Genetic architecture of cardiac dynamic flow volumes.

Cardiac blood flow is a critical determinant of human health. However, the definition of its genetic architecture is limited by the technical challenge of capturing dynamic flow volumes from cardiac imaging at scale. We present DeepFlow, a deep-learning system to extract cardiac flow and volumes from phase-contrast cardiac magnetic resonance imaging. A mixed-linear model applied to 37,653 individuals from the UK Biobank reveals genome-wide significant associations across cardiac dynamic flow volumes spanning from aortic forward velocity to aortic regurgitation fraction. Mendelian randomization reveals a causal role for aortic root size in aortic valve regurgitation. Among the most significant contributing variants, localizing genes (near ELN, PRDM6 and ADAMTS7) are implicated in connective tissue and blood pressure pathways. Here we show that DeepFlow cardiac flow phenotyping at scale, combined with genotyping data, reinforces the contribution of connective tissue genes, blood pressure and root size to aortic valve function.

Electrocardiographic deep learning for predicting post-procedural mortality: a model development and validation study.

BACKGROUND: Preoperative risk assessments used in clinical practice are insufficient in their ability to identify risk for postoperative mortality. Deep-learning analysis of electrocardiography can identify hidden risk markers that can help to prognosticate postoperative mortality. We aimed to develop a prognostic model that accurately predicts postoperative mortality in patients undergoing medical procedures and who had received preoperative electrocardiographic diagnostic testing. METHODS: In a derivation cohort of preoperative patients with available electrocardiograms (ECGs) from Cedars-Sinai Medical Center (Los Angeles, CA, USA) between Jan 1, 2015 and Dec 31, 2019, a deep-learning algorithm was developed to leverage waveform signals to discriminate postoperative mortality. We randomly split patients (8:1:1) into subsets for training, internal validation, and final algorithm test analyses. Model performance was assessed using area under the receiver operating characteristic curve (AUC) values in the hold-out test dataset and in two external hospital cohorts and compared with the established Revised Cardiac Risk Index (RCRI) score. The primary outcome was post-procedural mortality across three health-care systems. FINDINGS: 45 969 patients had a complete ECG waveform image available for at least one 12-lead ECG performed within the 30 days before the procedure date (59 975 inpatient procedures and 112 794 ECGs): 36 839 patients in the training dataset, 4549 in the internal validation dataset, and 4581 in the internal test dataset. In the held-out internal test cohort, the algorithm discriminates mortality with an AUC value of 0·83 (95% CI 0·79-0·87), surpassing the discrimination of the RCRI score with an AUC of 0·67 (0·61-0·72). The algorithm similarly discriminated risk for mortality in two independent US health-care systems, with AUCs of 0·79 (0·75-0·83) and 0·75 (0·74-0·76), respectively. Patients determined to be high risk by the deep-learning model had an unadjusted odds ratio (OR) of 8·83 (5·57-13·20) for postoperative mortality compared with an unadjusted OR of 2·08 (0·77-3·50) for postoperative mortality for RCRI scores of more than 2. The deep-learning algorithm performed similarly for patients undergoing cardiac surgery (AUC 0·85 [0·77-0·92]), non-cardiac surgery (AUC 0·83 [0·79-0·88]), and catheterisation or endoscopy suite procedures (AUC 0·76 [0·72-0·81]). INTERPRETATION: A deep-learning algorithm interpreting preoperative ECGs can improve discrimination of postoperative mortality. The deep-learning algorithm worked equally well for risk stratification of cardiac surgeries, non-cardiac surgeries, and catheterisation laboratory procedures, and was validated in three independent health-care systems. This algorithm can provide additional information to clinicians making the decision to perform medical procedures and stratify the risk of future complications. FUNDING: National Heart, Lung, and Blood Institute.

Race, Sex, and Age Disparities in the Performance of ECG Deep Learning Models Predicting Heart Failure.

BACKGROUND: Deep learning models may combat widening racial disparities in heart failure outcomes through early identification of individuals at high risk. However, demographic biases in the performance of these models have not been well-studied. METHODS: This retrospective analysis used 12-lead ECGs taken between 2008 and 2018 from 326 518 patient encounters referred for standard clinical indications to Stanford Hospital. The primary model was a convolutional neural network model trained to predict incident heart failure within 5 years. Biases were evaluated on the testing set (160 312 ECGs) using the area under the receiver operating characteristic curve, stratified across the protected attributes of race, ethnicity, age, and sex. RESULTS: There were 59 817 cases of incident heart failure observed within 5 years of ECG collection. The performance of the primary model declined with age. There were no significant differences observed between racial groups overall. However, the primary model performed significantly worse in Black patients aged 0 to 40 years compared with all other racial groups in this age group, with differences most pronounced among young Black women. Disparities in model performance did not improve with the integration of race, ethnicity, sex, and age into model architecture, by training separate models for each racial group, or by providing the model with a data set of equal racial representation. Using probability thresholds individualized for race, age, and sex offered substantial improvements in F1 scores. CONCLUSIONS: The biases found in this study warrant caution against perpetuating disparities through the development of machine learning tools for the prognosis and management of heart failure. Customizing the application of these models by using probability thresholds individualized by race, ethnicity, age, and sex may offer an avenue to mitigate existing algorithmic disparities.

Epistasis regulates genetic control of cardiac hypertrophy.

The combinatorial effect of genetic variants is often assumed to be additive. Although genetic variation can clearly interact non-additively, methods to uncover epistatic relationships remain in their infancy. We develop low-signal signed iterative random forests to elucidate the complex genetic architecture of cardiac hypertrophy. We derive deep learning-based estimates of left ventricular mass from the cardiac MRI scans of 29,661 individuals enrolled in the UK Biobank. We report epistatic genetic variation including variants close to CCDC141, IGF1R, TTN, and TNKS. Several loci not prioritized by univariate genome-wide association analysis are identified. Functional genomic and integrative enrichment analyses reveal a complex gene regulatory network in which genes mapped from these loci share biological processes and myogenic regulatory factors. Through a network analysis of transcriptomic data from 313 explanted human hearts, we show that these interactions are preserved at the level of the cardiac transcriptome. We assess causality of epistatic effects via RNA silencing of gene-gene interactions in human induced pluripotent stem cell-derived cardiomyocytes. Finally, single-cell morphology analysis using a novel high-throughput microfluidic system shows that cardiomyocyte hypertrophy is non-additively modifiable by specific pairwise interactions between CCDC141 and both TTN and IGF1R. Our results expand the scope of genetic regulation of cardiac structure to epistasis.

Epistasis regulates genetic control of cardiac hypertrophy.

The combinatorial effect of genetic variants is often assumed to be additive. Although genetic variation can clearly interact non-additively, methods to uncover epistatic relationships remain in their infancy. We develop low-signal signed iterative random forests to elucidate the complex genetic architecture of cardiac hypertrophy. We derive deep learning-based estimates of left ventricular mass from the cardiac MRI scans of 29,661 individuals enrolled in the UK Biobank. We report epistatic genetic variation including variants close to CCDC141, IGF1R, TTN, and TNKS. Several loci not prioritized by univariate genome-wide association analysis are identified. Functional genomic and integrative enrichment analyses reveal a complex gene regulatory network in which genes mapped from these loci share biological processes and myogenic regulatory factors. Through a network analysis of transcriptomic data from 313 explanted human hearts, we show that these interactions are preserved at the level of the cardiac transcriptome. We assess causality of epistatic effects via RNA silencing of gene-gene interactions in human induced pluripotent stem cell-derived cardiomyocytes. Finally, single-cell morphology analysis using a novel high-throughput microfluidic system shows that cardiomyocyte hypertrophy is non-additively modifiable by specific pairwise interactions between CCDC141 and both TTN and IGF1R. Our results expand the scope of genetic regulation of cardiac structure to epistasis.

A deep learning-based electrocardiogram risk score for long term cardiovascular death and disease.

The electrocardiogram (ECG) is the most frequently performed cardiovascular diagnostic test, but it is unclear how much information resting ECGs contain about long term cardiovascular risk. Here we report that a deep convolutional neural network can accurately predict the long-term risk of cardiovascular mortality and disease based on a resting ECG alone. Using a large dataset of resting 12-lead ECGs collected at Stanford University Medical Center, we developed SEER, the Stanford Estimator of Electrocardiogram Risk. SEER predicts 5-year cardiovascular mortality with an area under the receiver operator characteristic curve (AUC) of 0.83 in a held-out test set at Stanford, and with AUCs of 0.78 and 0.83 respectively when independently evaluated at Cedars-Sinai Medical Center and Columbia University Irving Medical Center. SEER predicts 5-year atherosclerotic disease (ASCVD) with an AUC of 0.67, similar to the Pooled Cohort Equations for ASCVD Risk, while being only modestly correlated. When used in conjunction with the Pooled Cohort Equations, SEER accurately reclassified 16% of patients from low to moderate risk, uncovering a group with an actual average 9.9% 10-year ASCVD risk who would not have otherwise been indicated for statin therapy. SEER can also predict several other cardiovascular conditions such as heart failure and atrial fibrillation. Using only lead I of the ECG it predicts 5-year cardiovascular mortality with an AUC of 0.80. SEER, used alongside the Pooled Cohort Equations and other risk tools, can substantially improve cardiovascular risk stratification and aid in medical decision making.

Development and validation of a rapid visual technique for left ventricular hypertrophy detection from the electrocardiogram.

Introduction: Left ventricular hypertrophy (LVH) detection techniques on by electrocardiogram (ECG) are cumbersome to remember with modest performance. This study validated a rapid technique for LVH detection and measured its performance against other techniques. Methods: This was a retrospective cohort study of patients at Stanford Health Care who received ECGs and resting transthoracic echocardiograms (TTE) from 2006 through 2018. The novel technique, Witteles-Somani (WS), assesses for S- and R-wave overlap on adjacent precordial leads. The WS, Sokolow-Lyon, Cornell, and Peguero-Lo Presti techniques were algorithmically implemented on ECGs. Classification metrics, receiver-operator curves, and Pearson correlations measured performance. Age- and sex-adjusted Cox proportional hazard models evaluated associations between incident cardiovascular outcomes and each technique. Results: A total of 53,333 ECG-TTE pairs from 18,873 patients were identified. Of all ECG-TTE pairs, 21,638 (40.6%) had TTE-diagnosed LVH. The WS technique had a sensitivity of 0.46, specificity of 0.66, and AUROC of 0.56, compared to Sokolow-Lyon (AUROC 0.55), Cornell (AUROC 0.63), and Peguero-Lo Presti (AUROC 0.63). Patients meeting LVH by WS technique had a higher risk of cardiovascular mortality [HR 1.18, 95% CI (1.12, 1.24), P < 0.001] and a higher risk of developing any cardiovascular disease [HR 1.29, 95% CI (1.22, 1.36), P < 0.001], myocardial infarction [HR 1.60, 95% CI (1.44, 1.78), P < 0.005], and heart failure [HR 1.24, 95% CI (1.17, 1.32), P < 0.001]. Conclusions: The WS criteria is a rapid visual technique for LVH detection with performance like other LVH detection techniques and is associated with incident cardiovascular outcomes.

Deep Learning Electrocardiographic Analysis for Detection of Left-Sided Valvular Heart Disease.

BACKGROUND: Valvular heart disease is an important contributor to cardiovascular morbidity and mortality and remains underdiagnosed. Deep learning analysis of electrocardiography (ECG) may be useful in detecting aortic stenosis (AS), aortic regurgitation (AR), and mitral regurgitation (MR). OBJECTIVES: This study aimed to develop ECG deep learning algorithms to identify moderate or severe AS, AR, and MR alone and in combination. METHODS: A total of 77,163 patients undergoing ECG within 1 year before echocardiography from 2005-2021 were identified and split into train (n = 43,165), validation (n = 12,950), and test sets (n = 21,048; 7.8% with any of AS, AR, or MR). Model performance was assessed using area under the receiver-operating characteristic (AU-ROC) and precision-recall curves. Outside validation was conducted on an independent data set. Test accuracy was modeled using different disease prevalence levels to simulate screening efficacy using the deep learning model. RESULTS: The deep learning algorithm model accuracy was as follows: AS (AU-ROC: 0.88), AR (AU-ROC: 0.77), MR (AU-ROC: 0.83), and any of AS, AR, or MR (AU-ROC: 0.84; sensitivity 78%, specificity 73%) with similar accuracy in external validation. In screening program modeling, test characteristics were dependent on underlying prevalence and selected sensitivity levels. At a prevalence of 7.8%, the positive and negative predictive values were 20% and 97.6%, respectively. CONCLUSIONS: Deep learning analysis of the ECG can accurately detect AS, AR, and MR in this multicenter cohort and may serve as the basis for the development of a valvular heart disease screening program.

Deep learning evaluation of biomarkers from echocardiogram videos.

BACKGROUND: Laboratory testing is routinely used to assay blood biomarkers to provide information on physiologic state beyond what clinicians can evaluate from interpreting medical imaging. We hypothesized that deep learning interpretation of echocardiogram videos can provide additional value in understanding disease states and can evaluate common biomarkers results. METHODS: We developed EchoNet-Labs, a video-based deep learning algorithm to detect evidence of anemia, elevated B-type natriuretic peptide (BNP), troponin I, and blood urea nitrogen (BUN), as well as values of ten additional lab tests directly from echocardiograms. We included patients (n = 39,460) aged 18 years or older with one or more apical-4-chamber echocardiogram videos (n = 70,066) from Stanford Healthcare for training and internal testing of EchoNet-Lab's performance in estimating the most proximal biomarker result. Without fine-tuning, the performance of EchoNet-Labs was further evaluated on an additional external test dataset (n = 1,301) from Cedars-Sinai Medical Center. We calculated the area under the curve (AUC) of the receiver operating characteristic curve for the internal and external test datasets. FINDINGS: On the held-out test set of Stanford patients not previously seen during model training, EchoNet-Labs achieved an AUC of 0.80 (0.79-0.81) in detecting anemia (low hemoglobin), 0.86 (0.85-0.88) in detecting elevated BNP, 0.75 (0.73-0.78) in detecting elevated troponin I, and 0.74 (0.72-0.76) in detecting elevated BUN. On the external test dataset from Cedars-Sinai, EchoNet-Labs achieved an AUC of 0.80 (0.77-0.82) in detecting anemia, of 0.82 (0.79-0.84) in detecting elevated BNP, of 0.75 (0.72-0.78) in detecting elevated troponin I, and of 0.69 (0.66-0.71) in detecting elevated BUN. We further demonstrate the utility of the model in detecting abnormalities in 10 additional lab tests. We investigate the features necessary for EchoNet-Labs to make successful detection and identify potential mechanisms for each biomarker using well-known and novel explainability techniques. INTERPRETATION: These results show that deep learning applied to diagnostic imaging can provide additional clinical value and identify phenotypic information beyond current imaging interpretation methods. FUNDING: J.W.H. and B.H. are supported by the NSF Graduate Research Fellowship. D.O. is supported by NIH K99 HL157421-01. J.Y.Z. is supported by NSF CAREER 1942926, NIH R21 MD012867-01, NIH P30AG059307 and by a Chan-Zuckerberg Biohub Fellowship.

Performance of a Convolutional Neural Network and Explainability Technique for 12-Lead Electrocardiogram Interpretation.

Importance: Millions of clinicians rely daily on automated preliminary electrocardiogram (ECG) interpretation. Critical comparisons of machine learning-based automated analysis against clinically accepted standards of care are lacking. Objective: To use readily available 12-lead ECG data to train and apply an explainability technique to a convolutional neural network (CNN) that achieves high performance against clinical standards of care. Design, Setting, and Participants: This cross-sectional study was conducted using data from January 1, 2003, to December 31, 2018. Data were obtained in a commonly available 12-lead ECG format from a single-center tertiary care institution. All patients aged 18 years or older who received ECGs at the University of California, San Francisco, were included, yielding a total of 365 009 patients. Data were analyzed from January 1, 2019, to March 2, 2021. Exposures: A CNN was trained to predict the presence of 38 diagnostic classes in 5 categories from 12-lead ECG data. A CNN explainability technique called LIME (Linear Interpretable Model-Agnostic Explanations) was used to visualize ECG segments contributing to CNN diagnoses. Main Outcomes and Measures: Area under the receiver operating characteristic curve (AUC), sensitivity, and specificity were calculated for the CNN in the holdout test data set against cardiologist clinical diagnoses. For a second validation, 3 electrophysiologists provided consensus committee diagnoses against which the CNN, cardiologist clinical diagnosis, and MUSE (GE Healthcare) automated analysis performance was compared using the F1 score; AUC, sensitivity, and specificity were also calculated for the CNN against the consensus committee. Results: A total of 992 748 ECGs from 365 009 adult patients (mean [SD] age, 56.2 [17.6] years; 183 600 women [50.3%]; and 175 277 White patients [48.0%]) were included in the analysis. In 91 440 test data set ECGs, the CNN demonstrated an AUC of at least 0.960 for 32 of 38 classes (84.2%). Against the consensus committee diagnoses, the CNN had higher frequency-weighted mean F1 scores than both cardiologists and MUSE in all 5 categories (CNN frequency-weighted F1 score for rhythm, 0.812; conduction, 0.729; chamber diagnosis, 0.598; infarct, 0.674; and other diagnosis, 0.875). For 32 of 38 classes (84.2%), the CNN had AUCs of at least 0.910 and demonstrated comparable F1 scores and higher sensitivity than cardiologists, except for atrial fibrillation (CNN F1 score, 0.847 vs cardiologist F1 score, 0.881), junctional rhythm (0.526 vs 0.727), premature ventricular complex (0.786 vs 0.800), and Wolff-Parkinson-White (0.800 vs 0.842). Compared with MUSE, the CNN had higher F1 scores for all classes except supraventricular tachycardia (CNN F1 score, 0.696 vs MUSE F1 score, 0.714). The LIME technique highlighted physiologically relevant ECG segments. Conclusions and Relevance: The results of this cross-sectional study suggest that readily available ECG data can be used to train a CNN algorithm to achieve comparable performance to clinical cardiologists and exceed the performance of MUSE automated analysis for most diagnoses, with some exceptions. The LIME explainability technique applied to CNNs highlights physiologically relevant ECG segments that contribute to the CNN's diagnoses.

A digital biomarker of diabetes from smartphone-based vascular signals.

The global burden of diabetes is rapidly increasing, from 451 million people in 2019 to 693 million by 20451. The insidious onset of type 2 diabetes delays diagnosis and increases morbidity2. Given the multifactorial vascular effects of diabetes, we hypothesized that smartphone-based photoplethysmography could provide a widely accessible digital biomarker for diabetes. Here we developed a deep neural network (DNN) to detect prevalent diabetes using smartphone-based photoplethysmography from an initial cohort of 53,870 individuals (the 'primary cohort'), which we then validated in a separate cohort of 7,806 individuals (the 'contemporary cohort') and a cohort of 181 prospectively enrolled individuals from three clinics (the 'clinic cohort'). The DNN achieved an area under the curve for prevalent diabetes of 0.766 in the primary cohort (95% confidence interval: 0.750-0.782; sensitivity 75%, specificity 65%) and 0.740 in the contemporary cohort (95% confidence interval: 0.723-0.758; sensitivity 81%, specificity 54%). When the output of the DNN, called the DNN score, was included in a regression analysis alongside age, gender, race/ethnicity and body mass index, the area under the curve was 0.830 and the DNN score remained independently predictive of diabetes. The performance of the DNN in the clinic cohort was similar to that in other validation datasets. There was a significant and positive association between the continuous DNN score and hemoglobin A1c (P ≤ 0.001) among those with hemoglobin A1c data. These findings demonstrate that smartphone-based photoplethysmography provides a readily attainable, non-invasive digital biomarker of prevalent diabetes.