Journal Pre-proofs

Towards explainability in artificial intelligence frameworks for heartcare: A

comprehensive survey

M.U. Sreeja, Abin Oommen Philip, M.H. Supriya

PII: S1319-1578(24)00185-X
DOI: https://doi.org/10.1016/j.jksuci.2024.102096
Reference: JKSUCI 102096

To appear in: Journal of King Saud University - Computer and

Information Sciences

Received Date: 7 February 2024

Revised Date: 10 June 2024
Accepted Date: 12 June 2024

Please cite this article as: Sreeja, M.U., Oommen Philip, A., Supriya, M.H., Towards explainability in artificial
intelligence frameworks for heartcare: A comprehensive survey, Journal of King Saud University - Computer and
Information Sciences (2024), doi: https://doi.org/10.1016/j.jksuci.2024.102096

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Towards explainability in Artificial Intelligence frameworks for heartcare:
a comprehensive survey
Sreeja M Ua Abin Oommen Philipb

Assistant Professor Assistant Professor

Department of Computer Science and Engineering Department of CSE - Cyber Security

Indian Institute of Information Technology, Indian Institute of Information Technology,

Kottayam Kottayam

E-mail: kishan.sreeja@gmail.com E-mail: abinphilip@iiitkottayam.ac.in

Supriya M Hc

Professor

Department of Electronics

Cochin University of Science and Technology

Kochi

E-mail: supriya.doe@gmail.com

Abstract

Artificial Intelligence is extensively applied in heartcare to analyze patient data, detect anomalies, and provide
personalized treatment recommendations, ultimately improving diagnosis and patient outcomes. In a field where
accountability is indispensable, the prime reason why medical practitioners are still reluctant to utilize AI models,
is the reliability of these models. However, explainable AI (XAI) was a game changing discovery where the so-
called back boxes can be interpreted using Explainability algorithms. The proposed conceptual model reviews the
existing recent researches for AI in heartcare that have found success in the past few years. The various techniques
explored range from clinical history analysis, medical imaging to the nonlinear dynamic theory of chaos to
metabolomics with specific focus on machine learning, deep learning and Explainability. The model also
comprehensively surveys the different modalities of datasets used in heart disease prediction focusing on how
results differ based on the different datasets along with the publicly available datasets for experimentation. The
review will be an eye opener for medical researchers to quickly identify the current progress and to identify the
most reliable data and AI algorithm that is appropriate for a particular technology for heartcare along with the
Explainability algorithm suitable for the specific task.

Keywords: Explainability, Electrocardiogram, Metabolomics, Electronic health record, data analytics, non-
linear dynamics

Acknowledgement: The research is funded under the Chief Ministers NavaKerala post-doctoral fellowship for
the project titled “A smart system for Ischemic heart disease prediction through Explainable AI”.No. KSHEC-
A3/344/ Govt. Kerala-NKPDF/2022 dated 16.05.2022 and File no. CUSAT/AC(C) C2/3871/2022

AUTHOR CONTRIBUTIONS
Sreeja M U: Conceptualization, Methodology, Validation, Investigation, Writing - Original Draft,
Editing

Abin Oommen Philip: Writing - Review & Editing, Visualization, Resources

Supriya M H: Writing - Review & Editing, Supervision, Project administration

Towards explainability in Artificial Intelligence frameworks for heartcare:

a comprehensive survey
Abstract

Artificial Intelligence is extensively applied in heartcare to analyze patient data, detect anomalies, and provide
personalized treatment recommendations, ultimately improving diagnosis and patient outcomes. In a field where
accountability is indispensable, the prime reason why medical practitioners are still reluctant to utilize AI models,
is the reliability of these models. However, explainable AI (XAI) was a game changing discovery where the so-
called back boxes can be interpreted using Explainability algorithms. The proposed conceptual model reviews the
existing recent researches for AI in heartcare that have found success in the past few years. The various techniques
explored range from clinical history analysis, medical imaging to the nonlinear dynamic theory of chaos to
metabolomics with specific focus on machine learning, deep learning and Explainability. The model also
comprehensively surveys the different modalities of datasets used in heart disease prediction focusing on how
results differ based on the different datasets along with the publicly available datasets for experimentation. The
review will be an eye opener for medical researchers to quickly identify the current progress and to identify the
most reliable data and AI algorithm that is appropriate for a particular technology for heartcare along with the
Explainability algorithm suitable for the specific task.

Keywords: Explainability, Electrocardiogram, Metabolomics, Electronic health record, data analytics, non-
linear dynamics

1. INTRODUCTION

Cardiovascular diseases are characterized by an inadequate supply of oxygen to the myocardial cells due to
various underlying reasons, leading to different types of heart diseases. Besides being the significant contributor
to mortality rate, heart disease is becoming highly prevalent resulting in a drastic growth in the number of people
affected year by year. The integration of AI in heart care is a revolutionary step in healthcare, AI technologies
being increasingly used to aid in early diagnosis, and treatment of heart-related conditions (Moghadas et al., 2020;
Liu et al., 2021; Amrani et al., 2021). AI algorithms are now used to analyze large collection of medical images
or health records with high accuracy to detect early signs of heart disease, including abnormalities, blockages, and
functional irregularities. AI trained models are used to analyze historical patient data to predict future events, such
as cardiac arrests or myocardial infarction leading to early intervention leading to reduction in mortality rate to a
great extent. Furthermore, AI is now serving as an invaluable decision support system for healthcare providers,
providing useful insights based on a vast amount of patient data.

While the boom of AI in heart care holds great promise, it also comes with challenges such as ensuring data
privacy, and identifying biases in AI models. Even though, the applications of artificial intelligence in heartcare
are rapidly growing, the involvement of deep learning models or the so-called black boxes, poses concerns over
the reliability or interpretability of the results especially in healthcare. There are several potential concerns owing
to which the conventional black box AI method still can’t completely be adapted to a critical domain like health.
One major concern is that the actual features that contribute to the disease are still uncertain. Especially in the
healthcare domain the accountability of the professional is a key factor: every decision has to be interpreted or
reasoned through objective proof. The same is true when the decision in healthcare has to rely on the outcome of
an AI model. The importance of fairness and mitigating biases in healthcare AI models cannot be emphasized
enough, as these models directly affect the integrity of the healthcare system (Dave et al., 2020; Siddiqui, 2022).
Biased AI models can lead to incorrect diagnoses, treatment recommendations, or patient management decisions.
Biases in healthcare AI can reinforce and exacerbate existing healthcare disparities. Certain demographic groups
may receive suboptimal care or face greater health risks if AI systems are not designed to be fair and equitable.

The proposed conceptual framework is a comprehensive survey in this direction to identify the most reliable
dataset or technique that spans the various technologies and result in intelligent and trustworthy decision making
in heartcare. The survey is a methodological review which extensively covers all the major researches used in
recent studies in this field, shedding light on the approaches employed, and datasets used with regard to technology
to assess and improve outcomes. A systematic search was conducted in major academic databases (e.g., Nature
medicine, Elsevier, Springer and equals) to identify relevant studies published between 2018 and 2023. The
keywords used span various terminologies related to intelligent heartcare, deep learning algorithms, data-driven
names, Explainability approaches in cardiovascular disease, etc. Out of above 250 results retrieved, nearly 120
papers were scrutinized for the survey. Studies were included if they focused on the advantages of AI in heartcare
as well as the limitation due to data biases further highlighting the need for incorporating Explainability in
intelligent heartcare models. Information was extracted from each selected study, including the algorithm used,
dataset incorporated, analysis techniques, and any reported limitations. The identified studies were categorized
into AI research method types based on different technologies in heartcare (such as ECG, chaos theory,
metabolomics, etc.), including and excluding Explainability approaches (Combi et al., 2022; Loh et al. 2022) .
The survey assessed the prevalence of each method, examined trends in their use over time, and identified
strengths and limitations associated with each approach. The conceptual framework of the proposed model is
shown in Figure 1. Figure begins with the different datasets or combination of data on which the various AI driven
technologies are applied which has been described in section 3. These technologies can further be categorized
based on the AI algorithms used beginning from basic ML algorithms to complex transformers, or extreme
learning machine models which is described in each subsection followed by review of state-of-the-art explainable
models wherever available. The main highlights of the survey framework are:

• A novel conceptual framework that identifies the importance of technology-specific models for heart
disease prediction and aids in determining the appropriate model for a particular use case.
• A unique review that encompasses all the available techniques for heart disease prediction with
emphasis on AI and XAI models applied on discrete technologies.
• An exhaustive survey that analyses the relevance of the several underlying techniques used in
intelligent heart disease prediction along with the significance of interpretability and Explainability
to achieve reliability in black box AI.
• A compact detailing of the available datasets used in the literature for experimentation.

The rest of the paper is organized as follows. Section 2 details the motivation behind the proposed framework.
Section 3 describes the type of data used by the different technologies followed by the various studies and the
technology driven exhaustive survey in section 4. The publicly available datasets in various categories for
experimentation are outlined in section 5. Section 6 consolidates the challenges identified and recommendations
followed by the concluding remarks in section 7.

2. MOTIVATION

Technology-driven intelligent heartcare has become highly sought after for advancement in healthcare. The
different technologies identified for review in the proposed framework where AI has been potentially applied
begins with medical imaging for processing ECGs, EEGs, MRIs and BCGs, data analytics for processing
Electronics health records (EHR) or Electronic medical records (EMRs), chaos theory involving non-linear
dynamics towards the most emerging domain in healthcare involving multi omics data specifically metabolomics.
The need for surveying technology-driven Artificial intelligence models in all domains stems from the fact that
the most important factors in a particular technology differs and consequently the approach to identify the features
also differ. Below are a few facts that demonstrate the significance of reviewing the existing technology-specific
AI models for intelligent heartcare with emphasis on Explainability.

• High-end diagnostic tests are not always affordable and accessible. And quite often the results are
delayed due to the complex lab-centric procedure. The deployment of Artificial intelligence in the
different domains of heartcare will reduce the need to depend on complex lab procedures are
thereby saving time leading to saving lives.
• AI algorithms used in heart care are mostly complex and challenging to interpret or explain, which
raises concerns about trust, acceptance, and understanding, especially in a critical domain like
healthcare. Identification of the significant features that contributed to the disease by the use of
explainable AI paradigm is a very powerful procedure in healthcare for identification of heart disease
 and for enhanced treatment options. Although, Explainable AI has been researched upon for medical
historical data and imaging techniques, it is rarely explored in other technologies like metabolomics
and non-linear dynamics which is worth studying.
• Existing surveys encounter challenges due to the diverse sources of data (e.g., different heart
conditions, demographics, data formats) and various AI techniques used (e.g., machine learning,
deep learning) making direct comparisons difficult. Many studies might have limited access to
comprehensive and large-scale datasets, potentially leading to limited generalizability and statistical
power in the findings. A major observation from the existing surveys is that a comprehensive
coverage of all types of intelligent heart care models in a technology driven manner was not found.
Due to the fast-paced advancements in technology, the information rendered by the existing surveys
become less relevant or accurate over time.
• Furthermore, there's often a lack of standardized evaluation criteria, metrics, and benchmarks for
assessing the performance of AI algorithms in heart care, making it challenging to compare different
AI models effectively.
• Effective integration of expertise from both the AI and healthcare domains is crucial. The lack of
interdisciplinary collaboration can result in knowledge gaps and insufficient understanding of both
technical and clinical aspects. The proposed survey has taken the expertise from expert in the field
leading to the proposed conceptual framework.

From the above factors, the importance of studying the existing recent literature in order to improve the
trustworthiness of intelligent models’ is certainly obvious. The recent works in the various technology specific
frameworks with emphasis on Explainability are surveyed in the following sections preceded by an overview of
the various types of input data used by the various technologies.

Medical Imaging
Patient Medical History Metabolomics
Electrocardiogram Nonlinear dynamics
Omics data Image Analytics
Echocardiography Chaos theory
Stress test Data analytics
Angiogram Cardio scan

Diagnostic
Transparent

Model specific
Explainable by design Decision tree KNN Bayesian

Local Global
Model specific Model specific
Integrated gradients Tree gain-based
Tree feature contribution Aggregate local
Feature Relevance
Simplification
Prognostic

Model agnostic
Model agnostic Partial dependence
Feature Relevance-SHAPley Permutation importance
Local explanation LIME

Figure 1 . Proposed Conceptual Framework

3. NATURE OF INPUT DATA

As the technology for diagnosing heart disease varies, so is the input data. The different modalities of data can be
categorized as structured data, signal data, images, times series and omics data.
3.1 Structured data

Structured data are those that have a standardized format which can easily be stored, accessed and manipulated.
This peculiarity ensures that structured data is the easiest form of data to process and identify patterns. However,
it is difficult to represent the all crucial forms of information related to heart data in a structured format. Structured
data in heartcare typically spans Electronic medical records (EMR) and electronic health records (EHR). EMRs
are essentially digital versions of the paper medical charts used by clinicians. They contain comprehensive medical
and treatment history of patients within a specific practice (Habib,2010; Kierkegaard, 2011)

• Compared to paper records, EMRs offer several advantages (LaTour and Eichenwald Maki, 2016;
HealthIT.gov, n.d.). Clinicians can use them to keep track of patient data over time, easily identify which
patients need preventive screenings or check-ups, check how patients are progressing on various health
parameters (like blood pressure or vaccinations), and monitor and enhance overall quality of care within
the practice. However, one limitation of EMRs is that it can be difficult to share the information with
specialists and other members of the care team. Sometimes, patient records may even have to be printed
and mailed, making EMRs not much more efficient than paper records in this regard.

• EHRs do all of these functions and many more. EHRs (Habib,2010; Kierkegaard, 2011) place a strong
emphasis on the patient's overall health, going beyond the usual clinical data gathered at the doctor's
office and taking a more comprehensive approach to a patient's care. The health organisation that initially
gathers and combines the information cannot be the exclusive audience for EHRs. They contain data
from every physician participating in the patient's care since they are designed to exchange information
with other health care providers, such as laboratories and specialists (Amatayakul, 2016; PubMed., n.d.;
Office of the National Coordinator for Health Information Technology., n.d.). EHR data may be
developed, maintained, and viewed by authorised doctors and employees across more than one healthcare
institution according to the National Association for Health Information Technology. EHRs are patient-
centred, real-time records that make information instantaneously and securely accessible to authorised
users. An EHR system is designed to go beyond the typical clinical data collected in a provider's office
and can be inclusive of a broader picture of a patient's care, even if it does contain the medical and
treatment histories of patients. One of the fundamental characteristics of an EHR is the ability of
authorised clinicians to produce and manage health information in a digital format that can be shared
with other physicians across multiple health care organisations. EHRs collect data from all doctors
involved in a patient's treatment and are designed to share information with other healthcare organisations
and providers.

Figure 2(a) shows the comparison of EHR and EMR structured data and Figure 2(b) shows an example data which
EMR as well as EHR.

3.2 Signals

Various technologies and their corresponding outputs that generate signal data are outlined below:

• Electrocardiogram (ECG): A straightforward test electrocardiogram is available to assess your heart's

electrical activity and rhythm (Krikler, 1987). During the test, electrodes placed on your skin detect the
electrical signals generated by your heart with each beat. These signals are captured by a machine and
evaluated by a doctor to detect any anomalies. A qualified healthcare professional, trained to conduct the
test, can administer it at a hospital, clinic or your GP surgery.
• BallistoCardioGraphy (BCG): The ballistocardiograph is a technique used to detect the forces generated
by the heart's contractions (Scarborough, 1956). It measures the upward recoil of the body caused by the
downward movement of blood through the descending aorta during each heartbeat. This creates a
recurring pattern of upward and downward movements as different segments of the aorta expand and
contract.
• MagnetoCardioGraphy (MCG): Magnetocardiography is a non-invasive technique used to measure the
magnetic fields produced by electrical currents in the heart (Baule and McFee, 1963). The method
involves highly sensitive equipment such as the superconducting quantum interference device (SQUID).
 By using a multichannel device to measure the magnetic field over the chest, it's possible to generate a
map of the magnetic field. Mathematical algorithms, taking into account the conductivity structure of the
torso, can be applied to locate the source of the activity. MCG is useful for locating sources of abnormal
rhythms or arrhythmia in the heart. Figure 3 shows the comparison of these three signals.

EMR EHR
Personal record Personal record with
with basic health extensive health
information for information that can
one practice be shared

(a)

(b)

Figure 2. (a). EMR vs EHR (b) Structured data EMR sample (EHR)

QRS Complex

R
40
Averaged MCG signal (pT)

20

T
P PR ST wave
Segment Segment
wave
0

PR Interval

Q -20
S QT Interval

0.0 0.2 0.4 0.6

Time (s)

Figure 3. Various heart signals (a) ECG (b) BCG (Kim et al., 2016) (c) MCG

3.3 Images

Different technologies and their corresponding output data resulting in images are outlined below:
 • Cardiac MRI: Cardiac MRI (Lee et al., 2018) is a tool used by doctors to identify or track heart illness.
Moreover, it is used to assess the structure and functionality of the heart in patients with both congenital
and acquired cardiac disorders. A strong magnetic field, radio waves, and a computer are all used in
cardiac magnetic resonance imaging (MRI) to provide precise images of the heart's internal and external
components. As there is no radiation involved, cardiac MRI may deliver the clearest pictures of the heart
in some circumstances. Heart MRIs use radio waves and magnets to make pictures of your heart, with
nothing you can see or feel entering your body.

Figure 4. Various heart images (a) MRI (UT Southwestern, January 2022) (b) SPECT MPI (Emory
University, 2013) (c) Cardiac CT (Two Views, January 2022)

• SPECT MPI Myocardial Perfusion: The heart's blood supply is assessed using a myocardial perfusion
SPECT (Single Photon Emission Computed Tomography) (Georgoulias et al., 2010) examination, often
known as a cardiac stress-rest test. Two sets of blood flow pictures are obtained: the first after a time of
rest, and the second after a stressful period that includes treadmill activity.
• Cardiac CT scan: A cardiac computed tomography (CT) (Bonow et al., 2011) scan creates pictures of
heart using a scanner and computer by combining multiple X-rays taken at various angles. This brief yet
thorough and high-resolution scan reveals to doctor any issues with heart's valves, arteries, aorta, and
other structures. The comparison of the various images is depicted in Figure 4.

3.4 Omics data

Technological advancements have made it possible to measure the molecules inside a tissue or cell. It is possible
to take a picture of the underlying biology of a system of interest at a resolution that has never been practical
before. Typically, omics refers to the science involved in measurements of these biological molecules. The whole
collection of small molecule metabolites present in a biological sample is known as the metabolome including
metabolic intermediates in carbohydrate, biochemical pathways, along with hormones and other signalling
molecules, as well as exogenous substances such as drugs and their metabolites (Zhang et al., 2011). The
metabolome is dynamic and can alter within a single organism as well as across animals of the same species for
a variety of reasons, mainly due to underlying illness. Recently, studies have shown the potential of using
metabolomics in the study of heart diseases. Nuclear magnetic resonance spectroscopy and mass spectrometry
may both be used to analyse the components of the metabolome (Weckwerth, 2003). Figure 5 shows a sample
metabolite spectrum for a data obtained from mass spectrometry.

Figure 5. Metabolite spectra of positive spectra from ms2 data

3.5 Time series data

Time series data exploit the notion of temporal order present in any data for arriving at a decision. For predicting
the presence of heart disease, time series data play an important role. ECG data, EHR data, as well chaos theory
indicates that the properties in these data evolve over a period of time giving a significant insight into the presence
of heart disease compared to their stationary counterparts (Parati et al., 1995; Lombardi et al., 1996). The chaotic
properties of data, including measurement choices and the visualisation of time domain attractors in the data, are
explored using chaos analysis. The source data is mean-adjusted and then integrated to aid in evaluating self-
similarity in long-term, non-stationary data. Heart rate is plotted against itself with a time delay in chaos plots
made from a standard ECG recording to better understand cardiac illness. Moreover, actual ECG readings are also
analysed in a time series perspective. Certain precious works have also emphasized that better insights can be
drawn out of EHRs by visualizing them as time series data, meaning that changes in certain features over time
contribute to the presence of heart disease. Figure 6 depicts the time series counterparts of the earlier mentioned
EHRs in Figure 6 (a) as well as ECGs in Figure 6 (b). Figure 6 (c) shows a chaos plot plotted on ECG against
ECG followed by Lorenz attractor plot along with the peculiarities in cardiac state at the onset of atrial fibrillation
depicting the importance of time series data.
heart rate achieved

of the peak exercise

of major vessels (0-3)

electrocardiographic

induced by exercise relative

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colored by flourosopy
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52 1 0 125 212 0 1 168 0 1 2 2 3 C1

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oldpeak

70 1 0 14558174
0 0
0 100
1 248
125 01 2.6
0 1220 00 13 1C2 0 2 C4
62 0 0 138 294 1 152106 1 00 125
1.9212
1 0 3 1 2 168C30 1 2 2 3 C1
70 1 0 145 174 0 1 125 1 2.6 0 0 3 C2
61 1 0 14852203
1 0
0 125
1 212
161 00 10 1682 01 13 2C2 2 3 C1
58 0 0 100 248 0 053122 0 1
1 0 140 2031 1 0 0 2 155C41 3.1 0 0 3 C2
61 1 0 148 203 0 1 161 0 0 2 1 3 C2
62 0 0 13853294
1 1
0 140
1 203
106 10 1.9
0 1551 13 3.12 0C3 0 3 C2
52 1 0 125 212 0 170168 1 00 145 2 0 2 1 3 125C11 2.6
1 174 0 0 3 C2
62 0 0 138 294 1 1 106 0 1.9 1 3 2 C3
58 0 0 10070248
1 0
0 145
0 174
122 00 11 1251 10 2.62 0C4 0 3 C2
53 1 0 140 203 1 061155 1 3.1
1 0 148 2030 0 0 1 3 161C20 0 2 1 3 C2
58 0 0 100 248 0 0 122 0 1 1 0 2 C4
61 1 0 148 203 0 1 161 0 0 2 1 3 C2
62 0 0 138 294 1 1 106 0 1.9 1 3 2 C3
Time
52 1 0 125 212 0 1 168 0 1 2 2 3 C1
series
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58 0 0 100 248 0 0 122 0 1 1 0 2 C4
53 1 0 140 203 1 0 155 1 3.1 0 0 3 C2

(a) (b)

(c)
 Figure 6. Time series data (a) EHRs as time series data (b) ECG as time series for two cycles (Fan et al., 2018) (c)
Chaos plots (left) ECG vs ECG plot (right) Bimodal distribution of cardiac states and cardiac state flickering before
the onset of atrial fibrillation (Lan et al., 2020)

4. PROPOSED AI-DRIVEN TECHNOLOGIES IN HEARTCARE: TOWARDS

EXPLAINABILITY

Several AI algorithms have shown amazing results in the past years. This success of AI largely depends on the
specific algorithm used as well as the underlying datasets experimented. AI driven technologies for heartcare
come in plenty although its complete use has not been realized in its entirety owing to the limitations in
accountability in a domain like healthcare. This section begins with an overview of explainability in heartcare
followed by the existing technologies from the literature that have shown amazing results in heartcare beginning
with machine learning, deep learning, ontologies, metabolomics and chaos theory. Each section covers the current
status and relevance of adopting explainability in heartcare in the respective technologies.

4.1 XAI in heartcare: an overview

AI has revolutionized health sector not to mention heart care. Precision medicine has become a boon to the
healthcare industry with the accurate and customised diagnosis leading to personalized medicine. Ever since AI
has been applied to medical domain, more insights have been mined from the historical data that we have in hand.
Even though, the different techniques that has been applied seem to vary based on the level at which the diagnosis
is introduced, AI algorithms has been acting as a key to all techniques. Lot of studies have emphasized the need
for artificial intelligence in heart disease (Jone et al., 2022; Koulaouzidis et al., 2022). Artificial intelligence in
imaging techniques is an indispensable part of cardiology recently (Sermesant et al., 2021). Another important
data based on which heart disease is being diagnosed is cardiac MRI, where artificial intelligence has been greatly
studied upon (Fotaki et al., 2022). Most expert models currently prevailing in heart care either make use of
machine learning algorithms or deep neural networks. Advanced models based on reservoir computing and
extreme learning machines have also been applied in intelligent cardio care and has recently shown astounding
results. AI models used in heart disease prediction have shown great promise, but they also have several
limitations, which have led to the development of explainable AI techniques to address these issues. A few
limitations are outlined below:

1. Black Box Nature: Most AI models are often considered "black boxes" because they make predictions
based on complex mathematical transformations of input data that are difficult to interpret (Rasheed et
al., 2022). This lack of transparency can make it challenging to understand why a model made a
particular prediction.

2. Limited Data: AI models require large and diverse datasets for training. In some cases, datasets for
specific heart diseases or subpopulations may be limited, leading to potential biases and reduced model
performance, especially for underrepresented groups.

3. Explanatory Gap: Many AI models can provide predictions, but they may not offer meaningful
explanations for their predictions (Loh et al., 2022). This makes it difficult for healthcare professionals
to trust and act upon the model's recommendations.

4. Continuous Learning: Healthcare data is dynamic, and diseases evolve over time. AI models need to
adapt to changing conditions and new medical knowledge, which can be challenging to implement
effectively.

5. Interpreting Complex Data: Cardiovascular health is influenced by a wide range of factors, including
genetics, lifestyle, and environmental variables. AI models may struggle to interpret and incorporate all
these factors effectively. (Oberste and Heinzl, 2022)

6. Data Quality: The accuracy of AI predictions heavily depends on the quality of the input data. If the
data contains errors, inaccuracies, or missing values, it can lead to erroneous predictions and
misdiagnoses (Rasheed et al., 2022).

7. Generalization Issues: AI models trained on a specific dataset tend to not generalize well on new or
unseen data or patient records (Petch et al., 2022). This can limit their applicability in real clinical
environments.
To address these limitations and enhance the trustworthiness of AI models in heart disease prediction, Explainable
AI (XAI) plays a crucial role. Explainable AI is a much-hypothesized paradigm recently that aids in how an AI
model, especially deep learning-based models can explain its decision-making process. The explanation for a
prediction, the input variables that were taken into account, and the weights or importance given to each variable
can be analysed with XAI algorithms. On the contrary, interpretable AI relates understanding the connections
between the input variables and the predictions as well as the reasoning behind the model's conclusions.
Explainability is required in deep learning models whereas interpretability is intrinsic in most machine learning
models like decision tree, regression, etc. A few approaches include Feature Importance Analysis by identifying
which input features are considered as most important by the model for making predictions, Local Explanations
which provide explanations for specific predictions, highlighting the factors that contributed to that prediction,
Saliency Maps which helps to visualize which parts of medical images (e.g., CT scans or MRI images) the model
focuses on when making a prediction and Rule-Based Models which creates rule-based models that mimic the
decision-making process of AI models in a more interpretable way. When applying explainable artificial
intelligence techniques to predict heart disease, a combination of model-agnostic and model-specific methods can
be used at both global and local levels.

1. Model-Agnostic Global Explainability:

• Feature Importance: Calculate and visualize feature importance scores to understand which
features (e.g., age, cholesterol levels, blood pressure) have the most significant impact on the
model's predictions for heart disease. Techniques like permutation feature importance and SHAP
(Lundberg and Lee, 2017) values can be used.

2. Model-Agnostic Local Explainability:

• LIME (Local Interpretable Model-agnostic Explanations): LIME introduced by Ribeiro et

al., (2016) is applied to explain why a specific patient received a particular prediction. LIME
generates a locally faithful, interpretable model that approximates the behaviour of the complex
model for that specific instance. This helps understand which features influenced the prediction
for an individual patient.
• SHAP Values (Local): SHAP was introduced by Lundberg and Lee (2017) whose values are
used at the local level to explain individual predictions for classification applications like heart
disease. SHAP values provide a more nuanced understanding of how each feature contributed to
a specific prediction.

3. Model-Specific Global Explainability:

• Decision Trees or Rule-Based Models: If decision tree-based models like Random Forest or
Gradient Boosting (Delgado-Panadero et al., 2022) are used, one can directly examine the tree
structures to understand the rules and pathways through which the model makes predictions
globally.

4. Model-Specific Local Explainability:

• Saliency Maps (for Neural Networks): If deep learning models like neural networks are used
for heart disease prediction, saliency maps (Selvaraju et al., 2017) can be computed to visualize
which parts of the input (e.g., ECG signals or medical images) were most influential in making
a particular prediction. This provides local insight into the model's decision process for specific
patients.

• Attention Mechanisms (for Sequence Data): If the heart disease prediction model relies on
sequential data (e.g., time-series data from ECGs), attention mechanisms within recurrent neural
networks (RNNs) (Elman, 1990) or transformers (Vaswani et al., 2017) can be used for analysis.
These mechanisms reveal which time steps or features the model attended to when making a
prediction for a specific patient.

The choice of XAI techniques depends on the type of model used and the nature of data. For heart disease prediction,
it's crucial to ensure that the explanations are medically interpretable and align with domain knowledge.
Additionally, providing both global and local explanations can offer a comprehensive understanding of model's
behaviour, aiding in trust and transparency in healthcare applications. A taxonomy of the explainability in ML
models is depicted in Figure 7.

Taxonomy of ML model explainability (Posthoc)

Local
Global (Entire
(Individual
model)
prediction)

Model specific Model agnostic Model specific Model agnostic

Saliency
Tree or rule Feature
maps, LIME
based importance
GradCAM

Partial
Shapely Value
Attention Tree SHAP Dependence
(SHAP)
plots

Figure 7. Taxonomy of ML model explainability

4.2 Machine Learning in heartcare

Machine learning models most frequently researched upon for heart disease prediction are based on support vector
machine, decision trees or ensemble learning (Stewart et al., 2021; Ahsan and Siddique, 2022). The focus is to
classify the different types of chest pains in cardio care. Particular interest over supervised learning for heart
disease classification has resulted from the astounding results produced by the same (Hagan et al., 2021).

Majority of the machine learning models utilise simple artificial neural network or K nearest neighbour for heart
disease prediction (Moghadas et al., 2020; Shafi et al., 2022; Sarrah et al., 2022). Other algorithms that are
popularly being used are support vector machine, naïve Bayes, random forest, logistic regression and decision
trees (Chae et al., 2022; Javan et al. 2021; Heilbroner et al., 2021; Karadeniz et al., 2021). R peak detection has
proven to be an indicator of heart disease which can be detected using principal component analysis (PCA) (Gupta
et al., 2020). Unsupervised methods also have recently proven to be effective for anomaly detection in heart
patients. DBSCAN (Nanehkaran et al., 2022; Silva-Aravena et al., 2022; Ramirez-Asis et al., 2022) is the most
common unsupervised ML clustering algorithm that has been popularly applied in clinical history of patients to
identify healthy instances and to categorise abnormal instances in cardiac patients. Machine learning algorithms
like gradient boost, decision tree etc can also be applied on datasets with computed tomography ECG images
(Shimizu et al., 2022). Coronary care unit stay being an expensive one, predicting the length of stay is crucial
(Rezaianzadeh et al., 2020). Similarly, classifying an incident based on the metadata of a patient into heart failure,
stroke, diabetes or hypertension is of great significance as a first step towards diagnosis. Simple artificial network,
Support vector machines have been proven to be successful based on patient meta data (Baashar et al., 2022).

4.2.1 Explainable ML in heartcare

Clinical validation and explainability are two essential components of integrating artificial intelligence (AI) into
the field of heartcare. Both are necessary for the effective acceptance and application of AI in clinical practice, but
explainability offers additional advantages that are above clinical validation strategies.

Clinical validation is the process of thoroughly testing AI models to make sure they function correctly and
consistently in actual clinical contexts. The legitimacy of AI technologies must be established through this
approach. Even in cases when the model has received clinical validation, doctors could be reluctant to trust AI
suggestions in the absence of explainability since they are unable to observe the decision-making process.
Physicians might be less confident to use AI tools if they don't provide comprehensible justifications for their
predictions. Continuous improvement based on user feedback is not facilitated by clinical validation alone. On the
other hand, explainable models enable continuous improvement and help identify underlying patterns and aspects
that clinical validation alone is unable to show, which can lead to new clinical discoveries and advances.

Explainable AI models promote ethical and legal compliance, enhance communication, builds trust, and enable
continuous learning. Explainability can therefore be incorporated into the creation and application of AI in heartcare
to provide more widely used and efficient AI solutions, which will eventually improve patient care and outcomes.
Experts and practitioners in healthcare stress that AI models' interpretability greatly improves their practical
applicability in cardiac care. Interpretable AI models have the potential to improve clinical outcomes and facilitate
more seamless integration of AI into heartcare practices through a variety of means, including fostering trust,
strengthening decision-making, increasing patient engagement, enabling continuous improvement, guaranteeing
regulatory compliance, and promoting equity. The clinical relevance of interpretable AI models and their impact
on heartcare along with expert views are outlined:

• Enhanced Diagnostic Accuracy and Precision: Clinicians can identify the factors that have the most
influence on a diagnosis by using interpretable AI models. For instance, knowing the significance of
particular biomarkers such as high troponin or BNP levels might aid clinicians in more precisely validating
diagnoses of myocardial infarction and heart failure. Clinicians can more precisely customise treatment
strategies by uncovering the underlying causes of AI-driven forecasts. For example, clinicians can
concentrate on interventions like tailored drug regimens and lifestyle changes to address specific risks if
an AI model predicts a high risk of heart failure based on a mix of clinical and genetic data. Dr. John
Smith, Cardiologist Trust and Adoption: "For AI to be truly integrated into heartcare, it must be
interpretable. As a clinician, I need to understand the 'why' behind AI recommendations. When an AI
model can explain that a patient's risk of heart failure is high due to specific factors like elevated BNP
levels and reduced ejection fraction, I am more confident in its use and more likely to adopt it into my
practice" (Esteva et al., 2019).
• Improved Patient-Clinician Communication and Trust: Improved patient-clinician communication is
made possible by interpretable AI models, which offer concise explanations for their predictions and
suggestions. To improve comprehension and compliance, physicians should clarify to a patient how
lowering their cholesterol could lessen the AI-predicted risk of a heart attack. When patients are aware of
the rationale behind their treatment regimens, they are more likely to follow them. Dr. David Lee, Heart
Failure Specialist Patient Engagement and Compliance: "When we can explain AI-driven insights to
patients, it significantly improves their understanding and engagement. Patients are more likely to follow
treatment plans if they understand the specific reasons behind them. For instance, explaining how a
combination of high blood pressure and diabetes increases their heart disease risk can motivate them to
adhere to prescribed medications and lifestyle changes" (Rudin, 2019).
• Personalized Medicine and Risk Stratification: Personalised medicine is supported by interpretable AI
algorithms that identify individual risk profiles. For instance, physicians can prioritise preventative
treatments catered to the specific risk factors of each patient if an AI model indicates that the patient has
a high hereditary risk for coronary artery disease (CAD). Patients can better comprehend their individual
health risks and the significance of attending a medical advice when personalised risk assessments are
communicated in a clear and concise manner. Through focused care and preventative techniques, this
customised strategy can improve patient outcomes.
• Facilitating Continuous Learning and Clinical Feedback: AI models that can be interpreted enable
continuous enhancement in response to clinical input. For example, if a particular patient type is repeatedly
misclassified by an AI model, physicians might offer input to enhance the accuracy and dependability of
the model. Interpretable models have the potential to detect correlations and novel therapeutic insights
that are complex in nature. For instance, the identification of novel biomarkers or unidentified heart
disease risk factors may result in improved diagnostic standards and more efficient treatment methods.
• Regulatory and Ethical Compliance: Interpretable AI models ensure that AI-driven recommendations can
be examined and verified by regulatory agencies, promoting transparency and accountability. They also
help meet regulatory requirements by offering concise justifications for their judgements. Furthermore,
recognising and resolving biases in AI models requires an understanding of how these algorithms make
judgements. Dr. Thomas Walker Health Informatics Expert Regulatory and Ethical Compliance:
"Regulatory bodies and ethical committees require transparency in AI models. Interpretability ensures that
we can meet these requirements by providing clear justifications for AI-driven decisions. This not only
helps in gaining regulatory approval but also assures patients and clinicians that the technology is safe and
reliable" (Goodman & Flaxman, 2017).

Interpretability and Explainability are both crucial in a domain like healthcare (Combi et al., 2022; Loh et al. 2022)
where the medical practitioners have to rely on AI models for decision making. Although interpretability nature of
ML models has its share of promise in heartcare (Petch et al., 2022; Rasheed et al., 2022, Yang et al., 2022;
Antoniadi et al., 2021; Tsarapatsani et al., 2022), specifically to ECG data (Anand et al., 2022; Ayano et al., 2022)
and electronic health records (Payrovnaziri et al., 2020; Srinivasu et al., 2022) is worth studying. The need of
ensuring interpretability in for medical imaging techniques is emphasized in the recent studies as the multi-
dimensional nature of image data specifically pose huge challenges associating it with real time problems
(Salahuddin et al., 2022; Lambert et al.,2022). However, the potentiality of supervised machine learning is rarely
addressed in the literature. The efficiency and potential for innovation of disease diagnosis, personalised medicine,
clinical trials, non-invasive image analysis, drug discovery, patient care services, remote patient monitoring,
hospital data, and nanotechnology in various learning-based automation in healthcare are assessed, as well as the
need for explainable artificial intelligence (AI) in healthcare. Similarly, knowledge driven Explainability has shown
increased acceptance in users as it has the potential to improve convey just the relevant medical knowledge and
increase formal understanding (Oberste et al., 2022).

In medical health records the most commonly used datasets for detecting cardiovascular diseases statlog heart
disease data set from the University of California. Two main principles required for explain ability in machine
learning is reduction of attributes without performance degradation and a model selection phase to interpret the
optimal model (Porto et al. 2021). For attribute reduction Principal component analysis can be employed along
with DBSCAN algorithm for learning model and the inherent Explainability of decision trees (Silva-Aravena et
al., 2022). However instead of attribute reduction methods feature selection can also be applied prior to
classification and has shown improved performance on Explainability (sci-xai) (Moreno-sanchez, 2021b). The
most commonly applied algorithms are model agnostic ones shap and partial dependence plot over ensemble ml
methods (Moreno-sanchez, 2021a).

Support Vector machines in combination with explainable AI has been proposed by Sajid et al. (2022) on custom
medical history dataset to identify the features that can detect heart disease at an early stage. Some other works
(Ordikhani et al., 2022) have emphasized the effect of Genetic algorithms, random forests, XGBoost and
AdaBoost (Guleria et al., 2022; Wang et al., 2021) on medical history data along with explainable Persian
Atherosclerotic CVD Risk Stratification (XPARS) applied on Isfahan Cohort Study. Patient readmission risk
with XGBoost and CatBoost along with ShapLey additive explainability denoting what has led to the chances of
readmission (Mohanty et al., 2022) has shown significant results. The time dependency component in heart data
has been explored by experts and a model has been put forth named SurvSHAP(t) for time dependent
Explainability (Krzyziński et al., 2022). Interpretability and Explainability may be balanced for machine learning
models based on combination of Random Forests and Fuzzy rule-based clustering on medical history datasets
(Bahani et al., 2021). Patients with acute coronary syndrome (ACS) are at high risk of heart failure (HF) Ren et
al. (2022). Early prediction and management of HF among ACS patients are essential to provide timely and cost-
effective care. Balanced Random Forests classifiers in combination with Shapley additive methods have been
effectively used for identifying exactly the features that lead to heart failure in such cases.

Arterial Hypertension is a specific disorder where people who possess it have greater chances of developing heart
related diseases (Balabaeva and Kovalchuk, 2022). It has been found that people with AH have certain factors
that distinguish them from other categories of patients. Machine learning models have been extensively applied
to assess the scale of intensity of attacks.

Analysis

Choosing the most explainable algorithm is based upon the specific requirements of the cardiac application,
including limitations related to accuracy, clarity, and computational efficiency. Decision trees and logistic
regression offer straightforward interpretation for straightforward tasks, such as determining whether heart disease
is present or absent. Random forests and Gradient Boosting Methods (GBMs) provide greater accuracy and
insights into the significance of features, but they are less interpretable. Decision trees are easy to use and
understand, but they tend to overfit the training set, especially when working with big, feature-rich cardiac
datasets. While GBMs create models sequentially where each new model corrects errors produced by the previous
one, Random Forests are an ensemble method that builds numerous decision trees and integrates their results to
increase accuracy and robustness. These models are useful for a variety of prediction applications and frequently
achieve excellent accuracy despite being computationally complex. They can find significant biomarkers from
huge datasets to detect and track heart disorders, and they can forecast patient outcomes, such as the chance of
heart attacks or strokes, based on clinical characteristics. Complex model interpretability is improved by SHAP
and LIME, which offer thorough, patient-specific explanations. By assigning a model's prediction to each input
feature and offering standardised explanations for various model types, SHAP values provide a unifying metric
of feature relevance. They give detailed explanations of how each feature influences a specific prediction, but
calculating SHAP values can be complicated, especially for large datasets or complex models, and may call for
more training. Furthermore, it is challenging to interpret the predictions of complex models like GBMs or neural
networks that are used in the risk estimation for heart disease. LIME (Local Interpretable Model-agnostic
Explanations) tackles this by explaining individual predictions of any machine learning model using a local
approximation and an interpretable model. The relevance of a feature can be consistently determined using SHAP
values, which compute each attribute's contribution to the model's prediction. For instance, the average projected
value of the target class or result for a specific observation in the Cleveland sample dataset is 0.541 according to
the literature (Guleria et al., 2022). According to the study on the dataset, the AdaBoost algorithm has a false
positive rate (FPR) of 0.17, meaning that 17% of the data was incorrectly identified as positive. Furthermore, a
true positive rate of 0.75 indicates that the model accurately classified 75% data as positive. Explainable-Ensemble
Classifiers were tested with AdaBoost, SVM, KNN, Bagging, LR, and Naive Bayes for the prediction of heart
disease on the Cleveland dataset. Of these, Naive Bayes, LR, and SVM produced results of 89% as reported in
the research showing the significance of ensemble models in explainability.

4.3 Deep Learning in heartcare

The availability of huge amount of clinical data in discrete modalities have led to the increased utilization of deep
learning models for heart disease prediction. Different architectures based on the different modalities of input and
the increased accuracies of results has led to a drastic shift in medical professionals relying on AI models.
Specialized architectures such as autoencoders, deep belief networks, convolutional neural networks and recurrent
ones have shown improved results on Electrocardiogram data (ECG) and Electroencephalography (Liu et al.,
2021; Amrani et al., 2021). Cardiac Magnetic resonance imaging (CMRI), being a non-invasive method for
analysing the overall structure of the heart, deep learning models capable of image segmentation and detection of
anomalies can be fruitful in identifying underlying heart related issues. 2D CNNs, 3DCNNs, Generative
Adversarial Networks and U-Nets are proven models for medical image segmentation and anomaly detection on
Cardiac MRI (Jafari et al., 2022a, Jafari et al., 2022b). The concept of self-attention-based learning has led to the
interesting and revolutionary discovery of transformer architecture, the application of which has rooted for
intelligent medical imaging and analysis for computer vision especially in cardio care (Parvaiz et al., 2022).
Recurrent neural networks have increasingly been used for CMRI data analysis and prediction of heart disease at
an early stage (Nancy et al. 2022). In combination with IoT and cloud computing, it becomes a boon for medical
professionals. However, the most common issue found in CMRI data is the presence of noise which can further
be alleviated using Hann filters which in combination with Fuzzy neural models can prove to be highly efficient
in potential abnormality detections (Doppala et al. 2020).

4.3.1 Transformers era

Although, initially introduced for natural language processing, transformers have now been extensively applied
for data analytics, computer vision as vision transformers and for other applications. Transformers The
conventional sequential models were used to remember required amount of information from sequences and forget
whatever was irrelevant. However, the results showed that the models could remember even better if the sequences
were processed in parallel with a weighted mechanism known as self-attention. This is where transformers come
into play. Transformers have shown improved results in almost all applications not to mention heart disease be it,
clinical history or medical imaging techniques. The basic structure of a transformer is shown in Figure 8.
 Output
Probabilities

Softmax

Linear

Add & Norm

Feed Forward

Scaled Dot-Product Attention Multi-Head Attention

Add & Norm Add & Norm

Multi-Head
Feed Forward Attention

Nx MatMul Linear

Nx
Add & Norm Add & Norm
SoftMax Concat

Multi-Head Masked Multi-

Attention Head Attention Scaled Dot-Product Attention
Scaled Dot-Product Attention
Mask Scaled Dot-Product Attention
h
Positional
+ + Positional
Encoding Encoding Scale
Linear
Linear Linear Linear
Linear
Linear Linear
Input Output Linear Linear
Embedding Embedding

MatMul

Inputs Outputs V K Q
(shifted right) Q K V

Figure 8. Transformer model architecture (Vaswani et al., 2017)

The attention mechanism for a classification problem where the output is a classification problem is given as in
equation (1).

𝑄𝐾𝑇
𝐴𝑡𝑡𝑒𝑛𝑡𝑖𝑜𝑛(𝑄, 𝐾, 𝑉) = 𝑠𝑜𝑓𝑡𝑚𝑎𝑥 𝑉 (1)
𝑑𝑘

The query (a vector representation of one word in the sequence) is contained in the matrix Q, together with all of
the keys K (vector representations of every word in the sequence, here the transpose hence T), and the values V
(again, vector representations of every word in the sequence) (Goodfellow et al., 2016). The word sequence in V
is identical to the word sequence in Q for the encoder and decoder, two multi-head attention modules. V, however,
differs from the sequence represented by Q for the attention module that is taking into consideration the encoder
and decoder sequences.

The first vision transformer for ECG image modelling was introduced in 2022 by Vaid et al. (2022) known as
HearBEit which when showed surprising results was adopted for later medical imaging tasks followed by several
other vision transformers for ECG data specifically (Che et al., 2021; Qiu et al., 2022). Transformers can also be
utilized for training large scale inputs in the form of multimodal transformers (Khader et al., 2022). The technique
was applied on radiographs and fundoscopy images and was seen to attain excellent results. Yet another
transformer architecture solely for cardiovascular dataset was CVT-Trans architecture used to classify the
continuous wavelet transforms (CWT) signals into five groups (Abbas et al., 2022). Ballisto-cardiogram data were
successfully processed and insights were formulated using the Heart Rate Transformers HRCTP-net (Pröll et al.,
2021).

4.3.2 Echo State Networks

As opposed to the conventional recurrent neural networks where training and weight updation is performed on
each and every layer, echo state networks work on the principle of reservoir computing. A sample structure of
echo state networks is depicted in Figure 9. The basic assumption behind the architecture is that there is a reservoir
of neurons where the connections and weights are randomly assigned and the weights are not updated, making it
a lighter model compared to the recurrent neural networks with large number of parameters. However, there is an
echo layer or the read-out layer forming the output where the weights undergo updation. Echo state networks have
shown better performance owing to its lighter and lesser training time and better results in heart disease predictions
as well. Bio inspired on chip reservoir computers are also popularly in use today (Chandrasekaran et al., 2020;
Liang et al., 2021). The same on-chip models have been used for real-time monitoring of heart patients based on
a combination of ECG and physiological data based from wearable devices (Chandrasekaran et al. 2021a and
2021b). The purpose of using ESNs however varies from application. ESNs have been used for data cleaning
purposes where reservoirs with single node architecture are used for ECG data (Elbedwehy et al., 2022) and also
for magnetocardiography signals acquired from sensor data (Shakya et al., 2021). Both of these data exhibit large
amount of noise in them making them inappropriate for training in neural networks directly. Certain approaches
have used a combination of architectures one for feature extraction such as autoencoders and the second one being
the recurrent reservoir (Shahi et al., 2022; Shahi 2022). Other combination approaches are based on reservoirs
followed by PCA and one class support vector machines with one class for real time implementation towards
warnings in heart disease (Abdennadher et al., 2021).

input weight internal weight Output weight

Win W Wout

u1 y1
x1
N reservoir
u2 neurons y2
x6

L output nodes
H input nodes

x2
u3 y3
x5

. .
. xN .
. x7 Feedback
.
. x3 weight
.
x4
uH yL

Input layer Dynamical reservoir

Output layer

Figure 9. Structure of an echo state network (Huang and Guang-Bin, 2015).

Yet another reason for employing reservoir computing models in heart disease is t enhance the energy efficiency
in wearable devices the model being light weight. Certain systems stress the need for combining patient clinical
history with ECGs for increased accuracy of AI models based on light weight RCs (Sadasivuni et al., 2022). A
powerful variation of reservoir computing approaches is stochastic spiking network in combination with reservoir
computing on heart beat rhythms for classification purposes where a sole feature is focused for ensuring minimum
overhead (Saw and Wong, 2022).

4.3.3 Extreme Learning Machines

ELMs are single hidden layer feed forward network where the weights of first layer are randomly initialized and
learning progresses only for the last layer. Even though not highly accurate as the conventional deep neural
networks, ELMs can be relied in scenarios where continuous retraining is required due to the issue of concept
drift. The function that governs the training of ELMs are as in equation (2).

𝑓𝐿(𝑥) = ∑𝐿𝑖=1 𝛽𝑖𝑔𝑖(𝑥) = ∑𝐿𝑖=1 𝛽𝑖𝑔 𝑤𝑖 ∗ 𝑥𝑗 + 𝑏𝑗 , 𝑗 = 1,….,𝑁 (2)

L is a number of hidden units, N is a number of training samples, 𝛽 is weight vector between the hidden layer and
output, w is a weight vector between input and hidden layer, g is an activation function, b is a vias vector, x is an
input vector (Huang et al., 2006).

Heart disease prediction is such an area where features and characteristics of patients tend to vary with a longer
period of time, hence ELMs are found to be a better option. ELMs work well with RNNs and are widely used for
arrhythmia classification (Kuila et al., 2022; SAYGILI, 2020) based on ECG data (Fathurachman et al., 2014).
Fuzzy clustering and k-medoids along with deep belief networks and Extreme learning machine were
experimented on several heart datasets and was found to produce amazing results (Irene et al., 2020). Combination
of gain ratio and ELM, where gain ratio is employed for feature selection and scores can be added as the weights
to the extreme learning methods (Safii et al., 2021).
Time domain and wavelet frequency features are crucial for ECG data. ELMs are efficiently used for classifying
the extracted features from heart beat signals (Xu et al., 2021). DWT can be used for decomposing the signal and
to retrieve the time-frequency features. Binary classifier-based ELMs are used on Heart rate variability signals
where features are extracted from decomposed HRV signals based on subspace decomposition of signals (Singh
et al., 2018). Barus and Surantha (2020) performs Arrhythmia classification using ELMs by using Short Time
Fourier Transform (STFT) for feature extraction. The different classes of arrythmia are Paced Beat (PB), Right
Bundle Branch Block (RBBB), Congestive Heart Failure (CHF), Atrial Fibrillation (AF) and the normal heart
condition Normal Sinus Rhythm (NSR).

4.3.4 Deep learning models with Explainability in heartcare

A larger share of works has been performed to address Explainability in deep learning models owing to the black
box nature of the algorithms. Dave et al. (2020) explores the effect of applying different types of Explainability
techniques on heart disease dataset. Feature based, example-based techniques SHAP, and LIME are applied on
the heart disease dataset and the results are compared to form insights into which healthcare domain most utilizes
from different types of techniques which are outlined below.

Vessel GAN

Vessel-GAN explainable GAN architecture has shown amazing results on CTA (Computed tomography
angiography) pictures generated from CTP (Computed Tomography perfusion) data (Wu et al., 2022). The
generator's characteristics directs to emphasise vessel-like forms in the generator. In particular, the difference
between produced and actual pictures is penalised using a discriminator network. Moreover, we provide a brand-
new generator design that may seamlessly include spatio-temporal representations and improve temporal
consistency.

Gradient Activation maps

Gradient weighted Class Activation Mapping (Grad-CAM) locates and highlights certain target regions in the
picture by using gradients of the target that flow through the neural network. Computer vision applications
including image classification, object recognition, semantic segmentation, image captioning, and visual question
answering, among others, have a huge future for grad-CAM. It also makes it possible to understand the algorithm's
predictions and their causes. Owing to the superior performance of GradCam on image data, it has been
extensively used in ECG data classification (Tzou et al., 2021; Anand et al., 2022, Duffy et al., 2021), with
multiple classes (Ganeshkumar et al., 2021) along with transfer learning (Apama et al., 2022) and federated
learning (Raza et al., 2022). Additionally, one dimensional CNNs with attention are also worth experimenting for
ECG data as proposed by Le et al (2022).

Recently, Holter monitors have grabbed a great deal of attention due to its ease of use they offer. Holter ECG data
consists of ECG data covered over an entire period of time so chances of missing an infrequent arrhythmia is rare.
Gradient activation mapping has been successfully applied to Holter monitor data as well along with
Convolutional neural network (Taniguchi et al., 2021). Figure 10 shows the working of GradCam with a sample
image that resulted in a false positive class from the authors previous work (Sreeja and Supriya, 2023).
 Figure 10. Sample illustration on GradCam (a) Heatmap for a false positive class image (b) Original ECG image (c)
GradCam

Siddiqui (2022) introduces a repeatable and testable model to evaluate explanations generated using SmoothGrad,
GradCAM and GradCAM++ where the training was conducted using a VGG-16 model. The evaluation is
performed compared to subject matter experts (SME) with the help of human experts. A form of stress test called
a Stress/Rest Myocardial Perfusion Imaging (MPI) Study compares the blood flow through the coronary arteries
and the heart muscle before and after physical exertion using PET or SPECT imaging. Grad CAM and CNNs have
been successfully applied on SPECT MPI data (Papandrianos et al., 2022a). A non-invasive method of evaluating
the anatomy and function of the circulatory system is cardiac magnetic resonance imaging, sometimes referred to
as cardiovascular MRI which is a reliable dataset from which insights on cardiac diseases can be detected.
Transformer led architectures with GradCAM has shown successful detections of patches that can be detected at
an early stage (Jafari et al., 2022b). Z-Alizadeh dataset was selected for the experiments.

Atrial Fibrillation detection: Atrial Fibrillation is a type of arrhythmia characterized by irregular and often very
rapid heart rhythm that can lead to blood clots in the heart. Literature suggests effective detection of AF with a
combination of EHR (Bender et al., 2022) and ECG data (Sangroya et al., 2022) on deep neural networks.
Attribution methods employed on DNN with ECG data and attribution methods chosen lets users understand the
relevance score over leads and classes allowing to learn what is crucial in AF prediction. The relevance scores
while applying attribution methods applied on visible P-waves and concordant T-waves showed negative scores
in AF classification. Furthermore, Explainability can also be achieved by symbolic rule based expert system for
deep neural network models designed to detect AF from ECG data.

LIME and SHAP

Each model can have local explanations using LIME and SHAP. This means that the predictions provided by
models that employ text, graphics, or tabular data may be explained using either way. On the one hand, LIME
builds a local explanation by fitting a straightforward model around a prediction. The relevance of each attribute
is quantified by SHAP using game theory on the other hand. In the end, while having somewhat distinct processes,
both methodologies are utilised to comprehend how attributes impact a predicted outcome.

LIME and SHAP will produce outcomes that are comparable, therefore the decision of which approach to utilise
ultimately comes down to the application. Nonetheless, one can concurrently confirm each other's explanations
using both approaches. While SHAP needs a whole sample to calculate SHAP values, LIME creates a modified
dataset to fit an explainable model. This indicates that LIME only needs one observation, but SHAP needs
several. As SHAP values are compared to the sample's average projected value, various samples will provide
somewhat different SHAP values. LIME and SHAP algorithms have been extensively used for arrhythmia
classification using CNNs (Singh and Sharma, 2022), temporal CNNs and deep taylor decomposition (Tang et al.,
2022) and DNNs.

BC features from abdominal CT images have proven to be a potential indicator of ischemic heart disease
prediction. Along with electronic health records and deep learning models they have shown astounding results in
IHD risk assessment. Clinical interpretability can be ensured using the integration of tissue level features and
health records (Zambrano et al., 2021). Apart from these, Pearson correlation analysis is also a proven methos for
bioinformatics based Explainability (Fang et al., 2020; Ye et al., 2021)). Recurrent neural networks have been
explored for the same where the different variants have been experimented for arterial dysfunctionalities based on
ECG data (Sanjana et al., 2020). The same can be extended to include attention mechanisms on electronic health
records for predicting heart failures and Explainability provided using LIME (Khedkar et al., 2020).

Table 1. XAI algorithms in heartcare with applications (Salih et al., 2023)

Reference Application XAI method

Classification (Disagreement between human and neural network for

Zhang et al. (2020)
automated motionartefact detection)
Grad-CAM and
 Saliency maps

Classification different CMR view(stress

Chauhan et al.
CAM
(2022)
testing, heart failureevaluation, arrhythmia evaluation, other)

Kucukseymen et
al. (2022) Classification (Heart failure patients with preserved ejection fraction.
Hospitalizedvs non-hospitalized)
SHAP

Cau et al. (2023) Classification (Takotsubo Cardiomyopathy vsacute myocarditis and control)

SHAP

Singh e tal. Classification (Prediction of all- cause mortality forpatients with coronary
(2022) artery disease)
SHAP, Grad-CAM

Tong et al. (2019) Segmentation

Guided backpropagation

Nurmaini et al. Grad-CAM and Guided

Classification (Predict congenitalheart diseases (CHDs))
(2022) backpropagation

Classification (pacemaker leads; enlarged left atrium;left ventricular

hypertrophy; Sex) and Regression (left ventricular end systolic and diastolic
Ghorbani et al. volumes; ejection fraction; phenotypes SmoothGrad
(2020)
of age and Height)

Classification (predict newbornwith pulmonary

Ragnarsdottir et al. Extend Grad-CAM to
(2022) 3D- CNNs
hypertension)

Jiao et al. (2022) Classification (Heartfailure vs control) Grad-CAM

Wang et al. (2022) Segmentation Grad-CAM

Classification (Myocardial infraction and coronary artery

Clough et al. (2019) TCAV
disease vs control)
Janik et al. (2021) Segmentation TCAV

Sreeja et al. (2023) Classification GradCam, sHAP, LIME

Analysis

Saliency maps highlight the input components that have the largest effect on the model's prediction and are
commonly presented as heatmaps. These maps offer concise visualisations that draw focus on the most important
parts of the input and may be used with a range of data sources, including text and images. However, the results
may not provide an accurate understanding of feature correlations and may be influenced by small changes in the
input. Grad-CAM (Gradient-weighted Class Activation Mapping) builds on saliency maps to create heatmaps
that are more detailed and visually appealing by including class-specific explanations. Due to its high
computational demand and primarily employed in convolutional neural networks (CNNs), its application to other
models is limited. Grad-CAM enables the localization of disorders by identifying specific regions in medical
pictures associated with heart abnormalities. LIME (Local Interpretable Model-agnostic Explanations) provides
an explanation for each individual prediction by locally approximating the deep learning model with a simpler,
interpretable model. Because parameter choices affect the quality of explanations, it's possible that LIME's
explanations fall short of accurately capturing the global behaviour of the model. LIME advances precision
treatment by revealing the underlying causes of a patient's predicted chances of heart disease. SHAP (SHapley
Additive exPlanations) values provide additive and consistent explanations across several models by using
cooperative game theory to assign an importance value to each feature for a prediction. Although SHAP can
provide an accurate understanding of feature relevance and provide an explanation for particular predictions,
calculating SHAP values can be challenging and require intricate calculations. The application of SHAP identifies
key factors that affect a patient's predicted risk of cardiovascular disease. DeepLIFT (Deep Learning Important
FeaTures) efficiently gives accurate information by decomposing a model's prediction into the contributions of
each input feature relative to a reference. DeepLIFT facilitates an easier understanding of the role of clinical
measures in heart disease risk prediction. Integrated gradients assign an attribution score to each feature by
averaging the gradients between the input and the output. This method yields smooth, consistent attributions that
are flexible to many situations, but it requires a lot of gradient calculations and careful baseline selection.
Integrated gradients illustrate how several variables contribute to heart disease risk estimations.

4.4 Ontology

Ontologies are shareable, machine interpretable formats for representing knowledge. In a domain like healthcare,
where large amount of context information and vocabulary are highly crucial, ontologies play a vital role.
Information is represented in the form of triples as subject relation and predicate, which ensures that the semantics
between various entities are ensured. Several medical ontologies exist integration of which might result in
successful models for heart disease analysis. Gene structure responsible for several diseases including heart
disease have been exploited using ontology knowledge base and ML classifiers (Jeipratha and Vasudevan, 2023).
Further, output rules from decision trees can be utilized for formulating rules in an ontology structure, having the
advantage that new rules can effectively be identified using Semantic web rule language from ontologies for
predicting cardiovascular diseases (El Massari et al., 2022). Multimodal information can be obtained from
structured data by using combination of Minkowski equation and logistics regression as in equations 1 and 2 (Yoo
et al., 2021; Lerjebo and Hägglund, 2022).

4.5 Non-linear dynamics, chaos theory in AI

Non-linear dynamics represent a world where unpredictability is paramount. Forecasting the unexpected based on
several parameters which do not actually have a direct and sudden implication on an eco-system. Chaos theory is
branch of nonlinear dynamics where the complex mathematics of nonlinearity results in surprising states which
are chaotic in nature and cannot be controlled. The basic principles of chaos theory are the butterfly effect
indicating that even a light butterfly flap can result in hurricanes, and fractal theory where fractals are infinite
patterns. Good and bad patterns need to be identified based on fractal analysis and have been found to produce
best results in early detection of diseases for advanced healthcare, especially in heart care for arrhythmia detection
(Gupta et al., 2020) and ECG based cardiac abnormalities (Saini and Gupta, 2022). Even though they seem to be
a simple theory, the basic concept of chaos by the father of chaos theory Edward Lorenz, describes that even
though the present state can compute a future condition, an approximation on present condition cannot determine
exactly an approximation of a future state. This can be exhibited using a simple logistic model which represents
a function of growing population. The logistic function is formulated by nonlinearity in difference equation to
verify each timestep as in (3).

𝑋𝑖+1 = 𝑅𝑋𝑖(1 ― 𝑋𝑖) (3)

Where the state at time i is shown as X, which is the dynamics of the system, and R is the growth rate (Goldstein,
1953). It should be noted that when R is extremely low, the system will die out and if it is too high, the values
cross a certain state and bursts after becoming stable for a certain period of time.

ML: Various ML based classifiers have been fed with nonlinear dynamic parameters such as measures of entropy
variability, complexity and chaotic values. The popular ML algorithms being employed are Support Vector
Machines, K-Nearest neighbour, multi-layer perceptron, decision tree classifiers
(Deng et al., 2023) and on a combination of fuzzy systems for heart attack prediction using morphological feature
from ECG data (Murugappan et al., 2021) or based on patient clinical history (Patro et al., 2021).

DL: Simple neural networks have been in use for ECG signal classification with respect to chaos theory (Sabrine
and Taoufik, 2022). Mazaheri & Khodadadi (2020) proposes the importance of meta-heuristic optimization
algorithm upon Feed forward neural network classifiers for faster results over the ECG data. Lyapunov exponent
values are crucial components in determining chaos as proposed by Zarei et al. (2022) which was fed into a hybrid
classifier formed by SVM, KNN and multi-layer perceptron to produce best results. Approaches for creating
chaotic error scatter map using master and slave systems in order to retrieve the chaotic points from an ECG signal
are also in use (Wang et al., 2020). This in combination with neural networks can be used for disease recognition.

Time series data processing: The possibility of using deep neural network on chaotic data which is conventionally
time series data has been emphasized in the literature (Yang and Shen, 2020). RNNs are the conventional neural
network that are used for time series analysis. The importance of meta heuristic optimization algorithms for faster
convergence have been stressed in various studies. Chaos-based whale optimization has been pointed out by
Priyanga et al. (2021) on electronic health records.

The advantages of training an echo state network for time series data due to the updations at just the read-out layer
have been mentioned earlier. The same can be applied for analysing unexpected values in the input data with
linear activations in the reservoir so that it can be used to analyse if unusual patterns are on the way (Bollt, 2021).
Simulations can be modelled to control a heart arrhythmia and can be systemised as a propagation using an ESN
(Veselý, 2022). Studies have also suggested the use of CNNs for tapping time series information and hence can
be applied to ECG data. Pre-trained models like AlexNet have been proven to produce best results when it comes
to CNNs. However, the one-dimensional ECG signal needs to be converted to two-dimensional images in order
to be sent to CNNs. Pair wise feature correlation is computed and concatenated with ECG and heart rate variability
measure before being fed to ALexNet to produce optimal classification results based on three major classes
congestive heart failure, arrhythmia, and normal sinus rhythm (NSR) (Eltrass et al., 2022).

4.6 The multi omics revolution

Omics data deals with information beginning with genomics, proteomics and leading to metabolomics. Multi
omics is the branch that has the potential to identify probable biomarkers due to the inherent property of DNA
structure in it. With the use of the revolutionary metabolomics, we can analyse a wide variety of metabolites in a
cell or tissue for decision making related to various diseases. Troponin-I has already been proven as a potential
biomarker for heart disease. However, it is definite that there are several hidden biomarkers that can be identified
with further research which various studies have put forward (Barberis et al., 2022).

The insights to be derived from multi omics data can be from Advanced ECG analysis, proofing in combination
with logistic regression (LR), random forest, decision tree and support vector machine (Gladding et al., 2021a;
Gladding et al., 2021b) or from Adipose tissue morphology, imaging (Rawshani et al., 2020). Buergel et al. (2022)
trained a network to learn disease-specific metabolomic states from 168 circulating metabolic markers measured
in several thousands of candidates from the UK Biobank and evaluated the performance of the model in four
cohorts to find metabolomes correlated with event rates in all the conditions.

Moskaleva et al. (2022) performs target metabolome profiling for classifying patients with CAD, HTA, and non-
CVD individuals. The target metabolites are amino acids, acylcarnitines, tryptophan catabolism, methylarginines
and the algorithms used are random forest, gradient boosting, multiple neural networks, and support vector
machines on custom collected dataset. To investigate metabolic indicators for the diagnosis of acute myocardial
ischemia, combination of metabolomics and machine learning algorithms and untargeted metabolomics using
high-resolution mass spectrometry and ultra-performance liquid chromatography can be used. The most useful
metabolites from a pool of 28 metabolites were selected using a combination of machine learning methods,
including gradient tree boosting (GTB), support vector machine (SVM), random forest (RF), logistic regression
(LR), and multilayer perceptron (MLP) models. The findings demonstrated that the MLP model outperformed
other algorithms in terms of classification accuracy and performance when it came to the metabolites L-threonic
acid, N-acetyl-L-cysteine, CMPF, glycocholic acid, L-tyrosine, cholic acid, and glycoursodeoxycholic acid (Cao
et al., 2022).

Since it makes it possible to uncover intricate patterns and associations from large datasets and improve our
understanding of disease causes, the integration of multi-omics data with machine learning is essential for cardiac
care. Combining the analysis of genetic, proteomic, and metabolic data, makes it easier to identify more accurate
biomarkers and create highly customised treatments resulting in improved patient outcomes. Further, the
advancement of precision medicine in cardiology can be achieved by using machine learning algorithms to predict
the course of a disease and the response to treatment. Genomic information provides the basic genetic information
in cardiac care, identifying inherited risks and possible targets for treatment. Genomics also helps in identifying
the exact variance and mutations that contribute to an individual's heart disease. Genomics also reveals the
potential genetic pathways involved in cardiovascular disease. It also provides an insight into what all are the
inherited and genetic targets for therapy. Whereas, by examining protein expression, changes, and interactions,
proteomics provides valuable insights into the functional effects of genetic variants and is crucial for
comprehending disease causes. Proteomics tries to study the proteins expressed by these genes and if the
abundance, modifications and interactions are directly contributing to the heart disease. Proteomics details on how
genetic variations affects the protein networks and functions which can be analysed using ml algorithms for
network analysis. On the other hand, metabolomics provides real-time diagnostic and prognostic information by
capturing metabolic alterations that correspond to the physiological state and progression of heart disease.
Metabolomics takes into consideration metabolites which are end products of cellular process and tries to find out
if they reflect the physiological state of the heart. Machine learning algorithms applied on metabolomics offers
input into how these metabolic pathways are altered during heart disease showing how genetic and protein changes
with overall metabolism. The complementary nature of all these omics data as mentioned above, helps in
identification of intricate patterns from heart data and prediction models is made possible by integrating several
omics types with machine learning as suggested from the recent researches.

4.6.1 Clinical Relevance and Validation of the biomarkers

1. Troponins (cTnI and cTnT): Troponins are proteins present inside the heart where elevated levels indicate
cardiac muscle injury. This has been widely validated through numerous clinical trials and troponin test has been
routinely used in clinical practice for heart attack detection. According to the Global Registry of Acute Coronary
Events (GRACE) study (Fox et al., 2003), increased troponin levels are substantially correlated with increased
mortality and adverse cardiovascular events in individuals with acute coronary syndrome.

2. B-type Natriuretic Peptide (BNP) and N-terminal proBNP (NT-proBNP) are peptides which are released due
to ventricular stress, indicating heart attack. Increased levels aid in detection, and management of heart failure.
These have been thoroughly tested in clinical trials and incorporated into recommendations for the treatment of
heart failure. According to the Breathing Not Properly Multinational Study (McCullough et al., 2002), NT-
proBNP levels are predictive of future cardiovascular events and mortality as well as correlated with the degree
of heart failure.

3. C-reactive Protein (CRP): An inflammatory marker used to evaluate cardiovascular risk is CRP. Elevations of
high-sensitivity CRP (hs-CRP) have been linked to a higher risk of cardiovascular events. Though not limited to
heart disease, its usefulness in predicting cardiovascular risk has been proven by numerous research. According
to the JUPITER study (Ridker et al., 2008), statin medication significantly lowers cardiovascular events in people
with elevated hs-CRP levels.
4. Lipid Profile (Total Cholesterol, LDL, HDL, Triglycerides): A significant risk factor for coronary artery disease
and atherosclerosis is dyslipidemia. For risk management and classification, lipid levels are essential. a mainstay
of cardiovascular risk assessment and management, having received extensive validation. Lipid management
guidelines are based on the Framingham Heart Study (Kannel et al., 1961), which showed a link between
cholesterol levels and the risk of cardiovascular disease.

5. Interleukin-6 (IL-6): Inflammatory cytokines like IL-6 are linked to elevated cardiovascular risk and
inflammation. being investigated and verified more and more in different cardiovascular populations. A higher
risk of coronary heart disease and stroke has been linked to greater levels of IL-6, according to research from the
Emerging Risk Factors Collaboration (Kaptoge et al., 2012).

6. Fibrinogen: Raised levels of fibrinogen, a blood clotting agent, have been associated with a higher risk of
thrombosis and cardiovascular events. Although less frequently utilised in standard clinical practice for
cardiovascular risk assessment, validated by a number of research. High fibrinogen levels are independent of other
risk variables in the prediction power of future cardiovascular events, as shown by the PROCAM study
(Prospective Cardiovascular Münster Study) (Assmann et al., 2002).

7. Myeloperoxidase (MPO): MPO is an enzyme linked to a higher risk of atherosclerosis and myocardial infarction
that is released during oxidative stress and inflammation which has been validated as a measure of cardiovascular
risk and oxidative stress in multiple investigations. According to a Cleveland Clinic study (Brennan et al., 2003),
patients who report with chest pain had higher MPO levels, which are predictive of significant adverse cardiac
events.

8. Galectin-3: Elevated levels of the fibrosis- and inflammation-related protein galectin-3 are linked to heart failure
and unfavourable cardiovascular outcomes. growing interest in its ability to treat heart failure as it is investigated
and validated more and more. The Diastolic Heart Failure in Elderly Assisted Living Residents Study (DEAL-
HF) (Ahmed et al., 2006) demonstrated that hospitalisation for heart failure and mortality are predicted by
galectin-3 levels.

Analysis

Several Machine learning algorithms have been experimented for identifying the features and for classifying the
data into different heart disease groups of which normal, CVD and hypertension are the common classes.
Typically, four multiclass classifiers—random forest, artificial neural networks, gradient boosting, and support
vector machines—were examined to find the best machine learning technique (Gladding et al., 2021a). The
random forest classifier had the highest accuracy (0.8). Twelve important metabolites were found by feature
importance analysis, which could create a panel for stratifying people with CAD, HTA, and non-CVD. Another
research uses six machine learning algorithms to apply a binary classification approach to differentiate between
the non-CVD and CVD groups: logistic regression, random forest, neural networks, gradient boosting, support
vector classifier, decision tree, and bagging classifier (Moskaleva et al., 2022). The best approach was chosen
based on quality metrics. Mostly, random forest showed best results in terms of predictive quality with AUCROC
and accuracy of 0.91. Gradient Boosting stands next with accuracy of 0.8 and AUCROC of 0.86. MLP classifier
also showed promising results (Moskaleva et al., 2022). Further experiments, based on the SHAP-based feature
importance model, 10 main features were identified which are Butyrylcarnitine, Acetylcarnitine, HIAA, Ornitine,
Kyn/trp ratio, Tyrosine, Propionylcarnitine, Choline, Isovalerylcarnitine, Hexanoylcarnitine, 5-
hydroxytryptophan, Threonine, Glycine, Palmitoylcarnitine, Quinolinic acid, Decenoylcarnitine, Carnitine,
Dodecenoylcarnitine, and Valine.

Case studies and applications

A few case studies and real-world applications where multi-omics data analysis has successfully identified novel
biomarkers for heart disease has been briefed here. Framingham Heart Study (Kannel et al, 1961): Started in 1948
in Framingham, Massachusetts, the Framingham Heart research is long-term, ongoing cardiovascular cohort
research. It has been useful in determining heart disease risk factors. To investigate cardiovascular disorders,
researchers used transcriptomics, proteomics, metabolomics, and genomes. Biomarker Discovery: Novel
biomarkers, such as particular genetic variations, proteins, and metabolites linked to cardiovascular risk, were
discovered through the integration of multi-omics data. The discovery of certain biomarkers, such as variations in
the PCSK9 gene, has prompted the creation of fresh approaches to treatment. Nowadays, PCSK9 inhibitors like
alirocumab and evolocumab are used to lower LDL cholesterol and lower the risk of cardiovascular disease.
The STARNET Study (Franzen et al., 2016): The objective of the Stockholm-Tartu Atherosclerosis Reverse
Network Engineering Task (STARNET) is to comprehend the hereditary foundation of atherosclerosis. This work
combined data from human atherosclerotic plaques, blood, and liver tissue with genomes, transcriptomics,
proteomics, and metabolomics analyses. New regulatory networks and important genes, like CXCL1 and IL-6,
linked to atherosclerosis have been discovered by researchers. The results have shed light on possible treatment
targets. Clinical trials are being conducted to examine the effectiveness of IL-6 inhibitors in lowering
cardiovascular events in people who are at high risk.

NIH Roadmap Epigenomics Project (Consortium et al., 2015): In order to get a deeper understanding of the
function of epigenetics in human health and illness, the NIH Roadmap Epigenomics Project seeks to map the
epigenome of both healthy and disease states. In order to investigate cardiac disease, the research has combined
epigenomics with other omics data. Coronary artery disease has been associated with epigenetic alterations, such
as DNA methylation patterns in particular genes (such NOS3 and PPARG). The potential for these biomarkers to
function as diagnostic instruments and targets for innovative therapeutic strategies is being investigated.

4.6.2 Explainability in metabolomics

The importance of exploring biological information and biomarkers for comprehending patient risk in a systems
biology framework is gaining high importance combined with the most recent developments in risk prediction of
recurrent cardiovascular events. Several significant works based on multi omics data that can result in potential
biomarkers for cardiovascular disease has been comprehensively reviewed by Westerlund et al. (2021).

Although, the introduction of explainable AI has revolutionized all techniques it still needs to be noted that omics
data in heartcare is still yet to benefit from Explainability. Metabolomics integrated with Explainability will
enhance clinical decision-making by making details of forecasts visible to the physician. One among the very few
works addressed with metabolomics and XAI related to cardiovascular disease prediction is for carotid
atherosclerotic disease prediction (Pezoulas et al., 2022). The condition is characterised when plaque (cholesterol,
fatty deposits, and other substances) accumulates in the carotid arteries, the arteries in your neck that carry blood
to your brain, causing them to narrow and stiffen. In the proposed work, high intima media thickness is used as a
prodromal stage of atherosclerotic carotid disease using metabolomics data from 2,147 individuals in the Young
Finns Study clinical trial. A novel use of the Gradient Boosted Trees was included into an explainable AI-based
pipeline (GBT). More particularly, the influence of the dropout rates in the "dart" booster in the loss function
topology was modified using a hybrid loss function.

A summary of the various discrete factors identified in the state-of-the-art intelligent heartcare are outlined in
Table 2 and those techniques for heartcare with Explainability and the algorithm names are outlined in Table 3.
(2022)
(2022)
(2022)
(2020)

Baashar et al.
Doppala et al.
Authors

Nanehkaran et al.

Chae et al. (2022)

Sarra et al. (2022)

Javan et al. (2021)

Ramirez-Asis et al.






Clincal/Medical history

ECG/EEG/BCG/MCG


Data

MRI

CT scan

Omic data







Data Analytics

Image/Signal processing

Chaos
Technique

Metabolomics

Others



 knn

DM

ANN
Others(PCA,
Covariance)


fuzzy

Cox Proportional





Hazards
SVM




DBSCAN

Genetic Algorithm


LR




Decision Tree
ML

NBC


Random Forest
Table 2 Summary of parameters analysed for AI based IHD prediction

Generalized Additive
Models

models
AdaBoost

XGBoost

Gradient Boost

Others


CNN


RNN(LSTM, GRU)

GAN

NN
DL

Bagging

Transformers

ESN/Reservoir
Computing
ELM


Others
 (2021b)

Bolt (2021)

Sabrine and
Mazaheri &
Authors

Veselý (2022)
Taoufik (2021)
Moreno-Sanchez

Shafi et al. (2022

Deng et al. (2023)

Khodadadi (2020)

Clincal/Medical history







ECG/EEG/BCG/MCG
Data

MRI

CT scan
Omic data


Data Analytics







Image/Signal processing






Chaos
Technique

Metabolomics

Others




knn

DM

ANN
Others(PCA,
Covariance)

fuzzy

Cox Proportional


Hazards
SVM

DBSCAN

Genetic Algorithm

LR



Decision Tree
ML

NBC


Random Forest

Generalized Additive

Models

models
AdaBoost


XGBoost


Gradient Boost

Others

CNN

RNN(LSTM, GRU)

GAN



NN

DL

Bagging

Transformers



ESN/Reservoir
Computing
ELM

Others
 (2021)
(2021)
(2021)
Authors

Priyanga et al.

Karadeniz et al.

Patro et al. (2021)

Zarei et al. (2022)

Murugappan et al.
Wang et al. (2020)

Gupta et al. (2020)

Nancy et al. (2022)





Clincal/Medical history





ECG/EEG/BCG/MCG
Data

MRI

CT scan
Omic data




Data Analytics





Image/Signal processing







Chaos
Technique

Metabolomics

Others





knn
DM

ANN


Others(PCA,
Covariance)


fuzzy

Cox Proportional





Hazards
SVM

DBSCAN

Genetic Algorithm

LR

Decision Tree
ML




NBC


Random Forest

Generalized Additive
Models

models
AdaBoost

XGBoost

Gradient Boost

Others

CNN



RNN(LSTM, GRU)

GAN



NN


DL

Bagging

Transformers


ESN/Reservoir


Computing
ELM

Others
 (2022)
(2022)

al. (2021a)

al. (2021b)
Eltrass et al.
Authors

Qiu et al. (2022)

Elbedwehy et al.
Che et al. (2021)

and Shahi (2022)

Shahi et al. (2022)

Chandrasekaran et
Chandrasekaran et
Clincal/Medical history








ECG/EEG/BCG/MCG
Data

MRI

CT scan
Omic data

Data Analytics









Image/Signal processing




Chaos
Technique

Metabolomics

Others

knn
DM

ANN
Others(PCA,
Covariance)

fuzzy

Cox Proportional
Hazards
SVM

DBSCAN

Genetic Algorithm

LR

Decision Tree
ML

NBC

Random Forest

Generalized Additive
Models

models
AdaBoost

XGBoost

Gradient Boost


Others



CNN




RNN(LSTM, GRU)

GAN

NN
DL

Bagging



Transformers





ESN/Reservoir
Computing
ELM

Others
 (2022)
(2021)
(2022)
(2021)

(2021a)
al. (2020)

Shakya et al.
Authors

Gladding et al.
Saw and Wong

Sadasivuni et al.
Chandrasekaran et

Liang et al. (2021)

Abdennadher et al.


Clincal/Medical history








ECG/EEG/BCG/MCG
Data

MRI

CT scan


Omic data


Data Analytics









Image/Signal processing

Chaos
Technique


Metabolomics

Others

knn
DM

ANN
Others(PCA,
Covariance)

fuzzy

Cox Proportional


Hazards
SVM

DBSCAN

Genetic Algorithm




LR

Decision Tree
ML

NBC


Random Forest

Generalized Additive
Models

models
AdaBoost

XGBoost

Gradient Boost

Others

CNN







RNN(LSTM, GRU)

GAN

NN
DL

Bagging

Transformers







ESN/Reservoir
Computing
ELM

Others
 (2022)
(2022)
(2020)

(2021b)
Buergel et al.
Authors

Gladding et al.
Rawshani et al.

Moskaleva et al.

Cao et al. (2022)

SAYGILI (2020)
Irene et al. (2020)




Clincal/Medical history




ECG/EEG/BCG/MCG
Data

MRI


CT scan


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Omic data

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
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

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Bagging

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
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Computing
ELM

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 al. (2014)
Barus and
Authors

Xu et al. (2021)

Surantha (2020)

Fathurachman et
Safii et al. (2021)

Kuila et al. (2022)

Singh et al. (2018)




Clincal/Medical history




ECG/EEG/BCG/MCG
Data

MRI

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Omic data


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
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Chaos
Technique

Metabolomics

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

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

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

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




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Transformers

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

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

Computing
ELM

Others
al.
al.

et. al.
zadeh

Wu et
das et
Authors

(2022)
(2022)
(2020)
(2020)

y et al.
Mogha

Mohant
Rezaian



Clincal/Medical history


ECG/EEG/BCG/MCG

MRI


CTP and CTA
Data

CT scan

Omic data

Others



Data Analytics



Image/Signal processing

Chaos
Technique

Metabolomics

Others

 knn


DM

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Others(PCA, Covariance)

fuzzy

Cox Proportional Hazards



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Genetic Algorithm

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Generalized Additive models

Models

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Gradient Boost

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CNN

RNN(LSTM, GRU)


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Table 3 Summary of parameters analysed for IHD prediction models with XAI

NN
DL

Bagging

Transformers

ESN/Reservoir Computing

ELM

Others




Opaque


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

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

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Local


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
l

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Globa

Model-Agnostic
(SHAP)
 al.
al.
al.

et al.
et al.
ski et

Anand
Authors

(2022)
(2022)
(2022)
(2022)
(2021)

Apama
Raza et
Tzou et

Krzyziń


Clincal/Medical history





ECG/EEG/BCG/MCG

MRI

CTP and CTA

Data

CT scan

Omic data

Others



Data Analytics




Image/Signal processing

Chaos
Technique

Metabolomics

Others

knn
DM

ANN

Others(PCA, Covariance)

fuzzy


Cox Proportional Hazards

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Generalized Additive models

Models

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

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

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
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

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l

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 al.

et al.
Duffy
Authors

(2022)
(2022)
(2021)
(2022)
(2021)

u et al.
Shimiz
hi et al.

Sajid et

Le et al.
Taniguc


Clincal/Medical history





ECG/EEG/BCG/MCG

MRI

CTP and CTA

Data

CT scan

Omic data

Others


Data Analytics





Image/Signal processing

Chaos
Technique

Metabolomics

Others

knn
DM

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fuzzy

Cox Proportional Hazards



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 LR

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Random Forest

Generalized Additive models

Models

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XGBoost


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



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GAN

NN
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ESN/Reservoir Computing

ELM

Others




Opaque



Transparent



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Model-specific
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Explainability

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Posthoc

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l

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


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 al.
al.
et al.
Authors

(2022)
(2022)

al. (2022)
Sangro
Bender

ianos et
ianos et

(2022a)

ya et al.
(2022b)
Papandr
Papandr

Guleria et

Clincal/Medical history



ECG/EEG/BCG/MCG

MRI

CTP and CTA

Data

CT scan

Omic data



Others


Data Analytics





Image/Signal processing

Chaos
Technique

Metabolomics

Others


knn
DM

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Others(PCA, Covariance)

fuzzy

Cox Proportional Hazards


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DBSCAN

Genetic Algorithm


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Random Forest

Generalized Additive models

Models

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XGBoost


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


CNN

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GAN

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
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

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
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

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
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l

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 et al.
et al.

(2022)
(2022)
(2022)
(2021)
(2022)
(2021)

ni et al.
Sharma

Siddiqui
Authors

mar et al.
Ganeshku

Singh and

Ordikhani

Tsarapatsa
Heilbroner




Clincal/Medical history




ECG/EEG/BCG/MCG

MRI

CTP and CTA

Data

CT scan

Omic data

Others




Data Analytics




Image/Signal processing

Chaos
Technique

Metabolomics

Others

knn
DM

ANN

Others(PCA, Covariance)

fuzzy

Cox Proportional Hazards

SVM

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LR


Decision Tree
ML

NBC



Random Forest

Generalized Additive models


Models

AdaBoost



XGBoost

Gradient Boost

Others





CNN

RNN(LSTM, GRU)

GAN

NN
DL

Bagging

Transformers

ESN/Reservoir Computing

ELM

Others







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Instrinsic

Model-specific
Local


Explainability

Model-agnostic
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
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l

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
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Model-Agnostic
(SHAP)
 and

et al.
Silva-

(2021)
(2022)
(2022)
(2021)
(2022)
Authors

Bahani et
Ren et al.

al. (2021)
al. (2022)

Zambrano
Balabaeva
Tang et al.
Aravena et

Kovalchuk
Wang et al.








Clincal/Medical history

ECG/EEG/BCG/MCG

MRI

CTP and CTA

Data

CT scan


Omic data

Others








Data Analytics


Image/Signal processing

Chaos
Technique

Metabolomics

Others


knn



DM

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Others(PCA, Covariance)


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
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

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LR




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ML

NBC



 Random Forest

Generalized Additive models

Models

AdaBoost

XGBoost


Gradient Boost

Others



CNN


RNN(LSTM, GRU)

GAN


NN
DL

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Transformers

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Others




Opaque





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




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Model-specific
Local



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
l

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




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(SHAP)
(2021)
(2021)
(2020)
(2021)

d et al.
(2021a)

(2022b)

Ye et al.
Sanchez
Moreno-
Authors

al. (2020)

Westerlun
Sanjana et
Fang et al.
Porto et al.
Jafari et al.





Clincal/Medical history



ECG/EEG/BCG/MCG


MRI

CTP and CTA

Data

CT scan

Omic data

Others





Data Analytics




Image/Signal processing

Chaos
Technique


Metabolomics

Others


knn
DM

ANN

Others(PCA, Covariance)

fuzzy


Cox Proportional Hazards

SVM

DBSCAN

Genetic Algorithm

LR



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ML

NBC


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Generalized Additive models



Models

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



XGBoost


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

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


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
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
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
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l

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Globa




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(SHAP)
 (2021)
(2022)

Abbas et
Authors

Khader et

al. (2022)
al. (2022)
al. (2022)
al. (2020)

Pröll et al.
Vaid et al.
Khedkar et

Pezoulas et

Clincal/Medical history






ECG/EEG/BCG/MCG

MRI

CTP and CTA

Data

CT scan


Omic data

Others


Data Analytics






Image/Signal processing

Chaos
Technique


Metabolomics

Others

knn
DM

ANN

Others(PCA, Covariance)

fuzzy

Cox Proportional Hazards

SVM

DBSCAN

Genetic Algorithm

LR

Decision Tree
ML

NBC

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Generalized Additive models

Models

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

XGBoost

Gradient Boost

Others





CNN


RNN(LSTM, GRU)

GAN


NN
DL

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




Transformers

ESN/Reservoir Computing

ELM

Others




Opaque




Transparent




Instrinsic

Model-specific
Local


Explainability

Model-agnostic
Posthoc


l

Model-specific
Globa

Model-Agnostic
(SHAP)
 5. DATASETS AVAILABLE

Several publicly available datasets available for experimentation under different input categories along with their
reference, use and short description is described in Table 4. It is worth mentioning that apart from public datasets,
majority studies have also used data collected from specific cohorts from hospitals specific to a certain region.

Table 4 Public datasets available for experimentation

Used in
Type Dataset Short description Reference

Moghadas et al. (2020),

UCI ML
Nanehkaran et al. (2022), Guleria et
repository
al. (2022), Ramirez-Asis et al.
containing
(2022), Moreno-Sanchez (2021b),
Statlog,
Porto et al. (2021), Fang et al.
Cleveland, contains 76 attributes, but all
(2020), Ye et al. (2021), Nancy et
Hungarian and published experiments refer to using (UCI, 2022)
al. (2022), Karadeniz et al. (2021) ,
Va long beach a prime subset of 14 of them
Patro et al. (2021), Safii et al.
heart disease
(2021), Fathurachman et al. (2014),
datasets
Sarra et al. (2022), SAYGILI
(Cleveland
(2020), Irene et al. (2020), Bahani et
most used)
al. (2021), Khedkar et al. (2020)

EHR records conssiting of 13 Davide et al. Krzyziński et al. (2022), Moreno-

Heart failure
clinical features (2020) Sanchez (2021a)

Programmatically collected
structured data from the EMR,
ConcertAI
including ICD codes, prescriptions,
EHR/EMR

from (ConcertAI,
and laboratory results, are joined Heilbroner et al. (2021)
CancerLinQ 2022)
with significant hand-curated factors
database
from provider notes and
incorporated into an uniform system

5000 individuals hospitalised with

moderate or severe COVID-19 and
800 nonhospitalized patients with
mild or asymptomatic COVID-19
are the subjects of an ongoing 5-year
Sarrafzadega
Isfahan Cohort multicentric prospective cohort
n et al. Ordikhani et al. (2022)
Study research in Isfahan. Morbidity,
(2022)
mortality, incident cases, or the
deterioration of underlying
noncommunicable diseases (NCDs)
and their risk factors are the ICC
endpoints.

‘health data of above 40,000 patients

Johnson et al. Tang et al. (2022), Javan et al.
MIMIC-III from ICUs of the Beth Israel
(2019) (2021) , Khedkar et al. (2020)
Deaconess Medical Center
 Used in
Type Dataset Short description Reference

303 patient records, with 54

attributes per patient divided into
Z-Alizadeh Alizadehsani Jafari et al. (2022a), Jafari et
four categories: demographic, exam
dataset. et al. (2013) al.(2022b)
and symptom, ECG, laboratory, and
echo aspects.

Raza et al. (2022), Singh and

48 half-hour segments of digitised,
MITBIH
11-bit, 360 samples per second per
Arrhythmia
channel, two-channel ambulatory
Database
ECG recordings with a 10 mV range
Sharma (2022), Sanjana et al.
(2020),Sabrine and Taoufik (2022),
Zarei et al. (2022), Wang et al.
(2020), Murugappan et al. (2021),
Moody and
Eltrass et al. (2022),
Mark (2001)
Pröll et al. (2021), Elbedwehy et al.
(2022), Liang et al. (2021), Saw and
Wong (2022), Abdennadher et al.
(2021), Xu et al. (2021), Barus and
Surantha (2020), Kuila et al. (2022)

a large dataset of 21799 clinical 12- Anand et al. (2022), Apama et al.
PTB-XL Wagner et al.
lead ECGs from 18869 patients of (2022), Deng et al. (2023), Vaid et
(Physiobank) (2022)
10 second length. al. (2022), Qiu et al. (2022)

Chapman and
Perez et al.
CPSC-2018 twelve led ECG recordings Le et al. (2022)
(2020)
(Physiobank)
ECG

AF Classification from a Short

Physionet- Single Lead ECG Recording: The Clifford et al. Sangroya et al. (2022), Gupta et al.
2017 PhysioNet/Computing in Cardiology (2017) (2020)
Challenge 2017

The China
Physiological
recordings from one normal ECG Liu et al.
Signal Ganeshkumar et al. (2021)
type and eight abnormal types (2018)
Challenge
2018

a significant collection of recordings

with expert annotations for research
into how myocardial ischemia
ST-T Database Taddei et al.
manifests in the ECG as well as for Singh et al. (2018)
- NSRCAD (1992)
the development and testing of
techniques for assessing ST and T
alterations in the ECG
MRI

CAD Dataset MRI dataset images Papandrianos et al. (2022a)

 Used in
Type Dataset Short description Reference

Danialsharifr
azi (2022)

short axis cardiac MR images and

York
the ground truth of their left Alexander et
University Doppala et al. (2020)
ventricles’ endocardial and al. (2008)
Cardio MRI
epicardial segmentations.

a scalable and expanding collection

of well-characterized digital
Goldberger et
All

PhysioBank recordings of physiologic signals Shafi et al. (2022

al. (2000)
and associated data. Contains 75
datasets

Dataset for wearable stress and

emotion detection comprises
physiological and motion
information collected from 15
Multimodal

people during a lab experiment

Chandrasekaran et al. (2021a),
WESAD using both a wrist- and a chest-worn Philip et al.
Chandrasekaran et al. (2020),
dataset device. It contains the following (2018)
Chandrasekaran et al. (2021b)
information: Blood pressure, pulse,
electrocardiogram, electromyogram,
electrodermal activity, body
temperature, respiration, and three-
axis acceleration

6. CHALLENGES AND RECOMMENDATIONS

The prime outcome of a survey is to recognize the challenges and areas for further investigation. A few
notable challenges that were discovered during the survey of the research works carried out in this framework
are outlined below, tackling of which may help to identify future research problems.

• Although, all technologies are worth studying and have given equally important results, the most
frequently explored areas are for tapping insights from electronic medical records or electronic health
records (EHR/EMR). Integrated approaches are worth studying and newer models need to be employed
for modelling networks capable of tapping information from multiple data sources.
• Technologies like metabolomics and chaos needs to be explored more given the potentiality of the
theories. AI research in these areas is significantly less in number although they have shown solid results
in generating useful insights related to heart health.
• Incorporating multiple sources of information can enhance the accuracy of results, but it can be
challenging to use them in a standardized format (Shen, 2021). Despite some models employing hybrid
information, further research is needed to establish a standardized approach for modelling this data.
• To enable meaningful system experimentation and analysis, it is crucial to establish standard benchmark
datasets for metabolomics, chaos theory, and hybrid data. Without such datasets, the effort invested in
analysing the available and new data may not yield useful outcomes. Hence, combining datasets under
standardized benchmark categories can facilitate easier experimental analysis across different areas.
 • Ontologies play a vital role in information representation and management. In a critical domain like
heartcare, context information plays a vital role (Barton et al., 2014). However, only a few works have
emphasized the need of utilizing ontologies for encoding the knowledge. Further research in this direction
will be a fruitful research endeavour.
• The applicability of AI models for heartcare for the benefit of common man is a much-researched subject.
Among the existing technologies, metabolomics has huge potential to be employed by a common man
owing to its capability of identifying biomarkers from any DNA sample like sweat, urine, etc. However,
Explainability as such has not yet been exploited much in the metabolomics domain.
• Similarly, even though Explainability is popularly used for AI models in healthcare, studies have shown
a spiked use of explainable ai in heartcare however on EHR and EMR data. But other areas like ECG,
chaos and metabolomics are areas worth exploring where Explainability would definitely yield highly
reliable and insightful results.

7. CONCLUSION

The rapid technological advancements in the field of healthcare have posed critical concerns in its applicability.
Although, the advent of AI has revolutionized heartcare sector, the applicability of the various discrete
technologies in the different scenarios are still a dilemma. Each technology has its own features, necessity, pros
and cons which needs to be comprehended before choosing a right technology for IHD prediction. The proposed
framework surveys the use Ai and computer driven modelling on the various technologies ranging from historical
data analytics, data mining, machine learning and advanced deep learning models on health records, ECG,
metabolomics, and nonlinear dynamics. The nature of different datasets along with the challenges and future
recommendations have been outlined. Although, results of the enhanced AI models are available in all
technologies are promising, it is the need of the hour to improve trustworthiness in healthcare and certain areas
where they are rarely explored like non-linear dynamics and metabolomics. Additionally, intelligent heartcare
models have huge impact if could deployed onto edge devices which can easily be used by common man and can
serve as a lifesaving boon resulting in reducing the mortality rate to a huge extent.

REFERENCES

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