ECG traces from 430 000 patients collected from 1984 to 2019. Deep neural networks were trained to predict new-onset AF (within 1 year) in patients without a history of AF. Performance was evaluated using areas under the receiver operating characteristic curve and precision-recall curve. We performed an incidence-free survival analysis for a period of 30 years following the ECG stratified by model predictions. To simulate real-world deployment, we trained a separate model using all ECGs before 2010 and evaluated model performance on a test set of ECGs from 2010 through 2014 that were linked to our stroke registry. We identified the patients at risk for AF-related stroke among those predicted to be high risk for AF by the model at different prediction thresholds. RESULTS: The area under the receiver operating characteristic curve and area under the precision-recall curve were 0.85 and 0.22, respectively, for predicting new-onset AF within 1 year of an ECG. The hazard ratio for the predicted high- versus low-risk groups over a 30-year span was 7.2 (95% CI, 6.9-7.6). In a simulated deployment scenario, the model predicted new-onset AF at 1 year with a sensitivity of 69% and specificity of 81%. The number needed to screen to find 1 new case of AF was 9. This model predicted patients at high risk for new-onset AF in 62% of all patients who experienced an AF-related stroke within 3 years of the index ECG. CONCLUSIONS: Deep learning can predict new-onset AF from the 12-lead ECG in patients with no previous history of AF. This prediction may help identify patients at risk for AF-related strokes.

Prediction of mortality from 12-lead electrocardiogram voltage data using a deep neural network.

The electrocardiogram (ECG) is a widely used medical test, consisting of voltage versus time traces collected from surface recordings over the heart1. Here we hypothesized that a deep neural network (DNN) can predict an important future clinical event, 1-year all-cause mortality, from ECG voltage-time traces. By using ECGs collected over a 34-year period in a large regional health system, we trained a DNN with 1,169,662 12-lead resting ECGs obtained from 253,397 patients, in which 99,371 events occurred. The model achieved an area under the curve (AUC) of 0.88 on a held-out test set of 168,914 patients, in which 14,207 events occurred. Even within the large subset of patients (n = 45,285) with ECGs interpreted as 'normal' by a physician, the performance of the model in predicting 1-year mortality remained high (AUC = 0.85). A blinded survey of cardiologists demonstrated that many of the discriminating features of these normal ECGs were not apparent to expert reviewers. Finally, a Cox proportional-hazard model revealed a hazard ratio of 9.5 (P < 0.005) for the two predicted groups (dead versus alive 1 year after ECG) over a 25-year follow-up period. These results show that deep learning can add substantial prognostic information to the interpretation of 12-lead resting ECGs, even in cases that are interpreted as normal by physicians.

Dopaminergic contributions to hippocampal pathophysiology in schizophrenia: a computational study.

Since the original formulation of the dopamine hypothesis, a number of other cellular-level abnormalities--eg, NMDA receptor hypofunction, GABA system dysfunction, neural connectivity disturbances--have been identified in schizophrenia, but the manner in which these potentially interact with hyperdopaminergia to lead to schizophrenic symptomatology remains uncertain. Previously, we created a neuroanatomically detailed, biophysically realistic computational model of hippocampus in the control (unaffected) and schizophrenic conditions, implemented on a 72-processor supercomputer platform. In the current study, we apply the effects of dopamine (DA), dose-dependently, to both models on the basis of an exhaustive review of the neurophysiologic literature on DA's ion channel and synaptic level effects. To index schizophrenic behavior, we use the specific inability of the model to attune to the 40 Hz (gamma band) frequency, a finding that has been well replicated in the clinical electroencephalography (EEG) and magnetoencephalography literature. In trials using 20 'simulated patients', we find that DA applied to the control model produces modest increases in 40 Hz activity, similar to experimental studies. However, in the schizophrenic model, increasing DA induces a decrement in 40 Hz resonance. This modeling work is significant in that it suggests that DA's effects may vary based on the neural substrate on which it acts, and--via simulated EEG recordings-points to the neurophysiologic mechanisms by which this may occur. We also feel that it makes a methodological contribution, as it exhibits a process by which a large amount of neurobiological data can be integrated to run pharmacologically relevant in silico experiments, using a systems biology approach.

Development of antipsychotic medications with novel mechanisms of action based on computational modeling of hippocampal neuropathology.

A large number of cellular level abnormalities have been identified in the hippocampus of schizophrenic subjects. Nonetheless, it remains uncertain how these pathologies interact at a system level to create clinical symptoms, and this has hindered the development of more effective antipsychotic medications. Using a 72-processor supercomputer, we created a tissue level hippocampal simulation, featuring multicompartmental neuron models with multiple ion channel subtypes and synaptic channels with realistic temporal dynamics. As an index of the schizophrenic phenotype, we used the specific inability of the model to attune to 40 Hz (gamma band) stimulation, a well-characterized abnormality in schizophrenia. We examined several possible combinations of putatively schizophrenogenic cellular lesions by systematically varying model parameters representing NMDA channel function, dendritic spine density, and GABA system integrity, conducting 910 trials in total. Two discrete "clusters" of neuropathological changes were identified. The most robust was characterized by co-occurring modest reductions in NMDA system function (-30%) and dendritic spine density (-30%). Another set of lesions had greater NMDA hypofunction along with low level GABA system dysregulation. To the schizophrenic model, we applied the effects of 1,500 virtual medications, which were implemented by varying five model parameters, independently, in a graded manner; the effects of known drugs were also applied. The simulation accurately distinguished agents that are known to lack clinical efficacy, and identified novel mechanisms (e.g., decrease in AMPA conductance decay time constant, increase in projection strength of calretinin-positive interneurons) and combinations of mechanisms that could re-equilibrate model behavior. These findings shed light on the mechanistic links between schizophrenic neuropathology and the gamma band oscillatory abnormalities observed in the illness. As such, they generate specific falsifiable hypotheses, which can guide postmortem and other laboratory research. Significantly, this work also suggests specific non-obvious targets for potential pharmacologic agents.