Ecg-based future atrial fibrillation prediction system and method

Abstract

Methods and systems for predicting the likelihood that a patient will suffer from atrial fibrillation are provided.SOLUTION: The method includes receiving electrocardiogram data associated with a patient, providing at least a portion of the electrocardiogram data to a trained model, receiving a risk score indicating a likelihood that the patient will suffer from atrial fibrillation within a predetermined time period from when the electrocardiogram data is generated, and outputting the risk score to at least one of a memory or a display for viewing by a medical practitioner or medical administrator. The system comprises at least one processor executing instructions for performing the steps of the method.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is based on and claims the benefit of and priority to U.S. Provisional Patent Application No. 62 / 902,266, filed September 18, 2019, U.S. Provisional Patent Application No. 62 / 924,529, filed October 22, 2019, and U.S. Provisional Patent Application No. 63 / 013,897, filed April 22, 2020, which are incorporated herein by reference in their entireties for all purposes.

[0002] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT Not applicable.

[0003] The field of the present disclosure is predictive ECG testing, and more particularly, systems and processes for predicting future medical or health conditions using deep learning to correlate "current" ECG results with future medical conditions. [Background technology]

[0004] Physicians routinely diagnose patient conditions and prescribe solutions to eliminate or minimize the effects of those conditions. For example, if a patient has a bacterial infection, a physician may prescribe an antibiotic known to kill the bacteria. Additionally, if a particular patient condition is known to usually be a precursor to a subsequent medical event, a physician may prescribe a solution to mitigate the effects of the subsequent condition. For example, for a patient suffering from atrial fibrillation (AF), a quivering or irregular heartbeat (arrhythmia) that can lead to blood clots, stroke, heart failure, and other cardiovascular-related complications, a physician may prescribe a blood thinner to reduce the likelihood of a subsequent stroke.

[0005] For most health conditions, the effectiveness of a treatment plan (e.g., its ultimate ability to eliminate or reduce the condition and / or its effects) is related to how early the condition is detected. Early detection typically means more treatment options that result in either a full / rapid recovery and / or a less severe clinical outcome. Thus, for example, if a physician detects AF soon after (or ideally just before) its onset rather than years later, the chances of successful treatment may be significantly higher. This is especially important for diseases like AF, where patients often do not even realize they have this potentially dangerous condition and end up in the hospital suffering irreversible brain damage (in the form of a stroke) without being treated before that damage occurs.

[0006] Similarly, in many cases, if a physician can identify that a currently healthy patient has a relatively high likelihood of developing a particular medical condition before the condition develops, the patient can be prescribed a treatment plan designed to help avoid that condition in the future. For example, in the case of AF, if a physician can identify that a patient who does not currently have AF has a significant risk of developing AF in the future, the patient can be counseled on how to modify their lifestyle or increase monitoring, for example, with a wearable device to detect AF, to prevent or reduce the likelihood of future adverse outcomes related to AF, such as stroke. For example, it is believed that the likelihood of AF in patients who do not currently have a history of AF can be significantly reduced by lifestyle choices including engaging in regular physical activity, eating a heart-healthy diet, managing high blood pressure, avoiding excessive amounts of alcohol and caffeine, quitting smoking, and maintaining a healthy weight; ideally, these options should be chosen by anyone who has a substantial risk of developing AF in the future.

[0007] The electrocardiogram (ECG) is perhaps the most widely used cardiovascular diagnostic test in the world, and the vast majority of people have undergone it at some point in their lives. Obtaining an ECG involves measuring electrical potentials at various locations across the body's surface, which is used to derive the voltage difference between the two locations. This voltage difference is plotted as a function of time, for example, after taking approximately 250–500 voltage samples per second. This plot of voltage as a function of time forms the basis of an ECG and is called an ECG trace. All muscles generate voltage differences during their normal functioning, and because the heart is essentially a large muscle, various aspects of cardiac function (e.g., whether the heart is beating too fast or too slow, or whether some parts of the heart are abnormally enlarged) can be derived from these voltage differences. Therefore, analysis of ECGs is used to diagnose and treat many different cardiac diseases.

[0008] An ECG can be obtained using at least two body surface potential recordings (such that a voltage difference can be calculated from the subtraction of the two potentials). When only one voltage difference is obtained, typically for a duration of at least 10 seconds, this is known as a "rhythm strip." One common ECG is the 12-lead ECG, in which voltage differences are obtained in 12 different directions (or "leads") across the body's surface. Typically, these are obtained while the patient is not engaged in physical activity (i.e., "resting"), but they can also be obtained during vigorous exercise ("stress"). While the resting 12-lead ECG is the most commonly obtained type of ECG, there is no limit to the number of different "leads" that can be obtained for an ECG. Machines for obtaining ECGs are ubiquitous in current clinical practice and consist of electrodes attached to the patient's body surface, which are then connected to multiple wires, and a machine capable of measuring the potential of each wire. The machine can then calculate the voltage difference between the different locations, ultimately producing an ECG trace. The ECG trace is visually examined by a physician to identify irregularities. AF is one of many irregularities that can then be identified from the ECF tracing.

[0009] Although traditional visual ECG analysis by a trained physician appears to be effective in assessing whether a patient currently has AF, traditional ECG analysis is not effective in predicting the likelihood of future AF or other medical events that may result from future AF (e.g., heart attack, stroke, death).

[0010] Population-based screening for AF is challenging. The annual incidence of AF in the general population is low, with a reported incidence of less than 10 per 1,000 person-years in individuals under 70 years of age. AF is often paroxysmal, with many episodes lasting less than 24 hours. Currently, the most common screening strategy is opportunistic pulse palpation, sometimes used in conjunction with a 12-lead electrocardiogram (ECG) during routine medical visits. This strategy may be appropriate in some populations. However, this strategy may miss many cases of AF. Summary of the Invention [Problem to be solved by the invention]

[0011] Thus, there is no way to ascertain the likelihood of future AF from analyzing an ECG tracing that does not currently contain features consistent with AF, even to the trained eye of a physician. Thus, if a physician determines that an ECG tracing does not contain evidence of AF, the patient is simply instructed that they do not currently have AF, without any awareness of the possibility of future AF or future AF-related complications. [Means for solving the problem]

[0012] In one aspect, the disclosure provides a method including receiving electrocardiogram data associated with a patient and an electrocardiogram configuration including a plurality of leads and a time interval, the electrocardiogram data including voltage data associated with at least a portion of the time interval for each lead included in the plurality of leads; receiving an age value associated with the patient; receiving a gender value associated with the patient; providing the age value, gender value, and at least a portion of the electrocardiogram data to a trained model, the trained model being trained to generate a risk score based on the input electrocardiogram data associated with the electrocardiogram configuration and supplemental information associated with the patient; receiving a risk score indicative of a likelihood that the patient will suffer from a medical condition within a predetermined time period from when the electrocardiogram data was generated; and outputting the risk score to at least one of a memory or a display for viewing by a medical practitioner or healthcare administrator.

[0013] The method may further include receiving electronic health record data associated with the patient and providing at least a portion of the electronic health record data to the trained model. The electronic health record data may include at least one of a blood cholesterol measurement, a blood count, a blood chemistry value, a troponin level, a natriuretic peptide level, blood pressure, a heart rate, a respiratory rate, an oxygen saturation level, a cardiac ejection fraction, a ventricular volume, a myocardial thickness, a heart valve function, a diabetes diagnosis, a chronic kidney disease diagnosis, a congenital heart disease diagnosis, a cancer diagnosis, a procedure, a medication, a cardiac rehabilitation referral, or a dietary consultation referral.

[0014] The method may further include determining that the risk score is higher than a predetermined threshold associated with the medical condition; in response to determining that the risk score is higher than the predetermined threshold, generating a report including information and / or links to sources of information associated with at least one of a treatment for the medical condition or a cause of the medical condition; and outputting the report to at least one of a memory or a display for viewing by a medical practitioner or healthcare administrator.

[0015] In the method, the time period may be one year.

[0016] In the method, the time period may be selected from the range of 1 day to 30 years.

[0017] In the method, the trained model may include a deep neural network including multiple branches, and the portion of the electrocardiogram data provided to the trained model may be provided to the multiple branches.

[0018] In the method, the trained model may include a deep neural network including a convolutional component and a dense layer component, and the convolutional component may include an inception block including multiple convolutional layers.

[0019] In the method, the plurality of leads may include Lead I, Lead V2, Lead V4, Lead V3, Lead V6, Lead II, Lead VI, and Lead V5. The electrocardiogram data may include first voltage data associated with Lead I and a first portion of the time interval, second voltage data associated with Lead V2 and a second portion of the time interval, third voltage data associated with Lead V4 and a third portion of the time interval, fourth voltage data associated with Lead V3 and a second portion of the time interval, fifth voltage data associated with Lead V6 and a third portion of the time interval, sixth voltage data associated with Lead II and a first portion of the time interval, seventh voltage data associated with Lead II and a second portion of the time interval, eighth voltage data associated with Lead II and a third portion of the time interval, ninth voltage data associated with Lead VI and a first portion of the time interval, tenth voltage data associated with Lead VI and a second portion of the time interval, eleventh voltage data associated with Lead VI and a third portion of the time interval, twelfth voltage data associated with Lead V5 and a first portion of the time interval, thirteenth voltage data associated with Lead V5 and a second portion of the time interval, and fourteenth voltage data associated with Lead V5 and a third portion of the time interval. The time interval may comprise a 10 second time period, the first portion of the time interval may comprise the first half of the time interval, the second portion of the time interval may comprise the third quarter of the time interval, and the third portion of the time interval may comprise the fourth quarter of the time interval. The trained model may include a first channel, a second channel, and a third channel, and the providing step may include providing first, sixth, ninth, and twelfth voltage data to the first channel, providing second, fourth, seventh, tenth, and thirteenth voltage data to the second channel, and providing third, fifth, eighth, eleventh, and fourteenth voltage data to the third channel.Each of the multiple leads may be associated with a time interval.

[0020] In the method, the electrocardiogram data may be indicative of a cardiac condition based on cardiological criteria.

[0021] In the method, the electrocardiogram data may not indicate a cardiac condition based on cardiological criteria.

[0022] In the method, the condition may be death.

[0023] In the method, the condition may be atrial fibrillation.

[0024] In another aspect, the present disclosure provides a method including receiving patient electrocardiogram data from an electrocardiogram device associated with a patient and an electrocardiogram configuration including a plurality of leads and time intervals, the patient electrocardiogram data including voltage data associated with at least a portion of the time intervals for each lead included in the plurality of leads; providing at least a portion of the patient electrocardiogram data to a trained model, the trained model being trained to output a risk score based on the input electrocardiogram data associated with the electrocardiogram configuration; receiving a risk score indicative of a likelihood that the patient will suffer from a medical condition within a predetermined time period from when the patient electrocardiogram data was generated; generating a report based on the risk score; and outputting the report to at least one of a memory or a display for viewing by a medical practitioner or a healthcare administrator.

[0025] In yet another aspect, the present disclosure provides a system including at least one processor coupled to at least one memory containing instructions: receiving electrocardiogram data associated with a patient and an electrocardiogram configuration including a plurality of leads and time intervals, the electrocardiogram data including voltage data associated with at least a portion of the time intervals for each lead in the plurality of leads; providing at least a portion of the electrocardiogram data to a trained model, the trained model being trained to output a risk score based on the input electrocardiogram data associated with the electrocardiogram configuration; receiving from the trained model a risk score indicative of a likelihood that the patient will suffer from a medical condition within a predetermined time period from when the electrocardiogram data was generated; and outputting the risk score to at least one of the memory or a display for viewing by a medical practitioner or healthcare administrator.

[0026] In still yet another aspect, the present disclosure provides a method including receiving electrocardiogram data associated with a patient and an electrocardiogram configuration including a plurality of leads and a time interval, the electrocardiogram data including voltage data associated with at least a portion of the time interval for each lead included in the plurality of leads; receiving demographic data associated with the patient; providing the electrocardiogram data and the demographic data to a trained model; generating information based on the electrocardiogram data; linking the information with the demographic data; generating a risk score based on the information and the demographic data indicative of a likelihood that the patient will suffer from a medical condition within a predetermined time period from when the electrocardiogram data was generated; receiving the risk score from the trained model; and outputting the risk score to at least one of a memory or a display for viewing by a medical practitioner or healthcare administrator.

[0027] In the method, the demographic data may include the patient's gender.

[0028] In the method, the demographic data may include the age of the patient.

[0029] In the method, the condition may be death.

[0030] In the method, the condition may be atrial fibrillation.

[0031] In the method, the time period may be at least six months. The time period may be at least one year.

[0032] In the method, the plurality of leads may include Lead I, Lead V2, Lead V4, Lead V3, Lead V6, Lead II, Lead VI, and Lead V5.

[0033] The method may further include generating a report based on the risk score and outputting the report to a display for viewing by a medical practitioner or healthcare administrator.

[0034] The file of this patent contains at least one drawing / photograph executed in color. Copies of this patent with color drawing(s) / photograph(s) will be provided by the Office upon request and payment of the necessary fee. [Brief explanation of the drawings]

[0035] [Figure 1] FIG. 1 illustrates an example system for automatically predicting an atrial fibrillation (AF) risk score based on electrocardiogram (ECG) data. [Figure 2] FIG. 2 illustrates an example of hardware that may be used in some embodiments of the system of FIG. 1. [Figure 3] FIG. 1 shows an example of raw ECG voltage input data. [Figure 4A] FIG. 1 illustrates an exemplary embodiment of a model. [Figure 4B] FIG. 10 illustrates another exemplary embodiment of a model. [Figure 5A] FIG. 4B illustrates an exemplary flow for training and testing the model of FIG. 4A. [Figure 5B] FIG. 5B shows a timeline for ECG selection according to FIG. 5A. [Figure 6A] FIG. 1 illustrates a flow diagram including the steps employed in identifying potentially preventable AF-related strokes among all recorded ischemic strokes in a stroke registry. [Figure 6B] FIG. 6B shows a timeline for ECG selection according to FIG. 6A. [Figure 7A] 1 is a bar graph of model performance as the mean area under the receiver operating characteristic. [Figure 7B] 10 is a bar graph of model performance as the average area under the precision-recall curve. [Figure 7C] 1 is a bar graph of model performance as the area under the receiver operating characteristic. [Figure 7D] 1 is a bar graph of precision-recall curves for a population with sufficient data to calculate a CHARGE-AF score. [Figure 7E] 1 is a graph of ROC curves with operating points marked for three models. [Figure 7F] Graph of event-free survival curves for high-risk and low-risk groups for the operating point shown in A for 30 years of follow-up. [Figure 7G] Plot of hazard ratios (HRs) with 95% confidence intervals (Cl) for the three models in subpopulations defined by age group, sex, and normal or abnormal ECG label. [Figure 7H] Plot of Kaplan-Meier (KM) event-free survival curves within the holdout set for men in the age groups <50 years, 50-65 years, and >65 years. [Figure 7I] Plot of Kaplan-Meier (KM) event-free survival curves within the holdout set for women in the age groups <50 years, 50-65 years, and >65 years. [Figure 7J]Plot of KM curves for low-risk and high-risk groups predicted by a model (Model M0 trained on ECG tracing, age, and gender) for first-onset AF for men in the age groups <50 years, 50-65 years, and >65 years. [Figure 7K] Plots of KM curves for model-predicted low- and high-risk groups of first-onset AF for women in the age groups <50 years, 50-65 years, and >65 years. [Figure 7L] 10 is a plot showing the cumulative distribution of time to onset of AF after ECG within a proof-of-concept model holdout set. [Figure 8A] 1 is a graph of a receiver operating characteristic curve with selected operating points. [Figure 8B] 8B is a graph of Kaplan-Meier curves of predicted low-risk and high-risk groups in normal and abnormal ECG subsets at the operating point of FIG. 8A. [Figure 9] 10 is a graph of model performance as a function of the definition of time to incident AF after ECG. [Figure 10] 10 is a graph of the selection of operating points on an internal validation set in a simulated deployment model. [Figure 11] 1 is a graph showing the sensitivity of the model to potentially preventing AF-related stroke occurring within 1, 2, and 3 years of ECG generation as a function of the percentage of the population targeted as being at high risk of developing incident AF. [Figure 12] Graph of percent of all incident AF (within 1 year after ECG) and stroke (within 3 years after ECG) in the population as a function of patients under a given age threshold. [Figure 13] FIG. 4B illustrates an exemplary process for generating a risk score using a model such as the model in FIG. 4A. [Figure 14] Graph showing incidence-free rate curves for predicted Afib and predicted Afib-free groups (likelihood threshold=0.5) with available follow-up. [Figure 15]Graph showing the top % patients with highest risk and positive predictive value across all operating points of the future Afib prediction system. [Figure 16] 1 is a bar graph of the performance of a mortality prediction model or system to predict one-year mortality by ECG measurements and ECG tracings with and without age and sex as additional features. [Figure 17] 10 is a graph showing mean KM curves for predicted survival and mortality groups in normal and abnormal ECG subsets >1 year post-ECG. [Figure 18] FIG. 1 illustrates a model architecture for a convolutional neural network with multiple branches, each processing multiple channels. [Figure 19A] Graph of the area under the receiver operating characteristic curve (AUC) for predicting 1-year all-cause mortality. [Figure 19B] 10 is a bar graph showing the AUC for various lead configurations derived from 2.5 second or 10 second tracings. [Figure 20A] 1 is a plot of ECG sensitivity versus specificity. [Figure 20B] Kaplan-Meier survival analysis plot of survival proportion versus years at the selected operating point (likelihood threshold=0.5, sensitivity: 0.76, specificity: 0.77). [Figure 21] Graph of predicted mortality outcomes by three different cardiologists before and after validation of model results. [Figure 22A] Graph of incidence-free rate versus number of years. [Figure 22B] Graph of positive predictive value versus the highest percentage of risk groups in the population. DETAILED DESCRIPTION OF THE INVENTION

[0036] Various aspects of the present disclosure will now be described with reference to the drawings, wherein like reference numerals correspond to like elements throughout the several views. It should be understood, however, that the drawings and the following detailed description related thereto are not intended to limit the claimed subject matter to the particular forms disclosed. Rather, the intent is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the claimed subject matter.

[0037] In the following detailed description, reference is made to the accompanying drawings, which form a part hereof, and in which are shown by way of illustration specific embodiments in which the present disclosure may be practiced. These embodiments are described in sufficient detail to enable those skilled in the art to practice the disclosure. It will be understood, however, that the detailed description and specific examples, while indicating examples of embodiments of the present disclosure, are given by way of illustration only and not limitation. Various substitutions, modifications, additional rearrangements, or combinations thereof may be made within the scope of the present disclosure, which will be apparent to those skilled in the art.

[0038] According to common practice, the various features illustrated in the drawings may not be drawn to scale. The illustrations presented herein are not intended to be actual views of any particular method, device, or system, but merely idealized representations employed to describe various embodiments of the present disclosure. Thus, for clarity, dimensions of various features may be arbitrarily increased or decreased. Additionally, some of the drawings may be simplified for clarity. Thus, the drawings may not depict all components of a given apparatus (e.g., device) or method. Additionally, like reference numerals may be used to denote like features throughout this specification and the drawings.

[0039] The information and signals described herein may be represented using a variety of different technologies and techniques. For example, data, instructions, commands, information, signals, bits, symbols, and chips that may be referenced throughout the above description may be represented by voltages, currents, electromagnetic waves, magnetic fields or particles, optical fields or particles, or combinations thereof. Some figures may illustrate signals as single signals for clarity of presentation and explanation. It will be understood by those skilled in the art that a signal may represent a bus of signals, and that the bus may have various bit widths, and that the present disclosure may be implemented with respect to any number of data signals, including a single data signal.

[0040] The various illustrative logic blocks, modules, circuits, and algorithmic activities described in connection with the embodiments disclosed herein may be implemented as electronic hardware, computer software, or a combination of both. To clearly illustrate this interchangeability of hardware and software, the various illustrative components, blocks, modules, circuits, and activities are described generally in terms of their functionality. Whether such functionality is implemented as hardware or software depends on the particular application and design constraints imposed on the overall system. Those skilled in the art may implement the described functionality in varying ways for each specific application, but such implementation decisions should not be interpreted as causing a departure from the scope of the disclosed embodiments described herein.

[0041] Additionally, it should be noted that the embodiments may be described in terms of a process that is depicted as a flowchart, a flow diagram, a structure diagram, or a block diagram. Although a flowchart may depict operational activities as a sequential process, many of these activities may be performed in a different order, in parallel, or substantially simultaneously. Additionally, the order of activities may be rearranged. A process may correspond to a method, a function, a procedure, a subroutine, a subprogram, etc. Furthermore, the methods disclosed herein may be implemented in hardware, software, or both. If implemented in software, the functions may be stored on or transmitted over as one or more instructions or code on a computer-readable medium. Computer-readable media includes both computer storage media and communication media, including any medium that facilitates transfer of a computer program from one place to another.

[0042] It should be understood that referring to elements herein using a designation such as "first," "second," etc. does not limit the quantity or order of those elements unless such limitation is expressly stated. Rather, these designations may be used herein as a convenient method of distinguishing between two or more elements or instances of an element. As such, reference to a first and a second element does not imply that only two elements may be used therein, or that the first element must somehow precede the second element. Also, unless otherwise specified, a set of elements may include one or more elements.

[0043] As used herein, the terms "component," "system," and similar terms are intended to refer to a computer-related entity, i.e., either hardware, a combination of hardware and software, software, or software in execution. For example, a component may be, but is not limited to, a process running on a processor, a processor, an object, an executable, a thread of execution, a program, and / or a computer. By way of illustration, both an application running on a computer and the computer may be a component. One or more components may reside within a process and / or thread of execution, and a component may be localized on one computer and / or distributed between two or more computers or processors.

[0044] The word "exemplary" is used herein to mean serving as an example, instance, or illustration. Any aspect or design described herein as "exemplary" is not necessarily to be construed as preferred or advantageous over other aspects or designs.

[0045] Furthermore, the disclosed subject matter may be implemented as a system, method, apparatus, or article of manufacture using standard programming and / or engineering techniques to produce software, firmware, hardware, or any combination thereof, to control a computer or processor-based device to implement aspects detailed herein. As used herein, the term "article of manufacture" (or alternatively, "computer program product") is intended to encompass a computer program accessible from any computer-readable device, carrier, or medium. For example, computer-readable media may include, but are not limited to, magnetic storage devices (e.g., hard disks, floppy disks, magnetic strips, ...), optical disks (e.g., compact disks (CDs), digital versatile disks (DVDs), ...), smart cards, and flash memory devices (e.g., cards, sticks). In addition, it will be understood that carrier waves may be employed to carry computer-readable electronic data, such as those used to send and receive email or to access networks such as the Internet or a local area network (LAN). Of course, those skilled in the art will recognize that many modifications can be made to this configuration without departing from the scope or spirit of the claimed subject matter.

[0046] Atrial fibrillation (AF) is associated with substantial morbidity, especially when undetected. If incipient AF could be predicted with high accuracy, screening methods could be used to detect it earlier. The present disclosure provides a deep neural network that can predict incipient AF from a resting 12-lead electrocardiogram (ECG). The predicted incipient AF can assist practitioners (e.g., cardiologists) in preventing AF-related adverse outcomes, such as stroke.

[0047] A 12-lead electrocardiogram may include lead I lateral (also referred to as lead I), lead II inferior (also referred to as lead II), lead III inferior (also referred to as lead III), lead aVR, lead aVL lateral (also referred to as lead aVL), lead aVF inferior (also referred to as lead aVF), lead V1 septal (also referred to as lead V1), lead V2 septal (also referred to as lead V2), lead V3 anterior (also referred to as lead V3), lead V4 anterior (also referred to as lead V4), lead V5 lateral (also referred to as lead V5), and lead V6 lateral (also referred to as lead V6).

[0048] Atrial fibrillation (AF) is a cardiac rhythm disorder associated with several significant adverse health outcomes, including stroke and heart failure. In patients with AF and risk factors for thromboembolism, early anticoagulation therapy has been shown to be effective in preventing stroke. Unfortunately, AF is often asymptomatic or minimally symptomatic, leading to unrecognized and untreated disease. Therefore, systems and methods for screening and identifying undetected AF could help prevent stroke.

[0049] Population-based screening for AF is challenging for two major reasons. First, the annual incidence of AF in the general population is low, with a reported incidence of less than 10 per 1,000 person-years in individuals under 70 years of age. Second, AF is often "paroxysmal" (i.e., patients experience recurrent episodes of AF over several time periods), with many episodes lasting less than 24 hours. Currently, the most common screening strategy is opportunistic pulse palpation, sometimes used in conjunction with a 12-lead electrocardiogram during a routine medical visit. This has been shown to be cost-effective in some populations and is recommended in some guidelines. However, studies of implantable cardiac devices suggest that this strategy misses many cases of AF.

[0050] Many continuous monitoring devices are currently available to detect paroxysmal and asymptomatic AF. Patch monitors can be worn for up to 14–30 days, implantable loop recorders provide continuous monitoring for approximately 3 years, and wearable monitors, sometimes combined with mobile devices, can be worn indefinitely. While continuous monitoring devices overcome the problem of paroxysmal AF, they still must address the overall low incidence of new-onset AF, and cost and convenience limit their use for widespread population screening.

[0051] This disclosure describes a system and method for accurately predicting future AF from an ECG, a widely available and inexpensive test.

[0052] FIG. 1 illustrates an example of a system 100 for automatically predicting an AF risk score based on ECG data (e.g., data from a resting 12-lead ECG). In some embodiments, the system 100 may include a computing device 104, a secondary computing device 108, and / or a display 116. In some embodiments, the system 100 may include an ECG database 120, a training data database 124, and / or a trained model database 128. In some embodiments, the computing device 104 may communicate with the secondary computing device 108, the display 116, the ECG database 120, the training data database 124, and / or the trained model database 128 over a communications network 112. As shown in FIG. 1, the computing device 104 may receive ECG data, such as 12-lead ECG data, and generate an AF risk score based on the ECG data. In some embodiments, the AF risk score may indicate a predicted risk of a patient developing AF within a predetermined time period (e.g., 3 months, 6 months, 1 year, 5 years, 10 years, etc.) from when the ECG was taken. In some embodiments, the computing device 104 can execute at least a portion of the ECG analysis application 132 and automatically generate an AF risk score.

[0053] System 100 may generate a risk score to provide a physician with a recommendation to consider additional cardiac monitoring for patients who are most likely to experience atrial fibrillation, atrial flutter, or another related condition within a predetermined time period. In some examples, system 100 may be indicated for use in patients 40 years of age or older with no history of current or prior AF. In some examples, system 100 may be indicated for use in patients without pre-existing and / or concurrent documentation of AF or other related conditions. In some examples, system 100 may be used by healthcare providers in combination with the patient's medical history and clinical assessment to inform clinical decision-making.

[0054] In some embodiments, the ECG data may or may not indicate a cardiac condition based on cardiological criteria. For example, the ECG data may indicate a fast heart rate. System 100 may predict a risk score indicating that a patient will suffer from a condition (e.g., AF) based on ECG data that does not indicate a given cardiac condition (e.g., a fast heart rate). In this manner, the system may detect patients at risk for one or more conditions even when the ECG data appears "healthy" based on cardiological criteria. System 100 may predict a risk score indicating that a patient will suffer from a condition (e.g., AF) based on ECG data that indicates a cardiac condition (e.g., a fast heart rate). In this manner, system 100 may detect patients at risk for one or more conditions when the ECG data indicates the presence of different conditions.

[0055] The ECG analysis application 132 may be included in the secondary computing device 108, which may be included in the system 100, and / or in the computing device 104. The computing device 104 may communicate with the secondary computing device 108. The computing device 104 and / or the secondary computing device 108 may also communicate over the communications network 112 with the display 116, which may be included in the system 100. In some embodiments, the computing device 104 and / or the secondary computing device 108 may cause the display 116 to present one or more AF risk scores and / or reports generated by the ECG analysis application 132.

[0056] Communications network 112 may facilitate communications between computing device 104 and secondary computing device 108. In some embodiments, communications network 112 may be any suitable communications network or combination of communications networks. For example, communications network 112 may include a Wi-Fi network (which may include one or more wireless routers, one or more switches, etc.), a peer-to-peer network (e.g., a Bluetooth network), a cellular network (e.g., a 3G network, a 4G network, a 5G network, etc., conforming to any suitable standard, such as CDMA, GSM, LTE, LTE Advanced, WiMAX, etc.), a wired network, etc. In some embodiments, communications network 112 may be a local area network, a wide area network, a public network (e.g., the Internet), a private or semi-private network (e.g., a corporate or university intranet), any other suitable type of network, or any suitable combination of networks. The communications links shown in FIG. 1 may each be any suitable communications link or combination of communications links, such as a wired link, a fiber optic link, a Wi-Fi link, a Bluetooth link, a cellular link, etc.

[0057] The ECG database 120 can include multiple ECGs. In some embodiments, the ECGs can include 12-lead ECGs. Each ECG can include multiple voltage measurements taken at regular intervals (e.g., at a rate of 250 Hz, 500 Hz, 1000 Hz, etc.) for each lead over a predetermined time period (e.g., 5 seconds, 10 seconds, 15 seconds, 30 seconds, 60 seconds, etc.). In some cases, the number of leads can vary (e.g., 1-12), and the respective sampling rates and time periods can vary for each lead. In some embodiments, the ECG can include a single lead. In some embodiments, the ECG database 120 can include one or more AF risk scores generated by the ECG analysis application 132.

[0058] The training data database 124 can include a large number of ECG and clinical data. In some embodiments, the clinical data can include outcome data, such as whether the patient developed AF during the time period following the date the ECG was taken. Exemplary time periods can include 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years. The ECG and clinical data can be used to train a model to generate an AF risk score. In some embodiments, the training data database 124 can include multi-lead ECGs and corresponding clinical data taken over a period of time (e.g., 10 seconds). In some embodiments, the trained model database 128 can include a large number of trained models capable of receiving a raw ECG and outputting an AF risk score. In other embodiments, digital images of the leads relative to the ECG can be used. In some embodiments, the trained model 136 can be stored on the computing device 104.

[0059] 2 is an example of hardware that may be used in some embodiments of system 100. Computing device 104 may include a processor 204, a display 208, one or more inputs 212, one or more communication systems 216, and memory 220. Processor 204 may be any suitable hardware processor or combination of processors, such as a central processing unit ("CPU"), graphics processing unit ("GPU"), etc., capable of executing programs, which may include processes described below.

[0060] In some embodiments, the display 208 may present a graphical user interface. In some embodiments, the display 208 may be implemented using any suitable display device, such as a computer monitor, a touch screen, a television, etc. In some embodiments, the input 212 of the computing device 104 may include an indicator, a sensor, an actuatable button, a keyboard, a mouse, a graphical user interface, a touch screen display, etc.

[0061] In some embodiments, communications system 216 may comprise any suitable hardware, firmware, and / or software for communicating with other systems over any suitable communications network. For example, communications system 216 may include one or more transceivers, one or more communications chips and / or chipsets, etc. In more specific examples, communications system 216 may include hardware, firmware, and / or software that can be used to establish coaxial connections, fiber optic connections, Ethernet connections, USB connections, Wi-Fi connections, Bluetooth connections, cellular connections, etc. In some embodiments, communications system 216 enables computing device 104 to communicate with secondary computing device 108.

[0062] In some embodiments, memory 220 may include any suitable storage device that may be used to store instructions, values, etc. that may be used by processor 204, for example, to present content using display 208, to communicate with secondary computing device 108 via communication system 216, etc. Memory 220 may include any suitable volatile memory, non-volatile memory, storage, or any suitable combination thereof. For example, memory 220 may include RAM, ROM, EEPROM, one or more flash drives, one or more hard disks, one or more solid-state drives, one or more optical drives, etc. In some embodiments, memory 220 may have encoded thereon a computer program for controlling the operation of computing device 104 (or secondary computing device 108). In such embodiments, processor 204 may execute at least a portion of the computer program to present content (e.g., a user interface, images, graphics, tables, reports, etc.), receive content from secondary computing device 108, transmit information to secondary computing device 108, etc.

[0063] The secondary computing device 108 may include a processor 224, a display 228, one or more inputs 232, one or more communication systems 236, and memory 240. The processor 224 may be any suitable hardware processor or combination of processors, such as a central processing unit ("CPU"), a graphics processing unit ("GPU"), or the like, capable of executing programs, which may include the processes described below.

[0064] In some embodiments, the display 228 may present a graphical user interface. In some embodiments, the display 228 may be implemented using any suitable display device, such as a computer monitor, a touch screen, a television, etc. In some embodiments, the input 232 of the secondary computing device 108 may include an indicator, a sensor, an actuatable button, a keyboard, a mouse, a graphical user interface, a touch screen display, etc.

[0065] In some embodiments, communications system 236 may comprise any suitable hardware, firmware, and / or software for communicating with other systems over any suitable communications network. For example, communications system 236 may include one or more transceivers, one or more communications chips and / or chipsets, etc. In more specific examples, communications system 236 may include hardware, firmware, and / or software that can be used to establish coaxial connections, fiber optic connections, Ethernet connections, USB connections, Wi-Fi connections, Bluetooth connections, cellular connections, etc. In some embodiments, communications system 236 enables secondary computing device 108 to communicate with computing device 104.

[0066] In some embodiments, memory 240 may include any suitable storage device that may be used to store instructions, values, etc. that may be used by processor 224, for example, to present content using display 228, to communicate with computing device 104 via communication system 236, etc. Memory 240 may include any suitable volatile memory, non-volatile memory, storage, or any suitable combination thereof. For example, memory 240 may include RAM, ROM, EEPROM, one or more flash drives, one or more hard disks, one or more solid-state drives, one or more optical drives, etc. In some embodiments, memory 240 may have encoded thereon a computer program for controlling the operation of secondary computing device 108 (or computing device 104). In such embodiments, processor 224 may execute at least a portion of the computer program to present content (e.g., a user interface, images, graphics, tables, reports, etc.), receive content from computing device 104, transmit information to computing device 104, etc.

[0067] Display 116 may be a computer display, a television monitor, a projector, or other suitable display.

[0068] Data selection and phenotype definition FIG. 3 is an example of raw ECG voltage input data 300. The ECG voltage input data includes three distinct, time-coherent branches after reducing the data representation from 12 leads to eight independent leads. Specifically, in the example shown in FIG. 3, leads aVL, aVF, and III may not need to be used because they are linear combinations of the other, retained leads. Adding these leads may adversely affect model performance due to data overloading (i.e., redundant information) from some leads, leading to overfitting. In some embodiments, these leads may boost model performance when they do not represent redundant information. Furthermore, lead I was calculated over a time interval of 2.5 seconds to 5 seconds using Goldberger's formula, −aVR=(I+II) / 2. In some embodiments, data may be acquired at 500 Hz. Data not acquired at 500 Hz (such as studies acquired at 250 Hz or 1000 Hz) may be resampled to 500 Hz by linear interpolation or downsampling. In some embodiments, there may be one branch with leads spanning the full 10 seconds, 20 seconds, or 60 seconds of one or more leads. In other embodiments, there may be different time periods for each branch (e.g., the first branch may include 0-2.5 seconds, the second branch may include 2.5-6 seconds, and the third branch may include 6-10 seconds). In some embodiments, the number of branches may correspond to the number of different periods (e.g., there may be 10 branches each receiving a subsequent 1-second lead sampled at 100 Hz, there may be four branches each receiving a subsequent 2.5-second lead sampled at 500 Hz, etc.). In some embodiments, models may be trained and maintained for multiple branches, leads, sampling rates, and / or sampling period structures.

[0069] As shown, the raw ECG voltage input data 300 may have a predetermined ECG configuration that defines the leads included in the data and the time interval over which each lead is sampled or measured. In some embodiments, for the raw ECG voltage input data 300, the ECG configuration may include Lead I having a time interval between 0 and 5 seconds, Lead V2 having a time interval between 5 and 7.5 seconds, Lead V4 having a time interval between 7.5 and 10 seconds, Lead V3 having a time interval between 5 and 7.5 seconds, Lead V6 having a time interval between 7.5 and 10 seconds, Lead II having a time interval between 0 and 10 seconds, Lead VI having a time interval between 0 and 10 seconds, and Lead V5 having a time interval between 0 and 10 seconds. The entire ECG voltage input data may have a time interval between 0 and 10 seconds. Thus, some leads may include data for the entire time interval of the ECG voltage input data, while other leads may include data for only a subset of the time interval of the ECG voltage input data.

[0070] In some embodiments, the ECG voltage input data 300 can be associated with a time interval (e.g., 10 seconds). The ECG voltage input data 300 can include voltage data generated by leads (e.g., Lead I, Lead V2, Lead V4, Lead V3, Lead V6, Lead II, Lead VI, and Lead V5). In some embodiments, the raw ECG voltage input data 300 can include voltage data generated by the leads over an entire time interval. In some embodiments, voltage data from some leads can only be generated over a portion of the time interval (e.g., the first half of the time interval, the third quarter of the time interval, the fourth quarter of the time interval) depending on what ECG data is available for the patient. In some embodiments, a digital image of the raw ECG voltage input data can be used, and each lead identified from the digital image and corresponding voltage (e.g., digital voltage data) can be estimated from an analysis of the digital image.

[0071] In some embodiments, the ECG voltage input data 300 includes first voltage data 304 associated with Lead I and a first portion of the time interval, second voltage data 308 associated with Lead V2 and a second portion of the time interval, third voltage data 312 associated with Lead V4 and a third portion of the time interval, fourth voltage data 316 associated with Lead V3 and a second portion of the time interval, fifth voltage data 320 associated with Lead V6 and a third portion of the time interval, sixth voltage data 324 associated with Lead II and a first portion of the time interval, and seventh voltage data 325 associated with Lead II and a second portion of the time interval. The trained model may include voltage data 328, eighth voltage data 332 associated with Lead II and a third portion of the time interval, ninth voltage data 336 associated with Lead VI and a first portion of the time interval, tenth voltage data 340 associated with Lead VI and a second portion of the time interval, eleventh voltage data 344 associated with Lead VI and a third portion of the time interval, twelfth voltage data 348 associated with Lead V5 and a first portion of the time interval, thirteenth voltage data 352 associated with Lead V5 and a second portion of the time interval, and fourteenth voltage data 356 associated with Lead V5 and a third portion of the time interval. In this manner, voltage data associated with portions of the time interval may be provided to the same channel of the trained model to estimate a risk score for the patient.

[0072] 4A is an example embodiment of model 400. Specifically, the architecture of model 400 is illustrated. In some embodiments, model 400 may be a deep neural network. In some embodiments, model 400 may receive input data as shown in FIG. The input data structure to the model 400 may include a first branch 404 including leads I, II, V1, and V5 (e.g., first voltage data, sixth voltage data, ninth voltage data, and twelfth voltage data) acquired from time (t)=0 (the start of data acquisition) to t=5 seconds, a second branch 408 including leads V1, V2, V3, II, and V5 (e.g., second voltage data, fourth voltage data, seventh voltage data, tenth voltage data, and thirteenth voltage data) from t=5 to t=7.5 seconds, and a third branch 412 including leads V4, V5, V6, II, and V1 (e.g., third voltage data, fifth voltage data, eighth voltage data, eleventh voltage data, and fourteenth voltage data) from t=7.5 to t=10 seconds, as shown in FIG. 3 . The branch arrangement can be designed to account for simultaneous morphological changes across a standard clinical acquisition due to arrhythmias and / or premature beats. For example, model 400 may need to synchronize which voltage information or data is acquired at the same time to understand the data. Because ECG leads are not all acquired simultaneously, the leads can be aligned to indicate to the neural network model which data was collected simultaneously. Note that not all leads need have voltage data across the entire time interval. This is an advantage of model 400, as some ECGs do not include data for all leads across the entire time interval. For example, model 400 can include 10 branches and be trained to generate a risk score based on receiving voltage data over subsequent 1-second periods from 10 different leads.As another example, model 400 may include four branches and be trained to generate a risk score based on responding to receiving voltage data from four different leads over a subsequent 2.5-second period. Some organizations, such as hospitals, may use a standardized ECG configuration (e.g., voltage data from ten different leads over a subsequent 1-second period). Model 400 may include an appropriate number of branches and be trained to generate a risk score for the standardized ECG configuration. Thus, model 400 can be tailored to whatever ECG configuration is used by a given organization.

[0073] In some embodiments, the model 400 may include a convolution component 400A, an inception block 400B, and a fully connected dense layer component 400C. The convolution component 400A may begin with inputs for each branch, followed by a convolution block. Each convolution block included in the convolution component 400A may sequentially include a 1D convolution layer, a rectified linear activation (RELU) activation function, and a batch normalization layer. This convolution block may then be sequentially followed by four inception blocks 400B, each of which may include three 1D convolution blocks concatenated across the channel axis with decreasing filter window sizes. Each of the four inception blocks 400B may be connected to a 1D MaxPooling layer, which in turn is connected to another single 1D convolution block and a final Global Average Pooling layer. The outputs for all three branches may be concatenated and fully connected to the dense layer component 400C. The dense layer component 400C can include four dense layers of 256, 64, 8, and 1 unit with a sigmoid function as the last layer. All layers in this architecture can enforce kernel constraints and may not include bias terms. In some embodiments, the adagrad optimizer optimizes the 1e -4A learning rate of 45, a linear learning rate decay of 1 / 10 before early stopping for efficient model convergence, and a batch size of 2048 may be used. In some embodiments, model 400 may be implemented using Keras with the TensorFlow backend in python, and default training parameters were used unless specified. In some embodiments, the AdaGrad optimizer is used with a 1e -4 45 A learning rate of 1 / 10, a linear learning rate decay of 1 / 10 before early stopping for efficient model convergence with a patience of 3 epochs, and a batch size of 2048 can be used. In some embodiments, different model frameworks, hypertuning parameters, and / or programming languages ​​may be implemented. Patience for early stopping was set to 9 epochs. In some embodiments, model 400 can be trained using NVIDIA DGX1 and DGX2 machines, which have 8 and 16 V100 GPUs, respectively, and 32 GB of RAM per GPU.

[0074] In some embodiments, model 400 can additionally receive electronic health record (EHR) data points such as demographic data 416, which can include age and sex / gender as input features to the network; sex can be coded as a binary value for both males and females, and age can be cast as a continuous numeric value corresponding to the date of acquisition for each 12-lead resting-state ECG. In some embodiments, other representations can be used, such as age groupings 0-9 years, 10-19 years, 20-29 years, or other grouping sizes. In some embodiments, other demographic data such as race, smoking status, height, and / or weight may be included. In some embodiments, EHR data points can include laboratory values, echo measurements, ICD codes, and / or care gaps. EHR data points (e.g., demographic data, laboratory values, etc.) can be provided to model 400 in a common location.

[0075] EHR data points (e.g., age and gender) may be fed into a 64-unit hidden layer and concatenated with other branches. In some cases, these EHR features may be extracted directly from a standard 12-lead ECG report. In some embodiments, model 400 may generate ECG information based on voltage data from first branch 404, second branch 408, and third branch 412. In some embodiments, model 400 may generate demographic information based on demographic data 416. In some embodiments, demographic information may be generated by inputting age and gender, which were input into a 64-unit hidden layer. The demographic information may be concatenated with the ECG information, and model 400 may generate a risk score 420 based on the demographic information and ECG information. Concatenating the ECG information with separately generated demographic information can allow the model 400 to separately disseminate the voltage data from the first branch 404, the second branch 408, and the third branch 412, as well as the demographic data 416, which can improve performance over other models that provide the voltage data and the demographic data 416 to the model on the same channel.

[0076] In some embodiments, model 400 may be included in trained models 136. In some embodiments, risk score 420 may indicate the likelihood that a patient will suffer from a medical condition within a predetermined time period from when electrocardiogram data (e.g., voltage data from leads) was generated. In some embodiments, the medical condition may be AF, mortality, ST-segment elevation myocardial infarction (STEMI), acute coronary syndrome (ACS), stroke, or other medical condition as described herein. In some embodiments, model 400 may be trained to predict a patient's risk of developing AF based on the ECG for a predetermined time period following acquisition of the ECG. In some embodiments, the time period may range from 1 day to 30 years. For example, the time period may be 1 day, 3 months, 6 months, 1 year, 5 years, 10 years, and / or 30 years.

[0077] 4B is another exemplary embodiment of model 424. Specifically, an alternative architecture for model 400 of FIG. 4A is illustrated. In some embodiments, model 424 of FIG. 4B can receive ECG voltage data generated over a single time interval.

[0078] 4B , the model 424 may include a single branch that can receive ECG voltage input data 428 generated over a single time interval (e.g., 10 seconds). As shown, the model 424 may receive ECG voltage input data 428 generated over a 10-second time interval using eight leads. In some embodiments, the ECG voltage input data 428 may include 5,000 data points collected over a 10-second period and eight leads, including Leads I, II, V1, V2, V3, V4, V5, and V6. The number of data points may vary based on the sampling rate used to sample the leads (e.g., a sampling rate of 500 Hz results in 5,000 data points over a 10-second time period). The ECG voltage input data 428 may be converted into an ECG waveform.

[0079] As described above, in some embodiments, the ECG voltage input data 428 is “complete” and can include voltage data from each lead (e.g., Lead I, Lead V2, Lead V4, Lead V3, Lead V6, Lead II, Lead VI, and Lead V5) generated over an entire time interval. Thus, in some embodiments, a predetermined ECG configuration can include Lead I, Lead V2, Lead V4, Lead V3, Lead V6, Lead II, Lead VI, and Lead V5 having a time interval of 0 to 10 seconds. The model 424 can be trained using training data having a predetermined ECG configuration including Lead I, Lead V2, Lead V4, Lead V3, Lead V6, Lead II, Lead VI, and Lead V5 having a time interval of 0 to 10 seconds. When all leads share the same time interval, the model can receive the ECG voltage input data 428 on a single input branch 432. Otherwise, the model can include a branch for each unique time interval and can be used as described above in connection with FIG. 4A .

[0080] The ECG waveform data for each ECG lead may be provided to a 1D convolution block 436, with layer definition parameters (n, f, s) referring to the number of data points input to the block, the number of filters used, and the filter size / window, respectively. In some embodiments, the number of data points input to the block may be 5000, the number of filters used may be 32, and the filter size / window may be 80. The 1D convolution block 436 may generate a downsampled version of the input ECG waveform data and output it to the Inception block. In some embodiments, the first 1D convolution block 436 may have a stride value of 2.

[0081] The model 424 can include an inception block 440. In some embodiments, the inception block 440 can include multiple sub-blocks. Each sub-block 444 can include multiple convolution blocks. For example, each sub-block 444 can include a first convolution block 448A, a second convolution block 448B, and a third convolution block 448C. In the example shown in FIG. 4B, the inception block 440 can include four sub-blocks, in order, with the output of each sub-block serving as input to the next sub-block. Each inception sub-block can generate and output a downsampled set of time-series information. Each sub-block can be configured with a filter and filter window as shown in the inception block 440 with associated layer definition parameters.

[0082] In some embodiments, the first convolution block 448A, the second convolution block 448B, and the third convolution block 448C may be 1D convolution blocks. The results from each of the convolution blocks 444A-C may be concatenated 452 by combining the results (e.g., an array) and inputting the concatenated results to a MaxPool layer 456 included in the subblock 444. The MaxPool layer 456 may extract positive values ​​for each moving 1D convolution filter window, providing another form of regularization, enabling model generalization and preventing overfitting. After completion of all four Inception block processes, the output is passed to the final convolution block 460 and then to a global average pooling (GAP) layer 464. The purpose of the GAP layer 464 is to average the final downsampled ECG features from all eight independent ECG leads into a single downsampled array. The output of the GAP layer 464 can be passed to a series of dense layer components 424C (e.g., in dense layer component 400C) as in connection with FIG. 4A . Additionally, optimization parameters can be set for all layers. For example, all layer parameters can enforce a kernel constraint parameter (max_norm=3) to prevent overfitting of the model. The first convolution block 436 and the last convolution block 460 can utilize a stride parameter of n=1, while each inception block 440 can utilize a stride parameter of n=2. The stride parameter determines the movement of all convolution layers across the ECG time series and can affect model performance. In some embodiments, the model 424 can also concatenate supplementary data such as age and gender as described above in connection with FIG. 4A , and the model 424 can utilize the same dense layer component architecture as the model 400. The model 424 can output a risk score 468 based on demographic and ECG information. Specifically, the dense layer component 424C can output a risk score 468.In some embodiments, the risk score 420 can indicate the likelihood that a patient will suffer from a medical condition within a predetermined time period from when the electrocardiogram data (e.g., voltage data from the leads) was generated. In some embodiments, the medical condition can be AF, mortality, ST-segment elevation myocardial infarction (STEMI), acute coronary syndrome (ACS), stroke, or other medical condition as described herein. In some embodiments, the model 400 can be trained to predict a patient's risk of developing AF based on the ECG for a predetermined time period following acquisition of the ECG. In some embodiments, the time period can range from 1 day to 30 years. For example, the time period can be 1 day, 3 months, 6 months, 1 year, 5 years, 10 years, and / or 30 years.

[0083] Figure 5A shows an example flow 500 for training and testing the model 400 of Figure 4A. 2.8 million standard 12-lead ECG traces were extracted from a medical database. All ECGs with a known time event or at least one year of follow-up were used during model training. A single random ECG was selected for each patient in the holdout set for model evaluation; the result is labeled "M0" in Figure 5B. Figure 5B shows the timeline for ECG selection according to Figure 5A. The traces were acquired between 1984 and June 2019. Additional retraining was performed only on resting 12-lead ECGs that: 1) were acquired in patients ≥ 18 years of age; 2) had complete voltage-time traces of 2.5 seconds for the 12 leads and 10 seconds for the three leads (V1, II, V5); and 3) were free of significant artifacts. This amounted to 1.6 million ECGs from 431k patients. The median (interquartile range) follow-up available after each ECG was 4.1 years (1.5–8.5 years). Each ECG was defined as normal or abnormal as follows: 1) a normal ECG was defined as having a pattern label of "normal ECG" or "within normal limits" with no other abnormalities identified; 2) all other ECGs were considered abnormal. Note that a normal ECG does not imply that the patient was free of cardiac disease or other medical diagnoses. All ECG voltage-time traces were preprocessed to ensure that the waveforms were centered on the zero baseline while preserving variance and magnitude features.

[0084] All studies from patients with documentation of preexisting or concurrent AF were excluded. The AF phenotype was defined as a clinically reported finding of atrial fibrillation or atrial flutter from a 12-lead ECG, or a diagnosis of atrial fibrillation or atrial flutter applied to two or more inpatient or outpatient visits over a 24-year time period or to a patient problem list from the institutional electronic health record (EHR). New diagnoses occurring within 30 days after cardiac surgery or within 1 year after a diagnosis of hyperthyroidism were excluded. Details of the applicable diagnosis codes and blinded chart review validation of the AF phenotype are presented in Table 1 below. Atrial flutter was grouped with atrial fibrillation due to the similar clinical consequences of the two rhythms, including risk of embolism and stroke, and the frequent coexistence of the two rhythms. In some embodiments, different data may be selected for the training, validation, and / or test sets of the model.

[0085] Table 1 shows the performance indicators for blinded chart review of AF phenotype definitions. Diagnostic codes (ICD 9, 10, and EDG) and corresponding descriptions may be used in defining AF phenotypes.

[0086] [Table 1]

[0087] AF was considered "new" if it occurred at least 1 day after the baseline ECG and the patient had no current or previous history of AF at that time. EHR data were used to identify the most recent eligible visit date for censoring. Eligible visits were limited to ECG, echocardiography, internal medicine outpatient visit, general practice outpatient visit, cardiology outpatient visit, inpatient visit, or surgical procedure.

[0088] For all experiments, the data were divided into a training set, an internal validation set, and a test set. The composition of the training and test sets varied by experiment, as described below; however, in all cases, the internal validation set was defined as a 20% subset of the training data that tracked the validation area under the receiver operating characteristic curve (AUROC) during training to avoid overfitting due to early stopping. Patience for early stopping was set to 9, and the learning rate was set to decay after 3 epochs when there was no improvement in the AUROC on the internal validation set during training.

[0089] Models were evaluated using AUROC, a robust metric of model performance that represents the ability to distinguish between two classes. A higher AUROC indicates better performance (perfect discrimination is represented by an AUROC of 1, and an AUROC of 0.5 is equivalent to good guesswork). Multiple AUROCs were compared by bootstrapping 1,000 instances (using random and variable sampling with replacement). Differences between models were considered statistically significant if the absolute value of the difference at 95% Cl was greater than 0. Models were also evaluated using the area under the precision-recall curve (AUPRC) as the mean precision score by calculating a weighted average of the precision achieved at each threshold with increasing recall.

[0090] Study design As illustrated in Figure 5A, two separate modeling experiments were performed.

[0091] DNN prediction proof of concept (POC) Using all ECGs from a 15-year period, patients were randomly divided into a training set (DO dataset: 80% of eligible studies) and a holdout test set (20%), with no patient overlap between the sets. Two versions of the model architecture were compared (as described above): one using only the ECG voltage-versus-time trace as input, and the other using the ECG trace as well as age and gender as input. The results derived from the holdout test set were denoted Model "M0." For comparison, a boosted decision tree-based model using only age and gender as input, as well as the published CHARGE-AF 5-year risk prediction model, were implemented in patients with all required data available (age, race, height, weight, systolic and diastolic blood pressure, smoking status, use of antihypertensive medications, and the presence or absence of a history of diabetes, heart failure, and myocardial infarction). In some embodiments, race and / or smoking status may not be used. To further evaluate model generalizability, 5-fold cross-validation (CV) was performed within the DO dataset to derive Models M1–M5. There was no overlap of patients between the training and test sets in each split. All ECGs with known time-to-event or follow-up were used during model training, and a single random ECG for a patient was selected from the test set for all models (M0 and M1–M5) to avoid overrepresenting patients with multiple ECGs.

[0092] To demonstrate that there was no bias from selecting a single random ECG from each patient in the POC model, the performance of the M0 model was determined to be stable and unbiased over 100 repeated random selections, with means and standard deviations of AUROC and AUPRC of 0.834 ± 0.002 and 0.209 ± 0.004, respectively, for the model with input of only the ECG trace, and 0.845 ± 0.002 and 0.220 ± 0.004 for the model with input of the ECG trace including age and sex.

[0093] Kaplan-Meier event-free survival analysis was also performed based on the proof-of-concept model with available follow-up data stratified by DNN model predictions. This used the optimal operating point to stratify the population into low-risk and high-risk groups. The optimal operating point for the M0 model was defined as the point on the ROC curve above the best iso-performance line (equal costs for positive and negative misclassification) in the internal validation set, and that threshold was applied to the test set. Data were censored based on recent consultation or onset of AF. Cox proportional hazards models were fitted to regress time to AF on the DNN model-predicted classification of low-risk and high-risk in the normal and abnormal ECG subsets. Hazard ratios with 95% confidence intervals (CIs) were reported for all data for models M0 and M1–M5, as well as for the normal and abnormal subsets (mean values ​​with lower and upper CIs). The Python lifelines package (version 0.24.1) was used for survival analysis.

[0094] Simulated Deployment Model To simulate a real-world deployment scenario—using a model to predict incident AF and potentially prevent AF-related stroke—a second modeling approach was used. All ECGs from a 15-year period were used as the training set. All ECGs from a 5-year period were used as the test set.

[0095] To account for potential variability in the clinical implementation of such models (i.e., matching performance to the range of available resources and desired screening characteristics), performance was evaluated across a range of operating points. The operating point could be a model risk threshold used to classify high or low risk of developing incident AF. For example, an operating point of 0.7 would indicate that model risk scores of 0.7 or greater are considered high risk, while risk scores below 0.7 are considered low risk. Overall model performance could therefore be measured using AUROC and AUPRC scores, which aggregate multiple operating point performance into a single metric. These points were defined based on the maximum Fb score (for b = 0.15, 0.5, 1, and 2) within the internal validation set. The Fb score is a function of precision and recall. A b value of 1 is the harmonic mean of precision and recall (e.g., sensitivity), a value of 2 emphasizes recall, and values ​​of 0.15 and 0.5 correspondingly attenuate the influence of recall. Given the substantial variation in AF incidence with age, the operating point was varied by age. ECGs obtained during the 5-year period with the highest risk for each patient were selected as the test set.

[0096] To link the deployed model predictions to potentially preventable stroke events, an internal registry of patients diagnosed with acute ischemic stroke was used. Over an 8-year period, representing the time interval included in this analysis, this registry included 6,569 patients who were treated for ischemic stroke. This registry was used to identify patients in the deployed model test set who developed an ischemic stroke after the test set ECG. Strokes were considered potentially preventable if the following criteria were met: 1) the patient had at least one ECG before the stroke that predicted a high risk of AF for a given operating point; 2) first-onset AF was identified within 3 days before the stroke or 365 days after the stroke; and 3) the patient was not on anticoagulation therapy at the time of the stroke. To allow for sufficient follow-up, strokes occurring within 3 years of the ECG were included, as shown in Figure 6A. Figure 6A is a flow 600 including steps employed in identifying potentially preventable AF-related strokes among all recorded ischemic strokes in a stroke registry. Figure 6B shows a timeline for ECG selection according to Figure 6A.

[0097] result The AUROC and AUPRC of the POC DNN model for predicting first-onset AF within 1 year in the holdout set (M0) were 0.83, 95% Cl [0.83, 0.84], and 0.21 [0.20, 0.22], respectively, for DNN-ECG, and 0.85 [0.84, 0.85] and 0.22 [0.21, 0.24], respectively, for DNN-ECG-AS. Figure 7A shows a bar graph of model performance as the mean area under the receiver operating characteristic. Figure 7B shows a bar graph of model performance as the mean area under the precision-recall curve. Bars represent the mean performance over 5-fold cross-validation, and error bars indicate the standard deviation. Circles represent M0 model performance in the holdout set. Three bars represent model performance for (i) the Extreme Gradient Boosting (XGB) model with age and gender as input, (ii) the DNN model with ECG voltage-time trace as input, and (iii) the DNN model with ECG voltage-time trace, age, and gender as input. There was sufficient data within the holdout set to calculate the CHARGE-AF score for 65% of patients. Within this subset, the DNN-ECG-AS demonstrated superior performance (AUROC = 0.84 [0.83, 0.85], AUPRC = 0.20 [0.19, 0.22]) compared to the CHARGE-AF score (AUROC = 0.79 [0.78, 0.80], AUPRC = 0.12 [0.11, 0.13]). Figure 7C is a bar graph of model performance (proof-of-concept model) as the area under the receiver operating characteristic, and Figure 7D is a bar graph of precision-recall curves for the population with sufficient data to calculate the CHARGE-AF score. Bars represent average performance over 5-fold cross-validation, and error bars indicate 95% confidence intervals. Circles represent M0 model performance on the holdout set. Three bars represent model performance for (i) an Extreme Gradient Boosting (XGB) model with age and gender as input, (ii) a DNN model with digital ECG traces as input, and (iii) a DNN model with digital ECG traces, age, and gender as input.

[0098] This performance represents a significant improvement over the XGBoost model using only age and gender (AUROC = 0.78, AUPRC = 0.13, p < 0.05 for 95% Cl differences by bootstrapping for both DNN models). Similarly, within the 65% of patients in the holdout test set for whom CHARGE-AF scores could be calculated (AUROC = 0.78, AUPRC = 0.13), the DNN also performed better (AUROC = 0.79, AUPRC = 0.12, see Figure 7B).

[0099] The KM curves and HRs for the three AF ​​prediction models in Figures 7A-7D are illustrated in Figures 7E-7G, with operating points marked on the corresponding ROC curves. In general, Figures 7E-7G illustrate the receiver operating characteristics (ROCs), event-free survival curves, and hazard ratios in subpopulations for three models evaluated in the holdout set: (1) a DNN model based on age and gender only (blue), (2) an ECG trace only (red), and (3) a DNN model based on ECG trace, age, and gender (black) for all ECGs in the holdout set. Figure 7E illustrates ROC curves with operating points marked for the three models. Figure 7F illustrates event-free survival curves for the high-risk and low-risk groups for the operating points indicated in A for a 30-year follow-up. Figure 7G shows plots of hazard ratios (HRs) with 95% confidence intervals (Cl) for the three models in subpopulations defined by age group, sex, and normal or abnormal ECG label. Note that there is no HR for Age < 50 for model (1), because no subjects were classified as high risk for first-onset AF by the model for that subpopulation.

[0100] The DNN model showed significant HRs of 6.7 [6.4, 7.0] and 7.2 [6.9, 7.6] for DNN-ECG and DNN-ECG-AS, respectively. When adjusting for age (in 10-year increments) and gender (the interaction between gender and model was significant), the HRs remained significant: 3.7 [3.6, 4.1] and 3.1 [2.7, 3.4] for the DNN-ECG model in women and men, respectively, and 3.8 [3.6, 4.1] and 2.9 [2.5, 3.4] for the DNN-ECG-AS model in women and men, respectively (Figure 7F). For unadjusted comparisons, the DNN model had higher HRs than the XGBoost model (age and gender) within all subsets defined by gender, age group, and ECG type (normal or abnormal).

[0101] Figure 7H shows the Kaplan-Meier (KM) event-free survival curves within the holdout set for men in the age groups <50, 50-65, and >65 years. Figure 7I shows the Kaplan-Meier (KM) event-free survival curves within the holdout set for women in the age groups <50, 50-65, and >65 years.

[0102] Figure 7J shows the model-predicted KM curves for low- and high-risk groups for first-onset AF for men in the age groups <50, 50-65, and >65 years. Figure 7K shows the model-predicted KM curves for low- and high-risk groups for first-onset AF for women in the age groups <50, 50-65, and >65 years.

[0103] Figures 7H and 7I show KM curves for age groups <50, 50–65, and >65 years for men and women, respectively. As expected, the survival curves for both sexes differ substantially across age groups. However, Figures 7J and 7K demonstrate that within each age group, the DNN model retains the ability to distinguish between high- and low-risk populations for the development of first-time AF for men and women, respectively. Specifically, Figures 7J and 7K show the incidence of AF over time in a cohort of patients, showing that at time zero, no patients had AF (100% event-free) and at time N, how many patients had incident AF. The model demonstrates sensitivity to age as a driving characteristic, as older patients typically predict a higher incidence of AF over time than younger patients in the cohort. Note that the superiority of the DNN model over age and gender alone is most evident in younger age groups; patients under 58 years of age were not predicted as high-risk by the XGBoost model.

[0104] Figure 8A shows the ROC curves with operating points marked for all data (black circles), the normal ECG subset (blue circles), and the abnormal ECG subset (red circles). Figure 8B shows the KM curves for the predicted low- and high-risk groups in the normal and abnormal ECG subsets at the operating points in Figure 8A. The shaded areas represent the 95% confidence intervals. The table below the graphs shows the potentially at-risk populations for a given time interval in the holdout test set. Furthermore, the DNN maintained high performance within the subgroup of ECGs clinically reported as "normal" as well as abnormal ECGs (Figures 7 and 8A). These results were observed to be generalizable and robust based on the comparable performance of cross-validated models (M1–M5) to the MO and the stability of the MO metrics with repeated iterations of random sampling within the holdout set. Finally, the model maintained high performance in the data subset in which AF developed 6 months after ECG (representing true incident cases, i.e., potentially paroxysmal cases with rapid onset between 1 day and 6 months after ECG were excluded), with an AUROC of 0.83 (Figure 9). Figure 9 plots model performance as a function of the definition of time to incident AF after ECG. The y-axis represents the area under the receiver operating characteristic curve (AUROC), and the x-axis represents different thresholds for defining incident AF: cases corresponding to "2" on the x-axis are those who developed AF at least 2 months after the baseline ECG (those who developed AF within the first 2 months after ECG were excluded). An AUROC of 0.87 was calculated for AF appearing exclusively between 1 and 31 days after sinus rhythm ECG, consistent with other findings for distinguishing paroxysmal AF from sinus rhythm.

[0105] DNN 1-year AF risk prediction is associated with long-term AF hazard AF survival as a function of DNN prediction (low vs. high risk for incident AF) is shown in Figure 8B. Although the proportion of patients predicted as high-risk 1-year event-free was high, high-risk prediction was associated with a significantly increased long-term hazard for AF over the next 30 years. Specifically, the hazard ratios were 7.2 (95% Cl: 6.9-7.56) for all ECGs, 8.2 (7.2-9.3) for normal ECGs, and 6.2 (5.9-6.5) for abnormal ECGs when comparing their predicted high vs. low risk for incident AF within 1 year. Furthermore, the median event-free survival times for the two groups identified as low-risk and high-risk were 13 and over 30 years for normal ECGs, respectively, and 10 and 28 years for abnormal ECGs, respectively.

[0106] Predicting first-onset AF could enable prevention of future strokes In the deployment experiment, the model trained on data from before 2010 and tested on data from 2010 to 2014 showed overall high performance for 1-year incident AF prediction, with AUROC and AUPRC of 0.83 and 0.17, respectively. Table 2 summarizes additional model performance characteristics (i.e., increasing emphasis on recall, e.g., sensitivity) at specific operating points determined by maximum F0.15, F0.5, F1, and F2 scores (Figure 10). Figure 10 shows a graph of operating point selection on the internal validation set for the deployment model simulated using the Fb score or Youden index. As a result of these different points, 1, 4, 12, and 20% of the overall population were flagged as high risk, corresponding to positive predictive values ​​of 28, 21, 15, and 12%, respectively, and 4, 17, 45, and 62% of strokes within 3 years of ECG were potentially preventable, respectively. In each of these cases, the number needed to screen (NNS) to find one new case of AF per year was low (4–9).

[0107] Table 2 summarizes the performance of models trained by ECG and age and sex to predict 1-year incident atrial fibrillation (AF) in deployment scenarios for four different operating points defined in an independent internal validation set.

[0108] [Table 2]

[0109] Regardless of the model, we observed that 3,497 of 181,969 (1.9%) patients had a stroke after an ECG in the expanded test set. Of these, 96, 250, and 375 patients had a stroke within 1, 2, and 3 years after the ECG, respectively, and received a new AF diagnosis between -3 and 365 days after the stroke. Of those 96, 250, and 375 patients, 84, 229, and 342 were not taking anticoagulants at the time of the stroke, indicating potentially preventable AF-related stroke (Figure 6A).

[0110] Figure 11 shows the model's sensitivity to potentially preventing AF-related strokes occurring within 1, 2, and 3 years after ECG as a function of the percentage of the population targeted as being at high risk for developing incident AF. The gray dotted lines represent the corresponding optimal operating thresholds from Table 2. Figure 11 illustrates the model's potential for selecting high-risk populations that can subsequently be screened for new AF with the goal of stroke prevention. Three conclusions can be drawn from Figure 11. First, the ability to identify potentially preventable AF-related strokes is proportional to the ability to identify new AF. Second, a substantial amount of incident AF can be identified by screening a relatively small percentage of the population. Third, the variable operating point allows for a trade-off between precision and recall that can be tailored to various priorities.

[0111] Of 181,969 patients with post-ECG ischemic stroke within the expansion test set (2010–2014), 3,497 (1.9%) patients were observed. Of these, 96, 250, and 375 patients had a stroke within 1, 2, and 3 years after ECG, respectively, and received a new diagnosis of AF within 365 days after stroke. Of those 375 patients, 342 were not taking anticoagulants at the time of stroke onset, 31 were taking anticoagulants for reasons other than AF, and two patients had insufficient records to determine whether they were being treated with anticoagulants at the time of stroke onset. Therefore, these 375 patients represent the cohort at risk for AF-associated stroke at the time of ECG.

[0112] When we applied the model (trained on data from before 2010) to this deployment test set, we observed good performance (AUROC = 0.83, AUPRC = 0.17) for predicting first-onset AF at 1 year. Using the operating point determined by the F2 score, we observed a sensitivity of 69%, a specificity of 81%, and a number needed to screen (NNS) of 9 to detect one case of first-onset AF at 1 year. Sixty-two percent (231 of 375) of patients who had an AF-related stroke within 3 years after ECG were predicted to be at high risk for first-onset AF (Figure 11). The NNS for identifying one patient who developed an AF-related stroke within 3 years from the high-risk prediction was 162. Table 3 summarizes the performance of the DNN model (by age and sex) for predicting first-onset AF at 1 year in the deployment scenario and its potential to identify patients at risk for AF-related stroke within 3 years of ECG. Results are presented based on model predictions using the full test set as well as specified population subsets that differed in demographic, clinical setting, or comorbidity characteristics. Table 3 shows favorable test characteristics in subgroups defined by age, sex, race, comorbidity, clinical setting, and CHA2DS2VASc score.

[0113] [Table 3]

[0114] This disclosure describes a deep neural network trained on 12-lead resting ECG data that predicts incident AF within one year with high performance (AUROC = 0.85) in patients without a history of AF. Furthermore, this DNN was demonstrated to outperform both a clinical model (CHARGE-AF) and a machine learning model using age and gender within the same dataset. The model's performance is noted to be superior to the reported performance of other models: CHARGE-AF (AUROC = 0.77), ARIC (AUROC = 0.78), and Framingham (AUROC = 0.78). It is also noted that the shorter prediction interval of model 400 (1 year compared to 5-10 years) allows for more actionable predictions, which retain significant prognostic potential over the next 30 years. Finally, the data suggest that identifying high-risk populations who can be targeted for screening (e.g., using wearable devices or continuous monitors) could potentially prevent a significant proportion of AF-related strokes.

[0115] Over 25% of all strokes are thought to be attributable to AF, and ~20% of AF-attributable strokes occur in individuals without a previous diagnosis of AF. Real-world scenarios were simulated by applying Model 400 to ECGs acquired over a 5-year period and cross-referencing predicted high-risk ECGs with future ischemic stroke rates deemed potentially preventable (without concurrent or subsequent identification of AF and current use of anticoagulation). A range of different model operating points was considered based on the expectation that implementation of such screening initiatives would vary in scope across different healthcare settings. These differences would be reflected in varying preferences for the total number of screenings versus the proportion of AF identified and the number of strokes potentially prevented.

[0116] At one end of this performance spectrum, where only the top 1% of the population was identified as high-risk, a positive predictive value of nearly 28% was observed for detecting 1-year AF (NNS for AF = 4). This precision translated into a screening yield (NNS) of 120–361 for incident strokes occurring between 0 and 3 years from baseline. However, this lower screening yield was offset by a lower overall recall (i.e., sensitivity) for preventable strokes (4% for strokes within 3 years after ECG). At the other end of the spectrum, where 21% of the population was identified as high-risk for developing AF, the preventable stroke recall rate improved substantially (62% for strokes within 3 years after ECG), but at the expense of a substantial increase in screening yield for AF (NNS = 9) and stroke (NNS = 162–542 for 3-year or 1-year incidence, respectively). These numbers relative to screening volume compare favorably with other well-accepted screening tests, including mammography (NNS476 preventing one breast cancer death in a 60-69 year old), prostate-specific antigen (NNS1410 preventing one death from prostate cancer), and cholesterol (NNS418 preventing one death from cardiovascular disease).

[0117] The Model 400 can be incorporated into routine screening so that all ECGs are evaluated and high-risk studies are flagged for follow-up and monitoring. Such enhanced monitoring can take many different forms, including systematic pulse palpation, systematic ECG screening, continuous patch monitors worn once or multiple times, intermittent home screening with devices such as Kardia Mobile, or wearable monitors such as the Apple Watch. While these methods can be used in isolation to screen for AF, using them in conjunction with DNN prediction models may help overcome challenges associated with the overall low incidence of AF in the general population, particularly in younger age groups. While age is generally considered the dominant risk factor in guiding AF screening strategies, this study found that 38% of all new AF cases (within 1 year of ECG) and 36% of all potentially preventable strokes (within 3 years of ECG) occurred in patients under 70 years of age.

[0118] Figure 12 is a graph of the percent of all incident AF (within 1 year after ECG) and stroke (within 3 years after ECG) in the population as a function of patients under a given age threshold. Model 400 could be used in all patients over the age of 18, outperforming models using only age and sex.

[0119] Model 400 can detect paroxysmal AF and predict first-onset AF. This is different from other techniques that focus solely on identifying paroxysmal AF without the ability to predict incident AF. As noted above, these results demonstrate that model 400 does both. One piece of evidence supporting our claim that the DNN model can truly predict first-onset AF is the continued separation of the Kaplan-Meier curves up to 30 years after the index ECG, as noted in Figures 7H-7K.

[0120] More than 25% of all strokes are thought to be attributable to AF, and ~20% of AF-attributable strokes occur in individuals not previously diagnosed with AF. Once AF is detected, anticoagulation therapy is effective in preventing stroke; however, screening for AF is challenging due to the paroxysmal nature of AF and the fact that it is often asymptomatic. Screening strategies involving patch monitors, wearables, and other devices can be used to detect AF but are most effective in populations with a high prevalence of AF. The fundamental goal in developing this predictive model is to identify high-risk populations that can be selected for additional monitoring with the goal of detecting AF before it leads to a stroke.

[0121] A real-world scenario was simulated by applying our model to all ECGs obtained within a large regional health system over a 5-year period and cross-referencing predicted high-risk ECGs with future ischemic stroke incidence rates deemed potentially preventable (concurrent / subsequent identification of AF). We found that a high percentage (62%) of patients suffering from AF-related stroke were correctly predicted as high-risk for AF. The NNS for identifying AF in one patient who later suffered an AF-related stroke was 162. This compares favorably with other well-accepted screening tests, including mammography (NNS476, preventing one breast cancer death in a patient aged 60–69 years), prostate-specific antigen (NNS1410, preventing one death from prostate cancer), and cholesterol (NNS418, preventing one death from cardiovascular disease). Not all patients with AF are at high risk for stroke, and scoring systems such as CHA2DS2VASc are commonly used to determine the need for anticoagulation therapy. A CHA2DS2VASc score of 2 or greater is the most commonly used cue point for initiating anticoagulation, and Table 3 shows that within that subgroup the model performed well, with an NNS of 8 to find one new case of AF. Table 3 also shows that 92% of patients predicted to be at high risk for AF who subsequently suffered an AF-related stroke had a CHA2DS2VASc score of 2 or greater and were potentially eligible for anticoagulation.

[0122] FIG. 13 is an example process 1300 for generating a risk score using a model. In some embodiments, the model may be model 400 of FIG. 4A. In some embodiments, the model may be model 424 of FIG. 4B. The risk score can indicate whether a patient will suffer from and / or develop a medical condition within a predetermined period of time (e.g., six months, one year, ten years, etc.). In some embodiments, process 1300 may be included in ECG analysis application 132 of FIG. 1. In some embodiments, process 1300 may be implemented as computer-readable instructions on one or more memories or other non-transitory computer-readable media and executed by one or more processors in communication with one or more memories or media. In some embodiments, process 1300 may be implemented as computer-readable instructions on memory 220 and / or memory 240 and executed by processor 204 and / or processor 224.

[0123] At 1304, process 1300 can receive patient data including ECG data. The ECG data can be associated with the patient. In some embodiments, the ECG data can include ECG voltage input data 300. In some embodiments, the ECG data can be associated with an electrocardiogram configuration including multiple leads and time intervals. The ECG data can include voltage data associated with at least a portion of a time interval for each lead included in the multiple leads. In some embodiments, the ECG data may include first voltage data associated with Lead I and a first portion of the time interval, second voltage data associated with Lead V2 and a second portion of the time interval, third voltage data associated with Lead V4 and a third portion of the time interval, fourth voltage data associated with Lead V3 and a second portion of the time interval, fifth voltage data associated with Lead V6 and a third portion of the time interval, sixth voltage data associated with Lead II and a first portion of the time interval, seventh voltage data associated with Lead II and a second portion of the time interval, eighth voltage data associated with Lead II and a third portion of the time interval, ninth voltage data associated with Lead VI and a first portion of the time interval, tenth voltage data associated with Lead VI and a second portion of the time interval, eleventh voltage data associated with Lead VI and a third portion of the time interval, twelfth voltage data associated with Lead V5 and a first portion of the time interval, thirteenth voltage data associated with Lead V5 and a second portion of the time interval, and fourteenth voltage data associated with Lead V5 and a third portion of the time interval.

[0124] The ECG data may include a first branch (e.g., “branch 1”) including Leads I, II, V1, and V5 acquired from time (t)=0 (the start of data acquisition) to t=5 seconds, a second branch (e.g., “branch 2”) including Leads V1, V2, V3, II, and V5 from t=5 to t=7.5 seconds, and a third branch (e.g., “branch 3”) including Leads V4, V5, V6, II, and V1 from t=7.5 to t=10 seconds, as shown in FIG. 3 . In some embodiments, process 1300 may receive demographic data and / or other patient information associated with the patient. Demographic data may include, for example, the patient's age and gender values ​​or additional variables (e.g., race, weight, height, smoking status, etc.) from an electronic health record. In some embodiments, process 1300 may receive one or more EHR data points. In some embodiments, EHR data points may include laboratory values ​​(blood cholesterol measurements such as LDL / HDL / total cholesterol, blood counts such as hemoglobin / hematocrit / white blood cell count, blood chemistries such as glucose / sodium / potassium / liver and kidney function labs, and additional cardiovascular markers such as troponin and natriuretic peptides), vital signs (blood pressure, heart rate, respiratory rate, oxygen saturation), imaging metrics (cardiac ejection fraction, ventricular volumes, myocardial thickness, heart valve function, etc.), patient diagnoses (diabetes, chronic kidney disease, congenital heart defects, cancer, etc.), treatments (procedures, medications, referrals for services such as cardiac rehabilitation, dietary counseling, etc.), echo measurements, ICD codes, and / or care gaps.

[0125] In some embodiments, the ECG data may be generated over a single time interval (e.g., 10 seconds). In some embodiments, the ECG data may include ECG voltage input data 428. In some embodiments, the ECG voltage input data may include 5000 data points collected over a 10 second period and eight leads, including Leads I, II, V1, V2, V3, V4, V5, and V6.

[0126] In some embodiments, the ECG data may include leads originally sampled at 500 Hz. In some embodiments, the ECG data may include leads originally sampled at 250 Hz and linearly interpolated to 500 Hz. In some embodiments, the ECG data may include leads originally sampled at 1000 Hz and downsampled to 500 Hz. Thus, a variety of ECG systems and / or sampling environments may be used with the same trained model.

[0127] At 1308, the process can provide at least a portion of the patient data to the trained model. In some embodiments, the trained model can be model 400. In some embodiments, process 1308 can provide ECG data to the model. In some embodiments, process 1300 can include providing first, sixth, ninth, and twelfth voltage data to a first channel; providing second, fourth, seventh, tenth, and thirteenth voltage data to a second channel; and providing third, fifth, eighth, eleventh, and fourteenth voltage data to a third channel. In some embodiments, the ECG data can include voltage data for all leads over an entire time interval, and process 1300 can include providing the voltage data to a single channel included in the trained model. In some embodiments, process 1308 can provide ECG data and demographic data and / or EHR data points to the model.

[0128] At 1312, process 1300 can receive a risk score from the model. In some embodiments, the risk score can be an AF risk score indicating a predicted risk of a patient developing AF within a predetermined time period from when the electrocardiogram data was generated. In some embodiments, the predetermined time period can be 3 months, 6 months, 1 year, 5 years, 10 years, 30 years, or any other time period selected from the range of 6 months to 30 years. In some embodiments, the predetermined time period can be at least 3 months (e.g., 3 months, 6 months, etc.). In some embodiments, the predetermined time period can be at least 6 months (e.g., 6 months, 1 year, etc.). In some embodiments, the predetermined time period can be at least 1 year (e.g., 1 year, 5 years, etc.). In some embodiments, the predetermined time period can be at least 5 years (e.g., 5 years, 10 years, etc.).

[0129] At 1316, the process may output the risk score to at least one of a memory (e.g., memory 220 and / or memory 240) or a display (e.g., display 116, display 208, and / or display 228). In some embodiments, the display may be in view of a practitioner or healthcare administrator. In some embodiments, process 1300 may generate and output a report based on the risk score. In some embodiments, the report may include the raw risk score and / or an image related to the risk score. In some embodiments, process 1300 may determine that the risk score is higher than a predetermined threshold associated with a medical condition (e.g., a risk score higher than the threshold may indicate that the patient will suffer from the medical condition within a predetermined time period). Process 1300 may then generate a report based on the determination that the risk score is higher than the predetermined threshold. In some embodiments, in response to determining that the risk score is higher than a predetermined threshold, process 1300 can generate a report to include information (e.g., text) and links (e.g., one or more hyperlinks) to sources about treatment for the condition, the cause of the condition, and / or other clinical information related to the condition. In some embodiments, process 1300 can generate a report from intermediate results stored in a standardized format, such as the standardized JavaScript Object Notation (JSON) format. The standardized format can also be converted using format conversion software for presentation to a healthcare provider, such as for conversion to the healthcare provider's electronic health record system. In some embodiments, process 1300 can generate a report to include test name, patient gender, patient date of birth, patient name, facility / physician name, and / or medical record number.In some embodiments, process 1300 can generate a report to include an ECG waveform, which may be, for example, a re-display of the original waveform data generated by the ECG or a redrawn waveform verified for similarity to the original waveform. In some embodiments, process 1300 can generate a report to include recommendations, such as treatment or monitoring recommendations. For example, the report may include a recommendation that the patient should be subject to additional cardiac monitoring, which is an important step forward in detecting undiagnosed disease. As another example, the report may include one or more recommendations for lifestyle modifications (e.g., weight loss, alcohol abstinence, etc.) shown to alleviate AF or other medical conditions, screening for undiagnosed AF or other medical condition triggers such as sleep apnea, conducting more frequent follow-ups, performing future ECGs, evaluating heart rate by pulse, or prescribing remote cardiac monitoring. Based on the information from the device in combination with other symptoms and clinical factors, the physician may proceed with one or neither of these actions or other appropriate patient management strategies. Process 1300 can then end.

[0130] Deep Neural Networks for Predicting Incident Atrial Fibrillation Directly from 12-Lead ECG Tracings Next, an example of a neural network trained on clinically acquired ECGs is described. 1.1 million Afib-free ECGs (from 237,060 patients) were extracted from 2.7 million clinically acquired 12-lead ECGs. The presence or absence of future incident Afib was determined for each extracted ECG via subsequent ECG studies and a problem list diagnosis generated by the attending physician. The prevalence of incident Afib was 7% in the overall population and 3% in the subset of 61,142 patients whose ECGs were interpreted as clinically normal.

[0131] A multiclass deep convolutional neural network was trained to predict 1-year incident Afib (i.e., the target output variable) using 5-fold cross-validation with 15 traces per ECG as input. Model performance was assessed by the area under the receiver operating characteristic curve (AUC), and Cox proportional hazards analysis was performed on the predicted group non-incidence curves. Additionally, to evaluate model performance in the context of opportunistic population screening, we estimated the positive predictive value (PPV) of the model as a function of the number of patients with the highest model-predicted risk to be screened.

[0132] Figure 14 shows the incidence-free curves for the predicted Afib and predicted Afib-free groups (likelihood threshold = 0.5) with available follow-up. The mean AUC of the prediction model was 0.75 ± 0.02. A unit risk score increase corresponded to a 45% increase in the odds of developing AF within 1 year (odds ratio: 1.45 [95% confidence interval (Cl): 1.15-1.66]). Even in the subset of ECGs interpreted as "normal" (e.g., where the physician could not visually identify an arrhythmia), the AUC was 0.72 ± 0.02.

[0133] Figure 15 is a graph showing the top % patients with highest risk and positive predictive value across all operating points of the prospective Afib prediction system. In a potential population screening setting, the interpretive performance corresponds to a PPV of 0.3 for screening the highest 1% at risk.

[0134] Deep neural networks can predict 1-year mortality directly from ECG signals, even when interpreted as clinically normal A total of 1,775,926 12-lead resting ECGs, along with age, sex, and vital status, collected from 397,840 patients over a 34-year period were extracted from the electronic health records of a single medical institution. Fifteen voltage-time 250-500 Hz traces (three standard "long" 10-second acquisitions and 12 "short" 2.5-second acquisitions) were extracted from each ECG, along with "ECG measures" (30 diagnostic patterns and nine standard measurements). A deep neural network was trained to predict 1-year mortality (e.g., variable output) directly from the ECG trace. Five-fold cross-validated models using different variable inputs and Cox proportional hazards survival analyses were performed on the predicted groups to compare performance. Good predictive accuracy was identified within the subset of 297,548 ECGs designated "normal" by physicians. A blinded study of three cardiologists was performed to determine whether features indicative of mortality risk could be identified within the ECG data.

[0135] FIG. 16 is a bar graph of the performance of a mortality prediction model or system to predict one-year mortality by ECG measurements and ECG tracings with and without age and sex as additional features.

[0136] FIG. 17 is a graph showing mean KM curves for predicted survival and mortality groups in normal and abnormal ECG subsets >1 year post-ECG.

[0137] A model trained on only 15 traces yielded an average AUC of 0.83, which improved to 0.85 after adding age and gender. This model outperformed another nonlinear model created from 39 ECG measurements (AUC = 0.77 and 0.81 without and with age and gender, respectively, p < 0.001, see Figure 16). Even within "normal" ECGs, model performance remained high (AUC = 0.84), with a hazard ratio of 6.6 (p < 0.005) beyond one year after the ECG (see Figure 17). In blinded studies, the patterns captured by the model were not visually apparent to cardiologists, even after labeling true positives (death) and true negatives (survival).

[0138] In some embodiments, the trained model can be included in the ECG analysis application 132 and used to predict one-year mortality using a process similar to process 1300 of FIG. 13 .

[0139] Many ECG machines create a "portable document format" (i.e., PDF) from the voltage-time traces, which can then be stored within the medical record. The underlying voltage data can be extracted from these PDFs by first converting the PDF to XML and then parsing the XML file for the underlying data points that make up each of the voltage-time traces. The XML may also be analyzed to determine the patient's age, sex, nine continuous numeric measurements output by the ECG machine (QRS duration, QT, QTC, PR interval, heart rate, mean RR interval, and P, Q, and T wave axes), and 30 categorical ECG patterns, including normal, left bundle branch block, incomplete left bundle branch block, right bundle branch block, incomplete right bundle branch block, atrial fibrillation, atrial flutter, acute myocardial infarction, left ventricular hypertrophy, premature atrial contractions, premature atrial contractions, first-degree block, second-degree block, fascicular block, sinus bradycardia, other bradycardia, sinus tachycardia, ventricular tachycardia, supraventricular tachycardia, prolonged QT, pacemaker, ischemia, low QRS voltage, intra-atrioventricular block, anterior infarction, nonspecific T wave abnormality, nonspecific ST wave abnormality, left axis deviation, right axis deviation, and early repolarization, which may be diagnosed by a physician. Code examples for converting from PDF to SVG format and from SVG to parsed data points are provided below in Appendix A.

[0140] Inclusions / Exclusions and Outputs from How to Read an ECG In some embodiments, a predictive model can be trained using a set of input variables, such as an ECG PDF, variables extracted from the PDF, and a desired output variable, such as one-year mortality. The model training phase provides labeled data (both inputs and outputs are known), allowing the model to learn how to best predict the output variable. After the model is trained, it can be deployed in situations where only the input variables are known and the output may include a predictive target of interest. An example target of interest may include the risk of one-year mortality given the current ECG.

[0141] For model training, a series of 12-lead ECG traces can be extracted from an institution's clinical database. Such a database can contain over 2.6 million traces, including traces acquired over a period of time, including months, years, or decades. In one example, resting 12-lead ECGs with 2.5 seconds of voltage-time traces for all 12 leads and 10 seconds for all three leads (V1, II, and V5) that have no significant artifacts and are associated with at least one year of follow-up or death within one year can be extracted. Artifacts may include those identified by ECG software at the time of the ECG, such as "technically limited," "motion / baseline artifact," "Warning: interpretation of this ECG, although attempted, may be adversely affected by data quality," "Acquisition hardware fault prevents reliable analysis," "Suggest repeat tracing," "chest leads probably not well placed," "electrical / somatic / power line interference," or an ECG output that includes "Defective ECG." The extraction may further include 15 voltage-time traces (three 10-second leads and twelve 2.5-second leads). As such, the final data set may include 1.8 million ECGs, 51% of which were stored at 500 Hz (Hz = samples per second) and the remainder at 250 Hz. A preprocessing step may include resampling the 250 Hz ECGs to 500 Hz by linear interpolation.

[0142] Other inputs to consider, including additional endpoints and EHR data Where additional data could inform the model, the extraction may include records from electronic health records with additional patient data such as patient status (alive / deceased), which may be generated by combining each patient's most recent clinical visit from the EHR with a regularly updated mortality index registry. Patient status is used as an endpoint to determine a prediction for 1-year mortality after the ECG, but additional clinical outcomes may also be predicted, including, but not limited to, mortality at any interval (1, 2, 3 years, etc.), mortality related to heart disease, cardiovascular disease, sudden cardiac death, hospitalization for cardiovascular disease, need for intensive care unit admission for cardiovascular disease, emergency department visits for cardiovascular disease, first occurrence of an abnormal heart rhythm such as atrial fibrillation, need for a heart transplant, need for an implantable cardiac device such as a pacemaker or defibrillator, need for mechanical circulatory support such as a left / right / biventricular assist device or a total artificial heart, need for a major cardiac procedure such as percutaneous coronary intervention or coronary artery bypass graft / surgery, new stroke or transient ischemic attack, new acute coronary syndrome, or first occurrence of any form of cardiovascular disease such as heart failure, or the likelihood of a diagnosis of other diseases for which information can be obtained from an ECG.

[0143] Furthermore, additional variables can be added to predictive models to both improve the accuracy of endpoint predictions and identify treatments that can positively impact predicted adverse outcomes. For example, model accuracy can be improved by extracting laboratory values ​​(blood cholesterol measurements such as LDL / HDL / total cholesterol, blood counts such as hemoglobin / hematocrit / white blood cell count, blood chemistry such as glucose / sodium / potassium / liver and kidney function labs, and additional cardiovascular markers such as troponin and natriuretic peptides), vital signs (blood pressure, heart rate, respiratory rate, oxygen saturation), imaging metrics (ejection fraction, ventricular volume, myocardial thickness, heart valve function, etc.), patient diagnoses (diabetes, chronic kidney disease, congenital heart defects, cancer, etc.), and treatments (procedures, medications, referrals for services such as cardiac rehabilitation, dietary counseling, etc.). Some of these variables are "modifiable" risk factors and can be used as inputs to models to indicate the benefit of using specific treatments. For example, a prediction may identify a patient as having a 40% chance of developing atrial fibrillation in the next year, but if the model could identify that the patient is taking a beta-blocker, the predicted risk would drop to 20% based on the increased data available to the predictive model. In one example, demographic data 416 and patient data 1304 may be supplemented with these additional variables, such as extracted laboratory values ​​or modifiable risk factors.

[0144] A machine learning model for implementing a predictive model may include a convolutional neural network with multiple branches, each processing multiple channels (model architecture illustrated in FIG. 18 below). FIG. 18 illustrates a model architecture for a convolutional neural network with multiple branches, each processing multiple channels. As illustrated, in some embodiments, the model may include five branches in which inputs of three leads (branch 1: [I, II, III], branch 2: [aVR, aVL, aVF], branch 3: [V1, V2, V3], branch 4: [V4, V5, V6], and branch 5 [V1-long, 11-long, V5-long]) may be utilized to generate predictions as simultaneous channels. In some multi-branch CNNs, each branch may represent three leads acquired simultaneously or during the same heartbeat. For branch 5, which may include a "long lead," the branch may be sampled for a duration of 10 seconds. For the other four branches, the leads may be sampled for a duration of 2.5 seconds.

[0145] In a typical 12-lead ECG, four of these branches of three leads are acquired over a 10-second duration. At the same time, a "long lead" is recorded over the entire 10-second duration. To improve the robustness of the CNN, the architecture can be designed to take these details into account, especially since abnormal cardiac rhythms cause the trace to change morphology throughout a standard 10-second clinical acquisition. Conventional models may miss abnormal cardiac rhythms that exhibit morphological deviations during longer 10-second readings.

[0146] The convolutional block may include a one-dimensional convolutional layer followed by batch normalization and rectified linear unit (ReLU) activation. In one example, the first four branches and the last branch may include four and six convolutional blocks, respectively, followed by a global average pooling (GAP) layer. The outputs of all branches may then be concatenated and connected to a series of dense layers, such as a series of six layers, including layers with 256 (with dropout), 128 (with dropout), 64, 32, 8, and 1 units, with a sigmoid function as the final layer. An Adam optimizer with a learning rate of 1e-5 and a batch size of 2048 may be computed for each model branch in parallel on a separate GPU for faster computation. Additional architectures may include (1) replacing the GAP layer with a recurrent neural network, such as a long short-term memory and gated recurrent units, (2) varying the number of convolutional layers by varying the filter size in all or many branches in the current architecture, or varying the number of branches in the architecture in addition to, (3) adding derived signals from time-voltage traces, such as power spectral density, to model training, and (4) adding tabulated or derived features from the EHR, such as lab values, echo measurements, ICD codes, and / or care gaps, in addition to age and gender. In one example, demographic data 416 and patient data 1304 may be supplemented with these additional tabulated or derived features from the subject's EHR.

[0147] training method The training data may be divided into multiple splits, with the final split reserved as a validation set. An exemplary distribution may include five splits, with 5 percent of the training data reserved as a validation set. For cross-validation, the data may be split so that the same patient is not present in both the training and test sets. Outcomes may be approximately balanced in the validation set. Training timing may be based on validation loss, which may be evaluated at each training interval. The loss (binary cross-entropy) evaluated on the validation set for each epoch may be sufficient as a criterion. For example, training may be terminated if the validation loss does not decrease for 10 epochs (as an early stopping criterion), and the maximum number of epochs may be set to 500. The exemplary model may be implemented using Keras with the Python TensorFlow backend, and default training parameters may be used. In other embodiments, other models, programming languages, and parameters may be used. A single branch of the above model may be used if all leads are sampled in a single common time period (e.g., 12 leads sampled from 0 to 10 seconds). Demographic variables can be added to the model to increase robustness and improve predictive value. As an example, demographic variables of age and gender can be added to the model by concatenating the following 64 hidden unit layers with other branches: In one example, training can be performed on an NVIDIA DGX1 platform with eight V100 GPUs and 32 GB of RAM per GPU. However, training can be performed via any computing device, including CPUs, GPUs, FPGAs, ASICs, and the like, and the duration can vary based on the effective computer power available on each training device. In one example, fitting the partition with five GPUs and each epoch took approximately 10 minutes.

[0148] For additional external validation, it may be advantageous to utilize data acquired at a particular hospital (e.g., Geisinger Medical Center, Rush, Northwestern) for training and test the model on all data acquired at other hospitals. Segmenting the training and validation sets by facility allows for the formation of additional independent validation of model accuracy.

[0149] Model operation After the model is fully trained, it can be used to predict one or more conditions associated with a patient based on the patient's ECG. As such, the input to the trained model includes, at a minimum, the ECG. The accuracy of the model can be increased by having additional clinical variable inputs, as described in detail above, and as such, can add additional utility (i.e., the ability to recommend treatment changes).

[0150] The output of the trained model may include the likelihood of a future adverse outcome (potential outcomes are described in detail above) and potential interventions that may be implemented to reduce the likelihood of the adverse outcome. An exemplary intervention that may be suggested includes informing the patient's physician that the risk of hospitalization may be reduced from 10% to 5% if the patient is given a beta-blocker medication.

[0151] Generating predictions from these models may include fulfilling the objective of determining future risk of adverse clinical outcomes, ultimately to assist clinicians and patients with earlier treatment and potential prevention as a result of even earlier intervention. The duration between the ECG and the final prediction (e.g., 1 year when predicting 1-year mortality) may vary depending on the clinical outcome of interest and the intervention that may ultimately be proposed and / or implemented. As noted above, models may be trained for any relevant duration after ECG acquisition, such as time periods including 1, 2, 3, 4, or 5 years (or more), and for any relevant clinical prediction. Additionally, for each relevant clinical prediction, interventions may similarly be suggested based on either model-learned correlations or publication of interventions. An example may include predicting that a patient will develop a-fib in the next year with a 40% probability; however, if the patient is prescribed a beta-blocker, that same patient may instead have a 20% chance of developing a-fib in the next year. Incorporating precision medicine into the earliest stages of care, such as when a patient receives their first ECG, allows treating physicians to make recommendations that can improve a patient's overall quality of life and prevent adverse outcomes before their health deteriorates and they seek advanced medical care. Furthermore, by incorporating additional variables above and beyond the ECG into the training phase of development, the model learns how certain treatments / interventions can positively impact patient outcomes—i.e., reduce the likelihood of an adverse clinical outcome of interest. During the operational phase, the model can take ECG and relevant clinical variable inputs and then output the predicted likelihood of an adverse clinical outcome with or without certain treatments / interventions. Even when the patient's current treatment is unknown, the model can make recommendations such as, "If this patient develops diabetes, the one-year probability of death will be reduced by 10% if blood glucose is properly controlled according to clinical guidelines."

[0152] Additional Example Model Operations In one embodiment, a fully trained model may predict the likelihood of a-fib and include further suggestions based on the patient's height, weight, or BMI that weight loss is necessary to improve the patient's overall response to treatment. A fully trained model may include a model that takes in the PDF of a clinically obtained 12-lead resting ECG and outputs a precise risk of death at one year as a likelihood ranging from 0 to 1, where the model also receives the patient's height, weight, or BMI and clinical updates of the patient over at least one year.

[0153] Figure 19A is a graph of the area under the receiver operating characteristic curve (AUC) for predicting 1-year all-cause mortality, and Figure 19B is a bar graph showing the AUC for various lead configurations derived from 2.5-second or 10-second tracings.

[0154] Using the inclusion / exclusion criteria and five-fold cross-validation method described above, the area under the receiver operating characteristic curve (AUC) for predicting 1-year all-cause mortality can be shown to be 0.830 using only ECG voltage-time traces (obtained directly from the PDF) and improving to 0.847 when age and sex are added as additional input variables (see the transparent [blue] bars in Figure 19A). Note that the AUC is a measure of model accuracy ranging from 0.5 (worst prediction accuracy, equivalent to chance) to 1 (perfect prediction). During a 12-lead ECG acquisition, all leads are acquired for a duration of 2.5 seconds, and three of the 12 leads (V1, II, and V5) are additionally acquired for a duration of 10 seconds. A model combining all 15 ECG voltage-time traces from the 12 standard leads (three leads acquired for 2.5 seconds and 12 leads acquired for 10 seconds) provided the best AUC compared to models derived from each single lead as input. Models derived from 10-second tracings had higher AUCs than models derived from 2.5-second tracings, demonstrating that data of longer duration provide more informative features to the model.

[0155] Figure 20A is a plot of ECG sensitivity versus specificity, and Figure 20B is a Kaplan-Meier survival analysis plot of survival proportion versus years at a selected operating point (likelihood threshold = 0.5, sensitivity: 0.76, specificity: 0.77).

[0156] To further investigate the predictive performance within the entire dataset and within the subset of ECGs interpreted by physicians as either "normal" or "abnormal," Kaplan-Meier survival analysis was performed using follow-up data available in the EHR for the two groups (survival / death at 1 year) predicted by the model at the selected operating point (likelihood threshold = 0.5, sensitivity: 0.76, specificity: 0.77). For normal ECGs, the median survival times (relative to the 5-fold mean survival curve) for the two groups predicted for 1-year survival and death were 26 and 8 years, respectively, and for abnormal ECGs, they were 16 and 6 years, respectively (see Figure 20B). Cox proportional hazards regression models were fitted for each of the five partitions, and the mean hazard ratios (including lower and upper 95% confidence intervals) for 1-year post-ECG survival and death predicted by the model were 4.4 [4.0-4.5] for all ECGs, 3.9 [3.6-4.0] for abnormal ECGs, and 6.6 [5.8-7.6] for normal ECGs (all p<0.005). Thus, the hazard ratios were greatest in the subset of normal ECGs, and the prediction of 1-year death from the model was a significant discriminator of long-term survival up to 30 years after clinical acquisition of the ECG.

[0157] Figure 21 shows a graph of predicted mortality outcomes by three different cardiologists before and after validating the model results. Another consideration of a well-trained model may include cases where the features learned by the model are visually apparent to cardiologists. For example, if 401 sets of paired normal ECGs are selected and submitted to a blinded study by three cardiologists, a measure of model performance relative to the cardiologists' visual inspection can be generated. Each pair may consist of true positives (normal ECGs correctly predicted by the model as death after one year) and true negatives (normal ECGs correctly predicted by the model as survival after one year) matched for age and sex. Figure 22A shows a graph of the event-free rate versus years. Figure 22B shows a graph of the positive predictive value versus the top percentage of risk groups in the population. In one study, cardiologists generally had low accuracy, ranging from 55 to 68% (10 to 36% higher than chance), for correctly identifying normal ECGs linked to one-year mortality. After allowing each cardiologist to examine a separate dataset of 240 paired ECGs labeled to indicate outcome, the predictive accuracy in repeating the original blinded examination of 401 paired ECGs remained low (50–75% accuracy, i.e., 0–50% better than chance) (see Figure 21). This suggests that the above model can identify features predictive of important clinical outcomes that cardiologists, importantly, are unable to visually identify despite years of clinical training.

[0158] Note that the reported accuracy for predicting outcome may be slightly improved by testing on only a single ECG from each patient. The figures above report the test data accuracy (AUC) from all ECGs from a patient, which may result in overestimating patients with more ECGs (i.e., a patient with 20 ECGs in their lifetime will contribute more to the accuracy assessment than a patient with only one ECG in their lifetime). Patients with more ECGs are typically sicker, making their clinical outcome more difficult to predict; therefore, overestimating these patients may result in a slight decrease in perceived accuracy (AUC).

[0159] Prediction of atrial fibrillation Atrial fibrillation (AF) is an abnormal cardiac rhythm that increases the risk of stroke. Therefore, predictive strategies for detecting the onset of AF before a stroke occurs are of great clinical importance. In one embodiment, a deep learning model can predict future AF directly from a 12-lead resting electrocardiogram (ECG) voltage-time trace, as extracted from a clinically acquired PDF.

[0160] For example, a dataset containing 2.7 million clinically acquired 12-lead ECGs may contain 1.1 million ECGs (from 237,060 patients) without AF. The presence or absence of future incident AF may be determined via subsequent ECG studies and problem list diagnoses within the electronic health record. The prevalence of incident AF was 7% in the overall population and 3% in the subset of 61,142 patients whose ECGs were interpreted as clinically normal. A model such as a multiclass deep convolutional neural network may be trained to predict 1-year incident AF using 15 ECG tracings as input using 5-fold cross-validation. In one example, model performance may be measured from the area under the receiver operating characteristic curve (AUC) and Cox proportional hazards analysis of the predicted group's non-incidence curve. Additional evaluation of model performance may be performed in the context of opportunistic population screening. For example, the positive predictive value (PPV) of the model as a function of the number of patients with the highest model-predicted risk to be screened may be calculated. Using a multi-class deep CNN with 15 ECG traces as input instances, the average AUC of the prediction model was 0.75, indicating that patients predicted to develop AF within the next year had a significantly increased long-term risk of developing AF 25 years or more after ECG acquisition (see Figure 22A). Even for the subset of ECGs interpreted as "normal" by physicians, the AUC was 0.720. In a potential population screening setting, this performance corresponded to a positive predictive value of 0.3 for screening the highest 1% at risk (see Figure 22B). This means that of the top 1% at risk, approximately 30% will eventually develop AF within the first year, and many more will develop AF over the next 25 years.

[0161] In summary, this is another example of using a model to predict the occurrence of a future clinically relevant event (atrial fibrillation within the next year). This prediction maintains reasonable accuracy even when the ECG is clinically interpreted as "normal" by the physician. Providing a prediction to the physician, especially in cases where the physician's clinical interpretation of the ECG is "normal," would greatly improve patient care. The model's predictions and therapeutic implications may be further improved by the inclusion of additional features in the training phase of model development, allowing even more relevant predictions regarding how treatments / interventions will reduce the risk of developing AF (e.g., if a patient is taking beta-blocker medication or has blood pressure within the normal range, they are likely to reduce the risk of developing AF, and the model can make these predictions) that can be included in the patient's treatment.

[0162] In some embodiments, the results reported by model 400 reflect the detection of paroxysmal AF and the prediction of incident AF. Intuitively, ECG characteristics that lead to high-risk prediction by DNNs are more prevalent in patients who already have AF but are currently in sinus rhythm. With this in mind, we would expect better model performance for identifying paroxysmal AF compared to predicting incident AF, which is exactly what we see. We also expect a decrease in the rate of first-onset AF over the course of a year. This is shown in Figure 7L and is consistent with the rapid identification of paroxysmal AF followed by a slower identification of cases representing incident AF. The strongest evidence supporting our claim that the DNN model can predict incident AF is the continuous separation of the KM-free survival curves up to 30 years after the index ECG, as noted in Figures 7E-7K. In other embodiments, results from model 400 may reflect structural changes occurring within the atria of patients with AF, and model 400 uses the ECG manifestations of this atrial myopathy to guide the prediction results it provides.

[0163] There are many different environments in which system 100 can be utilized and the methods disclosed herein can be implemented. With regard to the environment, one promising opportunity—particularly for integrated healthcare delivery systems—is the systematic screening of all ECGs in a healthcare system. For example, model 400 could be integrated into existing clinical workflows (such as through an EHR system) so that all ECGs are evaluated, and high-risk studies could be flagged for follow-up and monitoring. Such enhanced monitoring could take many different forms, including systematic pulse palpation, systematic ECG screening, continuous patch monitors worn once or multiple times, intermittent home screening with devices such as Kardia mobile, or wearable monitors such as the Apple Watch.

[0164] Appendix A CODE: (How to read an ECG) def convert_pdf_to_svg(fname, outname, verbose=0): "" Input: fname: PDF file name outname : SVG file name Output: outname : Returns the outname (the file is saved to disk) This will convert the PDF to SVG format and save it to the given outpath. "" (status, out) = subprocess.getstatusoutput(".join(['pdftocairo -svg', fname,' ', outname])) if (status != 0): logging.error('Error in converting PDF to SVG: {}'.format(out)) return outname def process_svg_to_pd_perdata(svgfile, pdffile=None): "" Input: svgfile - datapath to the svg file Output (returns): data: Data for 12 leads (15 or 12 traces available), scale_vales and decomposition units in a pandas dataframe Hard-coded values: 1) Signal length = 6 is assumed to be the calibration tracing at the beginning of the trace (by experiment) "" columnnames = np.array(['I', 'II', 'III', 'aVR', 'aVL', 'aVF', 'V1', 'V2', 'V3', 'V4', \ 'V5', 'V6', 'V1L', 'IIL', 'V5L']) doc = parse(svgfile) if pdffile is None: strn = os.path.splitext(os.path.basename(svgfile))[0] else: strn = os.path.splitext(os.path.basename(pdffile))[0] arrayindex = [np.array([strn, strn]), np.array(['x','y'])] data = pd.DataFrame(columns = ['PT_MRN','TEST_ID','filename','lead','x','y']) #,'scale_x','scale_y']) a = 0 spacingvals = [] scale_vals = [] try: siglen = [] for path in doc.getElementsByTagName('path'): tmp = path.getAttribute('d') tmp_split = tmp.split(' ') signal_np = np.asarray([float(x) for x in tmp_split if (x != 'M' and x != 'L' and x != 'C' and x != 'Z' and x != ")]) signalx = signal_np[0::2] signaly = signal_np[1::2] siglen.append(len(signalx)) siglen = np.array(siglen) # These are the calibration signals cali6sigs = np.where(siglen == 6)[0] minposcali = np.min(cali6sigs) tmpstart = list(range(minposcali, len(siglen))) last15sigs = np.array(list(set(tmpstart)- set(cali6sigs))) # Index to induction a = 0 for ind, path in enumerate(doc.getElementsByTagName('path')): if ind in last15sigs: if a > 14: continue tmp = path.getAttribute('d') tmp_split = tmp.split(' ') signal_np = np.asarray([float(x) for x in tmp_split if (x != 'M' and x != 'L' and x != 'C' and x != 'Z' and x != ")]) signalx = signal_np[0::2] signaly = signal_np[1::2] # Expects file names to be in ptmrn_testid format tmp = strn.split('_') try: pid, testid = tmp[0], tmp[1] except: pid = tmp[0] testid = tmp[0] data.loc[data.shape[0]] = [pid, testid, strn, columnnames[a], signalx, signaly] spacingx = [t -s for s,t in zip(signalx, signalx[1:])] spacingvals.append(np.min(spacingx)) a += 1 elif ind in cali6sigs: tmp = path.getAttribute('d') tmp_split = tmp.split(' ') signal_np = np.asarray([float(x) for x in tmp_split if (x != 'M' and x != 'L' and x != 'C' and x != 'Z' and x != ")]) signalx = signal_np[0::2] signaly = signal_np[1::2] scale_vals.append([np.min(signaly), np.max(signaly)]) if len(scale_vals) == 0: data = None return data sx = [x[0] for x in scale_vals] sy = [x[1] for x in scale_vals] startloc = [d[0] for d in data.x.values] leads_ip = len(startloc) a = np.sum(startloc[0:3] == startloc[0]) b = np.sum(startloc[3:6] == startloc[3]) c = np.sum(startloc[6:9] == startloc[6]) d = np.sum(startloc[9:12] == startloc[9]) if data.shape[0] == 15: e = np.sum(startloc[12:15] == startloc

[12] ) checkrhs = [3, 3, 3, 3, 3] checklhs = [a,b,c,d,e] assert checklhs == checkrhs scale_x = [sx[0:3],sx[0:3],sx[0:3],sx[0:3], sx[3:6]] scale_y = [sy[0:3],sy[0:3],sy[0:3],sy[0:3], sy[3:6]] elif data.shape[0] == 12: checkrhs = [3, 3, 3, 3] checklhs = [a,b,c,d] assert checklhs == checkrhs scale_x = [sx[0:3],sx[0:3],sx[0:3],sx[0:3]] scale_y = [sy[0:3],sy[0:3],sy[0:3],sy[0:3]] else: data=None return data scale_x = [y for x in scale_x for y in x] data['scale_x'] = scale_x[0:data.shape[0]] scale_y = [y for x in scale_y for y in x] data['scale_y'] = scale_y[0:data.shape[0]] data['minspacing'] = spacingvals[0:data.shape[0]] except: data = None return data

[0165] Thus, a properly trained deep neural network can predict incident AF directly from a 12-lead ECG tracing, even when the ECG is interpreted as clinically "normal." This approach has significant potential for targeted screening and monitoring of incipient AF to potentially minimize the risk of stroke.

[0166] Furthermore, deep learning can be a powerful tool for identifying patients with potential adverse outcomes (e.g., death) who may benefit from early intervention, even if they are interpreted as "normal" by their physicians.

[0167] While the invention is susceptible to various modifications and alternative forms, specific embodiments have been shown by way of example in the drawings and are herein described in detail. It should be understood, however, that the invention is not intended to be limited to the particular forms disclosed.

[0168] Accordingly, the present invention covers all modifications, equivalents, and alternatives falling within the spirit and scope of the present invention as defined by the following appended claims.

[0169] In order to apprise the public of the scope of the invention, the following claims have been prepared. [Explanation of symbols]

[0170] 100 systems 104 Computing Devices 108 Secondary Computing Devices 112 Communication Network 116 Display 120 ECG database 124 Training Data Database 128 pre-trained model database 132 ECG Analysis Applications 136 pre-trained models 204 processors 208 Display 212 input 216 Communication Systems 220 memory 224 processors 228 Display 232 input 236 Communication Systems 240 memory 300 Raw ECG voltage input data 304 First Voltage Data 308 Second Voltage Data 312 Third Voltage Data 316 Fourth Voltage Data 320 5th Voltage Data 324 6th Voltage Data 328 Seventh Voltage Data 332 8th Voltage Data 336 9th Voltage Data 340 10th Voltage Data 344 11th Voltage Data 348 12th Voltage Data 352 13th Voltage Data 356 14th Voltage Day 400 model 400A Convolution Components 400B Inception Block 400C fully bonded dense layer component 404 First Branch 408 Second Branch 412 Third Branch 416 Demographic Data 420 Risk Score 424 model 424C Dense Layer Component 428 ECG voltage input data 432 Single Input Branch 436 1D Convolution Blocks 440 Inception Block 444 subblocks 448A First Convolution Block 448B Second convolution block 448C Third convolution block 456 MaxPool layer 460 Last convolution block 464 Global Average Pooling (GAP) layer 468 Risk Score

Claims

1. receiving electrocardiogram data associated with a patient and an electrocardiogram configuration including a plurality of leads and a time interval, the electrocardiogram data including, for each lead in the plurality of leads, voltage data associated with at least a portion of the time interval; receiving an age value associated with the patient; receiving a gender value associated with the patient; providing the age value, the gender value, and at least a portion of the electrocardiogram data to a trained model, wherein the trained model is trained to generate a risk score based on input electrocardiogram data associated with the electrocardiogram configuration and supplemental information associated with the patient; receiving a risk score indicative of the likelihood that the patient will suffer from a medical condition within a predetermined time period from when the electrocardiogram data was generated; outputting the risk score to at least one of a memory or a display for viewing by a medical practitioner or healthcare administrator; A method comprising:

2. receiving electronic health record data associated with the patient; providing at least a portion of the electronic health record data to the trained model; The method of claim 1 further comprising:

3. 3. The method of claim 2, wherein the electronic health record data includes at least one of blood cholesterol measurements, blood counts, blood chemistry values, troponin levels, natriuretic peptide levels, blood pressure, heart rate, respiratory rate, oxygen saturation, cardiac ejection fraction, ventricular volumes, myocardial thickness, heart valve function, diabetes diagnoses, chronic kidney disease diagnoses, congenital heart disease diagnoses, cancer diagnoses, procedures, medications, cardiac rehabilitation referrals, or dietary consultation referrals.

4. determining that the risk score is higher than a predetermined threshold associated with the medical condition; generating a report in response to determining that the risk score is greater than the predetermined threshold, the report including information and / or links to sources of information associated with at least one of a treatment for the medical condition or a cause of the medical condition; outputting said report to at least one of a memory or a display for viewing by a medical practitioner or healthcare administrator; The method of claim 1 further comprising:

5. The method of claim 1 , wherein the time period is one year.

6. The method of claim 1 , wherein the time period is selected from the range of 1 day to 30 years.

7. The method of claim 1 , wherein the trained model comprises a deep neural network including multiple branches.

8. 8. The method of claim 7, wherein the portion of the electrocardiogram data provided to the trained model is provided to the plurality of branches.

9. The method of claim 1 , wherein the trained model comprises a deep neural network including a convolutional component and a dense layer component.

10. The method of claim 9 , wherein the convolutional component comprises an inception block including multiple convolutional layers.

11. 2. The method of claim 1, wherein the plurality of leads includes Lead I, Lead V2, Lead V4, Lead V3, Lead V6, Lead II, Lead VI, and Lead V5.

12. The electrocardiogram data includes first voltage data associated with Lead I and a first portion of the time interval, second voltage data associated with Lead V2 and a second portion of the time interval, third voltage data associated with Lead V4 and a third portion of the time interval, fourth voltage data associated with Lead V3 and the second portion of the time interval, fifth voltage data associated with Lead V6 and the third portion of the time interval, sixth voltage data associated with Lead II and the first portion of the time interval, seventh voltage data associated with Lead II and the second portion of the time interval, and seventh voltage data associated with Lead II and the second portion of the time interval.

12. The method of claim 11 , wherein the voltage data includes eighth voltage data associated with Lead VI and the third portion of the time interval, ninth voltage data associated with Lead VI and the first portion of the time interval, tenth voltage data associated with Lead VI and the second portion of the time interval, eleventh voltage data associated with Lead VI and the third portion of the time interval, twelfth voltage data associated with Lead V5 and the first portion of the time interval, thirteenth voltage data associated with Lead V5 and the second portion of the time interval, and fourteenth voltage data associated with Lead V5 and the third portion of the time interval.

13. 13. The method of claim 12, wherein the time interval comprises a time period of 10 seconds, the first portion of the time interval comprises a first half of the time interval, the second portion of the time interval comprises a third quarter of the time interval, and the third portion of the time interval comprises a fourth quarter of the time interval.

14. The trained model comprises a first channel, a second channel, and a third channel, and the providing step includes: providing the first voltage data, the sixth voltage data, the ninth voltage data, and the twelfth voltage data to the first channel; providing the second voltage data, the fourth voltage data, the seventh voltage data, the tenth voltage data, and the thirteenth voltage data to the second channel; providing the third voltage data, the fifth voltage data, the eighth voltage data, the eleventh voltage data, and the fourteenth voltage data to the third channel; 13. The method of claim 12, comprising:

15. The method of claim 11 , wherein each of the plurality of leads is associated with a time interval.

16. The method of claim 1 , wherein the electrocardiogram data is indicative of a cardiac condition based on cardiological criteria.

17. The method of claim 1 , wherein the electrocardiogram data does not indicate a cardiac pathology based on cardiological criteria.

18. The method of claim 1 , wherein the condition is death.

19. The method of claim 1 , wherein the condition is atrial fibrillation.

20. receiving patient electrocardiogram data from an electrocardiogram device associated with a patient and an electrocardiogram configuration including a plurality of leads and a time interval, the patient electrocardiogram data including, for each lead in the plurality of leads, voltage data associated with at least a portion of the time interval; providing at least a portion of the patient electrocardiogram data to a trained model, the trained model being trained to output a risk score based on the input electrocardiogram data associated with the electrocardiogram configuration; receiving a risk score indicative of the likelihood that the patient will suffer from a medical condition within a predetermined time period from when the patient electrocardiogram data was generated; generating a report based on the risk score; outputting said report to at least one of a memory or a display for viewing by a medical practitioner or healthcare administrator; A method comprising:

21. at least one processor coupled to at least one memory containing instructions, said at least one processor: receiving electrocardiogram data associated with a patient and an electrocardiogram configuration including a plurality of leads and a time interval, the electrocardiogram data including, for each lead included in the plurality of leads, voltage data associated with at least a portion of the time interval; providing at least a portion of the electrocardiogram data to a trained model, the trained model being trained to output a risk score based on the input electrocardiogram data associated with the electrocardiogram configuration; receiving a risk score from the trained model indicative of the likelihood that the patient will suffer from a medical condition within a predetermined time period from when the electrocardiogram data was generated; outputting said risk score to at least one of a memory or a display for viewing by a medical practitioner or healthcare administrator; and executing the instructions to perform the above steps.

22. receiving electrocardiogram data associated with a patient and an electrocardiogram configuration including a plurality of leads and a time interval, the electrocardiogram data including, for each lead in the plurality of leads, voltage data associated with at least a portion of the time interval; receiving demographic data associated with the patient; providing the electrocardiogram data and the demographic data to a trained model; generating information based on the electrocardiogram data; linking said information with said demographic data; generating a risk score based on the information and the demographic data indicative of the likelihood that the patient will suffer from a medical condition within a predetermined time period from when the electrocardiogram data was generated; receiving the risk score from the trained model; outputting the risk score to at least one of a memory or a display for viewing by a medical practitioner or healthcare administrator; A method comprising:

23. 23. The method of claim 22, wherein the demographic data includes the patient's gender.

24. 23. The method of claim 22, wherein the demographic data includes an age of the patient.

25. 23. The method of claim 22, wherein the condition is death.

26. 23. The method of claim 22, wherein the condition is atrial fibrillation.

27. 23. The method of claim 22, wherein the time period is at least six months.

28. 28. The method of claim 27, wherein the period of time is at least one year.

29. 23. The method of claim 22, wherein the plurality of leads includes Lead I, Lead V2, Lead V4, Lead V3, Lead V6, Lead II, Lead VI, and Lead V5.

30. generating a report based on the risk score; outputting said report on said display for viewing by a medical practitioner or healthcare administrator; 23. The method of claim 22, further comprising:

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