Circulation Research

COMPENDIUM ON ATRIAL FIBRILLATION

How Will Machine Learning Inform the Clinical

Care of Atrial Fibrillation?
Konstantinos C. Siontis, Xiaoxi Yao, James P. Pirruccello, Anthony A. Philippakis, Peter A. Noseworthy

ABSTRACT: Machine learning applications in cardiology have rapidly evolved in the past decade. With the availability of machine
learning tools coupled with vast data sources, the management of atrial fibrillation (AF), a common chronic disease with
significant associated morbidity and socioeconomic impact, is undergoing a knowledge and practice transformation in the
increasingly complex healthcare environment. Among other advances, deep-learning machine learning methods, including
convolutional neural networks, have enabled the development of AF screening pathways using the ubiquitous 12-lead ECG to
detect asymptomatic paroxysmal AF in at-risk populations (such as those with cryptogenic stroke), the refinement of AF and
stroke prediction schemes through comprehensive digital phenotyping using structured and unstructured data abstraction
from the electronic health record or wearable monitoring technologies, and the optimization of treatment strategies, ranging
from stroke prophylaxis to monitoring of antiarrhythmic drug (AAD) therapy. Although the clinical and population-wide impact
of these tools continues to be elucidated, such transformative progress does not come without challenges, such as the
concerns about adopting black box technologies, assessing input data quality for training such models, and the risk of
perpetuating rather than alleviating health disparities. This review critically appraises the advances of machine learning
related to the care of AF thus far, their potential future directions, and its potential limitations and challenges.

Key Words: artificial intelligence ◼ atrial fibrillation ◼ ECG ◼ electronic health record ◼ machine learning ◼ natural language processing
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M PRIMER ON MACHINE LEARNING

achine learning (ML) has the potential to impact
the practice of clinical medicine. However,
because ML is a broad term that encompasses
the set of algorithms that learn from data—as opposed to
human-crafted rules—the term could reasonably describe
much of classical statistics. So, what has changed in the
past decade that has caused so much attention? Break-
throughs in deep neural networks (deep learning), paired
with biobank-scale data, explain the increasing interest
in applying ML to medicine, from fully automated inter-
pretation of echocardiograms,1 to the detection of aortic
valve pathology without high-definition visualization of
the valve,2 to the detection of electrocardiographic (ECG)
patterns that indicate a patient’s age and sex3 or ejec-
tion fraction,4 to the prediction of acute kidney injury.5 In
this article, we review the contributions from deep learn-
ing and other ML techniques to the clinical care of atrial
fibrillation (AF) and discuss where we perceive the field
to be headed (Figure 1).
TECHNIQUES
Increasingly voluminous and complex data are being ana-
lyzed in efforts to understand the basis for the develop-
ment of AF, its prognosis, and potential therapies. These
data include electrocardiographic signals, raw echocar-
diographic images, genome sequences, and the entire
contents of electronic health records (EHRs). The vast-
ness and complexity of these data have spurred the use
of sophisticated analytic techniques from the field of ML,
which sits at the confluence of statistics and computer
science.6 Although ML leverages traditional statistical
methods, ML approaches may have incrementally supe-
rior performance when the inputs are complex (image
data, for instance), the features of the input data can-
not be readily discerned (subtle patterns only seen by
a convolutional neural network [CNN], for instance), or
the relationships between input data are complex and

Correspondence to: Peter A. Noseworthy, MD, Department of Cardiovascular Diseases, Mayo Clinic, 200 1st St SW, Rochester, MN 55905. Email noseworthy.peter@
mayo.edu
For Disclosures, see page 166.
© 2020 American Heart Association, Inc.
Circulation Research is available at www.ahajournals.org/journal/res

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 Siontis et al
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Nonstandard Abbreviations and Acronyms
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AAD antiarrhythmic drug
AF atrial fibrillation
AI artificial intelligence
AUC area under the curve
BNP B-type natriuretic peptide
CNN convolutional neural network
EHR electronic health record
FHS Framingham Heart Study
LA left atrial
LAA left atrial appendage
ML machine learning
NLP natural language processing
OAC oral anticoagulation
nonlinear. Here, we aim to provide a brief overview of ML
concepts, as well as intuitive explanations for a focused
set of specific machine learning algorithms from the
research that is reviewed in the remainder of this article.
At the most abstract level, machine learning methods
fall into 1 of the 3 categories: supervised, unsupervised,
and reinforcement learning. Most methods reviewed in
this study rely on supervised learning, which requires
data to have a label when training an algorithm. That
label is often as simple as a binary outcome: for example,
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development of the CHA2DS2-VASc stroke risk model
required a data set in which individuals’ baseline charac-
teristics and their stroke outcomes were known.7 Unsu-
pervised learning approaches detect relationships within
the data itself, without requiring a specific label to train
against. A common example is clustering, used by Levy
et al,8 to identify groups of similar patients in an analysis
of dofetilide dosing. That same paper then applies rein-
forcement learning, which takes the perspective of an
agent, tasked with maximizing a future reward (eg, suc-
cessful dofetilide initiation) by making decisions at each
step in time (eg, choosing the dose of dofetilide). In prin-
ciple, such a system can permit discovery of an improved
set of decisions (such as choice of antiarrhythmic medi-
cation dose), even when humans do not know how to
decide the value of such decisions. These approaches
hold promise for the discovery of treatment patterns and
outcomes that may emerge in large data sets but may
not be obvious to observers of routine clinical practice.
While ML is a broad field, most of the work cited in this
review applies supervised learning using 1 of 3 specific
algorithms: ordinary regression, random forests, or deep
CNNs. In ordinary regression, an outcome of interest (such
as stroke) is predicted by projecting out the linear contribu-
tions from variables that are included in the model because
they are thought to be correlated (such as age and sex). The
predictors that are incorporated into the regression model
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Machine Learning in AF
are chosen by humans, but the way they are weighted in
making a prediction is learned from the data. Many rou-
tinely used clinical risk stratification tools (for instance,
those used in the prediction of stroke or bleeding risk in
patients with known AF) were derived using regression.
Random forests combine the categorical predictions
made by a set of decision trees. Decision trees perform
classification (such as whether an individual will develop
a stroke); a series of branching steps is performed, and
at each step, the tree chooses a feature (such as sex
or an age cutoff) that best splits the remaining data in
its branch. Single decision trees tend to overfit to the
training data, which causes poor generalization to new
data, and therefore random forests are popular because
they overcome this tendency. Like regression, the predic-
tors in a random forest are preselected, but the relative
importance of each predictor, as well as the thresholds
chosen for each split, are learned from the data. This
approach may be useful to help select among various
treatment choices using categorical variables.
The nodes of the first layer in a neural network pass
input (eg, the pixels from a transthoracic echocardio-
graphic image) to hidden layers. Each node in a hidden
layer receives input from several (or potentially all) nodes
in the prior layer. Ultimately, (in the papers reviewed in this
article), a final output layer predicts a label (eg, whether
or not a left atrial appendage [LAA] thrombus is present).
The way each node weights its inputs is adjusted during
iterative training to produce more accurate responses.
Deep neural networks simply have many hidden layers
between the input layer and the output layer; however,
depth imposes substantial computational costs, which
arise due to the large number of connections.
Many neural networks, especially those that interpret
image data, use a convolutional process that mimicks how
the visual cortex processes images. In a CNN, an image
(or other input data) is broken down into components/
feature abstractions, and convolutions are used to iden-
tify local correlations between the input data. Convolution
permits a given neuron in a deeper layer to receive input
from only a small subset of nearby nodes in the prior layer.
Within a given layer, this preserves only local relation-
ships, although long-range relationships can be learned
in deeper layers of a convolutional network. Unlike many
other ML methods, not only can deep-learning models
associate input features with an output of interest, they
can also learn features from raw data itself. Such models
are particularly valuable for the classification of images
or complex biophysical signals like ECG or echocardio-
graphic data, though their value in interpreting these tests
as a whole is not always evident because these feature
abstractions do not always yield clear explanations.9
The tools of ML (particularly neural networks) often
have vast capacity to effectively memorize (overfit to)
data sets if care is not taken to guard against this. A
model that is overfit to a particular data set is likely to
 Siontis et al
Figure 1. Applications of machine learning in the clinical care of AF.
AAD indicates antiarrhythmic drug; AF, atrial fibrillation; EHR, electronic health record; ML, machine learning; OAC, oral anticoagulation; and LAA,
left atrial appendage.
generalize poorly to new data. To minimize this risk, data
sets are commonly split into separate training and valida-
tion sets to allow derivation and testing of networks on
nonoverlapping data. For example, when training a deep
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neural network, ML practitioners use a training set to
update model parameters, and a validation set to assess
whether each step of training is continuing to produce
improvement in the model’s performance. When the
training set still shows improved outcome prediction with
each additional step of training but the validation set is
no longer doing so, the model is at the point where it is
likely to begin overfitting. In this case, the model is finding
a solution that improves performance only on the training
data set, but this is not generalizable to a separate data
set. The optimal solution, on the other hand, will have
similar performance in both training and validation data
sets. Neural networks commonly have other tools to pre-
vent overfitting, such as dropout, in which nodes of the
network are probabilistically (and temporarily) dropped
from the network during training. This effectively adds
noise to the process and reduces the tendency to overfit.
For additional details of ML techniques in medicine,
several recent reviews provide more in-depth descrip-
tions.10–12 In the remainder of this review, we address
specific past, present, and potential future applications
of ML in the clinical care of AF.
AF SCREENING
AF is notoriously difficult to screen for as it is often tran-
sient and asymptomatic. Moreover, AF symptoms may be
Circulation Research. 2020;127:155–169. DOI: 10.1161/CIRCRESAHA.120.316401
Machine Learning in AF
COMPENDIUM ON ATRIAL
FIBRILLATION
vague and attributed to other conditions, making AF diag-
noses elusive.13 An estimated 1 million Americans may
have undiagnosed AF.14 Among patients with implanted
cardiac devices (pacemakers and defibrillators), up to
half of them have asymptomatic high-rate atrial episodes
over long-term follow-up, and a dose-response relation-
ship has been proposed between the duration of these
episodes and the risk of stroke.15 ML approaches can
allow streamlined, targeted, and higher-yield screen-
ing for AF. In this section, we first describe the current
status of AF screening and challenges; then, we review
existing AF risk scores that could be used to target AF
screening initiatives and an ML algorithm to screen for
unrecognized AF based on sinus rhythm ECGs; finally,
we explore how ML approaches could facilitate transla-
tion of AF prediction algorithms to clinical practice and
discuss future directions.
Current Status of AF Screening and Challenges
AF screening can be done directly by ECG recordings
or indirectly by assessing pulse irregularity. Screening
methods can be largely grouped into 4 categories: (1)
pulse palpation; (2) blood pressure monitors; (3) ECGs,
including standard 12-lead ECG, single-lead ECG in
handheld devices, patches, belts, smartphones, watches,
etc; and (4) photo-plethysmography, either by stand-
alone devices or by smartphone cameras and applica-
tions.16,17 The performance of these screening tests
varies (Table 1), but a recent meta-analysis of 19 AF
screening studies found that the yield of screening was
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 Siontis et al
Table 1. Performance of Different AF Screening Methods
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Sensitivity, %
FIBRILLATION
Pulse palpation 87–97
BP monitors 30–100
Single-lead ECG screening 94–100
Photo-plethysmography via 87–100
smartphone applications
AF indicates atrial fibrillation; and BP, blood pressure.
Adapted from Lowres et al.46
not influenced by the screening method used.46 The
most powerful driver of the screening yield appears
to be the age of the study population. Intermittent or
continuous screening via an ECG monitoring patch or
repeated recordings using a handheld ECG can improve
the yield; however, they are also more costly and bur-
densome.47,48 ML approaches can improve the yield of
these screening methods. Notably, ML approaches have
been applied to signals obtained from the single-lead
ECG or photo-plethysmography. For instance, a deep
neural network has been developed to passively detect
AF from photo-plethysmography signals obtained from
the Apple Watch.35
Existing AF Risk Scores to Guide AF Screening
Initiatives
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Over the past decade, several risk scores to predict
the risk of AF have been developed and validated
(Table 2).49–52 These models largely include similar
risk factors, for example, age, sex, race, height, weight,
blood pressure, heart failure, etc. In fact, even the simple
CHA2DS2-VASc score, designed as a stroke risk stratifi-
cation tool in AF patients, has demonstrated a C statistic
of 0.69 to 0.74 for predicting AF.52–59 Minor differences
of these models are attributable to the fact that includ-
ing certain risk factors improved model performance in
one cohort but not in another cohort. For example, in
the CHARGE-AF study (Cohorts for Heart and Aging
Research in Genomic Epidemiology Atrial Fibrillation),
the addition of left ventricular hypertrophy and PR inter-
val did not meaningfully improve the findings.51 Nota-
bly, these models were all developed using regression
methods. Although ML methods can potentially increase
the model performance in comparison to traditional sta-
tistical methods, the improvement is not likely to be
clinically meaningful without the addition of other types
of data beyond these clinical risk factors. Population-
specific bias and residual confounding are also likely to
affect ML-based prediction models, not unlike traditional
prediction models.
Novel risk factors have also been explored, including
blood and imaging biomarkers and genetic markers.60,61
However, adding these risk factors to the existing models
158   June 19, 2020
Machine Learning in AF
Specificity, % References
70–81 Harris et al,18 Cooke et al19
86–97 Wiesel et al,20,21 Kearley et al,22 Stergiou et al,23 Marazzi et al,24 Wiesel et al25
76–97 Kearley et al,22 Lau et al,26 Tieleman et al,27 Vaes et al,28 Doliwa et al,29 Kaasenbrood,30
Jacobs et al,31 Orchard et al,32 Lowres et al,33 Bumgarner et al34
80–100 Tison et al,35 Lewis et al,36 McManus et al,37 Guo et al,38 Dorr et al,39 Bonomi et al,40
Chan et al,41 Krivoshei et al,42 Conroy et al,43 Bashar et al,44 Brasier et al45
often leads to only small improvements in model per-
formance. For example, in the FHS study (Framingham
Heart Study), 3 echocardiographic measurements (left
atrial [LA] diameter, left ventricular wall thickness, and
left ventricular fractional shortening) were all associated
with AF, but the addition of these risk factors did not
meaningfully improve the performance of the prediction
model,49 and the addition of BNP (B-type natriuretic
peptide) improved the C statistic from 0.78 to 0.80.62
The addition of BNP also improved the C statistic of
the CHARGE-AF score from 0.77 to 0.79.63 In another
study, the addition of genetic information improved the
C statistic from 0.72 to 0.74.64 Most importantly, these
novel risk factors are typically not available in large
asymptomatic populations and, therefore, may have lim-
ited applicability to everyday practice. Thus, rather than
having patients undergo testing for biomarkers, echo-
cardiography, or genetic tests to predict AF risk, it may
be less expensive and potentially of higher yield to sim-
ply use prolonged monitoring approaches, for example,
a patch, to diagnose AF.
Artificial Intelligence Algorithm to Predict
Unrecognized AF Based on Sinus Rhythm
ECGs
None of the above-mentioned risk prediction models
are used in routine practice to guide AF screening. A
key reason is that they all predict the mid-to-long-term
risk of AF, for example, 5-year or 10-year, rather than
the contemporaneous risk of unrecognized AF. However,
the ECG may offer a window into the electrophysiologi-
cal remodeling occurring in patients with AF such that
systematic feature extraction from the ECG may detect
patients who are more likely to have a history of or a
risk of paroxysmal AF. There is indeed a long record of
investigation assessing such features, including, for
example, P wave fractionation by signal-averaged ECG65
and other P wave indices on the standard ECG.66 Tak-
ing such approaches several steps further, the availability
of powerful computational tools and large data sets has
led to the development of methods for the comprehen-
sive association of the sinus rhythm ECG with probabil-
ity of concomitant or imminent AF that is based on the
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 Siontis et al Machine Learning in AF

Table 2. Existing AF Prediction Models

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Study Name Derivative Cohort Outcome Risk Factors in the Model Performance

FIBRILLATION
FHS49 4764 participants 10-y risk of atrial fibrillation or atrial flutter Age, sex, BMI, SBP, HTN treatment, PR Internal validation C statistic
in FHS on ECG interval, clinically significant cardiac murmur; 0.7849; external validation
HF 0.65–0.7350,51,53,54
ARIC50 14 546 participants 10-y risk of atrial fibrillation or atrial flutter Age, race, height, SBP, HTN treatment, Internal validation C statistic
from ARIC based on standard 12-lead ECG and smoking status, precordial murmur, LVH, 0.7850
diagnosis codes listed on hospital discharge left atrial enlargement, diabetes mellitus,
and death certificate coronary heart disease, and HF
CHARGE- 18 556 participants 5-y risk of atrial fibrillation ascertained from Age, race, height, weight, SBP, DBP, current Internal validation C statistic
AF51 from ARIC, CHS, ECGs and hospital discharge diagnosis smoking, HTN treatment, diabetes mellitus, 0.765, external validation C
and FHS codes MI, and HF statistic 0.66–0.7551,54–56,58
C2HEST52 471 446 Chinese Atrial fibrillation on ECG or Holter over 11 y CAD/COPD, HTN, age ≥75 y, systolic HF, Internal validation C statistic
subjects thyroid disease 0.75; external validation C
statistic 0.6552
Partners57 206 042 participants 5-y risk of atrial fibrillation ascertained from Sex, age, race, smoking status, height, Split-sample internal
from Partners hospital diagnostic codes, cardiology tests, weight, blood pressure, and cardiovascular validation with C statistic
and medications and cardiometabolic disease labels of 0.77

ARIC indicates Atherosclerosis Risk in Communities; AF, atrial fibrillation; BMI, body mass index; CAD, coronary artery disease; CHARGE-AF, Cohorts for Heart and
Aging Research in Genomic Epidemiology Atrial Fibrillation; CHS, Cardiovascular Health Study; COPD, chronic obstructive pulmonary disease; DBP, diastolic blood
pressure; FHS, Framingham Heart Study; HF, heart failure; HTN, hypertension; LVH, left ventricular hypertrophy; MI, myocardial infarction; and SBP, systolic blood pressure.

assessment of the ECG as a whole and extends beyond
any a priori defined ECG features.
To assess the likelihood of AF in the short term, a
group of Mayo Clinic investigators developed a CNN to
predict AF based on a standard 12-lead ECG obtained
during sinus rhythm.67 The algorithm was developed using
454 789 digitally stored ECGs recorded from 126 526
patients, it was validated in a separate internal validation
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Unlike the traditional risk prediction models that com-
prise predefined variables, the CNN described above is
agnostic as we do not know what ECG features the CNN
is seeing and which factors drive its performance. It is
likely that the algorithm performance is based on numer-
ous ECG signatures that are known risk factors of AF
(eg, left ventricular hypertrophy, P wave amplitude, atrial
ectopy, and heart rate variability), as well as others that
are currently unknown or are not obvious to the human

data set containing 64 340 ECGs from 18 116 patients

and tested on another 130 802 ECGs from 36 280
patients. The model applied convolutions on a temporal
axis and across multiple leads to extract morphological
and temporal features during the training and validation
process. Patients with at least 1 ECG showing AF within
31 days after the sinus rhythm ECG were classified as
positive for AF. In the testing data set, the algorithm dem-
onstrated a C statistic of 0.87, a sensitivity of 79.0%, a
specificity of 79.5%, and an accuracy of 79.4% in detect-
ing patients with documentation of AF within 31 days fol-
lowing the sinus rhythm ECG using only information from
the sinus rhythm ECG (Figure 2). Therefore, the algo-
rithm aims to detect nearly concomitant unrecognized
AF, rather than predicting long-term AF risk. This algo-
rithm may facilitate targeted AF surveillance (eg, using
an ambulatory rhythm monitoring patch or implantable
loop recorder) in subsets of high-risk patients. ECGs are
ubiquitously performed for a variety of screening, diag-
nostic, and monitoring purposes, thereby providing ample
opportunities for the application of this algorithm. The
ultimate clinical utility of this approach will be determined
by the observed positive and negative predictive values
of the algorithm when applied to a given population and
by the cost and downstream consequences, particularly
for patient outcomes, related to follow-up diagnostic
testing and therapies.
eye.68 It is also likely that the ECG contains information
that correlates with known clinical risk factors, as indeed
the ECG has been shown to predict age, sex, and ejec-
tion fraction.3,4
Important questions need to be addressed before
this tool can be widely used clinically. The algorithm was
derived from a selected population in a large tertiary
care institution with higher prevalence of AF than in less
selected, general populations. Therefore, external validity
and generalizability remain to be determined. The incre-
mental value of this approach above and beyond clinical
factors and risk scores requires further investigation. In
fact, the value of standard clinical factors in identifying
concomitant (rather than future) AF is largely unknown.
Also, the impact of widespread application of this tool in
general or primary care populations in terms of down-
stream testing, treatment utilization, costs, patient-
reported quality of life, and hard outcomes (stroke,
bleeding, death) is yet unknown.
ML for Implementing AF Prediction Algorithms
ML algorithms may facilitate implementation of traditional
risk prediction models like CHARGE-AF but also of the
artificial intelligence (AI)-enabled ECG algorithm. In a
large-scale retrospective analysis using data from almost
3 million individuals with no history of AF in the UK Clinical

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 Siontis et al Machine Learning in AF
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Figure 2. Development of a convolutional network to detect nearly concomitant AF based on a single 12-lead sinus rhythm ECG.
AF indicates atrial fibrillation; AUC, area under curve; NSR, normal sinus rhythm; and SR, sinus rhythm. Reprinted from Attia et al67 with
permission. Copyright ©2020, Elsevier.

Practice Research Datalink, Hill et al69 developed and
comparatively assessed traditional statistical approaches
and novel ML models for AF prediction based on routinely
collected patient data. These models included logistic least
absolute shrinkage and selector operator, random forests,
support vector machines, CNNs, Cox regression, and
published AF risk models, such as CHARGE-AF. A time-
varying CNN, which considered 100 different baseline
predictors, was identified as the optimal model achieving
an area under the curve (AUC) of 0.83 for AF prediction
as opposed to 0.73 with the CHARGE-AF score and 0.70
with logistic regression. Importantly, the optimal time-vary-
ing CNN added useful insights into the risk prediction of
AF by confirming known baseline AF risk factors (such
as age, previous cardiovascular disease, antihypertensive
medication usage) and identifying additional time-varying
predictors (such as proximity of cardiovascular events,
body mass index, pulse pressure, and the frequency of
blood pressure measurements).
To calculate risk scores like CHARGE-AF or the optimal
CNN described by Hill et al, data will need to be abstracted
from the EHR. Some information, for example, age, sex,
and blood pressure, might be directly obtained from pre-
defined areas in the record such as the Demographics
or Vital Signs tabs where such information is entered for
each patient (structured data fields). Other diagnoses, like
diabetes mellitus, heart failure, and myocardial infarction
are more ambiguous. Relying on diagnosis or procedure
codes to determine medical history assumes that such
codes have been correctly adjudicated by the healthcare
professional and correctly entered into the EHR. How-
ever, the complexity of current and previous coding sys-
tems allows the potential for significant inconsistencies in
coding between different professionals, thereby reducing
the reliability of prognostic scores derived solely based on
diagnostic codes. Natural language processing (NLP) has
the potential to improve the determination of diagnoses by
extracting information from free-text clinical documenta-
tion from the EHR. The goal of NLP is to structure unstruc-
tured free-text data by using a variety of approaches,
ranging from rule-based model training for recognition of
linguistic patterns, to hybrid training of a model using text

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 Siontis et al
vectorization and output tags that are fed into ML models,
to completely unsupervised topic modeling. In turn, several
different word embedding, text classification, text extrac-
tion, and topic modeling algorithms are used and continu-
ously refined in this active area of investigation. Because
NLP is not restricted by predefined diagnostic codes, an
optimized NLP model has the ability to recognize even
complex language patterns by comprehensively assessing
all available documentation, thus improving the accuracy
in capturing potentially ambiguous diagnoses. Second,
the goal of screening for AF is to identify the patient who
may benefit from oral anticoagulation (OAC) should AF be
detected since not all patients with AF need OAC. Some
patients may have a low stroke risk that does not warrant
intervention; others may have contraindications to OAC so
that a diagnosis of AF would not change their manage-
ment. Ideally, screening for otherwise clinically silent AF
should only be implemented for patients who are eligible
for OAC per current guidelines (eg, CHA2DS2-VASc ≥2
in men or ≥3 in women70) and who do not have contrain-
dications (eg, recurrent major bleeding or severe coagu-
lopathy). The determination of eligibility for OAC in large
numbers of patients will also require abstracting data from
the EHR for calculation of their CHA2DS2-VASc scores.
However, it should also be noted that ML may allow for
better stroke risk stratification than the CHA2DS2-VASc
score (discussed later in this review).
Recently, investigators have developed digital phe-
notyping algorithms to use both structured data (eg,
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diagnosis and procedure codes, prescription drugs, vital
signs, laboratory tests, etc) and unstructured data (eg,
clinical notes abstracted via NLP) to determine medi-
cal history, such as diabetes mellitus, heart failure, and
peripheral artery disease, which have superior perfor-
mance than relying on structured data alone.71–73 Another
group of researchers have also developed a framework
for phenotyping and developed R packages that can be
easily executed by other investigators to develop digi-
tal phenotyping algorithms if all data are available.74,75 In
repositories, such as the Phenotype KnowledgeBase,
researchers can upload and share their algorithms as well
as implement and validate algorithms developed by other
groups.76 The Phenotype KnowledgeBase repository
already contains algorithms for 50 to 60 medical condi-
tions and many have demonstrated good performance
when implemented across different health systems.77–81
Future Directions for Leveraging ML to Improve
AF Screening
For large health systems, the AI-enabled ECG-based AF
prediction could service as a low-cost mass screening
tool,67 and a next step would be to investigate whether
including additional clinical risk factors from CHARGE-
AF and other novel risk factors (eg, blood biomarkers,
imaging modalities, and even polygenic risk scores) can
Circulation Research. 2020;127:155–169. DOI: 10.1161/CIRCRESAHA.120.316401
Machine Learning in AF
further improve the model performance. For example,
COMPENDIUM ON ATRIAL
addition of other established risk factors to the AI ECG
algorithm may further increase its prognostic performance
FIBRILLATION
in a synergistic fashion without necessarily increasing the
costs and complexities of implementing the prediction
algorithm as long as the information on such additional
risk factors can be readily obtained via the EHR.
Furthermore, the predicted risk, regardless of
CHARGE-AF, AI ECG, or polygenic risk scores, is a con-
tinuous value, whereas the clinical action is a binary deci-
sion (eg, whether or not to use prolonged AF monitoring).
To translate the prediction model to everyday practice, a
threshold must be established to help providers decide
which patients should receive long-term monitoring. To
facilitate such decisions, providers will need to know
the positive predictive value and negative predictive
value associated with different risk thresholds. A study
is underway to address this question for the AI-enabled
ECG algorithm in a general asymptomatic population.82
A subsequent question would be how to scale the AI
algorithms to the broad population. One challenge is that
the algorithms need to be revalidated or adapted when
applied to a different population. The utilization of block-
chain technology may allow the generation of a decen-
tralized marketplace for the secure and traceable sharing
of large amounts of patient data across institutions for
the retraining and testing of AI tools.83,84 Moreover, not
every clinic has the capacity and infrastructure for data
acquisition and processing like the large health systems
where the AI algorithms were originally developed. Suc-
cessful implementation of these AI solutions will also
require extensive training and support, for example, help-
ing clinicians understand what they are supposed to do
when they receive AI-generated results.
From an individual’s perspective, the availability of smart
devices to capture the patterns and changes of physical
activity, resting heart rate, weight, and sleep may provide
additional opportunities to refine AF prediction. One exam-
ple is an initiative of Yale University to build a patient-cen-
tered health data sharing platform, called Hugo, which is a
smartphone application that aggregates data from EHRs
of multiple health systems, pharmacies, personal devices
(eg, activity monitors, digital weight scales, and single-lead
ECGs) and allows the collection of patient-reported out-
comes.85 This new tool could provide patients a compre-
hensive overview of their healthcare data and allows them
to share data with researchers and interact with clinicians
and researchers in real time (eg, report symptoms and
respond to questionnaires). This comprehensive data col-
lection tool could provide an opportunity to leverage mul-
tiple data sources to refine AF risk prediction.
AF TREATMENT
Advances in pharmacological and interventional therapies
have led to improvement in quality of life and reduction in
June 19, 2020   161
 Siontis et al
AF-related morbidity in patients with AF over the past 2
COMPENDIUM ON ATRIAL
decades. Nevertheless, AF is a heterogeneous syndrome
and not all patients carry the same risks of AF-related
FIBRILLATION
complications nor respond to the same set of treatments
in a similar manner. The challenge of truly individualized
risk stratification (particularly for stroke) and treatment
selection remains largely unmet. In this section, we review
the current status and future directions of ML methods
to help improve risk stratification for AF-related morbid-
ity and optimize the delivery of care, including treatment
selection and monitoring in patients with AF.
Stroke Risk Stratification
Since AF was recognized as a major risk factor for stroke
>40 years ago, efforts to achieve meaningful individual-
ized risk stratification have evolved.86 Current guidelines
endorse the widely used CHA2DS2-VASc score as the
preferred risk stratification scheme to identify patients in
whom initiation of OAC may be warranted.7 The score is
based on simple clinical variables, it is generally easy to
apply in daily practice and most healthcare providers are
familiar with it. However, it is not always straightforward
to accurately ascertain all the clinical risk factors to cal-
culate the CHA2DS2-VASc score for the individual patient
at a certain time point or over longitudinal follow-up due
to inaccuracies of sampling the EHR or when one has to
rely on patient-reported history. As discussed in the pre-
vious section, ML approaches using both structured and
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unstructured data with NLP offer promise in automating
and improving risk phenotyping and identifying high-risk
patients who will benefit from OAC initiation.
Despite its widespread utilization, the CHA2DS2-VASc
score has been criticized for its relatively weak discrimi-
natory ability. The C statistic was only 0.606 in its deriva-
tion cohort.7 Subsequent attempts to refine the score with
the addition of other clinical risk factors resulted in only
modest improvements in prognostic performance, and
these iterations have not gained popularity in clinical prac-
tice.87–89 The common denominator of all these scores,
and potentially a reason why they fail to completely cap-
ture the magnitude of risk, is that they are solely based
on demographic and comorbid clinical factors. This over-
simplified predictive modeling does not reflect the com-
plex pathogenesis of thromboembolism in AF. Other key
phenotypic characteristics, such as the type of AF (par-
oxysmal versus nonparoxysmal) and burden, as well as
electrophysiological characteristics, LA and LAA macro-
and micro-anatomy and function are not considered. For
example, mounting data suggests that thromboembolic
risk may be higher with persistent rather than paroxys-
mal AF90 and with increasing AF burden determined by
implantable device monitoring.91 An increasing body of
evidence also supports the extent of LA fibrosis quanti-
fied by cardiac magnetic resonance imaging92 and even
the LAA morphology,93 among other imaging variables, as
162   June 19, 2020 Circulation Research. 2020;127:155–169. DOI: 10.1161/CIRCRESAHA.120.316401
Machine Learning in AF
incremental markers of stroke risk above and beyond the
CHA2DS2-VASc score. Similarly, the potential incremental
value of circulating biomarkers (myocardial, inflammatory,
and procoagulant)94 and electrocardiographic markers
(such as P wave amplitude, duration, and axis)95 has not
been routinely assessed in risk calculations in practice
alongside conventional clinical factors.
The feasibility and accuracy of ECG and image analy-
sis integration into AI methods has been well demon-
strated. Harnessing the power derived from large data
sets, CNNs may be developed to allow the use of each
of the above markers as readily applicable and low-cost
predictors of stroke risk and to refine decision-making
regarding OAC use. Indeed, in a recent analysis of rhythm
monitoring data from implantable devices in >3000
patients with established AF diagnoses in the Veter-
ans Health Administration, 3 ML models based on AF
burden indices were trained for the prediction of stroke,
including CNNs, random forest, and L1 regularized logis-
tic regression.96 Random forest achieved a C statistic of
0.662 (test data set) and a CNN had a C statistic of
0.702 (validation data set), whereas CHA2DS2-VASc had
an AUC of ≤0.5 in both data sets for stroke prediction.
That study only included 71 stroke cases. Performance
may be improved by accumulation of much larger data
sets for derivation and validation. Integration of the AF
burden signature models with clinical variables may
also lead to incremental improvements. Indeed, when
CHA2DS2-VASc score was combined with random forest
and CNN, this resulted in an AUC of 0.696 in the valida-
tion data set and an AUC of 0.634 in the test data set,
yielding the highest average AUC on nontraining data.
Similar approaches can be undertaken for any of the
potential risk markers described above. However, beyond
single biomarkers, ML approaches to automatically and
reliably capture the full breadth of demographic, clinical,
imaging, circulating biomarker, and ECG data from EHR
sources can allow the development of inexpensive and
scalable multicomponent tools for automatic detection of
patients who are both at risk of AF and AF-related stroke
based on EHR using structured and unstructured data.
Such models may be incorporated into EHR systems
whereby they can be continuously internally validated and
refined based on newly collected clinical information and
events (such as a new stroke event), thereby providing the
most up-to-date and precise estimations of risk to the cli-
nician. Similarly, the application of ML methods to the vast
amount of data collected via wearable ECG technologies
or implanted cardiac devices can enable the real-time
application of AF and stroke risk modeling based on clini-
cal factors and rhythm signatures (heart rate variability,
atrial ectopy burden, AF patterns, among others). Inohara
et al97 recently performed unsupervised cluster analysis in
≈10 000 patients with AF in the ORBIT-AF registry (Out-
comes Registry for Better Informed Treatment of Atrial
Fibrillation) incorporating patient demographics, medical
 Siontis et al
history, medications, vital signs, laboratory data, imaging
parameters, and electrocardiographic parameters. They
identified 4 clinically relevant phenotypes of AF, each with
distinct associations with clinical outcomes (low comor-
bidity, behavioral comorbidity, device implantation, and
atherosclerotic comorbidity clusters). Importantly, conven-
tional risk factors, such as AF type and LA size, were not
significant drivers of cluster classification to further refine
stroke risk modeling.
Hypothesizing that stroke risk may vary longitudinally
based on rhythm patterns, a rhythm-guided, non–vitamin
K antagonist OAC (NOAC)-in-pocket approach may
prove feasible and safe. The stroke risk can be estimated
in a time-to-event manner, and the predicted risks at
different time points (1-year risk, 5-year risk, etc) can
be calculated. Early experiences of intermittent NOAC
use for AF detected by implanted cardiac device moni-
toring were underpowered to demonstrate a reduction
in clinical end points,98,99 but the effectiveness of this
approach may be improved with the real-time application
of ML methods, allowing short-term prediction of AF and
patient-directed OAC even before AF becomes manifest.
OAC in High-Risk Groups Without Known AF
For patients with cryptogenic stroke, current guidelines
recommend ambulatory rhythm monitoring to assess for
otherwise asymptomatic AF. However, the sensitivity of
this approach to detect AF is rather low particularly with
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short duration of monitoring. Longer periods of monitor-
ing, for example, with the routinely used implantable loop
recorders, can lead to higher rate of AF diagnoses, but
this invasive approach is costly and may be unnecessary
in some cases. Bypassing prolonged rhythm monitoring,
the routine use of OAC even before AF is documented
has been considered and tested in 2 clinical trials using
rivaroxaban and dabigatran.100,101 Both of these trials dem-
onstrated an increase in the risk of bleeding compared
to aspirin and no reduction in recurrent strokes, indicating
that the benefit of OAC may not outweigh the harm of
increased bleeding in patients without documented AF. It
is also possible that any effect of these NOACs on recur-
rent stroke risk reduction was attenuated due to the fact
that only a minority of these cryptogenic strokes was truly
related to AF. A tool to better detect unrecognized AF may
help limit OAC use to patients who are most likely to bene-
fit. Applying the paradigm described previously,67 a patient
with cryptogenic stroke could be treated with OAC based
on an AI-enhanced ECG demonstrating a high AF prob-
ability. This would obviate the need for prolonged ambula-
tory rhythm monitoring with implantable or other monitors,
reduce unnecessary resource utilization, and reduce the
time off therapeutic OAC. Similarly, an AI-enabled ECG
or other AI-enabled diagnostic tool that can identify with
high fidelity patients with heart failure who are likely to
have undiagnosed or future AF and subsequent risk for
Circulation Research. 2020;127:155–169. DOI: 10.1161/CIRCRESAHA.120.316401
Machine Learning in AF
complications (stroke and worsening heart failure) may
COMPENDIUM ON ATRIAL
allow the early institution of effective therapies. This goal
was not met when low-dose rivaroxaban was tested
FIBRILLATION
against placebo in patients with heart failure with reduced
ejection fraction, coronary artery disease, and no AF in the
COMMANDER HF trial (A Study to Assess the Effective-
ness and Safety of Rivaroxaban in Reducing the Risk of
Death, Myocardial Infarction, or Stroke in Participants With
Heart Failure and Coronary Artery Disease Following an
Episode of Decompensated Heart Failure).102 Finally, the
potential value of empirical OAC in asymptomatic all-com-
ers who are predicted to have an elevated risk for both AF
and AF-related stroke on the basis of AI-enabled prog-
nostication is a thought-provoking approach that requires
further testing and clinical validation.
Optimizing Treatment Choices
AF treatment is truly multidimensional. It includes consid-
erations of symptom management and prevention of AF-
related complications with pharmacological (antiarrhythmic
medications, rate control medications, OACs), catheter
ablation, and device-based interventions (LAA occlusion
and pacemakers). Despite improvements in outcomes of
AF patients treated with contemporary approaches in cen-
ters with expertise, significant uncertainties remain, further
complicating decision-making on behalf of clinicians and
patients. The availability of large data sets, such as admin-
istrative claims-based data sets and those originating from
large clinical trials, allows the in-depth phenotyping of
associations between different treatments and clinical out-
comes. In the study by Inohara et al,97 unsupervised learning
identified phenotypically and prognostically distinct clus-
ters of AF patients, which were also characterized by dis-
tinct treatment patterns, such as rate versus rhythm control,
specific AAD use, and antithrombotic strategies. Traditional
methodologies can be augmented with ML approaches
integrating routinely collected information in the setting of
retrospective and prospective studies enriched with widely
available EHR-derived information. These tools can inform
shared decision-making in determining an optimal selec-
tion of a wide range of current treatment dilemmas. Spe-
cific examples include the following:
1. NOAC versus warfarin: The use of NOACs has
increased rapidly over the past decade, and their
advantages over warfarin are clear and well dem-
onstrated. However, the NOACs are not without
limitations, and in some populations, warfarin may
be the preferred OAC either due to specific clinical
reasons or due to healthcare resource limitations.
This is particularly relevant for populations where
there is paucity of clinical trial data on NOAC out-
comes, such as in patients with end-stage renal
disease in whom warfarin remains heavily used.103
2. OAC versus LAA occlusion: In the United States,
the Watchman device is the only currently
June 19, 2020   163
 Siontis et al
FDA-approved device for percutaneous LAA
COMPENDIUM ON ATRIAL
occlusion in high-risk patients intolerant of long-
term OAC.104,105 Both OAC and LAA occlusion,
FIBRILLATION
however, can be associated with treatment failures,
that is, they do not universally eliminate stroke risk.
Also, the Watchman implantation procedure car-
ries periprocedural risks and significant healthcare
expenditures, which prohibits more liberal use in
most AF patients. On the other hand, OACs are
associated with non-negligible bleeding risks and
the inconvenience of a daily medication. Thus,
identifying patients who are likely to benefit the
most or the least from the Watchman procedure
becomes a priority. ML methods integrating clinical
factors with advanced imaging analytics, including
LA structure and function, as well as LAA size and
morphology, are likely to play a role in that regard.
3. Catheter ablation versus AAD: Numerous clinical tri-
als, including the recently completed CABANA trial
(Catheter Ablation vs Antiarrhythmic Drug Therapy
for Atrial Fibrillation),106,107 have shown catheter
ablation to be a reasonable first-line treatment for
patients with symptomatic AF, particularly paroxys-
mal. Nevertheless, significant treatment effect het-
erogeneity exists among patient subgroups, such
that generalizability of clinical trial results to clinical
practice becomes challenging. ML approaches that
consider the entire patient phenotype may offer a
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means of discrimination among those who are likely
to respond to ablation versus those more likely to
respond to AADs.
Warfarin Treatment Monitoring
Despite the uptake of NOACs, warfarin remains widely
used in the United States. Among other known limita-
tions, warfarin has a narrow therapeutic window. Poor
anticoagulation control as indicated by the time in thera-
peutic range has been associated with adverse clinical
outcomes in AF patients.108 Also, defining an optimal
dose can be challenging in patients newly starting the
medication as there is significant variability in dosing
requirements among individuals. ML approaches inte-
grating demographic, clinical, and even pharmacoge-
nomic data have been successfully developed to improve
the ability to predict warfarin dosing in the individual
patient.109,110 Furthermore, adherence to OACs is gener-
ally suboptimal and has only modestly improved with the
increased use of NOACs.111 In a randomized trial, Labo-
vitz et al112 tested the impact of a smartphone-based
monitoring intervention that automates directly observed
therapy using AI to visually confirm medication ingestion.
Adherence was 100% and 50% in the intervention and
control groups, respectively, as determined by plasma
drug concentration levels,112 suggesting the feasibility
and potential clinical utility of such tools.
164   June 19, 2020 Circulation Research. 2020;127:155–169. DOI: 10.1161/CIRCRESAHA.120.316401
Machine Learning in AF
Antiarrhythmic Drug Management
AADs are commonly used in the management of AF and
other arrhythmias but require close monitoring due to the
risk of potentially fatal ventricular proarrhythmia related to
drug-induced QT prolongation, a side effect that is most
prominent with dofetilide and sotalol. These medications
are initiated under ECG monitoring in the hospital. Dose
adjustments may subsequently be needed depending on
the degree of QT prolongation, concomitant QT-prolong-
ing drugs, and potential changes in renal function as both
sotalol and dofetilide are predominantly renally metabo-
lized. However, the QT interval is an imperfect marker for
monitoring because it does not accurately reflect plasma
concentration or proarrhythmic potential. A group of Mayo
Clinic investigators developed a deep-learning model to
predict dofetilide plasma concentration in 42 subjects using
the ECG.113 This deep-learning approach predicted plasma
dofetilide concentrations with good correlation (r=0.58). In
a different multicenter study (n=354 patients), Levy et al8
used ML approaches including supervised, unsupervised,
and reinforcement learning to identify the optimal dosing
strategy for dofetilide loading. A reinforcement learning
algorithm informed by unsupervised learning was able to
predict dosing decisions with an accuracy of 96.1%.8
Beyond dofetilide, Hu et al114 tested ML methods to
predict appropriateness of initial digoxin dosing in 307
patients, including patients with AF, and distinguishing
between patients with drug-drug interactions and those
without interactions. Among several ML models tested
using demographic, clinical, and laboratory data, random
forest provided the highest AUC (0.912) followed by mul-
tilayer perceptron with an AUC of 0.813 in the no drug
interactions group. The AUC of random forest was the
best for the group of patients with interactions (0.892),
followed by a classification and regression tree model
(AUC, 0.795) and multilayer perceptron (AUC, 0.777).114
Applications for Catheter Ablation
Pulmonary vein isolation is the cornerstone of the cur-
rent ablative management of AF. Pulmonary vein isolation
is effective in paroxysmal trigger-dependent AF, but out-
comes of ablation are at best modest in persistent AF, and
many patients require repeated procedures. A very large
body of literature over >10 years has examined the incre-
mental value of linear ablation, ablation of nonpulmonary
vein triggers, complex fractionated electrograms or targets
guided by phase mapping in addition to pulmonary vein iso-
lation, but none of these approaches has been consistently
shown to further improve long-term success rates of abla-
tion.115,116 These investigations, however, have been ham-
pered by relatively small sample sizes and limited power.
Mounting evidence suggests the role of nonpulmonary
vein triggers and substrate particularly in nonparoxysmal
AF and in patients with comorbidities, such as obstructive
 Siontis et al
sleep apnea.117 Indeed, the pathogenesis of AF, especially
persistent, is so heterogeneous that a one size fits all abla-
tion approach is unlikely to benefit all patients.
Tailored approaches to AF ablation have been many
years in the making. Recently, Boyle et al118 have reported
pioneering work attempting to determine atrial ablation tar-
get sites based on computational modeling of MRI-defined
atrial fibrosis. AI methods have the potential to even fur-
ther enhance decision-making for a truly personalized
selection of an ablative approach. Development of such AI
models would incorporate not only imaging data but also
clinical factors, data from ECG in sinus rhythm and/or AF,
and information from invasive electroanatomic mapping,
including, for example, voltage and activation maps in sinus
rhythm and AF. Ultimately, a trained model would interface
with the proceduralist in real time to indicate the critical
areas that should be targeted for ablation in that particular
patient. Large-scale multicenter collaborations are required
for such a model to be realized as information from a very
large number of patients and procedures, as well as rigor-
ous post-ablation follow-up, are required.
LIMITATIONS AND CHALLENGES OF ML
While large amounts of data can strengthen the power
of ML models, it becomes increasingly difficult to criti-
cally assess their quality. This becomes even more criti-
cal when deep-learning convolutional models are used
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whereby nonlinear data transformations and multiple
convolutions make it difficult to track how the data was
internally handled and what aspects of the input data
most heavily weighed on the model output.119
One of the major concerns with deep-learning ML
methods is that it is a black box given the agnostic nature
of how a set of input data is analyzed to derive an output.
Explainability of deep-learning algorithms is therefore an
important area of ongoing investigation. Another concern
is that such black box models may not allow patients and
providers to engage into meaningful shared decision
making because it is unknown what drives the recom-
mendation provided by the model. The counterargument
to that concern is that such an unbiased approach may
actually be able to enhance shared decision making as
it does not provide any recommendations based on pre-
conceived notions that humans unavoidably carry into
shared decision-making interactions to some extent.
SOCIETAL AND LEGAL CONSIDERATIONS
As ML evolves from a purely research tool to one that is
directly used in clinical care, it is important to consider its
societal and legal implications. A recent example under-
scored the potential for ML to reflect and even compound
disparities in care. Obermeyer et al120 assessed a risk model
that is in active clinical use to predict healthcare system
Circulation Research. 2020;127:155–169. DOI: 10.1161/CIRCRESAHA.120.316401
Machine Learning in AF
expenditure. Those at the highest end of predicted health-
COMPENDIUM ON ATRIAL
care use were assigned to a special program seeking to
improve care coordination. They observed that for any given
FIBRILLATION
set of inputs, black patients were assigned a lower score
than white patients; if this racial disparity was corrected, the
number of black patients who qualified for assistance would
have tripled. Because black patients accrued less health-
care cost for any given degree of wellness, the algorithm
was correctly predicting cost, but was seemingly doing so
by encoding the racial disparities seen in the training data.
Aware of such potential harms, several groups have started
developing frameworks to guard against bias and potentially
to decrease healthcare disparities across populations.121,122
In order for ML applications to have a meaningful impact
on population health and well-being, these applications
need to be easily scalable so that they can reach their target
populations who are most likely to benefit. In the example
of screening for AF, the populations needing it the most are
primary care populations outside of cardiology subspecialty
care and typically outside of academic medical centers. In
these settings, the familiarity with AI may be lower than in
specialty practices actively engaged in research. We must
remain mindful in our application of AI technologies so not
to perpetuate or exacerbate health disparities.
Finally, the regulatory and legal landscape may pose
a challenge to fully realizing the benefits of ML in clinical
care. For example, tort law favors the standard of care,
so when an ML algorithm makes recommendations that
deviate from the standard—which may be seen as a goal
of personalized medicine—the liability risk may hinder
physicians from following the potentially more accurate
guidance provided by ML tools.123
CONCLUSIONS
The clinical application of ML is at its infancy, but it has
the potential to contribute to the care of AF in the mod-
ern era (Figure 1). With several remaining challenges and
uncertainties ranging from screening to risk stratification
and treatment of AF and its complications, the ongoing
advances driven by ML show promise as discussed in
this review. What will it take for the full potential of ML
to be realized? Clinical validation, internal and external
replication consistency, and generalizability with an eye
toward application in various healthcare settings regard-
less of available resources, as well as consideration of
regulatory issues, should all be key components of a rig-
orous research platform that will allow us to realize the
potential of ML while ensuring a patient-oriented focus
in the care of AF.
ARTICLE INFORMATION
Affiliations
From the Department of Cardiovascular Medicine (K.C.S., P.A.N.), Robert D and
Patricia E Kern Center for the Science of Health Care Delivery (X.Y.), and Division
June 19, 2020   165
 Siontis et al
of Health Care Policy and Research, Department of Health Sciences Research
COMPENDIUM ON ATRIAL
(X.Y.), Mayo Clinic, Rochester, MN; Broad Institute, Cambridge, MA (J.P.P., A.A.P.);
and Division of Cardiology, Massachusetts General Hospital, Boston (J.P.P.).
FIBRILLATION
Disclosures
A. Philippakis is a Venture Partner at GV, the corporate venture capital group of
Alphabet. J. Pirruccello is supported by the John S. LaDue Memorial Fellowship
for Cardiovascular Research. The other authors report no conflicts.
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