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Clinical applications of machine learning in cardiovascular disease and its

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 European Heart Journal (2018) 0, 1–14 CLINICAL REVIEW
doi:10.1093/eurheartj/ehy404

Clinical applications of machine learning in

cardiovascular disease and its relevance to
cardiac imaging
Subhi J. Al’Aref1†, Khalil Anchouche1†, Gurpreet Singh1, Piotr J. Slomka2,
Kranthi K. Kolli1, Amit Kumar1, Mohit Pandey1, Gabriel Maliakal1,
Alexander R. van Rosendael1, Ashley N. Beecy1, Daniel S. Berman2,
Jonathan Leipsic3, Koen Nieman4, Daniele Andreini5, Gianluca Pontone5,
U. Joseph Schoepf6, Leslee J. Shaw1, Hyuk-Jae Chang7, Jagat Narula8, Jeroen J. Bax9,
Yuanfang Guan10, and James K. Min1*
1
Department of Radiology, NewYork-Presbyterian Hospital and Weill Cornell Medicine, New York, NY, USA; 2Departments of Imaging and Medicine and Biomedical Sciences,
Cedars-Sinai Medical Center, Los Angeles, CA, USA; 3Departments of Medicine and Radiology, University of British Columbia, Vancouver, BC, Canada; 4Departments of
Cardiology and Radiology, Stanford University School of Medicine and Cardiovascular Institute, Stanford, CA, USA; 5Centro Cardiologico Monzino, IRCCS Milan, Italy; 6Division
of Cardiovascular Imaging, Department of Radiology and Radiological Science and Division of Cardiology, Department of Medicine, Medical University of South Carolina,
Charleston, SC, USA; 7Division of Cardiology, Severance Cardiovascular Hospital and Severance Biomedical Science Institute, Yonsei University College of Medicine, Yonsei
University Health System, Seoul, South Korea; 8Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA;
9
Department of Cardiology, Heart Lung Center, Leiden University Medical Center, Leiden, The Netherlands; and 10Department of Computational Medicine and Bioinformatics,
University of Michigan, Ann Arbor, MI, USA

Received 21 March 2018; revised 29 May 2018; editorial decision 22 June 2018; accepted 6 July 2018

Artificial intelligence (AI) has transformed key aspects of human life. Machine learning (ML), which is a subset of AI wherein machines au-
tonomously acquire information by extracting patterns from large databases, has been increasingly used within the medical community,
and specifically within the domain of cardiovascular diseases. In this review, we present a brief overview of ML methodologies that are
used for the construction of inferential and predictive data-driven models. We highlight several domains of ML application such as echo-
cardiography, electrocardiography, and recently developed non-invasive imaging modalities such as coronary artery calcium scoring and
coronary computed tomography angiography. We conclude by reviewing the limitations associated with contemporary application of ML
algorithms within the cardiovascular disease field.
...................................................................................................................................................................................................
Keywords Machine learning • Cardiovascular disease • Coronary computed tomography angiography • Echocardiography

..
Introduction .. driving. While the adoption of ML in the information technology
.. sector is nearly ubiquitous, its introduction into the medical field
..
Machine learning (ML), an extension of the century-long quest for .. has been much more subdued. The landscape, however, is rapidly
artificial intelligence (AI), has altered our collective conception of .. changing. Equipped with novel ML frameworks, increasing compu-
..
information and its seemingly boundless potential for guiding .. tational power and the availability of big data, the ML community is
change. Machine learning is broadly defined as the ability of a sys-
.. now concentrating its efforts squarely at complex tasks in the
..
tem to autonomously acquire knowledge by extracting patterns .. healthcare sector. These efforts have borne their fruits, for ex-
from large data sets.1 This field has sparked tremendous innovation
.. ample, in radiology, where an ML platform has been demonstrated
..
in all sectors of the technology industry, from speech recognition .. to be as effective as a human radiologist in validating presumptive
and sentiment analysis to spam filters, chat-bots and autonomous
.. diagnoses.2 In pathology, ML has uncovered entirely new
.
* Corresponding author. Tel: þ1-212-746-6192, Fax: þ1-212-746-0129, Email: jkm2001@med.cornell.edu
†
The first two authors contributed equally to the content of the manuscript.
Published on behalf of the European Society of Cardiology. All rights reserved. V
C The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.

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 2 S.J. Al’Aref et al.
..
prognostic histological features in breast cancer.3 More recently, in ..
clinical cardiology, it has been shown that ML is more adept in the ..
..
prediction of either cardiovascular or all-cause mortality than clin- ..
ical or imaging modalities used separately.4,5 Altogether, the po- ..
..
tential for ML to fundamentally change the way we practice ..
medicine is now well-appreciated.6 In this review, the goals are ..
..
three-fold: (i) to outline in detail the general methodology ..
employed in ML endeavours for a clinical audience; (ii) to highlight ..
..
some of the avenues in which ML has found application in cardi- ..
ology; and (iii) to note a few limitations for its expanded use in ..
..
healthcare. ..
..
..
..
..
Overview of machine learning ..
..
Machine learning, a broad discipline with foundations in mathematics
..
..
and computer science, proposes a set of novel algorithms and meth- ..
odologies for the construction of inferential and predictive data-
..
..
driven models. It is important, however, to first clearly delineate what ..
..
ML can and cannot do. Machine learning does not constitute general ..
intelligence. Rather, it is used to tackle classes of well-defined prob- ..
..
lems, which were historically too difficult, if not altogether impossible, ..
to solve with rule-based paradigms (‘if . . . then . . .’). A representative ..
..
and often-cited early application of ML is that of handwritten digit ..
recognition.7 Early research in the field focused on the development ..
..
of models capable of correctly assigning labels (0–9) to a set of images
containing hand-written digits. Rather than delineating explicit criteria
for the classification of each of the ten digits such as characteristic
symmetries and geometric configurations, ML proposes using vast
troves of data (in this case, other images of handwritten digits along
with their correct labels) to ‘learn’ mathematical representations of
these characters. Such representations can then be extended to
make prediction on previously unseen images. This is an example of
supervised learning, a framework in which a computer learns directly
from large quantities of correctly labelled examples.8 It is within this
context that it is vital to keep in mind that, as of now, state-of-the-art
ML algorithms are still focused on discriminative learning and not gen-
erative modelling, thus are incapable of deciphering underlying true
probability distribution and infer like humans. Unsupervised learning,
on the other hand, does not necessitate any pre-defined human input;
in this framework, an algorithm attempts to autonomously derive
conclusions from unlabeled data. A common example of unsuper-
vised learning is cluster analysis, where a dataset, without a priori
knowledge of its true labels, is partitioned into clusters of ‘similar’
objects. The third type is known as reinforcement learning, which is
reward-based learning that is typically used in robotic and gaming
applications. We focus in this review primarily on supervised ML,
which has found the widest applicability to date.
Data
In order to employ the tools and techniques of supervised ML, data
must first be framed appropriately. Datasets generally consist of a set
of objects characterized by a number of features and their associated
labels. For instance, a dataset might consist of patients represented
by clinical and medical imaging parameters, with their associated
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clinical outcomes, e.g. experienced a stroke/did not experience a
stroke. Such information can be most compactly represented using
matrix notation, whereby each row of a design matrix X corresponds
to an object and each column to a feature, with its matching label
contained in a vector y. Once raw data has been gathered and stored
in a matrix, a number of pre-processing steps are then performed be-
fore it can be further manipulated. Typically, the categorical features
are represented numerically using a technique known as one-hot
encoding. One-hot encoding is the process of binarization of categor-
ical values in order to transform the values into a format that has
been observed to work well for classification and regression algo-
rithms. Additionally, given the numerous imperfections which can
plague imported datasets such as sparsity, the presence of outliers,
and inter-variable differences in scale, further transforms such as im-
putation of missing data and normalization are then employed to as-
sist in standardization. As it happens, many of these transforms are
actually necessary prerequisites in the application of ML algorithms
that rely on gradient descent, a frequently used numerical optimiza-
tion algorithm. There are numerous strategies that can then be
employed to determine the optimal feature representation of the
objects in a dataset once it has been preprocessed, comprising the
full gamut from feature selection (only the most ‘predictive’ features
are used in the construction of a model) to feature extraction (multi-
dimensional feature vectors are projected to a lower dimensionality
subspace allowing for a more succinct representation of each object).
.. Beyond this, feature engineering can also be performed, a labour-inten-
.. sive process whereby handcrafted features are added to a dataset in
..
.. the hopes of achieving enhanced classification. More novel ML frame-
.. works, such as deep learning, automate this difficult task. These meth-
..
.. odologies have been well characterized in the ML literature and are
.. typically adapted empirically to the problem at hand.9
..
..
..
..
.. Algorithms
..
..
.. Supervised ML algorithms can be employed to tackle both classifica-
.. tion and regression problems. The goal in the former task is to cor-
..
.. rectly assign a binary or multi-class label, while in the latter, it is to
.. correctly predict a real-valued output. Conveniently, many ML algo-
..
.. rithms are sufficiently flexible to accomplish both types of analysis
..
.. with only minor adaptations, although constraints such as interpret-
.. ability, computational cost, and type of available data need to be con-
..
.. sidered in tailoring the choice of algorithm. We focus in this review
.. primarily on classification tasks. Machine learning algorithms fre-
..
.. quently employed in practice include linear and logistic regression,
.. artificial neural networks (ANN), support vector machines (SVM),
..
.. and tree-based methods. These individual models can then be com-
.. bined with one another using ensemble learning, a methodology which
..
.. leverages the power of multiple weak classifiers to achieve optimal
.. overall performance. Datasets used in ML projects are typically parti-
..
.. tioned into training, validation, and test subsets: the training set, which
.. encompasses the bulk of all available data, is used for the primary de-
..
.. velopment of the model; the validation set is used to estimate overall
.. model performance or to fine-tune its hyperparameters.
..
.. Hyperparameters, as opposed to standard model parameters, are
.. weighted factors set before the learning process begins. Thereafter,
..
. repeated multi-fold training/validation (cross-validation) is
 Clinical applications of machine learning in cardiovascular disease 3

Figure 1 Schematic diagram of splitting dataset for training machine learning model. Dataset is typically split into training and test subsets. The
training set is used to develop the model in question, while the test set is used to assess its generalizability. During cross-validation, the training set is
divided into two subsets; one is used to train the model and the second subset is used to validate the model at each iteration. Shown in the figure is
an example of four-fold cross-validation wherein 75% of the training dataset was used for training and the remaining 25% was used for validation the
results at each iteration.

Figure 2 Simplified representation of the decision boundary for model (A) underfitting, (B) optimal fitting, and (C) overfitting. An underfitted model
is incapable of representing the actual data distribution. Usually in such cases, one should chose a more complex model such as increasing the degree
of polynomia for regression. However, increasing the complexity beyond a certain limit can lead to an overfitted model. These models perform well
on the training datasets but may fail on unseen datasets. Therefore, a trade-off between model complexity and data representation is desirable to ob-
tain an optimally fitted model.

performed, which removes the variance in the created model due to .. ‘learns’ by iteratively adapting its internal parameters to fit the training
..
just one random split selection into just one training and validation .. data via optimization of an objective function (Table 1). Ultimately,
set. Finally, an independent (external) test set can be used to assess
.. the challenge of ML is to efficiently perform these steps, while avoid-
..
its generalizability once completely optimized (Figure 1). Once an al- .. ing over-fitting (Figure 2). That is, the constructed model should not be
gorithm and training framework is settled upon, the algorithm then
.. so specific to the noise in the data on which it was initially trained so

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 4 S.J. Al’Aref et al.

Figure 3 Machine learning model capacity and error on a bias-variance spectrum. Bias refers to the error that is introduced by constructing an ex-
cessively simple model with poor prediction accuracy. Variance, on the other hand, refers to the error incurred by building an excessively complex
model, attuned to noise in the training data. Here, we plot the training error vs. model capacity to show the bias-variance spectrum. Two distinct
zones exist, namely, overfitting and underfitting zones. During model training, there may exist a hinge point that represents the achievable optimal
capacity of the model. Prior to this point, the model has high bias and is underfitted. Subsequent to the hinge point, if trained, the model will eventually
become overfitted and have high variance.

..
as to perform well in both training and validation, only to fail in repro- ..
ducing those results on an independent test set. In ML parlance, such ..
..
models are often said to be characterized by ‘high variance’ (Figure 3). ..
Convolutional neural networks (CNNs) are a class of ML based ..
..
approaches aptly suited for image analysis. Convolutional neural net- ..
works require minimal pre-processing and are generally composed ..
..
of multiple convolution layers, where multiple kernels/filters of ..
shared weights are used to find local patterns in organized data such
..
..
as images. Convolutional neural networks consist of an input and an ..
output layer, as well as intermediary hidden layers. Each layer is con-
..
..
nected in an end-to-end manner, and weights are trained using back- ..
propagation. Convolutional neural networks have become the ‘go-
..
..
to’ approach for feature extraction in cardiovascular imaging sets,
and examples of such networks include U-Net, VGG, Faster R-
CNN.10 A significant limitation associated with CNN is highlighted by
adversarial examples, wherein CNNs erroneously misclassified a
completely unrecognizable image into a recognizable object with
high confidence (for instance, calling pixelated noise as an animal).11
Towards this, a class of unsupervised learning based CNNs, called of
generative adversarial networks (GANs) has been proposed and is
still an active area of research for data augmentation. Another recent
breakthrough towards mitigating such pitfalls is the inception of
Capsule Networks (CapsNet) that instead of stacking deeper layers
has capsules of CNN layers.12,13
Performance metrics and model
refinement
Two crucial decisions must be made early in the construction of an
ML pipeline: namely, the selection of a performance metric and the
designation of appropriate benchmarks. These measures are of para-
mount importance, as they are used to quantify the degree to which
the constructed model is successfully achieving its designated task
and will guide all subsequent adjustments (such as gathering more
data, fine-tuning hyperparameters, employing regularization, or using
an entirely different learning algorithm) (Figure 4). The choice of a
performance metric is largely problem-dependent. For example,
while accuracy is often an intuitive and convenient metric for use in a
binary classification problem, it may actually mask poor model per-
formance if it is attempting to predict an exceedingly infrequent
event, such as the occurrence of a rare disease. In such a scenario, a
classifier which indiscriminately labelled all patients as ‘normal’ might
.. achieve near perfect accuracy, while actually misclassifying every oc-
.. currence of the disease. In the medical literature, the performance of
..
.. a classifier is typically reported using a receiver-operating characteris-
..
.. tic curve along with its corresponding area under the curve (AUC or
.. C-statistic), which allows for the quantification of both sensitivity and
..
.. specificity at every classifier threshold. Other performance metrics
.. also exist, such as squared error. Importantly, it should be noted that
..
.. ML, for datasets with real-life complexity, may give very high accura-
.. cies but without guaranteeing correct prediction. Given any task, it is
..
.. then merely a matter of experimentation to determine the optimal
.. model with the greatest potential for generalizability. Theoretically,
..
.. the lowest attainable error is known as the Bayes error rate. This ceil-
.. ing on performance exists because most phenomena studied in the
..
.. natural world are permeated by noise. Consider, for example, two
.. patients characterized by identical clinical parameters; while it may be
..
.. reasonable to assume that such individuals will, on average, experi-
.. ence similar clinical outcomes, it is impossible to make such a claim
..
.. with absolute certainty because the system being approximated is
.. probabilistic rather than deterministic.

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 Clinical applications of machine learning in cardiovascular disease 5

Table 1 An overview of algorithms commonly used in machine learning

Algorithm Overview Illustration

....................................................................................................................................................................................................................
Artificial neural An ANN consists of a set of nodes (often referred to as ‘neurons’) configured in layers
networks (input, hidden, and output), connected to one another via weighted edges. Input feature
(ANN) vectors are processed sequentially by every layer in the net via non-linear transforma-
tions, before an output (e.g. a class label) is generated upon reaching the final layer.
During the training process, if the output of the ANN is incorrect, the edge weights are
incrementally adjusted to account for the error via an algorithm known as back-propa-
gation. The ANN is foundational to deep learning.

Support vector The SVM classifier is constructed by projecting training data into a higher dimensional
machine (SVM) space via mappings known as kernels, and devising in this new space a boundary (for-
mally known as a hyperplane), which maximizes separation between the classes. New
examples are then projected into this higher dimensional space, where this previously
learned boundary is used to assign labels.

Decision Tree The decision tree is the simplest tree-based machine learning model. The aim is to recur-
sively construct a tree structure, which can accurately assign labels given an input fea-
ture vector by creating the appropriate ‘splits’, a process known as recursive
partitioning. Importantly, trees can be combined using ensemble learning to yield potent
classifiers such as random forests and boosted trees.

k-Nearest neigh- In KNN, every object being classified is compared to its k nearest training examples via a
bours (KNN) distance function, where k is an integer; its label is then assigned by majority vote.

.. streamlined hospital-care and cut costs.29,30 Modern ML models are

Domains of application ..
.. now able to identify different wave morphologies (QRS complexes, P
Machine learning has yet to find a prominent role in clinical cardi-
..
.. and T waves) with high precision; using this information, clinically sig-
ology. While a plethora of studies have been published during the .. nificant parameters such as heart rate, axis deviation, and interval
past decade examining its potential utility in various clinical contexts,
..
.. lengths can then be calculated. Models have also been proposed for
currently, there is no consensus regarding the manner in which to .. the high fidelity detection of both ST-changes as well as common
construct and apply such models or objectively evaluate their results.
..
.. rhythm disturbances, such as atrial fibrillation and interventricular
In light of this, we highlight in this review the numerous domains with- .. conduction delay (more complex arrhythmias, however, still often
..
in cardiovascular medicine where ML algorithms have been .. necessitate human validation). At the root of this automation are
employed, ranging from coronary artery disease evaluation to heart .. storied ML algorithms, including ANN, SVM, and hidden Markov
..
failure phenotyping (Table 2). .. models.31 In recent years, numerous ECG pre-processing, feature ex-
.. traction and classifier algorithms have been detailed in an ever-
..
.. expanding literature using tools borrowed primarily from the fields
.. of signals processing and wavelet analysis.32–37 The accuracy of these
Electrocardiography ..
.. models has been historically evaluated using annotated public domain
Automated electrocardiogram (ECG) interpretation, an enterprise .. ECG repositories, such as the Massachusetts Institute of
..
initially undertaken in the 1960s with the advent of digital ECG .. Technology—Beth Israel Hospital (MIT-BIH) arrhythmia and
machines, is now almost universal.28 It was the first instance in which
.. European ST-T databases.38,39 For example, Zhao et al. proposed a
..
rudimentary AI (likely a rule-based expert system) effectively . simple but highly predictive framework in which ECG tracings were

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 6 S.J. Al’Aref et al.
Figure 4 A general outline of the step-by-step approach to machine learning.
..
characterized using both a wavelet transform and autoregressive ..
modelling. These feature vectors were then used to classify the trac- ..
..
ing as one of five common arrhythmias using an SVM ML algorithm ..
with a Gaussian kernel. This methodology achieved test set classifica- ..
..
tion accuracies of 100%, 98.66%, 100%, 99.66%, and 100% for sinus ..
rhythm, left bundle branch block, right bundle branch block, prema-
..
..
ture ventricular contraction, and premature atrial contraction, re- ..
spectively, on the MIT-BIH dataset.33 Similarly, a number of pre-
..
..
processing algorithms and classifiers have been proposed for the de- ..
tection of ischaemic changes. For example, a neural network for the
..
..
detection of ST-changes proposed by Afsar et al.,40 using wavelet-
transformed ECG signals as input, achieved a sensitivity of 90.75%
and positive predictive value of 89.2% on the European Long-Term
ST-T Database. More recently, the Stanford Machine Learning Group
used a 34-layer convolutional neural network, a form of deep learn-
ing) to detect a broad range of arrhythmias and found that the model
exceeded the average cardiologist performance in both recall and
precision compared to board-certified cardiologists.41
Echocardiography
Two-dimensional echocardiography (2DE) is ubiquitously used to
guide the diagnosis and down-stream management of numerous
cardiac pathologies. Detailed echocardiography, however, is
resource-intensive, often resulting in visual estimation rather than
precise calculation.42 Machine learning proposes to automate many
of these processes. There are already a number of widely-adopted
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commercial softwares developed for the functional analysis of 2DE
data (e.g. EchoPAC by GE healthcare, QLAB by Philips etc.), which
can perform an assortment of tasks ranging from segmentation and
detection of anatomic landmarks to blood tracking. All results from
such analyses, however, are wholly dependent upon careful annota-
tion of input data, which is implicitly deferred to the clinician. That is,
in order to use these tools, the physician evaluating the imaging study
must manually select the correct study, choose an appropriate win-
dow, and specify which parameters to compute. These steps, while
trivial in the evaluation of an individual echocardiogram, become limi-
.. tations when analysing significantly larger datasets. Khamis et al.14
.. demonstrated that apical two-chamber (A2C), apical four-chamber
..
.. (A4C), and apical long-axis (ALX) images could be correctly classified
..
.. using a novel spatio-temporal feature extraction and supervised dic-
.. tionary learning. This methodology achieved diagnostic accuracies of
..
.. 97%, 91% and 97% for A2C, A4C, and ALX images, respectively. In
.. 2015, Knackstedt et al.15 demonstrated that the ejection fraction and
..
.. longitudinal strain could be reliably and reproducibly computed from
.. echocardiographic data using commercially available proprietary ML
..
.. software. The automated values generated were compared with
..
.. those obtained via visual estimation and manual tracing, demonstrat-
.. ing significantly improved speed (automated analysis was completed
.. within an average of 8 s) without any loss in accuracy. More recently,
..
.. a number of deep learning architectures have been proposed for left
.. ventricular volume estimation and segmentation, as well as viewpoint
..
.. classification.43,44 Finally, ML has also been utilized to detect and char-
.. acterize valvular and anatomic pathology, as well as to enhance the
..
. quality of existing echocardiograms16–18,45–50 (Figure 5 and Table 2).
 Clinical applications of machine learning in cardiovascular disease
Figure 5 Spectrum of applications for advanced machine learning algorithms in clinical echocardiography.
Coronary artery calcium scoring ..
..
and coronary computed ..
..
tomography angiography ..
..
..
Non-invasive imaging has become instrumental in establishing the ..
presence of coronary artery disease (CAD) and subsequent deter-
..
..
mination of downstream prognosis. Coronary artery calcium (CAC) ..
scoring and/or coronary computed tomography angiography
..
..
(CCTA) provide the ability to assess atherosclerosis both qualitative- ..
ly and quantitatively, while CCTA can further provide information on
..
..
stenosis severity of a particular atherosclerotic lesion. Machine learn- ..
..
ing algorithms have been extensively used for optimization of infor-
mation extraction from such imaging modalities. For example, Takx
et al.51 used an ML-based approach that used supervised classification
systems, including direct classification with the nearest neighbour
classifier, and two-stage classification with nearest neighbour and
SVM classifiers for the automation of CAC scoring in low-dose, non-
contrast enhanced, non-ECG-gated chest CT. They found that such
an approach resulted in acceptable reliability and agreement when
compared to a manually determined reference standard for CAC
scoring. Similar results were obtained by Isgum et al.52,53 when com-
paring the accuracy of an automated CAC scoring system with that
of manually annotated scans. Furthermore, Kang et al.54 used a two-
step ML algorithm, utilizing an SVM algorithm as one of the base deci-
sions, in order to automate the process of coronary stenosis evalu-
ation on CCTA. They found that such an approach resulted in an
accuracy of 94% and an AUC of 0.94 for the automated detection of
non-obstructive and obstructive CAD.
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7
For the assessment of the functional significance of atherosclerotic
lesions, an automated ML-based algorithm segmented the coronary
tree with and without accounting for the partial volume effect (PVE).
Partial volume effect could lead to overestimation of lumen area in
coronary vessels with a small diameter, which is an important param-
eter in the determination of the haemodynamic significance of a cor-
onary lesion. As such, incorporation of the PVE improved the AUC
for the detection of haemodynamically significant CAD from 0.76 to
0.80 when compared with invasively assessed fractional flow reserve
(FFR).55 Machine learning has also been used to compute a fractional
flow reserve (FFRCT) directly from CT angiographic features without
the traditional computational fluid dynamics approach and showed
..
.. incremental prognostic value for the determination of the risk of fu-
.. ture adverse events.56–58 In related work, ML (LogitBoost algorithm)
..
.. has been applied by Dey et al.20 in a multicentre study of 254 patients
... with CCTA to predict the probability of low value by invasive FFR by
..
.. considering a number of CCTA image features derived by vessel ex-
.. traction and plaque characterization software. Machine learning
..
.. exhibited higher AUC (0.84) than any individual CCTA image meas-
.. ures, including stenosis severity (0.76), low-density non-calcified pla-
..
.. que (0.77), or total plaque volume (0.74). Such techniques may allow
.. clinical implementation of a risk score for the identification function-
..
.. ally significant lesions (low invasive FFR) by rapid non-invasive CCTA
.. image analysis.
..
.. CT-based imaging has been also used for the determination and
.. quantification of myocardial perfusion, in an effort to increase
..
.. CCTA’s accuracy for the detection of physiologically significant cor-
.. onary stenosis. A trained AdaBoost classifier that incorporates three
 8 S.J. Al’Aref et al.

Table 2 Summary of contemporary data on published literature using machine learning algorithms in cardiovascular
medicine

Study Objectives and key findings Algorithm/tool Sample size

....................................................................................................................................................................................................................
Echocardiography
Khamis Automated view classification of three standard echocardiographic views Spatio-temporal feature 309 clips
et al.14 Accuracy 97% for apical two-chamber, 91% for apical four-chamber, 97% for extraction and diction-
apical long axis. Overall accuracy 95% ary learning based
classification
Knackstedt Echocardiographic left ventricular ejection fraction determination compared AutoLV (TomTec-Arena 255 patients
et al.15 with reference manual tracking 1.2, TomTec Imaging
ICC 0.83. Mean bias -0.3, 95% CI -1.5–0.9 Systems,
Unterschleissheim,
Germany)
Automated echocardiographic assessment of mitral regurgitation Support vector machine 102 patients
Moghadda- Accuracy of 99.5%, 99.4%, 99.3%, and 99.6% to detect none, mild, moderate,
si et al.16 and severe mitral regurgitation, respectively
Sengupta Differentiation between constrictive pericarditis vs. restrictive cardiomyopathy Associative memory clas- 94 patients
et al.17 AUC of 0.962/accuracy 93.7% using (speckle tracking) sifier-based machine
learning algorithm
Narula Discrimination between hypertrophic cardiomyopathy from physiological Ensemble model building 143 patients
et al.18 hypertrophy seen in athletes (artificial neural net-
AUC 0.795; sensitivity 87% and specificity 82% for optimal cut-off points of work, support vector
the model machines and random
forest)
Computed tomography
Motwani Prediction of 5-year all-cause mortality among patients undergoing CCTA for LogitBoost 10 030 patients
et al.4 suspected CAD
AUC 0.79 using clinical and CCTA variables; AUC 0.64 for segment stenosis
score
Han et al.19 Prediction of abnormal FFR among patients undergoing CCTA (and resting CT Gradient boosting classi- 252 patients
myocardial perfusion analysis derived using ML) fier for CT perfusion
AUC 0.75 for model including ML derived CT perfusion analysis vs. AUC 0.68 analysis
without CT perfusion
Dey et al.20 Prediction of FFR using semi-automated quantitative CCTA to derive plaque Boosted ensemble 254 patients
information algorithm
AUC 0.84 for the integrated ML model, compared to 0.77 for low density
non calcified plaque volume
Rosendael Prediction of major cardiovascular events among patients undergoing CCTA Extreme gradient boost- 8844 patients
van et al.21 for suspected CAD. Only CCTA variables were used by the ML model ing (XGBoost)
AUC 0.771 for ML model; AUC 0.701 for segment stenosis score
Myocardial perfusion imaging
Arsanjani Prediction of obstructive CAD (>_70% stenosis) on ICA from automated single LogitBoost 1181 patients
et al.22 photon MPI analysis
AUC 0.94 for ML model (clinical and quantitative MPI variables); significantly
higher than expert MPI reading
Arsanjani Prediction of early coronary revascularization by quantitative MPI analysis LogitBoost 713 patients
et al.23 AUC 0.81 for ML model including MPI and clinical variables. AUC 0.77 for
standalone perfusion measures
Betancur Prediction of MACE using clinical information combined with MPI data, inte- Boosted ensemble 2619 patients
et al.24 grated by ML algorithm
AUC 0.81 for ML model; significantly higher than a ML model including only
MPI data (AUC 0.78) or five-point scale visual diagnosis by a physician
(AUC 0.65) or standard image quantification (AUC 0.71)
Continued

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 Clinical applications of machine learning in cardiovascular disease 9

Table 2 Continued

Study Objectives and key findings Algorithm/tool Sample size

....................................................................................................................................................................................................................
Dey et al.25 Prediction of impaired myocardial flow reserve on PET using quantitative pla- Boosted ensemble 51 patients
que features from CCTA algorithm
AUC 0.83 for composite score including all quantitative CCTA features; AUC
0.66 for quantitative stenosis severity
Heart failure
Frizzell Prediction of 30-day readmission of patients with heart failure A tree-augmented naive 56 477 patients
et al.26 AUC for 5 ML models using different algorithms ranging from 0.607 to 0.624; Bayesian network, a
AUC 0.589 for prior validated electronic health records model random forest algo-
rithm, and a gradient-
boosted model
Mortazavi Prediction of 30-day hospital readmission rates among patients with heart Random forests, boosting, 977 patients
et al.27 failure random forests com-
AUC 0.628 for ML model to predict all cause readmission and 0.678 for heart bined hierarchically
failure readmission vs. 0.533 and 0.543 for logistic regression, respectively with support vector
machines

AUC, area under the receiver operating curve; CAD, coronary artery disease; CCTA, coronary computed tomography angiography; CI, confidence interval; FFR, fractional flow
reserve; ICA: invasive coronary angiography; ICC, intraclass correlation coefficient; MACE: major adverse cardiovascular events; ML, machine learning; MPI, myocardial perfu-
sion imaging; PET: positron emission tomography; SPECT, single photon emission computed tomography; ML, machine learning.

myocardial features obtained from rest CCTA images, such as nor-

.. fold cross validation with 126 patients.63 Such fully automated algo-
..
malized perfusion intensity, transmural perfusion ratio, and myocar- .. rithms for direct image analysis by ML may facilitate processing of
..
dial wall thickness showed a sensitivity of 0.79 and a specificity of .. very large image datasets. For instance, images from picture archiving
0.64, with an overall accuracy of 0.70, for establishing the presence of .. and communication system can be segmented out and fed into other
..
obstructive CAD.59 Additionally, a supervised approach using a gradi- .. ML layers in order to establish a diagnostic and a prognostic course.
ent boosting classifier to analyse resting CT perfusion images ..
..
improved the ability to detect ischaemia (defined as invasive FFR ..
<0.80) over diameter stenosis (AUC of 0.75 vs. AUC of 0.68, re- ..
spectively).19 Overall, ML has contributed to the ability to further
..
.. Single-photon emission computed
prognosticate cardiovascular outcomes with the incorporation of .. tomography and positron
..
anatomical and functional information from CT-based imaging, such .. emission tomography
as all-cause mortality4 and cardiovascular events,60 in addition to add- ..
..
ing incremental prognostic information from traditional risk stratifica- .. Evaluation of myocardial perfusion, as a direct correlate with the
tion modalities.61 .. presence of obstructive CAD, has been traditionally performed with
..
Recently, fully automated methods for image segmentation in car- .. single-photon emission computed tomography (SPECT) stress test-
diac CT have been proposed using deep learning methods. In con-
.. ing. Machine learning has been employed to improve diagnostic per-
..
trast to conventional ML, which typically requires pre-computed .. formance as well as combine imaging modalities in order to maximize
image features, deep learning allows direct input of image data. A fully
..
.. discriminatory ability. For instance, an SVM approach was used to lo-
automated algorithm for thoracic and epicardial adipose tissue identi- .. calize the mitral valve plane during SPECT acquisition, which is im-
..
fication and quantification from non-contrast calcium scoring CT .. portant for the accurate assessment of myocardial perfusion.64 Three
datasets, based on CNNs, was recently trained and validated with .. hundred and ninety-two SPECT scans were used for training and val-
10-fold cross validation in 250 CT image sets by Commandeur et al.62
..
.. idation, with the ML derived model exhibiting an AUC of 0.82 for de-
The correlation of fully automated results with expert cardiologist .. tection of obstructive CAD, compared to the performance of two
..
manual segmentation of thoracic and epicardial fat volume yielded .. experts (AUC of 0.79 and 0.81) and unadjusted mitral valve plane
correlations of 0.945 and 0.926 respectively and no bias. The vari- .. (AUC 0.63). In further efforts to improve fully automatic image ana-
..
ation of deep learning vs. expert was equivalent to the variation be- .. lysis, deep learning has been applied directly to nuclear cardiology
tween two experienced observers. Fully automated segmentation by .. polar map images in a large multi-centre multi-national study (1638
..
deep learning took as little as 3 s for one patient as compared to 10– .. patients) by Betancur et al.65 They demonstrated that deep learning
11 min by the cardiovascular experts. The use of deep learning in .. could outperform current clinical standard—total perfusion deficit—
..
combination with SVM has been also proposed by Zreik et al.63 for .. for the identification of obstructive CAD, while improving per-
the automated analysis of CCTA images for ischaemic changes within .. patient and per-vessel AUCs. This is notable because in a previous
..
the myocardium. The automated analysis yielded an AUC of 0.74 for .. large study in a different population, total perfusion deficit quantifica-
detection of functionally significant stenosis by FFR in repeated 10- .. tion was equivalent to board certified expert readers even if all

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 10 S.J. Al’Aref et al.

..
available clinical information was used for the prediction of the pres- ..
..
Heart failure
ence of obstructive CAD.66
.. In recent years, ML has been leveraged in an attempt to facilitate heart
Machine learning was further applied to integrate quantitative per- ..
fusion, function and clinical data, to improve the diagnostic and prog- .. failure diagnosis, classification, severity estimation, and prediction of
..
nostic performance of SPECT imaging. Arsanjani et al.22,67 used .. adverse events (with a particular emphasis on 30-day re-hospitaliza-
LogitBoost and SVM for incorporating quantitative perfusion, func- .. tions).75 Of note, a predominance of models reported in the medical
..
tional and clinical variables from myocardial perfusion imaging and .. literature were trained on exceedingly small cohorts (often less than
showed that the diagnostic performance of SPECT was significantly .. one hundred patients), rendering generalization of such results ques-
..
improved compared to expert readers. Furthermore, ML has been .. tionable despite seemingly adequate classification performance.76,77
shown to be superior at predicting early revascularization after .. The aforementioned section will focus on the application of ML
..
SPECT as well as prediction of MACE events23,24 (Table 2). .. for diagnostic situations in heart failure, keeping in mind that signifi-
Machine learning has also been used to harness incremental .. cant strides have been achieved with the application of ML in the
..
information on the presence of coronary artery dysfunction .. realm of prediction and outcomes research.26,27,78–83 For example,
using positron emission tomography (PET) in combination with .. Yang et al. proposed a two-layer binary SVM classification scheme
..
CCTA. Quantitative stenosis, plaque burden, and myocardial mass .. trained on clinical parameters from 289 patients, in which individuals
were combined by a boosted ensemble ML algorithm into a risk
.. were first either diagnosed with heart failure or, if the diagnosis was
..
score to predict impaired myocardial flow reserve as quantified .. uncertain, relegated to a secondary triage. Individuals in the latter
on PET. Discrimination for the occurrence of coronary artery
.. group were then categorized as either heart failure-prone or healthy.
..
dysfunction was superior with the ML-derived risk score, with an .. In this model, the overall classification accuracy was 74.4%, with accu-
AUC of 0.83 compared to an AUC of 0.66 with quantitative
.. racies of 78.79%, 87.5%, and 65.85% for identification of healthy,
..
stenosis.25 .. heart failure-prone and heart failure patients, respectively.84 In a simi-
.. lar scheme, Aljaaf et al. proposed a decision-tree model trained on
..
.. the Cleveland Clinic Heart Disease Data Set, consisting of 297
.. patients each characterized by 13 clinical parameters, which stratified
..
.. individuals into one of five risk categories for the development of
Miscellaneous imaging modalities .. heart failure. Model performance was evaluated using 10-fold cross-
..
There has been limited application, thus far, of ML algorithms on .. validation on the training set, with a mean AUC of 0.91 and classifica-
.. tion accuracy of 86.5%.85 Using an electronic health record-derived
other invasive and non-invasive cardiovascular imaging modalities ..
such as magnetic resonance imaging (MRI), intravascular ultrasound .. registry containing 536 patients, Wu et al.86 demonstrated that logis-
..
(IVUS), and optical coherence tomography despite the wealth of in- .. tic regression and boosting could potentially be used to predict the
formation provided from such acquisitions. For instance, a supervised .. development of heart failure more than 6 months before a formal
..
machine learning approach incorporating three-dimensional right .. clinical diagnosis was made, with a reported AUC of 0.77 on 10-fold
ventricular systolic motion, imaged using cardiac MRI, was shown to
.. cross-validation. In 2013, Austin et al. attempted to construct a binary
..
significantly improve survival prediction in individuals with pulmonary .. tree-based classifier (using random forests, bagged regression trees,
hypertension when added to traditional clinical, conventional imaging,
.. and boosted regression trees) capable of correctly distinguishing be-
..
haemodynamic and functional data (AUC of 0.73 vs. 0.60, respective- .. tween heart failure with preserved ejection fraction and heart failure
ly; P < 0.01).68 Further, recent application of deep learning has been
.. with reduced ejection fraction, trained and validated on 3697 and
..
used for segmentation of anatomic structures and characterization of .. 4515 heart failure patients, respectively. Each subject included in the
ventricular mass and function imaged on cardiac MRI.69–72 In regards
.. study was characterized by demographic and clinical variables, includ-
..
to virtual histology assessment on IVUS, Zhang et al.73 performed .. ing presenting vital signs, physical exam findings; symptoms; labora-
.. tory tests; and prior medical history. Overall, tree-based ensemble
baseline and 1-year follow-up scans on stable angina patients on statin ..
therapy, and showed that a machine learning approach that utilized .. classifiers performed significantly better than conventional classifica-
.. tion and regression trees, but logistic regression was superior to all of
SVM classifiers could predict the occurrence of high-risk coronary ..
plaque features, in a specific location, using focal vascular features and .. the aforementioned classification schemes.87
..
demographic parameters. Optical coherence tomography, on the ..
other hand, was used to image coronary arteries of children with ..
..
Kawasaki disease, and subsequent application of a fully automated tis- .. Lessons learned
sue classification algorithm resulted in a classification rate of up to ..
..
96%, specifically when localizing the medial layer of the coronary .. The current body of research exploring the utility of ML in the clinical
arteries.74 In summary, the abundance of clinical data coupled .. realm reveals several important lessons. First, the availability and free
..
with the rapid expansion of imaging modalities could lead to the .. dissemination of data is a necessary prerequisite for progress in the
creation of a reality wherein ML methodologies offer real-time guid- .. clinical application of ML. Indeed, the continued development and
..
ance to imaging parameters, providing feedback during image acquisi- .. refinement of algorithms for the analysis of ECGs can largely be attrib-
tion, while simultaneously identifying pathology as the test is in .. uted to public ECG databases encouraging continued experimenta-
..
progress. Final correlation between images and baseline clinical .. tion. To the best of our knowledge, there currently exist no such
parameters could further provide information on short and long-
.. publicly available datasets for more advanced cardiac imaging modal-
..
term outcomes. . ities, including echocardiography and CCTA. Therefore, a bridge

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 Clinical applications of machine learning in cardiovascular disease
..
should be created between those with access to or possession of ..
data, and the machine learning community at large. Secondly, ECGs, ..
..
much like the hand-written digits of the MNIST (Modified National ..
Institute of Standards and Technology) dataset, lend themselves par- ..
..
ticularly well to ML because of their inherent simplicity—they are, ..
after all, merely a collage of time series, for which we have a mature ..
..
and expansive toolkit. It is unclear, however, how to best tackle prob- ..
lems which involve more complex data, such as time-resolved or 3D ..
..
images. Third, there is a dearth of potential features with which to rep- ..
resent cardiovascular disease. While the analysis of genomic data has ..
..
become commonplace in oncology, offering new avenues for the ap- ..
plication of ML, the same cannot be said of cardiovascular disease, ..
..
where data is often limited to clinical parameters, advanced imaging ..
modalities and invasive haemodynamic assessments. Nonetheless, the ..
..
UK Biobank initiative (found at http://www.ukbiobank.ac.uk) has been ..
recently established in order to address this gap and provide compre-
..
..
hensive cardiovascular data. Lastly, the lack of standardization across ..
datasets and reported performance metrics makes identification of
..
..
optimal models for clinical integration challenging, if not altogether im- ..
possible. With regards to cardiovascular images, there are unintended
..
..
biases that are introduced due to differences in the acquisition (i.e. ..
..
hardware) and processing (i.e. software) systems. Generative adver- ..
sarial networks are a class of algorithms that can be used to generate ..
..
images that on the surface appear to be identical to real images, and as ..
such has been used to circumvent some of these inherent biases: for ..
..
instance, GANs have been used for noise reduction in low-dose CT,88 ..
as well as image generation across multiple cardiovascular modalities
in order to standardize and expand the amount of data available for a
given task.89
Limitations of machine learning
While modern ML can often yield accurate predictions, the inability
of the querying human being to fully grasp the complexity of these
algorithms’ inner workings—the so-called ‘black box’—can be prob-
lematic when decisions often carry life-changing implications.90 While
a machine may be capable of accurately predicting an outcome of
interest, the absence of a familiar logic underlying its output may give
pause to the clinician charged with interpreting it. Consider this ex-
ample: an automated cancer diagnosis tool is deployed in a hospital
seeking to curtail costs. This tool, developed using an ML model
trained on many tens of thousands of immaculately curated path-
ology specimens, is found on average to be at least as accurate as a
physician in detecting the presence of malignancy. However, in some
situations for certain deep learning algorithms, it is not yet possible to
directly translate the abstraction process leading to a particular deci-
sion to its users. It cannot do so, of course, because its conclusions
are based on calculations made through various levels of abstraction
that is intractable manually. Practically, the question then becomes
whether such a system can be trusted at all? Precedent exists in medi-
cine, where we do not understand Lithium’s mechanism of action,
but use it freely to treat psychiatric illness. Moreover, can such a sys-
tem in any way supersede a physician’s judgement if their respective
recommendations conflict? It has recently been demonstrated that
deep neural nets can be coerced into making incorrect decisions by
using carefully engineered inputs, raising the concern that such
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11
systems are perhaps not yet ready for mainstream integration.11 As
such, there is a need for systematic (at time intervals) checking by
humans if the algorithms are performing well.
Machine learning, despite being data-driven, can often be riddled
with traditional biases. While harmless in most commercial settings,
these can become problematic in the high-stakes healthcare space,
where precision is of the utmost importance. One such pitfall is selec-
tion bias, which includes sampling and observer selection bias. While
selection bias is often mitigated in well-structured clinical trials, it is
difficult to identify and remedy in the datasets used in ML. In a some-
what overstated example, consider a machine learning model built
using a hospital’s electronic health record; such a model might very
well under-predict the occurrence of some disease, but only because
the patients from whom it learned generally receive adequate routine
screening. In a less benign expression of selection bias, there have
been numerous reported cases of ML going awry, not because the
base algorithm was itself flawed, but rather because it drew conclu-
sions from deeply flawed data. In rare moments of transparency, a
number of online applications were met by public outcry when users
became aware of overt racial and socioeconomic discrimination. As it
happens, these automated behaviours had been unknowingly intro-
duced into the platforms through the use of unfiltered data streaming
from the Internet, where such views are commonly broadcasted
under the veil of anonymity.91–93 While there have been no such
reported incidents in the healthcare setting, further work is necessary
for developing methodologies to rule out clinically non-relevant
.. biases before a machine’s clinical decision-making can be trusted.
..
.. There are many other hurdles, which will have to be addressed
.. and overcome by the medical community before ML can find mean-
..
.. ingful integration in clinical workflows. Many of the contemporary
.. debates regarding ML applications in other industries, such as autono-
..
.. mous driving, find parallels in our discussion. Who, for example, will
.. regulate this industry—will it be the Food and Drug Administration
..
.. and equivalent government agencies, and if so, is it adequately
.. equipped to objectively assess the effectiveness of this new method-
..
.. ology? When mistakes occur in the delivery of care due to digital
.. error, as they inevitably will, who will be held responsible—will it be
..
.. the doctor who queried the machine or the individuals who engi-
.. neered the platform? Lastly, how will machine-assisted work be
..
.. remunerated: will it de-value the labour of the physician workforce,
.. enhance its effectiveness, or both? Our collective answers to these
..
.. fundamental questions will shape the course and history of this
.. expanding technology.
..
..
..
..
..
.. Conclusion
..
.. The rapid digitalization of healthcare presents itself with the oppor-
..
.. tunity to tackle important medical questions using ML. While trad-
.. itional statistical methods remain the lingua franca of medical
..
.. research, ML proposes a novel toolset for navigating a rapidly shifting
.. landscape. Additionally, ML could provide a powerful platform for in-
..
.. tegration of clinical and imaging data, which would be useful for multi-
.. factorial and complex cardiovascular diseases such as heart failure. In
..
.. this review, we highlight the recent applications of ML within cardio-
.. vascular medicine, with emphasis on cardiac imaging. ML promises to
..
. transform medical research which could lead to optimization of day-
 12 S.J. Al’Aref et al.

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