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Machine Learning Libro2
Machine Learning Libro2
Shivani Chandra
Artificial
Intelligence
and Machine
Learning in
Healthcare
Artificial Intelligence and Machine Learning in
Healthcare
Ankur Saxena • Shivani Chandra
Artificial Intelligence
and Machine Learning in
Healthcare
Shivani Chandra
Amity University
Ankur Saxena Noida, Uttar Pradesh, India
Amity University
Noida, Uttar Pradesh, India
ISBN 978-981-16-0810-0 ISBN 978-981-16-0811-7 (eBook)
https://doi.org/10.1007/978-981-16-0811-7
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Contents
v
vi Contents
7.4 Challenges.........................................................................................141
7.5 Summary............................................................................................142
References....................................................................................................142
8 Applications of Machine Learning Algorithms in Cancer
Diagnosis......................................................................................................................... 147
8.1 Introduction.......................................................................................148
8.1.1 Machine Learning in Healthcare.........................................148
8.1.2 Cancer Study Using ML......................................................149
8.2 Machine Learning Techniques..........................................................150
8.3 Machine Learning and Cancer Prediction/Prognosis........................152
8.3.1 Cancer: The Dreaded Disease and a Case Study
for ML..................................................................................152
8.3.2 Machine Learning in Cancer...............................................154
8.3.3 Dataset for Cancer Study.....................................................155
8.3.4 Steps to Implement Machine Learning................................157
8.3.5 Tool Selection for Cancer Predictions.................................158
8.3.6 Methodology, Selection of ML Algorithm, and
Metrics for Performance Measurement of ML
in Cancer Prognosis.............................................................159
8.4 Results and Analysis..........................................................................163
8.4.1 Liver Cancer Dataset...........................................................163
8.4.2 Prostate Cancer Dataset.......................................................168
8.4.3 Breast Cancer Dataset..........................................................174
8.5 Major Findings and Issues.................................................................179
8.6 Future Possibilities and Challenges in Cancer Prognosis..................179
References....................................................................................................180
9 Use of Artificial Intelligence in Research and Clinical Decision
Making for Combating Mycobacterial Diseases............................................183
9.1 Introduction of Technological Advancements and High
Throughput Data in Genomics and Proteomics Work.......................184
9.1.1 High Throughput Screening of Tuberculosis......................185
9.1.2 High Throughput Screening of Leprosy..............................187
9.1.3 High Throughput and Ultra-High Throughput
Screening of Compound Libraries for Drug Discovery
and Drug
Repurposing.........................................................................190
9.2 High Volume Data and the Bottleneck in Data Analysis..................192
9.2.1 Development of Omics Data...............................................192
9.2.2 NGS and its Use in Clinical Decision-Making,
Proteomics, Docking, Simulations, Drug Screening
(Repurposing of Drugs).......................................................195
9.3 Advent of Artificial Intelligence (AI) & Machine
Learning (ML)...................................................................................196
9.3.1 Machine Learning and Deep Learning (DL)
Algorithms...........................................................................196
Contents ix
xi
List of Figures
xiii
xiv List of Figures
Fig. 1.25 Output of different classifiers ..... .... .... .... .... .... .... .... .... ... 31
Fig. 1.26 Code for dividing the dataset into training and testing set . .. .. .. . 31
Fig. 1.27 Output of train and test size of dataset .............................. 31
Fig. 1.28 Code to train a model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
...........
Fig. 1.29 Confusion matrix of SVM model ................................... 32
Fig. 1.30 Confusion matrix of KNN model ................................... 32
Fig. 1.31 Confusion matrix of Naive Bayes model . . . . . . . . . . . . . . . . . . . . . 33
......
Fig. 2.1 Global prevalence of diabetes mellitus (Source: American
Diabetes Association). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
.......
Fig. 2.2 B a s i c flow chart of a disease diagnostic AI model .. .... .. . . ... . .. 42
Fig. 2.3 Reinforcement learning architecture .......... .......... .......... .. 44
Fig. 2.4 Machine learning applications in diabetes management . . . . . . . . . . 45
Fig. 2.5 Flow chart of methodology . 48
.................................. .......
Fig. 2.6 Confusion ma tr ix of k- means clus tering . 49
.. .... .... .... .... .... ... .
Fig. 2.7 Performance chart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
..........
Fig. 2.8 F1 scores of the classification models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Fig. 3.1 .
Most commonly used models of artificial intelligence
in healthcare ........................................................... 62
Fig. 3.2 Categories of machine learning used in personalized medicine.
The data is obtained by the search of algorithms in PubMed . . . . . 63
Fig. 3.3 Supervised and unsupervised learning models mostly used in
personalized medicine. The data is obtained by the search
of algorithms in PubMed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
...........
Fig. 3.4 Decision-making by classification in SVM . . . . . . . . . . . . . . . . . . . . 66
.....
Fig. 3.5 Process of the ANN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Fig. 4.1 ............
Artificial intelligence can help in gaining insights from the
heterogeneous datasets (clinical, omics, environmental,
and lifestyle data), mapping genotype-phenotype relationships,
and identifying novel biomarkers for patient diagnostics and
prognosis against a specific disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
..
Fig. 4.2 Application of artificial intelligence in various steps of drug
discovery process (Paul et al. 2020) . . . .... .... .... .... .... .... .... . 80
Fig. 4.3 Some examples of pharmaceutical companies collaborating
with artificial intelligence (AI) organization for healthcare
improvements in the field of oncology, cardiovascular diseases,
a n d central nervous system disorders (Paul et al. 2020) . . . . . . . . .. 84
Fig. 5.1 Modified VGG-16 model. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
.......
Fig. 5.2 Modified EfficientNetB4 model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
...
Fig. 5.3 Modifi ed In cep tion- Re sN et- V2 mode l . . 95
.. .... .... .... .... .... ... ..
Fig. 5.4 Modified Inception-V3 model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
....
Fig. 5.5 Comparison between accuracies on testing dataset generated
b y r e tr a in ed tr a n s f e r lea r n in g mod e ls 96
. . .. . . ... . ... . .. .. .. .. .. . ...
Fig. 5.6 Comparison between various evaluation parameters such as
accuracy, sensitivity, specificity, and area under the curve on
t e s t i n g dataset generated by retrained transfer learning models 97
..
List of Figures xv
Fig. 6.1 Daily COVID-19 confirmed, death, and recovered cases .. .. .. ... 105
Fig. 6.2 Highly affected regions for COVID-19 confirmed, active,
recovered, and tested cases in India ................................. 106
Fig. 6.3 COVID-19 confirmed, active, recovered, and tested cases
in India . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
................
Fig. 7.1 Flowchart of the study by Fang et al. to assess the performance
of CT scans for the detection of COVID-19 comparison
t o R T- PC R ( r e p r o d u c e d f r o m ( F a n g e t a l. 2 0 2 0 ) ) 116
. . . .. ............
Fig. 7.2 Chest X-ray image on day 3 of a COVID-19 patient (left)
clearly indicates right mid and lower zone consolidation; on day
9 (right) is seen worsening oxygenation with diffuse patchy
airspace consolidation in the mid and lower zones.
(Case courtesy of Dr. Derek Smith, Radiopaedia.org, rID:
75249) . .......................................................... ...... 116
Fig. 7.3 CT scan image performed to assess the degree of lung injury
of the patient in Fig. 7.2 on day 13 (left coronal lung window,
right axial lung window). Multifocal regions of consolidation
and ground-glass opacifications with peripheral and basal
predominance. (Case courtesy of Dr. Derek Smith,
Radiopaedia.org, rID: 75249) ...... ...... ....... ...... ....... ...... . 117
Fig. 7.4 Typical convolutional network framework for classifying
COVID-19 cases, which takes as input CXR images and passes
through a series of convolution, pooling, and dense layers and
uses a softmax function to classify an image as COVID-19
infected with kprobabilistic values between l0 and 1 . . . . . . . . . . . . . . . . 119
signal gc Fl! , kl!m to enable cross-layer connectivity.
(Reproduced m from (Khan et al. 2020a))..........................................123
Fig. 7.6 COVID-Net architecture. (Reproduced from (Wang and Wong
2020)) . . . . . ...................................................... ....... 123
Fig. 7.7 CoroNet architecture. AEH and AEP are the two autoencoders
trained independently on healthy and non-COVID pneumonia
subjects, respectively. TFEN is a Feature Pyramid-based
Autoencoder (FPAE) network, with seven layers of
convolutional encoder blocks and decoder blocks, while
CIN is a pre-trained ResNet-18 network.
(Reproduc e d fr o m (K ho b ah i e t al. 2 02 0) ) . 125
. . .. . . ... . ... . .. .. ....
Fig. 7.8 COVNet architecture. Features are extracted from each CT scan
slice which are combined using max-pooling operation and
submitted to a dense layer, which generates scores for the three
classe s . ( Rep r od u c ed fr o m ( L i e t a l. 20 20 )) 126
. . .. . . ... . ... . .. .. ...
Fig. 7.9 Block diagram of the subsystem (a) performs a 3D analysis
of CT scans, for identifying lung abnormalities, and subsystem
(b) that performs a 2D analysis of each slice of CT scans, for
xvi List of Figures
xix
Practical Applications of Artificial
Intelligence for Disease Prognosis 1
and Management
Abstract
Artificial intelligence (AI) is an emerging field, which provides enhanced
capabilities of decision-making to the machines. The extremely popular
applica- tion of machine learning approaches in the area of disease prognosis
and man- agement is the “precision medicine,” which can be described as deciding
the best treatment options based on features, such as attributes of the patients
and the
treatment undertaken. By knowing the hidden pattern of the data and its knowl-
edge, computers can predict the future events. Thus, it helps the machine to
learn effortlessly without any human intervention and makes easy to do
complicated decision- making process. The objective of this chapter is to
comprehend and explore the applications of artificial intelligence for the better
management of the early prognosis and treatment protocols for diseases. The focus
of the chapter will be towards the application of artificial intelligence techniques
to medical data management. These techniques can analyse different types of
data retrieved from patient samples, such as structured images, features based
on patient vitals for predicting the probability of the outcome of a disease and
design a better treatment protocol.
Keywords
Artificial intelligence · Disease management · Disease prognosis · MATLAB
· Predictive modelling
Maschinelles Lernen
Deep Learning
as the “thinking machine” (Wu 2019). This AI system responds to the stimulation
consistent with the traditional responses made by human and is provided with the
human capacity for contemplation, intention, and judgment. The AI helps the
computer/system to make decision, which normally requires human-level
expertise and helps people to predict or forecast the outcome or deal with issues as
they come up (Vijay 2013). According to the Darrell M. West (West 2018) report,
the AI system have three qualities, i.e. intelligence, intentionality and adaptability.
An intelligent system can be build using the umbrella of techniques under artificial
intelligence (AI) that performs human activities well (Fig. 1.1).
The machine learning (ML) is the subset of an artificial intelligence that helps a
computer/system to learn from the environment automatically without any human
intervention and applies that learning to make better decisions. Machine learning
uses its various algorithms or techniques to learn, characterize and improve the
data, so that it predicts better outcomes. The ML techniques/algorithms find the
patterns first and then perform the action based on these patterns. Machine
learning can be classified under four categories: (a) supervised learning, (b)
unsupervised learning,
(c) semi-supervised learning and d) reinforcement learning.
Supervised Learning
Supervised learning can be defined to be a type of machine learning, where both
the input and the output is provided to the system (Akella 2020). The algorithm
works by training the labelled data in a manner that the machine is able to learn and
develop patterns between the input and the output data. It finds the pattern that tell
us how we can categorize or classify datapoints in data. The labelled data means
known description, which is given to instances of data. For example, there are 20
different
1.1 Overview of Application of AI in Disease Management 3
people who have different symptoms with cancer test results. According to the test
results, we can place a tag or label to each patient, whether he/she is cancer
positive or negative. Hence, the labelled data provides a shape to output. So, the
process of supervised learning signifies that the machine will learn the pattern and
classify the data. Same patterns can be used to find the unseen data. Supervised
learning can be split into two forms:
(a) Classification: It is the supervised machine learning algorithm that classify the
input data from pre-defined classes. The algorithms help to predict the categorial
output from the labelled data.
(b) Regression: It is the supervised learning algorithm that finds the relationship
between the variables/features. The regression algorithm predicts the output
when the input is given by finding the relationship b/w the features.
• K-nearest neighbour.
• Support vector machine.
• Naive Bayes.
• Decision tree.
• Random forest.
• Linear regression.
• Logistic regression.
• Linear discriminant analysis.
Unsupervised Learning
The second category of the algorithms is the unsupervised learning. In this case,
the machine is only provided with the input values/data, and there is no fixed
output provided to the system. This is the reason why the unsupervised learning
algorithms doesn’t have labelled data. It predicts the output by finding the hidden
pattern from the input data. In comparison with the supervised learning, the
problem is not
properly defined in unsupervised learning. It is also called lazy learning, but it can
find a new way to solve the problem and predict the output from its own. In the
process of unsupervised learning of machine, an unlabelled input data is provided.
This data is used by unsupervised learning algorithm to hypothesize a pattern
within the data on its own. Using the pattern, datapoint instances are grouped.
Data matching with the similar pattern and group is predicted as the output
(Akella 2020). It is applicable in anomaly detection, segmentation, etc. The
unsupervised learning is of two types:
• Hierarchical clustering.
• K-means clustering.
• Principal component analysis.
• Neural networks.
• DBSCAN.
Semi-Supervised Learning
The third category of algorithm for machine learning is the semi-supervised learning,
which uses both labelled and unlabelled data to build a prediction model. The
difference between the above algorithms and semi-supervised method is that the
unlabelled data is more in number to the labelled data. Semi-supervised method
thus can be considered a fusion of both the supervised and unsupervised learning.
The algorithms of the semi-supervised learning include the following: heuristic
approaches, generative models, cluster assumption, graph-based methods, lower-
density separation, manifold assumption and continuity assumption.
Reinforcement Learning
The final category of machine learning algorithms is the reinforcement learning
that focuses on finding the best way to take in a situation that will maximize
correct outcome in a situation. The decisions are made sequence-wise. In each step
that the algorithm takes on the path to total outcomes, it can either have a positive or
negative output. The overall result is thus the sum of all positive and negative
outcomes along the path. The algorithm goal is to find the best way that maximizes
the outcome. The algorithms that come under reinforcement learning include Q-
learning, policy itera- tion and deep Q network.
Deep learning (DL) is considered to be a subclass of machine learning algorithms;
it can also be called the higher version of machine learning that forms multilayer
progressively to excerpt features/attributes from the input data to make better and
more reliable predictions. The deep learning (DL) provides the computer/system
the ability to understand the data from a lower level all the way up to the chain and
helps to improve the performance over time and make decisions at any time (Wu
2019). Deep learning (DL) methods are able to work on both supervised and
unsupervised tasks. It makes resemblance to many brain development theories of the
human brain. The deep learning (DL) algorithms/techniques include:
Prevention
Assistance
Diagnosis
Doctors
Treatment
Machine learning (ML) models in some cases still need intervention by humans
to get favourable outcome. The deep learning (DL) models uses artificial neural
network (ANN); it is designed in a resemblance of biological neural network of
the human brain. It analyses the structure logically like the human draws
inference.
AI, along with ML and DL methods, has led to a huge impact in the healthcare
sector. These approaches have allowed to undertake a number of innovations in
the domains of disease management, i.e. identification of biomarker of a disease,
disease prognosis and diagnosis, drug development and personalized medicine
(Fig. 1.2).
The rapid growing availability of healthcare medical data and advancement in
technologies, such as big data, has led to achieving the applications of AI in the
disease management (Datta et al. 2019). Artificial intelligence (AI) in disease
management helps people to have healthier and longer lives. Machine learning
(ML) techniques/algorithms, such as those discussed in the above section, have
the capability of solving complex healthcare concerns, by separating hidden
healthcare information from an enormous dearth of data quantity of data and help
in making informed decisions that help in disease management. An important
application of machine learning (ML) is the process of structuring the different
types of medical data, such as genomic data, imaging data, etc., and accurately
investigating the same. AI/ML uses these types of data and the extract the
potential features/attributes that can be assisted for disease screening/diagnosis and
prediction purposes and decision-making in disease treatment and management in
real time. This makes the work of clinicians less complex and provides better
understanding that helps in managing and treating the disease severity in the
patients.
Another important application of AI/ML has been observed in various stages of
drug development process. The utility of AI/ML techniques lies primarily in the
identification of drug targets and their validation, the repurposing of the drugs, the
design of new drugs, improvisation of the R&D processes of drug development
and analysing biomedicine data. AI/ML can lead to better decision-making for all
these applications, which would lead to faster clinical trials and less expensive
drugs.
Another field, wherein AI/ML plays a major role, is in the identification of
biomarkers for the disease and personalized medicine. The output generated from
the methods such as supervised ML can be successfully employed in the diagnosis of
6 1 Practical Applications of Artificial Intelligence for Disease Prognosis.. .
Disease prognosis and diagnosis are one of the most important aspects of disease
management. However, with the traditional clinical practices, predicting an outcome
of an underlying condition is very difficult (Croft et al. 2015). To solve this problem,
the disease prognosis was coming into trend that helps to predict the likelihood of
future outcomes of the onset of disease that was more useful for clinicians to give the
proper treatment to patients. The disease prognosis was still leading the limitation
in generalizability to local settings and validity of the study (Lee et al. 2017).
AI/ML leads to a robust transformation in the medical practice. It is helping the
doctors and clinicians to diagnose patients more accurately, making predictions
and prognosis about the patient’s future health, and help to suggest the required
treatment of a disease. Artificial intelligence (AI) may create many fears, mainly in
the clinical
setting, that AI could lead to the reduction of clinician expertise. However, there
has been a better acceptance and scope of AI/ML in the clinical setting, where it is
believed that these approaches will in turn benefit the clinicians to make better and
informed decisions. In a scenario, where a patient is suffering from multiple
comorbidities, relating the diagnosis to both the physical and genetic features
could be hard and time-consuming. In such cases, AI/ML could aid with the
clinicians quantitatively and qualitatively for an early detection and treatment plan
1.1 Overview of Application of AI in Disease Management 7
Artificial Intelligence
Data
Input
Image genetics EP
data Clinical Notes in Human Language
Output
Fig. 1.3 Overall process of the application of AI in disease prognosis and diagnosis
for a better outcome. Machine learning (ML) algorithms can be useful in the
principle for analysing the clinical data, such the data from the electronic health
records (EHR), imaging data and genetic data. The main objective of these
techniques is to cluster the patient’s characteristics for predicting the disease
occur- rence and outcome. The alternative approach is to analyse the information
from the
unstructured data generated from the clinical notes or medical journals. This is
achieved through the natural language processing (NLP) methods. This approach
is useful for converting the raw unstructured information into a machine-readable
format for analysis using sophisticated AI/ML algorithms. Application of these
methods, AI/ML can create a system, which is more accurate and efficient for
making the diagnosis and treatment protocols. For example: AI is used to obtain
phenotypic characteristics from case reports to enhance the accuracy of diagnosis for
congenital abnormalities (Fig. 1.3).
In the recent decade, there have been much advances and better treatment
modalities for the major life-threatening diseases, such as cardiovascular
disorders, neurological disorders and cancers (Zheng et al. 2005). There have been
reports where AI is able to make an early diagnosis of cardiovascular disorders
using the image data of cardiac patients (Dilsizian and Siegel 2014), such as CT scan
and ECG scan data. Likewise, AI/ML has a tremendous potential in the management
of stroke- related cases, through early prediction, forecasting and prognosis of stroke,
for better treatment and assessment. A device was built that helps in the early
diagnosis of stroke, using machine learning algorithms (PCA and fuzzy) that learn
and under- stand the patients in human detection phase, and starting stroke phase,
the device/
8 1 Practical Applications of Artificial Intelligence for Disease Prognosis.. .
model was able to detect the stroke and can stimulate and assess the medical
action, thus making it feasible (Villar et al. 2015). The confirmatory accurate
diagnosis and also treatment in neurological disorders are still lacking. Here,
artificial intelligence (AI) in neurosciences provides the better understanding of
intelligent working of biological brains. AI/ML aims to mimic the human thinking
functions. A study was done to predict the neurological disorders in the people and
its conditions using machine learning techniques (KNN, HMM, MLP and Bayes),
the predictions made on brain oscillation characteristics, sleeping and neonatal
data. Many AI/ML-based automated CAD systems have been built that include
various classifier algorithms (SVM, ANN, KNN, etc.) developed for different
neurological disorders, such as
Parkinson’s disease, Alzheimer’s disease, etc. (Raghavendra et al. 2019).
AI/ML has been utilized to develop devices that are useful in monitoring tremors
which are helpful for better detection of epileptic conditions. The application of AI
integrated electroencephalogram learning can help in preventing the sudden unex-
pected death in epilepsy (SUDEP) (Patel et al. 2019). A study says artificial neural
network (ANN) gave the highest accuracy (>95) in Parkinson’s disease detection,
and the SVM algorithm knows to be a successful algorithm in predicting the severity
of symptoms (Belić et al. 2019).
In oncology, the IBM Watson has developed a system that can be reliable for
the identification of cancer at an early stage. Different algorithms and classifiers have
the potential of offering prognosis for cancer patients (Huang et al. 2020). For
example, this clinical image can be examined using AI/ML techniques for recognizing
the skin cancer subtypes. The quick diagnoses and prognosis can potentially reach
through- out the recovering of the analysis measures on electronic health records
(EHR) or electrophysical (EP), imaging and genetic data, and this shows the
power of AI. Apart from these three main diseases, the AI/ML techniques had
been used in other diseases also: for example, AI/ML is able to examine the ocular
image data for the diagnosis of all cataract diseases.
Biomarkers are defined as the quantifiable entities that are observed in biological
fluids that provide an understanding of whether a patient has a disease. The
biomarkers are the measurable indicators that help to give an idea about the presence
or severity of a disease, infection or exposure. Thus, biomarker is very useful for
disease diagnosis/prognosis, drug design and development precision medicine.
The biomarkers play various roles for curing a disease of patients by knowing the
exact stage of disease (Reddy 2019). It can be classified as:
• Prognostic biomarker.
• Diagnostic biomarker.
• Risk biomarker.
• Predictive biomarker.
1.1 Overview of Application of AI in Disease Management 9
Multidimensional Data
Fig. 1.4 AI/ML techniques help to identify the biomarker of a disease from multidimensional data
genes, in a study network that was built to identify the most potential biomarker
CREB1 that helps to know the progression of prostate cancer (Pawar et al. 2020).
Biomarkers are also used to predict the longevity of a person, called longevity
biomarker. The longevity biomarker combined with AL/ML techniques has the
ability to cure the age-associated disorders and helps to improve the lifespan
(Colangelo 2020). In a recent scenario, digital biomarker is in fashion, such as Fitbit,
Misfit, Jawbone, Apple Health, Sleep as Android, WIWE, Moca Care and
Skeeper—in other words, fitness trackers, step counters, health apps, sleep
sensors, pocket ECG, blood pressure or other health parameter measuring devices
are very
popular nowadays (The Medical Futurist 2018). The digital biomarkers are the
data that the consumers instantly get the information about the health and disease
management from digital health technology that describes, controls and predicts
the health-related outcome. The AI/ML technologies collect and analyse and make
patterns from a large amount of data (e.g. EHR records) to create a digital
biomarker (McCarthy 2020).
time. AI/ML techniques help to identify and validate the drug targets, de novo
drug design and drug repurposing more accurately. Using artificial intelligence
(AI), R&D efficiency has been also improved. This can be achieved by the
collection and analysis of the biomedical data, which can help in better decision-
making clinical trials. The potential uses of AI offer the chances of solving the
inadequacies and ambiguities that are witnessed by the traditional drug discovery
protocols and avoid any bias generated due to the human intervention. The role of
AI in drug development can be further detailed through Fig. 1.5.
The application of AI in the field of drug development is observed in the
prediction of synthetic paths of drug-like compounds (Merk et al. 2018),
identifica- tion of the pharmacological properties, characterization and efficacy
testing of protein receptors and analysing the association between the drugs and
the targets (Schneider 2017). Using AI/ML techniques, it is possible to identify
pathways of the targets, using the omics-based data, and this could lead to
generating new biomarkers and identify the therapeutic targets. This will further
pave the way for personalized medicine and uncover better relationship between
the disease and the drug efficacy. Deep learning methods had shown excellent
response in suggesting prospective drug compounds and precisely predict the drug
properties, by analysing the toxicity of the drugs for risks in its administration. AI
has been pivotal in solving number of problems of analysing the larger datasets
and can help improvise the screening of number of compounds, which is a lot
time-consuming process (Mohs and Greig 2017). Some of the examples of AI in
drug development can be seen through a study, where the therapeutic targets were
predicted using computational approaches, which were referred to as open targets.
This is a large collection of the disease and gene association. Further, in this study,
it was predicted that using a neural network classifier of more than 71% has the
maximum potential of better
12 1 Practical Applications of Artificial Intelligence for Disease Prognosis.. .
animal models (Ferrero et al. 2017). Another major milestone was achieved by the
IBM Watson for the Drug Discovery Group. This group has developed an AI-
based platform, which was able to identify RNA-binding proteins, which were linked
to the occurrence of amyotrophic lateral sclerosis (ALS) (Bakkar et al. 2018).
Through previous literature, thus, we can infer that AI/ML plays a major role in
the process of drug development at many levels. The application of AI/ML can
lead to a much faster processing for the drug development and can also provide
better accuracy with the drugs being identified. Methods, such as supervised
learning, involving classification and regression methods can help in the diagnosis
of the diseases, drug efficacy and ADMET prediction (Guncar et al. 2018).
Alternatively, unsupervised methods are useful in the discovery of disease
subclasses through clustering techniques. The third category of algorithms, such as
reinforcement learning, can be useful for predicting the de novo designing of
the drugs (Chen et al. 2018). Thus, AI/ML can be highly useful as a tool for the
identification of new compounds and repurpose the existing drugs.
1.2.1 KAGGLE
1.2.2 Csv
The comma-separated list (CSV) is one of the most common file formats
supported by the Kaggle. It is usually accessible for tabular data. CSVs uploaded
in Kaggle should have field names on the header row in a readable format. On
clicking “Data”
tab of a dataset, a preview of the file’s contents is visible in the data explorer. This
makes it significantly easier to understand the contents of a dataset; an example is
shown in Fig. 1.7, as there is no need to open the data in a notebook or download
it. CSV files will also have associated column descriptions and column metadata.
The column descriptions allow you to assign descriptions to individual columns of
the dataset, making it easier for users to understand what each column means.
1.2.3 JSON
JSON is also the most common file format for tree-like data that provides multiple
layers, such as the branches on a tree. For example:
For JSON files, the data tab will present an interactive tree with the nodes in
the JSON file attached. You can click on the individual keys to open and
disintegrate sections of the tree and can explore the structure of the dataset as you
go along with it. JSON files do not support column descriptions or metrics.
1.2.4 SQLite
Kaggle supports database files in the form of lightweight SQLite format. SQLite
databases consist of multiple tables, and each of it contains data in a tabular
format. These tables support large datasets better than CSV files. The data tab
represents each table in a database separately. The SQLite tables include column
metadata and column metrics sections.
Fig. 1.7 An example to show the preview of the file’s contents is visible in the data explorer by
clicking on the data tab of dataset on Kaggle. (www.kaggle.com)
14 1 Practical Applications of Artificial Intelligence for Disease Prognosis.. .
1.2.5 Archives
Archives are not a file format, but Kaggle also supports for files compressed using
the ZIP file format as well as other common archive formats. These compressed
files take up less space on the disk in comparison to uncompressed files, thus
making them faster to upload to Kaggle and allowing you to upload datasets that
will otherwise exceed the dataset size limitations. The archives do not populate
with previews for individual file contents, but you can still browse the contents by
the file name. The ZIP files and other archive formats can be the best choice for
making image datasets available on Kaggle.
Datasets in Kaggle website is not a common Machine Learning (ML) dataset.
Every dataset present in Kaggle consist of a community where people could
discuss about data, discover new logic and methods from existing code and can
create their own ML project using dataset in the Kaggle notebooks. We can find
many different interesting datasets from all the field of all shapes and sizes. We
can find the dataset through the data tab columns, newsfeed (if you logged in
website) and tags and by searching the interested dataset from the search box (Fig.
1.8).
Fig. 1.9 UCI machine learning repository home page (including search box). (archive.ics.uci.edu)
The archive has put up a great impact; till now, it’s been cited about more than
1000 times and makes its presence in computer science field in one of the 100
most
cited papers. By clicking the dataset description, tab users will be able to get the
details about a particular dataset; they can even search for the desired dataset through
the search box tab or by clicking on “View ALL Datasets” tab. The users even can
download the datasets, which is divided into various categories, for example,
according to the size of the dataset, or dataset can be used for a particular machine
learning method. We can view all dataset present in UCI Machine Learning by
clicking “View ALL Datasets” tab shown in Figs. 1.10 and 1.11. Currently, there are
507 datasets present in the repository.
For ease in searching the suitable dataset for AI/ML/DL task, the UCI Machine
Learning Repository provides the columns “Browse Through:” shown in Fig. 1.11,
in different sections such as “Default Task”, “Attribute Type”, ‘Data Type”,
“Area”, “Attributes” and “# Instances”. These section helps to filter searching, so that
we can get our interested dataset for our task. When we select dataset and
click on it,
16 1 Practical Applications of Artificial Intelligence for Disease Prognosis.. .
Fig. 1.11 List of datasets present in UCI Machine Learning Repository after clicking “View ALL
Datasets” tab. (archive.ics.uci.edu)
repository will provide all the information and also include the case study about
dataset in new window. From the “Data Folder” tab, we are able to download dataset
file present in that directory. The “Data Description” tab provides a description about
the dataset (Fig. 1.12).
1.2.7 HealthData.gov
Fig. 1.12 Example of dataset window opened in UCI Machine Learning Repository. (archive.ics.
uci.edu)
Logistic regression model is the type of supervised learning technique that predicts
the probability of a dependent qualitative variables. The logistic regression was
termed as a function, which states an algorithm method known as the logistic
function. It is a sigmoid function which forms a S-shaped curve, in which we can
take any real value number that will be converted into a value that will be between
1 and 0, but that value will not be equal to 1 or 0 (Brownlee 2016).
1= 1 þ e—value
Here, e is represented as base of the natural log, and -value in the equation is
represented as the real number value that is needed to be transformed. This
function provides a plot that shows the numeric values — between 5 and 5, in which
logistic function is used to convert these values into the range of 1 and 0. The
algorithm on the basis of logistic function works is called maximum likelihood
estimation (MLE). MLE calculates the regression coefficient of the model that
provides an accurate probability prediction of binary-dependent
categorical/qualitative variables. The MLE algorithm works in an iterative process;
thus, it will stop when the convergence criteria will meet. Therefore, any event will
have its probability between 1 and 0.
Logistic regression is represented by an equation, which looks similar to linear
regression equation. The input values/instances (x) are linearly combined to value of
coefficient or we can refer to them as weights which predicts the value of an
output ( y) (Brownlee 2016).
The equation of logistic regression:
eðb0þb1ωxÞ
y¼
ð1 þ eðb0þb1ωxÞ Þ
Here, y is represented as the output which is predicted, b1 is called coefficient
of the input value x (single value) and b0 is the intercept. Input data in each
column is associated with b coefficient (constant value), which can be obtained with
the help of train dataset. The description of the model will be saved in a memory or
file, which consists of coefficients.
The dependent categorical variable in the logistic regression model is called the
binary variable, which contains an encoded numeric value 1 (e.g. positive) or 0
(e.-
g. negative). The model predicts p(y¼1), which is the function of x. Logistic
regression algorithm fits the model that consists of binary classification data in an
accurate manner by finding the best path for it. The logistic regression models are
called to be members of generalized linear models. The logistic regression model
predicts the probability of values between the range of 1 and 0. The prediction of
probability through the logistic regression algorithm seems to be more accurate
1.3 Review of Artificial Intelligence Techniques on Disease Data 19
compared to other classifiers such as Naïve- Bayes, KNN, etc. The coefficients,
which are formed by logistic model, provide a significance for each input value/
variable. The logistic regression models are mostly applicable, if the given data is
categorical in nature, for example, cancer is malignant or not (1,0).
Logistic regression model is mostly used for classification task. It does not require
to find any linear connection between dependent and independent variables. It is
already able to manage different types of relations by using a non-linear log
transformation to the predicted odds ratio. The model is useful in avoiding
underfitting and overfitting. The logistic regression model needs large dataset,
which is required for maximum likelihood estimation (MLE). It is difficult for the
model to estimate MLE on small dataset.
There are three kinds of logistic regression model:
1. Binary logistic regression: Known as the categorical data, which contains two
possible outcomes. For example: infected (1) and not infected (0).
2. Multinomial logistic regression: The categorical data, which contains more than
two possible outcomes. For example: severe disease (1), mild disease (2) and
no disease (0).
3. Ordinal logistic regression: When there are more than two categories in an
order wise. For example: hospital facility rating from 1 to 5.
1. Input layer: It takes input values or non-dependent variables for building a model.
2. Hidden layer.
3. Output layer: It generates predictions.
The process of artificial neural network (ANN) model is shown in the flow
chart given in Table 1.1 (Fig. 1.14).
All the linkages present in the artificial neural network (ANN) model has the
same calculation. A sigmoid relation is presumed between the input nodes and the
20 1 Practical Applications of Artificial Intelligence for Disease Prognosis.. .
By employing the linkage and the inputs between both the input and hidden node,
we activation rate of the hidden node is calculated.
Activation-rate of the output nodes is calculated activation- rate of hidden nodes and
linkages output nodes
Error-rate of the output nodes is calculated and links are adjusted between hidden and
output nodes
calculated weights and error at output node will be used to drop the error to
hidden nodes
This procedure will be repeated in an iterative manner, till the convergence criteria
are met
1
¼
ð1 þ eð—f :ÞÞ
The artificial neural network (ANN) algorithm helps to understand the increase/
decrease of dataset impact and understand the situations where the model fits the
best. The artificial neural network (ANN) model is very useful in disease
management-related problem, such as disease diagnosis, cancer prediction, speech
recognition, duration of disease prediction (HIV-AIDS) (Park and Chang 2001),
image prediction analysis and its interpretation. For example: an automated
electro- cardiographic (ECG) was implemented, which was useful in the
diagnosis of myocardial infarction (Bartosch-Härlid et al. 2018) and drug
development. It is also applicable in non-clinical problems that include
improvement in the organiza- tional management in healthcare fields (Goss and
Vozikis 2002), predicting the key indicators, such as the cost price or utilization of
facilities (Kaur and Wasan 2006). Artificial neural network (ANN) model usually
is used as a decision supporting model that helps the healthcare suppliers and the
healthcare system with a cost- effective solution to time and resource handling
(Nolting 2006).
• Support vectors: The support vectors are called datapoints, which are located near
to the optimal hyperplane. Support vector helps to define the separating line.
• Hyperplane: Hyperplane helps to divide the dataset into classes.
• Margin: Margin tells the distance between the datapoints from different classes
based on support vectors.
• SVM kernels: The SVM kernels help to separate the non-separable datapoints
efficiently by adding more dimension to it. The types of kernel are:
– Linear
– Polynomial
– RBF In SVM model process, the first aim is to identify the points from the
given two classes, which is nearest to the hyperplane. These identified points
are
called support vectors. After that, the model will calculate the distance between
the hyperplane and the support vectors shown in Fig. 1.11. This distance
between them is called margin. The main goal is to increase the margin, and for
that, process goes on iteratively. The hyperplane, which has the highest
marginal rate, is called suitable separating line for dividing the two classes
(Pupale 2018). SVM model builds the decision-based separating line in such a
precise manner, in order to have a division between the two classes as wider as
possible. The SVM model works well in high-dimensional spaces. Its relative
memory is efficient. The SVM model is very useful in situations such as when
dimensions of the data are higher compared to instances of number. The SVM
model is very useful in predictive modelling, such as in the diagnosis/prognosis
of disease (e.g. breast cancer) (Patrício et al. 2018), identifying and classifying
the genes and patients on the basis of genes or other biological problems. SVM
modelling is called to be an optimistic approach for predicting medication
adherence in heart failure patients (Lee et al. 2010). A device e-doctor is a web-
based application that makes an automated diagnosis about health-related
problems (Karakülah et al. 2014). The device was built on SVM
model/algorithm that analyses the data and then proceed to decisions, based on
their knowledge. With the help of EHR record data, the SVM model is able to
understand each health-related problem that can be diagnosed by the device
(Kampouraki et al. 2013).
women. The main element of danger for this neurological disease is age factor. As in
many cases, people suffering from Parkinson’s have their early-stage encounter with
the disease at the age of 60; about more than 5 per cent of people suffering from
Parkinson’s disease encounter with early stage of disease that may begin at their 40s.
The outset of this disease is frequent; it may be inheriting, or some forms could be
linked to a specific gene mutation (Michelle 2019).
Parkinson’s disease impaired the nerve cells, which is an important part of the
brain that maintains and controls all the movement within the brain. A chemical
called dopamine is produced by the nerve cells, which is important for brain
working. But due to Parkinson’s, these nerve cells get damaged, and when dopamine
production gets low, it causes difficulty in movement. The researchers still do not
know what are the reasons that lead to the death of the nerve cells that produce
dopamine. Parkinson’s also affects the patient’s the nerve cell terminal, which
produces the chemical known as norepinephrine; it is a chemical messenger,
which is crucial for sympathetic nervous system, that helps to supervise various
involuntary body functions, such as breathing, heart beating, blood pressure and
reflexes. The loss of norepinephrine may cause panic attacks, stress, fatigues, high
blood pressure, depression difficulty in digesting food, hypotension, etc.
The symptoms of Parkinson’s disease are:
Some other symptoms are depression, mood swings, difficulty in eating and
speaking, constipation and sleep disruptions. There are still gaps in treating
Parkinson’s disease. There is no confirmed medical test is that can surely reveal
Parkinson’s disease. Thus, it causes difficulty in diagnosing the disease accurately.
Even after diagnosis, there is still no such confirmed remedy for Parkinson’s disease.
There are some medications used to manage the disease but still not very much
effective.
The artificial intelligence (AI) and machine learning (ML) are emerged as a
new weapon that helps to fight with Parkinson’s disease. The AI/ML techniques
help clinicians/neurologists to diagnose the disease and understand the disease
prognosis. Artificial intelligence (AI) and neurological disorders in combination
will help researchers to have strong insights on disease progression, so that they
will be able
to develop full proof plan for more effective treatments than performing the tradi-
tional medical diagnosis treatment that take lot of time to reveal. With the help of AI,
the costs related to treatment and healthcare system will be reduced. In a study, a
model was proposed on thalamocortical dysrhythmia (TCD) that was used to give
a brief detail on the different types of neurological diseases. It was distinguished
through an oscillatory pattern, in which the resting-state alpha activity was taken
over from cross-frequency coupling of high- and low-frequency oscillations
(Vanneste et al. 2018). Support vector machine (SVM) learning was used as a
24 1 Practical Applications of Artificial Intelligence for Disease Prognosis.. .
two classes: class 1, Parkinson’s disease patient [1], and class 2, healthy person
[0]. After retrieving, we will import the Parkinson’s disease data in MATLAB
editor script using “readtable ( )” function (Fig. 1.15).
By running this code, the given dataset will be imported in MATLAB, and our
dataset will be seen in the command window of MATLAB shown in Fig. 1.16.
The dataset looks like this in MATLAB.
Data preprocessing is the process that is used to prepare/format the raw data, making
it suitable for building machine learning model. It is a one of the major processes
required for building ML model. The data preprocessing step includes the following:
checking missing value, categorical data dealing and feature scaling (standardization
or normalization).
After running this code, a logical table will form the dataset in the command
window, where “0” is denoted as “no missing value” and “1” is denoted as
“missing value”. The output of our dataset doesn’t show any missing value, which
is shown in Fig. 1.18.
Like this, we can identify the missing value in a dataset easily.
Outlier Detection
An outlier is called an instance, which diverges from an overall pattern on a
sample that could affect in implementing the machine learning model. On
MATLAB, we can analyse and detect outlier using MATLAB function “isoutlier( )”,
which helps to identify the outlier in dataset; if there is outlier in the dataset, we
can remove it is using ¼“rmoutlier(data, method)” method
mean/median/quartiles/grubbs/gesd. We
will check outlier on the dataset and the code will again give the logical table, where
“0” is denoted as no outlier and “1” is denoted as outlier, and if there is any, we will
remove it (Fig. 1.19).
So, like this, we can detect and analyse the outlier in the dataset.
1.4 Case Study: Parkinson’s Disease Prediction 27
Feature Scaling
Feature scaling is a method that standardizes the features present in the dataset
into a given fixed range. The feature scaling step, using the standardisation
method, is needed on the given dataset, because the given dataset contains
datapoints with different ranges. Thus, it needs to be in standardized range;
otherwise, it will create problems in building classifier, as many classifiers (such
as SVM) are sensitive to ranges of datapoints. The standardization formulae will use
a code for feature scaling step on MATLAB. The formulae of standardization are
given below:
Xnew ¼ Xi — Xmean=Standard Deviation
We will apply feature scaling step on the features of the dataset, not on the
label class (Fig. 1.20).
After feature scaled step, the given dataset gets scaled. The data preprocessing
part is completed. Now, we will do the feature selection from the given
Parkinson’s disease dataset that helps to reduce the overfitting problems and can
provide good accuracy of machine learning (ML) model. For feature selection, we
will be using the principal component analysis (PCA) algorithm on a given
dataset. PCA is a ML
method/technique that helps to reduce the dimensions of multivariate datasets
28 1 Practical Applications of Artificial Intelligence for Disease Prognosis.. .
Fig. 1.22 Output of explained variance percentage along with graphical representation
In predictive modelling part, we will first divide the given dataset in train and test set.
The ideal ratio for the division of dataset is 80:20, 60:40 and 70:30. Here, we will
divide the given dataset into 60:40 ratio as train (60%) and test/validation (40%)
set. The cvpartition( ) MATLAB function helps to do random partition on set of
data to a specific size. The holdout method does the partition of data exactly into
two part or subset for training and validation (Fig. 1.26).
The given dataset has 195 instances; therefore, according to 60:40 ratio, the above
code will divide the dataset of 117 instances as train size and 78 as test/validation
size shown in Fig. 1.27.
After train and test division, will we now train our classifier/model (SVM,
KNN and Naive Bayes) on train set (consists of 117 instances). Crossval ( )
function helps to cross-validate the classification model, which means, it helps to train
the model on train set, and this is done by putting cv in code. We train the
models/classifiers only one time (Fig. 1.28).
30 1 Practical Applications of Artificial Intelligence for Disease Prognosis.. .
Fig. 1.24 Building classifier (SVM, KNN and Naive Bayes) code
1.4 Case Study: Parkinson’s Disease Prediction 31
Fig. 1.26 Code for dividing the dataset into training and testing set
In the performance validation part, the trained model/classifier (SVM, KNN and
Naïve Bayes) will make prediction on test or validation or unseen data (78 instances),
called performance validation. The prediction made by the predictive model will
1.4 Case Study: Parkinson’s Disease Prediction 33
show results in a form of confusion matrix. Confusion matrix helps to know the
performance of a predictive model. It shows the ways, in which a predictive model
gets confused in making predictions. The correct and incorrect prediction numbers
are sum up with values and divided into each class. The prediction is made by
SVM, KNN and Naive Bayes models, and confusion matrix is shown in Figs.
1.29, 1.30 and 1.31:
In the above figures, there are two classes: “0” is denoted as “healthy person” and
“1” is denoted as “Parkinson’s disease patient”. The other terms mean:
• True positives (TP): These are the instances which the model predicted as “0”
(healthy person), and in an actual case also, they are healthy persons.
• True negatives (TN): These are the instances which the model predicted as “1”
(Parkinson’s disease patient), and in an actual case also, they are Parkinson’s
disease patients.
• False positives (FP): These are the instances which the model predicted as “0”
(Healthy Person), but in an actual case, they are Parkinson’s disease patient.
This type of error is also called a “Type I error.”
• False Negatives (FN): The instances which model predicted as “1” (Parkinson’s
disease patient), but in actual case, they are healthy persons. This type of error
is also called a “Type II error”.
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Abstract
According to the ninth edition of IDF Diabetes Atlas 2019, the worldwide
prevalence of diabetes mellitus in 2019 was 463 million and has been estimated
to escalate to 700 million, owing to a 51% increase in diabetes cases by 2045. It
consequentially increases the risk of cardiovascular diseases by 3%,
nephropathy by 5.9% and neuropathy by 10%. Another troublesome factor is
the healthcare expenditure for diabetes management; the average diabetes-
related health expen- diture per person has multiplied 2.38-folds between the
years 2010 and 2019. This chapter aims to enhance our understanding on the
predictability of the onset of diabetes mellitus. We have developed built
multiple (no.) machine learning models based on Pima Indians of Arizona, a
niche which is highly susceptible to diabetes, and sourced the dataset from the
National Institute of Diabetes and Digestive and Kidney Diseases, which will
help the readers to understand that this
emerging information technology is becoming society’s most progressive tool
and further may effectively use the information for their research endeavours.
Keywords
Diabetes mellitus · Artificial intelligence · Machine learning · Classification
2.1 Introduction
deaths every year. According to WHO projects, diabetes deaths will double
between 2005 and 2030 (Sarwar et al. 2010).
Over the years, developments in information technology, statistics and
computer has inspired many researchers to employ computational methods and
multivariate statistical studies to analyse disease prognostics, which outpace the
accuracy of empirical studies. This chapter will highlight the artificial
intelligence (AI) approach especially machine learning for diabetic predictions.
We explore how AI assists diabetic diagnosis and prognosis, specifically with
regard to its unprecedented accuracy, which is even higher than that of general
statistical appli- cation. We also constructed the model-based different approaches
and attributes. Finally, comparison has been executed based on classification of
model, which can be considered as clinical implementation of AI. Hence, this
chapter delivers a novel perspective on how AI can expedite automated diabetic
diagnosis and prognosis, contributing to the improvement of healthcare in the
future.
T2DM
90%
protein tyrosine phosphatase and ZnT8A zinc transporter protein against the
pancreatic β cells is the diagnostic of this disease. These individuals are highly
susceptible to ketoacidosis. Risk factors for type 1 diabetes are family history
(genetic predisposition), autoantibodies, environmental factors, dietary
deficiencies such as low vitamin D and specific geographic locations such as
Sweden and Finland (Knip et al. 2005).
2. Type 2 diabetes, also termed as non-insulin-dependent condition that majorly
affects the adults (20–79 yr. old), contributing to 95% of prevailing diabetes
cases, is associated with obesity and insulin resistance that leads to decreased
insulin production overtime. Study suggests that insulin resistance might improve
with weight loss and treatment of hyperglycaemia but it can rarely be brought
to
normal levels. There are multiple risk factors for type 2 diabetes and
prediabetic individuals: obesity, physical inactivity, age, susceptible race
(Hispanics, Ameri- can Indians), hypertension, polycystic ovarian syndrome,
gestational diabetes mellitus and anomalous cholesterol and triglyceride levels.
3. Gestational diabetes mellitus is observed in 7% of all pregnant women world-
wide. It often occurs due to hormonal imbalances that occur during pregnancy,
leading to insulin resistance that subsides after pregnancy (American Diabetes
Association 2015). Common risk factors for GDM are age, obesity, family
history and susceptible race.
Pharmaceutical Therapy
The basic medication provided to individuals suffering from type 1 diabetes mellitus
is insulin treatment to counter this autoimmune disease. In patients where this
therapy is inefficacious, beta cell transplants and autoimmune blocking drugs are
in clinical trials (Szadkowska et al. 2006; Szadkowska et al. 2008; Pietrzak et al.
2009). Metformin is the most commonly used medication, along with sodium-
glucose co-transporter 2 inhibitors sold under the names phlorizin, dapagliflozin,
amylin analogues, glucagon-like peptide 1 receptor agonists (exenatide,
liraglutide) and di-peptidyl peptidase-4 (saxagliptin, vildagliptin) inhibitors
(Frandsen et al. 2016; George and McCrimmon 2013; Otto-Buczkowska and
Jainta 2018). Non- glycaemic treatments employ angiotensin-converting enzyme
inhibitors, such as ramipril, often used in the cases of patients with nephropathy
(National Collaborating Centre for Chronic Conditions (UK) 2008).
Self-Monitoring
Structured and personalised self-monitoring of blood glucose (SMBG) is an
organised method of observing glucose levels that reveals glycaemic patterns
throughout the day. Presently it is theorised that glycaemic variability contributes
to diabetes complications independently of glycosylated haemoglobin (HbA1c)
levels. To assess diurnal glucose excursions, SMBG has also been established as a
useful tool as it helps to monitor diet control and treatment response and in general
increases a patient’s understanding of hypoglycaemia, thereby reducing their anxiety
(J Meneses et al. 2015; Kirk and Stegner 2010; Schnell et al. 2013).
Although the pharmacological management of diabetes is sought after and
provides several therapeutic opportunities, particularly in the type 2 diabetes
mellitus, the changes in the lifestyle are essential: by maintaining proper diet and
2.3 Role of Artificial Intelligence in Healthcare 41
physical activities, one can reduce obesity associated with this type of diabetes
(Nathan et al. 2009).
of false positives and therefore provide improved accuracy in the detection of diverse
diseases (Ahmed et al. 2020).
for classification of new data. The accuracy from this ANN-based classification
model was 96%.
Juan Wang developed a deep learning-based model for the detection of cardio-
vascular diseases. This model consists of a 12-layer convolutional neural network
to distinguish breast arterial calcifications (BAC) from non-BAC and applies a
pixel- wise, patch-based method for BAC identification. The performance of the
system is evaluated by employing both free-response receiver operating characteristic
(FROC) analysis and calcium mass estimation (Parthiban and Srivatsa 2012). The
FROC analysis indicates that the deep learning technique achieved a level of
detection comparable to the human experts. The calcium mass quantification test
revealed that the inferred calcium mass is close to the actual values showing a
linear regression, which yields a coefficient of determination of 96.24%.
Parthiban and Srivatsa (Challa et al. 2016) designed a machine learning model for
the diagnosis of heart diseases. By using naive Bayes algorithm, an accuracy of
74% was achieved. SVM provided the highest accuracy of 94.60. K. N. Reddy and
his co-worker have created an automated diagnosis model for Parkinson’s disease
by employing multilayer perceptron, random forest, Bayes network and boosted
logistic
regression (Burkov and Lutz 2019). Amongst the four models boosted logistic
regression algorithm obtained the highest accuracy of 97.16% with an n area
under the ROC curve of 98.9%.
Supervised Learning
• The dataset is a pool of labelled examples.
• The goal of a supervised learning is to use the dataset to produce a model that
takes a feature vector x as input and output information that allows deducing
the
label for this feature vector.
• It majorly solves classification and regression problems.
• Decision trees, random forest, k-nearest neighbours and logistic regression are the
examples of supervised machine learning algorithms.
Unsupervised Learning
• The dataset is a pool of unlabelled examples.
• The goal of an unsupervised learning is discover hidden pattern within the dataset
where the output is not predefined.
• It can solve complex clustering and association problems.
• k-means for clustering and a priori algorithm for association are the examples
of unsupervised machine learning algorithms.
Semi-Supervised Learning
• This combination will contain a very small amount of labelled data and a very
large amount of unlabelled data.
• The goal of a semi-supervised learning algorithm is to improve supervised
learning algorithm by using unlabelled data.
• It can solve problems of classification, regression, clustering and association.
Reinforcement Learning
• The machine is thriving in an environment where it recognises the state of that
particular environment as feature vector in data.
• Each action brings different kind of rewards and can transfer the agent to
another state (Sutton 1992).
• The goal of reinforcement learning is to make the system learn a policy.
• The policy is a function of the feature vector of a state that is considered as an
input, and the outputs are an optimal action to implement in that state.
• If an action is ideal, it maximises the anticipated average reward. A simple
figure describing the architecture of reinforcement learning is shown in Fig. 2.3
(Bishop 2006).
2.5 Machine Learning 45
There are several applications of diabetes based on machine learning (Fig. 2.4).
Insulin Controller
An automated artificial pancreatic system improves the efficiency of glucose
moni- toring and liberates a patient from the hectic treatment regimen. Essentially the
three major parts of an n artificial pancreas are the continuous glucose monitoring
system, smart insulin controller and insulin delivery pumps (Bothe et al. 2013).
For critical patients specifically studies are being conducted to develop algorithm
for accurate insulin dose prediction and diet regimes that will be used as
temporary management of glucose levels.
Reinforcement learning (RL) algorithms regulate insulin in a closed loop to
deliver patient-specific insulin dosage plans that are responsive to the instant needs
of the patients. RL provides advantage of expansion to infinite state sets, which
allows the measurement of the variations in the glycaemic levels throughout
CGM. However, the method has been vastly used in silico, so the success of RL
algorithms for CGM in real patients (in vivo) is yet to be proved (Tyler et al.
2020). Tyler et al. have designed a k-nearest neighbours-based decision support
system to detect causes of high and low glucose levels and offer weekly insulin
dosage suggestions to T1DM patients taking multiple daily injection therapies
(Donsa et al. 2015).
Lifestyle Support
Carbohydrate consumption and physical exercise are vital factors for managing
diabetes mellitus. While the former raises the blood glucose values, the latter is
Detection of Hypoglycaemia/Hyperglycaemia
The identification of hypoglycaemia and hyperglycaemia is considered as a
charac- teristic classification problem. For a given set of input factors, the model
should identify the occurrence of a hypoglycaemic or hyperglycaemic condition.
The prediction can be condensed to a binary classification case, which is easier to
predict than continuous predictions of blood glucose levels. Ghosh et al. propose a
model based on the hybrid approach of non-linear autoregressive exogenous input
modelling and genetic algorithm for deriving an index of insulin sensitivity (Seo
et al. 2019). Machine learning can also be used to improve the accuracy of CGM
systems. Seo et al. used machine learning algorithms (a random forest and support
vector machine) using a linear function or a radial basis function, a k-nearest
neighbour and a logistic regression to detect hypoglycaemia by utilising data-
driven input factors (Qu et al. 2012).
For predicting whether a patient is diabetic or not, there are five different algorithms:
logistic regression, support vector machine, k-nearest neighbours, decision tree
and random forest in machine learning predictive models, of which details are
given in Fig. 2.5.
2.6.1 Dataset
The dataset used in this study has been originally obtained by the National
Institute of Diabetes and Digestive and Kidney Diseases. The objective is to find
whether a patient has diabetes or not, given certain values for different parameters.
All the patients considered in this dataset are females above 21 years old.
There are 768 instances available in this dataset. The independent parameters for
this dataset are number of times the patient was pregnant, plasma glucose
concentration level, diastolic blood pressure, triceps skinfold thickness, serum
insulin in 2 h, body mass index, diabetes pedigree and age of the patient discussed
in Table 2.2. There is a dependent variable outcome that tells if the patient is
diabetic or not. Of these 768 instances, there are 268 instances of diabetes, and
the rest of the instances are non-diabetic.
The first step is to count the number of instances with missing values for each
independent parameter. There are 227 missing values for the skin thickness
parame- ter, which accounts for 30% of the total instances. Also there are 374
(49%) missing
48 2 Automated Diagnosis of Diabetes Mellitus Based on Machine Learning
True label
250
200
1 159 109
150
100
0 1
Predicted label
values for serum insulin in 2 h parameter. These two parameters are eliminated
from our dataset as filling the missing values with placeholders could skew the
classifica- tion model and decrease the accuracy of the model. For the rest of the
parameters, missing values are replaced by substituting them with the median
values.
For the model to give better accuracy, it could be helpful to look if there are
any anomalies that could be weeded out before we train our model. k-means is a
clustering algorithm that can be used for such purposes. With the help of this
clustering algorithm, we can see if we can form two clusters and observe how well
they can separate the instances into its respective prediction categories. The confu-
sion matrix in Fig. 2.6 shows the misclassification after we apply k-means
clustering to our 768 instances.
We can see that 569 instances were correctly clustered with a success rate of 74%.
We keep these 74% instances, while eliminating the rest. This clears the anomalies in
our dataset, and the classification model can give predictions with a greater confi-
dence. The final step of the preprocessing involves standard scaling of all the
values between 0 and 1 using min-max scaling.
Five different classification models have been created to see which model
performs best. These classifiers are logistic regression (LR), support vector
classifier (SVC), k-nearest neighbour (KNN) classifier, decision tree (DT) and
random forest (RF). The parameters for all the models were declared such that the
maximum accuracy could be acquired after tenfold cross-validation. For KNN, the
best result was observed when the number of neighbours was set to 5. For RF, the
maximum accuracy was obtained when the maximum depth was set to 4.
50 2 Automated Diagnosis of Diabetes Mellitus Based on Machine Learning
Logistic Regression
Logistic regression is a variant of linear regression. This model helps us to
probabi- listically model binary variables. This model is also called linear
regression, which makes use of logit link. Logit here means the natural logarithm
of an odds ratio. Logistic regression is quite useful when testing postulation of
relationships between outcome dependent variables and one or more independent
variables or parameters. The resultant plot while categorising instances of data
appears linear in the middle but curved at the ends. This S-shaped plot is known as
sigmoid. The advantages include faster computing due to low computational power
requirements. Also we can make inference about relationships between independent
parameters and output. The major disadvantage of logistic regression is that this
models non-linear problem and often fails to capture complex relationships (Peng
et al. 2002; Tambade et al. 2017).
K-Nearest Neighbours
What differentiates k-nearest neighbours or KNN from other machine learning
algorithms is that it directly uses instances of data for classification instead of first
building a model. There is an adjustable parameter k that represents the number of
nearest neighbours that are needed to estimate the membership of the class. No
other information or details are required during the time of model construction.
The estimate of class membership P(y|x) is the ratio of members of class y
amongst the k nearest neighbours of x (Losing et al. 2016; Kotsiantis et al. 2007).
Flexibility can be introduced with the help of altering the value of parameter k.
Large values of k means less flexibility, while smaller number of k means more
flexibility. The advantage of KNN is that the neighbours can explain the result
after classification takes place. The disadvantage of KNN is that one can only
define the parameter k with the help of trial and error as there is no other way to
figure it out (Dasarathy 1991; Ripley 2007).
2.6 Methodology for Development of an Application Based on ML 51
Decision Tree
In this algorithm, the instances of the dataset are split into treelike structures
according to a set of criteria that results in maximization of separation of data.
This tree or flow chart is made up of nodes that represent a test on an attribute,
while each branch of the node represents the outcome of the test, and the leaf node
represents the classification. This whole path from the root to individual leaf is
said to make up the classification rules. Drawbacks include instability, i.e. a small
change in data can significantly alter the structure of optimal decision trees. Also a
multistep look ahead that considers different combinations of variables may result in
different and sometimes even better classifications. The advantage is that this
classification model is very easy to interpret since the classification rules are
clearly defined by the flow chart (Breiman et al. 1984; Quinlan 1993).
Random Forest
This algorithm is an ensemble type of learning algorithm where it constructs multiple
decision trees and outputs the class that is the mode of classes outputted by
individ- ual trees. Random forests tend to be better than decision trees since
decision trees tend to overfit on training dataset while random forest algorithm
provides a more generalised approach. It can also produce high-dimensional data
by employing feature selection techniques. The disadvantages are that random
forests are known to overfit on some noisy classification problems (Wyner et al.
2017; Biau et al. 2008).
2.6.4 Results
Performance Chart
105
100
95
90 Accuracy
Sensitivity Specificity
85
80
SVC RFKNN DT LR
Models
LR DT KNN RF
SVC
of prediction. Table 2.3 represents the evaluation parameters of the five models
used in the study. The random forest model outperforms the other four models in
terms of accuracy (99.3%), sensitivity (98.75%), specificity (99.74%) and F1 score
(0.992) proves to be most suitable for the automated diagnosis of diabetes
mellitus. A performance chart and F1 score distribution that compares all the five
models based on their evaluation parameters are shown in Figs. 2.7 and 2.8.
2.7 Conclusion
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56 2 Automated Diagnosis of Diabetes Mellitus Based on Machine Learning
Abstract
Personalized medicine is one of the largely considered approaches toward an
accurate and safer treatment. At the same time, the medicine domain alone cannot
maintain the modest outlay of the personalized medicine-centered treatment.
Somehow, the accuracy of the medication and diagnosis using personalized
medicine is lower when manualized than when involving artificial intelligence.
Machine learning is one of the mostly used artificial intelligence models in
convergence with high-throughput technologies. Natural language processing
and robotics in convergence with machine learning are highly regarded in
practicing an effective personalized medicine. Though machine learning is in
the scenario of precision medicine first followed by personalized medicine, it still
has to be accepted in the society for better development. This chapter gives an
insight into how and where the artificial intelligence is used in the personalized
medicine.
Keywords
Personalized medicine · Artificial intelligence · Medication · Diagnosis
3.1 Introduction
The field of medicine has grown significantly due to the integration of artificial
intelligence (AI). Even the field of personalized medicine is being amalgamated with
AI; however, it is still in its early stage and is facing a lot of issues (Awwalu et al.
2015). This fusion relies greatly on the algorithms of AI (Awwalu et al. 2015), but
AI-driven platforms, AI-based analytics tools, etc. are also being used. For example,
phenotypic personalized medicine (PPM) with the help of quadratic phenotypic
optimization platform (QPOP) maximizes the desired outcome for combination
therapy and their initial doses by selecting the drugs, and also PPM with the use of
CURATE.AI dynamically recommends the most effective dosing approach: in the
first case, QPOP is the AI-driven platform, whereas in the second case, CURATE.AI
is the AI-driven platform (Blasiak et al. 2019). AI-based analytics tools are being
extensively used to reduce the costs which arise while overcoming the huge
amount
of collected patient data, for example, Sapientia, Congenica’s clinical genomic
analysis platform, uses Exomiser (an AI-based analytics tool) to increase the speed
of annotation and prioritization of variants from whole-exome sequencing (WES)
in the diagnosis of rare diseases. Sapientia also enhances clinical decision-making
by organizing the data in an easy manner, which helps to reduce the time taken for
diagnosis by a huge margin (Suwinski et al. 2019). Other than the costs that arise
while overcoming the huge amount of patient data, there are some other
challenges that are faced when AI is being integrated with personalized medicine
such as research costs, implementation costs, and government regulations. One of
the major issues that is not being faced as of right now but may occur in the future
is the threat of automation of the jobs of many healthcare personnel (Awwalu et al.
2015). Talking about the future, it may happen that by the use of AI-powered
robotics one would be able to manufacture efficient and precise treatments, and it
may also be possible that one would be able to foretell in which way the treatment
strategy is going on the basis of AI-based simulation studies (Schork 2019). For
the most part, it can be said that successful integration of AI in personalized
medicine will save a lot of lives and may make the overall field of medicine
impeccable.
At present, most of our medicines follow a particular standard or a “one fits all”
approach, despite the fact that various studies indicate that specific characteristics
of
an individual such as age, gender, height, weight, diet, and environment can
influence the pharmacological effect of a drug. It has been found that even race
plays a role in the responsiveness of a drug, for example, Blacks require higher
concentrations of atropine and ephedrine to dilate their pupils when compared to
the Mongols (Tripathi 2013).
The pharmacodynamics of a drug is also affected by the genetics of an individual,
the dose of a drug needed to produce the same effect may vary by four- to sixfold
among different individuals, and this is because of the differing rate of drug
metabolism, which depends on the amount of microsomal enzymes present within
the individual which again is genetically controlled (Tripathi 2013). As sometimes
drugs have different effects on different individuals, it sometimes happens that a
drug which provides the desired effect in one person causes an adverse effect or
causes no effect at all in another person, even though it follows every standard.
For example, a number of antihypertensive drugs interfere with the sexual
function of men but not in women (Tripathi 2013). Another example can be of
triflupromazine: its single dose induces muscular dystonias in some individuals
but not in others (Tripathi 2013). Because of these reasons, healthcare
practitioners are trying to find
3.2 Personalized Medicine 59
new ways to help their patients, and some of them are turning toward an emerging
concept known as personalized medicine. It is referred to as “tailoring of medical
treatment to the individualistic characteristics of each patient” (Tripathi 2013). It
does not mean that a drug is created specifically for each patient, but rather it is a
concept in which grouping of patients on the basis of their susceptibility toward a
disease or their response toward a therapy is done (Tripathi 2013). This
individualized approach helps the healthcare practitioners to provide their patients
with a specialized treatment that is more precise, impactful, and efficient than the
traditional treatment.
Personalized medicine is also sometimes referred to as stratified medicine or
precision medicine. Precision medicine takes a group’s common genetic patterns,
their response toward drugs, their environment, and their lifestyles into account
and provides the medical professionals with the information that they need to
create
specific treatments for their illnesses (Gameiro et al. 2018). Along with all of this,
specific biomarkers are also taken into consideration: for example, Herceptin is
used for the treatment of breast cancer when it is caused by the overexpression of
HER-2 protein, whose biomarker is HER-2/neu receptor; Zelboraf is used for the
treatment of melanoma when it is caused by defect in V600E, whose biomarker is
BRAFV600E (Esplin et al. 2014).
Personalized dosing is also a very important part of personalized medicine as
the standard adult dose is for medium-sized individuals. For children, unusually
obese or lean individuals, the dose may be calculated on the basis of body mass
index (Tripathi 2013). In one study, it was predicted that personalized dosing of
warfarin could help in the prevention of 17,000 strokes and 43,000 emergency
room visits in the USA; this prediction was later tested in 3600 patients, which
resulted in 30% reduction in hospitalizations (Cutter and Liu 2012).
Another subset of personalized medicine that is newly emerging is
“personalized sequencing”; it uses sequencing technologies such as whole genome
sequencing and whole exome sequencing, and it also uses the data from the
Human Genome Project.
Personalized sequencing has advanced the way of studying and treating cancer.
Some of the ways of personalized sequencing which have impacted cancer care
are personalized tumor DNA sequencing, germline sequencing, and cancer cell
DNA sequencing. An example of personalized tumor DNA sequencing impacting
the treatment of cancer is the discovery of a loss-of-function mutation in TSCl in
around 5% of advanced bladder cancer cases by the use of whole exome
sequencing, and this was correlated with tumor sensitivity to everolimus, which
suggested that these bladder cancer patients may be treated by everolimus therapy.
As for germline sequencing, it helps to assess underlying patient risk which occurs
due to known alterations and causes hereditary cancer predisposition syndromes
such as Li-Fraumeni syndrome which further helps in the implementation of
preventative measures and screening protocols for early detection. But, still, germline
sequencing has not made much of an impression on cancer (Cutter and Liu 2012).
Coming back to the vast area of personalized medicine, some other examples are
the following:
60 3 Artificial Intelligence in Personalized Medicine
• The dose of digestive enzyme supplement given during the treatment of cystic
fibrosis is adjusted on the basis of volume and type of food ingested, number of
meals, body mass gain, growth rate, type of enzyme used, and the response to
the enzyme (Marson et al. 2017).
• For colorectal cancer patients with KRAS mutations, new treatments are being
prepared as KRAS mutations are a predictive marker of resistance toward
cetuximab and panitumumab (Pritchard and Grady 2011).
• By the use of gene expression profiling, acute myeloid leukemia patients are
being grouped on the basis of their level of risk, according to which the
intensity of their therapy is being tailored (Ken Redekop and Mladsi 2013).
• By the use of personalized topical therapeutics, it was found that the rate of
healing of wounds had significantly increased both statistically and clinically
(Dowd et al. 2011).
• Treatment of non-small cell lung cancer (NSCLC) patients with EGFR
mutation with gefitinib led to longer progression-free survival, compared to
NSCLC patients with no EGFR mutation (Jackson and Chester 2014).
Even though only a few personalized medicines are in practice, there is a need
to incorporate this field into our clinical setting as it allows the patients to be
treated with the most suitable medicines and therapies. This will lead to an
improvement in the safety and efficacy of the drugs, as they will be tailored
according to the needs of the subgroup, which will, in turn, lower the cases of
adverse effects caused by drugs (Gurwitz and Manolopoulos 2018). Despite the
fact that this field is new, it holds a lot of prospects; one of the reasons for this is
the advancement in technology. For example, the development of diagnostic imaging
for monitoring therapeutic efficacy can allow researchers and healthcare
practitioners to select a therapy, plan a treat- ment, monitor an objective response,
and plan a follow-up therapy, which will lead to the enhancement of the field of
personalized medicine (Ryu et al. 2014). Another example of this can be
theranostics, another emerging field, in which one pharma- ceutical agent is used
to diagnose disease, provide therapy, and monitor the progress of the treatment
and the efficacy. This allows the monitoring of drug levels in targeted tissues and
therapeutic response of the patient according to which the treatment can be
adjusted to suit the needs of the patient, therefore leading to the concept of
personalized medicine (Jo et al. 2016). Efforts are going on to personalize even the
traditional Chinese medicines by the use of systems biology (Zhang et al. 2012).
Also, a lot of work is going on in the development of personalized medicines for
the treatment of chronic lymphocytic leukemia (Rozovski et al. 2014), smoking
cessation (Nagalla and Bray 2016), thrombosis (Bierut et al. 2014), etc.
When a device is said to possess artificial intelligence (AI), it mimics the human
intelligence. However, a hope that artificial intelligence can cede the human
intelli- gence can make the future promising. Artificial intelligence can result in
several
3.4 Use of Artificial Intelligence in Healthcare 61
With the evolving lifestyle, threat to the human life has been developing, and the
medical world needs a leverage which can drive the diagnosis to attain maximum
accuracy. The convergence of machine learning (ML) and different high-throughput
technologies elevates the degree of diagnosis accuracy in the medical field. ML is
a key method for higher disease prediction rate. Though ML can be effectively
combined with many other predictive techniques, as shown in Fig. 3.1, ML is
integrated hugely with other AI techniques such as robotics and vision in
healthcare. ML and robotics have come together to surpass the conventional surgical
procedures such as suturing. ML also helps the robot attain optimum workflow
modeling by training the same. This training helps the robot increase the surgical
skills and can effectively reduce the time spent on suturing.
Computer vision and machine learning together have improved recently. Image
analysis and processing are two of the functions involved in computer vision.
However, there is an interlude between healthcare and computer vision. This gap
seems to be covered by introducing the machine learning algorithms into computer
vision. The medical diagnoses in healthcare include image analysis for which
computer vision can help thoroughly after being trained with the previous data.
Prior the use of ML in medicine, high-throughput technologies such as
62 3 Artificial Intelligence in Personalized Medicine
Artificial Intelligence
Robotics Vision
Maschinelles Lernen
Deep Learning
• Training phase.
• Predictive phase.
Maschinelles Lernen
Supervised Learning
Unsupervised Learning
Semi Supervised
Learning Reinforcement
Learning
Fig. 3.2 Categories of machine learning used in personalized medicine. The data is obtained by the
search of algorithms in PubMed
64 3 Artificial Intelligence in Personalized Medicine
Learning Models
Learning Models
Fig. 3.3 Supervised and unsupervised learning models mostly used in personalized medicine. The
data is obtained by the search of algorithms in PubMed
This model comes under supervised learning. It is called naïve due to its use of
strong independent comparison between the feature vector and input variables.
Naïve Bayes model uses the Bayesian algorithm, which is developed in two
phases
3.6 Use of Different Learning Models in Personalized Medicine 65
as training phase and testing phase, respectively. This model performs multi-class
predictions resulting in discriminant functions and probabilistic generative
models. Personalized medicine is in close relationship with pharmacogenomics
when administration of the drug comes down to taking adverse drug reactions,
molecular diagnostics, and classification of DNA into consideration. Hence, it is
important to optimize every feature vector and consider these parameters
individually to obtain
better prediction models (Sampathkumar and Luo 2014).
It is known that thiopurine methyltransferase (TPMT) is a metabolic enzyme
and participates in methylation of drugs such as azathioprine and 6-
mercaptopurine that are widely used in treating autoimmune diseases. TPMT
polymorphism results in adverse drug reactions due to the toxicological effects of
the mentioned drugs. In such cases personalization of medicine comes into the
picture. An individual
screened with any of such anomalies cannot be put into the “one drug fits all”
category. This is only one such example, but there are many syndromes which can
lead the patient to death when the type of drug and its dosage are administered
according to the standards and not on the basis of patient’s independent factors
(Katara and Kuntal 2016).
Bekir Karlik et al. developed a model using Bayesian algorithm for
personalized cancer treatment. They used the pharmacogenetic data of TPMT
polymorphism. They opted for naïve Bayes model as it can calculate probabilities
of a single patient explicitly besides breaking the difficulty in “a priori” prediction.
Their developed tool identified the TPMTs or SNPs for treating leukemia in the
genome. They found
utilization of naïve Bayes model more effective than the conventional DNA
microarray to identify the polymorphisms that are responsible for adverse drug
reactions (Karlık and Öztoprak 2012).
SVM is a part of supervised learning. SVM is being used in healthcare and mainly
in personalized medicine since decades. SVM mainly involves in classification of
the support vectors and thereby predicting the category of the new input data. The
algorithms of SVM focus on regression analyses and categorization. SVM is
highly advantageous in many cases as it does not only calculate the linear
probability but also takes nonlinear data into consideration. SVM also is involved
in fault or anomaly detection and hence is used widely in oncology (Grinberg et
al. 2020).
The treatment of personalized oncology varies from the normal in few steps
such as accurate prognosis according to the drug response. Breast cancer is one of
the mostly affected cancers. However, breast cancer is not only due to the
underlying etiology but can also be due to many different molecular etiologies that
result in a malignant/benign tumor in the breast. Since many years, personalization
of the treatment toward breast cancer has come into light for this very reason of
having multiple subsets of molecular biomarkers that result in the disease.
Millions of lives could have been saved by now if the biomarker targeted
approach was used in the
66 3 Artificial Intelligence in Personalized Medicine
Support vectors of
Category 1
Maximum margin
Support Vectors
of Category 2
Output 1
Input 1
Input 2
Input 3
Output 2
Hidden Layers
extraction. ANN is a feed-forward network where input can be given only in the
forward direction. ANN can be a single perceptron/layer or multiple perceptrons
as shown in Fig. 3.5. It has one input layer where the data is input, single/multiple
hidden layers where the data is processed, and an output layer which results in the
decision. Linear/nonlinear properties in ANN are aggregated and weighed through
the hidden layers, and, hence, any complex relationship can be found out
effectively as shown in Fig. 3.5 (Papadakis et al. 2019).
However, ANN is poor in finding the gradient, and, hence, recurrent neural
network (RNN) and convolution neural network (CNN) come into the picture.
RNN and CNN propagate backward. The looping connection of weighing the data
across the hidden perceptrons increases the accuracy of the output.
ANN can be used in optimization of the treatment, disease relapse prediction,
accurate diagnosis, and many such other applications. Several researches show
that cancer has been diagnosed accurately using the feature data. Few years ago,
Microsoft has come up with the idea to diagnose and optimize the treatment
using AI.
Naushad et al. developed an ANN model to predict breast cancer. They consid-
ered not only genetic polymorphisms but also nutrient and population-based
variables into consideration. As discussed, the causes for breast cancer are many,
and, hence, the biomarkers can be of different types. They investigated the
suscepti- bility toward the cancer due to micronutrient modulation. The accuracy
rate of this model came out to be 94.2% (Naushad et al. 2016).
Many other studies showed that when method combining ANNs in genetic
algorithm, the results were very accurate and rapid. Personalized medicine heavily
deals with sequencing one’s DNA to obtain any anomalies or polymorphisms. The
polymorphisms if any present in an individual would mostly lead to developing a
68 3 Artificial Intelligence in Personalized Medicine
disease, and, hence, any such have to be identified for early diagnosis. Many of the
cancers include different molecular polymorphisms. Diagnosis is followed by
treat- ment optimization, which can be accurately designed by the neural networks
from weighing every parameter through different hidden nodes. ANNs are a step
above the models that use linear regression as there is not much statistical
knowledge that needs to be known beforehand while dealing with neural
networks.
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Artificial Intelligence in Precision Medicine: A
Perspective in Biomarker and Drug Discovery 4
Abstract
Clinical care is gradually transiting from the standard approach of “signs and
symptoms” toward a more targeted approach that considerably trusts biomedical
data and the gained knowledge. The uniqueness of this concept is implied by
“precision medicine,” which amalgamates contemporary computational
methodologies such as artificial intelligence and big data analytics for
achieving an informed decision, considering variability in patient’s clinical,
omics, lifestyle,
and environmental data. In precision medicine, artificial intelligence is being
comprehensively used to design and enhance diagnosis pathway(s), therapeutic
intervention(s), and prognosis. This has led to a rational achievement for the
identification of risk factors for complex diseases such as cancer, by gauging
variability in genes and their function in an environment. It is as well being
used for the discovery of biomarkers, that can be applied for patient stratification
based on probable disease risk, prognosis, and/or response to treatment. The
advanced computational expertise using artificial intelligence for biological
data analysis is also being used to speed up the drug discovery process of
precision medicine. In this chapter, we discuss the role and challenges of
artificial intelligence in the advancement of precision medicine, accompanied
by case studies in biomarker and drug discovery processes.
Keywords
Artificial intelligence · Biomarker · Diagnosis · Drug discovery · Omics data
· Precision medicine · Prognosis
The concept of precision medicine eliminates the “one size fits all” approach and
strives giving patient cohorts treatment regimens, which are beneficial and with
minimal/no side effects. Besides the genetic and clinical factors, the
environmental features (the immediate physical surroundings, diet, lifestyle, etc.) also
influence our health. With the combination of multidimensional and heterogeneous
datasets, the knowledge gained may aid in potent treatment as well as planning for
effective prevention and screening. Thus, precision medicine entails insight how
elements from the environment interact with the genome, causing influencing
variations and mapping the genotype-phenotype relationships. Imperatively its
focus is not on the creation of person-specific drugs or medical devices but rather
on the ability to classify individuals into cohorts or subpopulations that differ in
their susceptibility for a particular disease or in their response to a specific
treatment. Therefore, it needs
to be emphasized that “precision” in “precision medicine” is being used in a
colloquial sense, to mean both “accurate” and “precise” and not to be misinterpreted
as implying unique treatments designed for each patient (Guide and Conditions
2015).
In the past 5 years, precision medicine has enabled key developments for complex
diseases such as cancer, with the perspective of better understanding and
facilitating predictive diagnosis as well as advancing prognosis. Availability of
genetic tests and advanced diagnostics can indicate prospective therapeutic agents
for distinct neoplasms in different tissues (Wang and Wang 2017). For example, in
oncology, the detection of HER-2 indicating the treatment of breast cancer with
trastuzumab is one of the most successful examples of precision medicine marker
(Pinto et al. 2013), also the presence of the BCR/ABL or PML/RARA
translocation, indicating specific treatments for leukemias, or the presence of
V600E mutation, indicating specific treatment in melanomas (Deng and
Nakamura 2017).
Pharmacogenomics has established drugs used in the treatment of infectious
diseases which may show diverse consequences for the reason that genetic profiles
differ in patients. This pharmacogenomic application indicated that because of this a
few medications may cause adverse side effects and dosages need to be adjusted
or the drug should be avoided for certain patients. In the treatment of a few viral
diseases, detection of specific mutations causing resistance to antivirals has been
recognized (Hauser et al. 2017). To determine the best treatment, presence of
polymorphisms in genes involved in drug metabolism or in the major
histocompati- bility complex is important. Therefore, in addition to infectious
diseases and cancer, researchers are also targeting metabolic diseases, for
example, being optimistic to developing genetic tests to access and predict the
risk of diseases such as type 2 diabetes and cerebrovascular diseases (Della-
Morte et al. 2016; Scheen 2016; König et al. 2017).
Precision medicine is a complex process, involving numerous technologies to
guide tailor-made patient diagnosis, prognosis, and treatment pathways. This is
primarily reliant on distinctive data inputs such as clinical, genomic, lifestyle, and
environmental features. Therefore, there is an imperative need of approaches for
integrating, exploring, and translating the knowledge from these massive datasets
diversely generated from the advancement of sequencing and other clinical
74 4 Artificial Intelligence in Precision Medicine: A Perspective in Biomarker.. .
The definition and use of biomarker have evolved over the years and may best
illustrated as “characteristic that is objectively measured and evaluated as an
indica- tor of normal biologic processes, pathogenic processes, or pharmacologic
responses to a therapeutic intervention” (Atkinson et al. 2001; Slikker 2018). In
clinical settings, the use of biomarkers have primarily wedged varied aspects
associated to
diagnosis and prognosis of diseases. The discovery of novel biomarkers provides a
strategic opportunity for the advancement of healthcare and in reduction of
associated costs. Therefore, they can be considered to play a key role in the
development of precision medicine, providing a strategic opportunity for technolog-
ical developments to improve clinical care (Slikker 2018). Considering its
importance and to reduce obstacle in their development, US NIH (National Institutes
of Health) and FDA (Food and Drug Administration) have developed the BEST
(Biomarkers, EndpointS, and other Tools) resource, giving glossary of important
definitions and their hierarchical relationships and capturing differences between
biomarkers and their clinical assessments (Biomarker Working Group 2016;
FDA-NIH Biomarker Working Group 2016). Artificial intelligence under these
settings exploring the multidimensional datasets can thus accelerate the biomarker
discovery process and provide a strategic opportunity for biomarker-driven thera-
peutic strategies, to improve human health and reduce the healthcare cost (Fig.
4.1). Consequent to a particular disease, artificial intelligence can help inferring
insights from the poly-omics (genome, epigenome, transcriptome, proteome,
metabolome, microbiome) datasets in association with clinical and environmental
factors. The prior knowledge with novel insights shall aid insinuating interactions
and/or discovering relationship acumen into pleiotropy, complex interactions, and
context-specific behavior. These multidimensional datasets can be trained using
AI algorithms to discover relevant genotypic structures, which could be
consequently mapped with a significant phenotype. Thereafter, it may be used
for diagnostic
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Fig. 4.1 Artificial intelligence can help in gaining insights from the heterogeneous datasets (clinical, omics, environmental, and lifestyle data), mapping
genotype-phenotype relationships, and identifying novel biomarkers for patient diagnostics and prognosis against a specific disease
75
76 4 Artificial Intelligence in Precision Medicine: A Perspective in Biomarker.. .
Based on the diagnosis of a disease, clinicians may decide treatment pathway(s) for a
patient with consideration to the patient’s clinical history. In the past decade or so,
efforts have been made to enable predictive diagnosis for diseases such as cancer,
cardiac arrhythmia, gastroenterology, and other diseases. Data heterogeneity has
been a major obstacle in the development of these early diagnostic applications.
However, AI can aid in overcoming this challenge, as AI-trained algorithms can
extract relevant knowledge from genomic and clinical datasets, such as disease-
specific clinical molecular signatures or cohort-specific patterns. These genotype-
phenotype relationships will render clinical management with an early diagnosis and
patient stratification. In turn this should boost clinical decision-making among the
available treatments, or mandatory treatment alterations, providing personalized
bedside care to each patient.
The first set of AI-based applications in clinical diagnostics approved by the US
FDA uses computer vision and is based on medical scans and/or pathological
images: for example, the automated quantification of blood flow via cardiac MRI
(Retson et al. 2019); determination of ejection fraction from ECG (Asch et al. 2019);
mammography-based detection and quantification of breast densities (Le et al.
2019); detection of stroke, brain bleeds, and other conditions from CAT scans
(FDA approves stroke-detecting AI software 2018); and diabetic retinopathy screen-
ing via dilated eye examination (van der Heijden et al. 2018). Furthermore, in
cardiac arrhythmia, AI methods using deep neural networks can detect and
classify arrhythmias, especially atrial fibrillation and cardiac contractile
dysfunction (Tison et al. 2018; Attia et al. 2019; Hannun et al. 2019).
In addition to the conventional biomarkers, the focus is also on the exploration
of digital biomarkers using hypothesis-driven approaches based on objective data,
such as the data from wearable devices, adapting AI with IoT (Internet of Things)
(Nam et al. 2019). Key applications are in development for digital biomarkers that
might assist in early identification of spinal injuries and predict BP (blood
pressure) status, which can facilitate early diagnosis and treatment of spinal and
cardiovascular diseases, respectively (Guthrie et al. 2019; Nam et al. 2019).
enabled by AI for effective and timely precision medicine delivery (Chen et al.
2018).
Precision medicine to its core is aimed at understanding the disease process in
individual patients so that they can be divided into subgroups according to the
different causes and influences of the disease. This promises delivery of more
accurately personalized care to patients through drug discovery innovations and
repurposing of drugs. Involvement of artificial intelligence is possible from the
bench to the bedside as it can assist in the decision-making during various iterative
phases of drug discovery, and it can help to determine the effective and
appropriate therapy for a patient and, most importantly, assist in managing the
clinical data generated and use it for future drug development (Duch et al. 2007;
Vyas et al. 2018). In totality the drug discovery opportunities are completely
different from the earlier times. Based on individual genetic variations and clinical,
environmental, and lifestyle data, new therapeutic targets need to be located along
with accelerated development of novel drugs or repurposed candidates and
codevelopment of diag- nostic tools for efficacious treatment of patient groups
(Baronzio et al. 2015; Blasiak et al. 2020).
In the coming time, artificial intelligence is going to lead us toward fully
addressing the human diseases through a thorough understanding of human
biology. Incorporation of AI in healthcare will speed up the various processes
involved in understanding the disease process in different patient subgroups and
subsequent development of precision medicine. Various statistical and deep
learning methods which rely on data interpretation will pave a way for diagnosis
and classification of diseases and disease subtype among patients. The use of
machine learning, cluster- ing, and feature finding methods could be helpful in the
discovery of disease targets in an accurate and fast manner (Sellwood et al. 2018;
Mak and Pichika 2019). The use of neural networks, big data, and data mining
algorithms along with enhanced statistical analysis on experimental data will
enhance our ability for de novo drug design. Based on various genetic makers and
improved patient information, repurposing and combination therapies of drugs
will improve the area of precision medicine.
A very strong determinant of success of a drug discovery process is, firstly, the
detailed understanding of the disease process and, secondly, drug-target identifica-
tion and validation. Artificial intelligence enables the evaluation of vast amount of
structural and functional genomic data, proteomic data, and in vitro and in vivo
assays. Artificial intelligence algorithms also analyze large amount of research
data available at various private and public platforms to help up better understand
the disease process and pathways associated, which was not possible earlier. Some
AI-based platforms have already been developed, which utilize extensive literature
information, genomic data, disease-associated data, and other relevant data for target
identification and validation in days rather than months, e.g., Open Targets, IBM
Watson for drug discovery, Benevolent Platform, etc.
The process of compound screening and lead optimization is the most time-
consuming and costly step in the entire drug discovery process. The process involves
selection of candidate using combinatorial chemistry, high-throughput screening,
and virtual screening. The implementation of artificial intelligence to explore the
chemical space makes it possible to identify novel and high-quality molecules with a
reduced cost and time. The idea is to search for bioactive compounds by using
80
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Fig. 4.2 Application of artificial intelligence in various steps of drug discovery process (Paul et al. 2020) om
ark
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.
4.3 Role of Artificial Intelligence: Drug Discovery for Precision Medicine 81
AI-based virtual screening to help select appropriate molecules for further testing.
This can be done by using publicly available chemical spaces including PubChem,
ChemBank, DrugBank, and ChemDB. Some molecules can also be extracted from
mining the research literature using AI-based techniques, which can be further
modified to develop some workable analogues. To speed up the initial phase of
drug screening, potential lead molecules can be efficiently screened by medicinal
chemists by application of artificial neural networks, support vector machines,
Bayesian classifiers, and k-nearest neighbors and other algorithms on millions of
compounds.
AI-based systems can help to reduce the number of compounds for synthesis
and subsequent testing in vitro and in vivo by screening only the most promising
compounds and hence help in reduction of R&D expenditure by decreasing the
dropout rate. The compounds can be filtered during the screening process based on
predicted pharmacokinetic properties, bioactivity, and toxicity. Several programs
have been used to predict the lipophilicity, solubility, and drug-target interactions.
Some of the examples are ALGOPS; neural networks based on the ADMET
predictor, which predicts the lipophilicity and solubility; graph-based
convolutional neural networks (CVNN), which predicts solubility of molecules; and
ChemMapper and the similarity ensemble approach (SEA), for predicting drug-
target interactions to access the advanced based on input features. Several AI-
based approaches predict the toxicity of the compound based on similarities
among compounds. Some major biopharma companies working in different areas
such as cardiovascular diseases and fibrosis have started collaborating with AI-
based companies for de novo design of molecules, antibodies, DNA, and peptides.
One of the successful cases is a de novo designed compound using AI, which was
developed in just 25 days by Insilico Medicine and was found to be 15 times faster
than traditional biopharma process (Mayr et al. 2016; Segler et al. 2018).
It has already been established that AI techniques can help to speed up and
increase the success rates in drug development, but it is always recommended to
validate the AI techniques before applying to the drug development process.
The synthesis of chosen molecules is the most important step in the drug develop-
ment process. AI is valuable at this stage too, owing to its ability to deduce the
optimal synthetic route and to prioritize molecules based on the ease of synthesis
(Alanine et al. 2012; Okafo et al. 2018). The synthesis of compounds begins with
fragmenting a target compound into building blocks and then establishing an optimal
reaction process for synthesis of the compound. The optimization of reaction is the
most challenging step with chances of failure of the rate of synthesis. AI would aid in
predicting the best sought-after reactions by predicting and working upon the
cause of high failure in this process. Artificial intelligence can be used to automate
chemical synthesis with minimal manual operation using synthesis robots
combined with artificial intelligence. Currently, for the selection of the synthesis
route, various
82 4 Artificial Intelligence in Precision Medicine: A Perspective in Biomarker.. .
systems are available to assist the chemists such as CAOCS (computer-aided organic
compound synthesis) (Paul et al. 2020). From a group of building blocks, filtering
out only the most promising ones for synthesis of target compounds using well-
known reactions can be achieved by using an AI platform named 3 N-MCTS.
Computer-aided organic compound synthesis using 3 N-MCTS is achieved by
using three different deep neural networks with Monte Carlo tree search.
Clinical trial is a very important stage of drug discovery which can be 6–7 years long
and requires a substantial financial investment. Despite such a big investment in
terms of time and money, only one out of ten molecules on an average becomes
successful, which is a massive loss to the industry. During the conduct of the
trials, multiple factors such as from inappropriate patient selection, shortage of
technical requirements, and poor infrastructure contribute to the failure (Bain et al.
2017).
Patient selection in various phases of clinical trials is a very crucial process.
During the clinical trial process, the therapeutic responses of patients are very
uncertain. For a predictable, accurate, and quantifiable assessment of the response
4.3 Role of Artificial Intelligence: Drug Discovery for Precision Medicine 83
The repurposing of drugs has become more promising with the inclusion of AI in
drug discovery. Application of an existing therapeutic to a new disease is a cost-
effective and fast drug discovery application because the new drug is qualified to
go directly to Phase II trials for a different indication without having to pass
through Phase I clinical trials and toxicology testing again (Corsello et al. 2017).
AI-based deep neural networks and reinforcement learning are used to identify drug
molecules exhibiting certain patterns in the molecular structure that can suggest
their use in other new diseases. AI-based methods can efficiently mine the
research data from literature and help to identify certain compounds, which can be
repurposed for other diseases. In the later stages AI-based tools are efficient in
market prediction and analysis. In some cases AI-based nanorobots are also being
used for efficient delivery of drugs (Hernandez et al. 2017).
With the promise of providing better healthcare to the patients and as a way
forward toward precision medicine, a new sync has started developing between
pharmaceu- tical companies and AI companies. Pharmaceutical companies,
hospitals, and other healthcare agencies have started to work along with AI
companies in the hopes of developing better healthcare tools. The joint ventures
with the aim of improving the diagnosis through biomarkers, target identification,
and novel drug design have already begun through tool development, data
analysis, and data exchange with the aim of (Mak and Pichika 2019). Various
partnerships between pharmaceutical industries and AI companies on a global scale
were recently developed as depicted in Fig. 4.3.
AI has shown great promise in rapidly evolving drug design process through
accurate and fast predictions of the existing as well as newly designed compounds
84 4 Artificial Intelligence in Precision Medicine: A Perspective in Biomarker.. .
Fig. 4.3 Some examples of pharmaceutical companies collaborating with artificial intelligence
(AI) organization for healthcare improvements in the field of oncology, cardiovascular diseases, and
central nervous system disorders (Paul et al. 2020)
and better exploration of drug targets. These advancements will serve as the most
important contributing factors for the betterment of healthcare services, improve-
ment in terms of efficiency in clinical trials, enhancement in stratified medicine,
and
References 85
more. Presently, drug discovery costs billions and takes around 12–15 years to
complete. This trend is unsustainable in this fast-changing world, and positive
change is extremely essential (Paul et al. 2020). These collaborations will help not
only to improve upon the existing design space but also to discover and explore
rare molecules that have properties of extreme importance, which were impossible
to identify by solely relying on conventional methods. In the present scenario, it is
a challenge to develop a drug especially while including the genetic/genomic
infor- mation, environmental factors, and lifestyle of individuals for precision
medicine development. It takes thousands of studies to analyze known side effects
and unknown interactions. However, once available, such an AI algorithm
approach would prove invaluable in further hastening drug development efforts.
AI will revolutionize how drugs are discovered and will reinvent the
pharmaceutical indus- try along with precision medicine.
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Transfer Learning in Biological and
Health Care 5
Abstract
Transfer learning is the advancement over conventional machine learning in
which we transfer the newly obtained knowledge to existing knowledge. Tradi-
tional machine learning makes a basic assumption that the distribution of training
data and testing data should be the same. But in numerous real-world cases, this
identical-distribution assumption of training data and testing data does not hold at
all. For example, suppose if we have a model to recognize a face from an image in
traditional machine learning, we cannot retrain this model to detect tumors in
the brain because they belong to a different domain. But using transfer learning,
we can retrain this model to detect tumors as well. The identical-distribution
assump- tion might be violated in cases where data from one new domain
comes, while there are only available labeled data from a similar other domain.
Labeling the new data in the old domain can be costly for any organization, and
it is also inappropriate to throw away the newly obtained data just because it is
from another domain.
In this chapter, we retrained various state-of-the-arts convolutional deep
learning models using transfer learning by supplying the data related to brain
tumors using transfer learning technique.
Keywords
5.1 Introduction
After computers came into existence in the 1950s and 1960s, various algorithms
were constructed and developed, which enable us to model and analyze a large
amount of data. This leads to the existence of initial machine learning techniques.
Three branches of machine learning emerged in the very beginning. These are
classical works that include neural networks by Rosenblatt (Rosenblatt 1962),
statistical methods by Nilsson (Nilsson and Machines 1965), and symbolic
learning by Hunt et al. (Hunt et al. 1966).
Over the years, these three techniques were enhanced to construct improved
techniques (Michie et al. 1994): pattern recognition or statistical methods, such as
the Bayesian classifier and k-nearest neighbors classifier; inductive learning, such as
decision trees; and artificial neural networks (ANN), such as the multilayered
feedforward neural network (MLP) including back propagation (Kononenko
2001). Machine learning algorithms discover patterns in data that are finding a
predictive relationship between different variables. Mostly, we can say that finding
where the probability of mass concentrates on the joint distribution of all the
observations
observed (LeCun et al. 2015).
Earlier machine learning algorithms have limited abilities to process data and
signal in their natural/raw form. The development of a machine learning system or
pattern-recognition system requires domain expertise and strict engineering to
design a feature extraction algorithm from scratch that transformed the natural/raw
data into a feature vector or suitable internal representation of the data from which
a machine learning classifier could detect or classify patterns based on the input
provided (LeCun et al. 2015).
To overcome the earlier machine learning limitations, artificial intelligence
com- munity introduces deep learning.
Deep learning has turned out to be outperforming earlier machine learning
techniques in terms of finding intricate patterns within high-dimensional data, and,
therefore, it has applications in many different domains such as fields of science,
business, and government (LeCun et al. 2015).
Using deep learning one can solve various complex problems with ease as
compared to traditional machine learning approaches; such complex problems
include computer vision, natural language processing, signal processing, anomaly
detection system, recommendation system, and so on.
Deep learning outperforms earlier machine techniques in the field of image
recognition and speech recognition. It has been found that deep learning also
outperforms machine learning in the field of bioinformatics such as predicting the
activity of possible drug molecules, analyzing a large amount of particle
accelerator data to provide its analysis, reconstructing brain circuitry, and
predicting the effects of various mutations in noncoding DNA region of the gene
of disease samples (LeCun et al. 2015).
More surprisingly, various tasks related to natural language understanding are
sentiment analysis, topic classification, language translation, and question answering
that show the most promising results when done using deep learning algorithms
(LeCun et al. 2015).
Several machine learning techniques work well only under common assumptions,
i.e., the training and testing samples should be obtained from the same distribution
and also with the same feature space. When this distribution changes, then most of
the statistical models require rebuilding again from scratch by using newly
obtained
5.2 Methodology 91
In the field of deep learning, companies such as Google, Facebook, and Microsoft
and some researchers regularly contributed to giving us high-performance and
optimized convolutional deep learning models that are trained on millions of
image samples belonging to over 1000 different classes containing over a billion
trainable parameters. Training of such models requires a huge amount of computa-
tional power, which is quite impossible to arrange for individuals or independent
researchers.
Transfer learning in the perspective of deep learning is defined as fine-tuning of
weights and biases of an existing trained model by retraining it using the newly
collected data. Training a model using the transfer learning technique inherits the
characteristic of the features of the previous data on which it was trained on a
model as well as the features of the newly obtained data.
5.2 Methodology
We have curated our dataset from an open-source repository known as Kaggle; see
Table 5.1. We divided our complete data into three individual parts, namely, training
dataset on which we perform training, validation dataset on which we perform cross-
validation, and testing dataset on which we perform testing; see Table 5.2.
Our training dataset consists of a total of 193 brain CT scan images, out of
which 119 image samples are of patients having a tumor in their brain and the rest 74
image samples are of healthy patients.
Our validation dataset consists of a total of 50 brain CT scan images, out of which
31 image samples are of patients having a tumor in their brain and 19 image
samples are of healthy patients.
Our testing dataset consists of a total of ten brain CT scan images, out of which
five image samples are of patients having a tumor in their brain and five image
samples are of healthy patients.
Table 5.1 Description of dataset: we have in total 253 brain MRI images out of which 155 are
having tumor and 98 are normal
Category Quantity Total
Tumor-containing MRI scans 155 253
Healthy MRI scans 98
Table 5.2 Description of dataset type: we have in total 253 brain MRI images. We split our whole
dataset into three different parts: training, validation, and testing dataset
Dataset Number of images of tumor Number of images of normal
type patients patients Total
Training 119 74 253
Validation 31 19
Testing 5 5
5.2 Methodology 93
We also use image augmentation which increases our model generality and
robustness to unknown sample images. We are using shearing, rotation, flipping,
and skew image augmentation.
We are using Keras Image Generator API to load, scale, and image augmentations
of our database.
5.2.3.1 VGG-16
VGG-16 is developed by Andrew Zisserman and Simonyan in 2014 at the Visual
Geometry Group Lab of Oxford University (Karen Simonyan and Andrew
Zisserman 2018). This model achieved top five test accuracy of 92.7% on the
ImageNet dataset. This ImageNet dataset contains 14 million images belonging to
1000 different classes.
The input image size of the VGG-16 model is 224 × 224 3, i.e., 224 image
height ×
224 pixel image width 3 channels (RGB).
We use Keras application VGG-16 class to create our transfer learning model
using “ImageNet” weights along with some modifications as described in Fig. 5.1.
We retrained the VGG-16 model with Adam optimizer along with exponential
learning rate decay and binary cross-entropy loss function.
Fully connected layer with 1 unit and having activation function "sigmoid"
5.2.3.2 EfficientNet
EfficientNet is developed by Mingxing Tan and Quoc V. Le in ICML 2019 (Tan
and Le 2019). Efficient Net achieved top-1 accuracy of 84.4 and top-5 accuracy of
97.1% on the ImageNet dataset. The complete model consists of 66 million
parameters in total.
The input image size of the EfficientNetB4 model is 229 × 229 3, i.e.,
229 image height × 229 pixel image width 3 channels (RGB).
We use Keras application EfficientNetB4 class to create our transfer learning
model using “ImageNet” weights along with some modifications as described in
Fig. 5.2. We retrained the EfficientNetB4 model with Adam optimizer along with
exponential learning rate decay and binary cross-entropy loss function.
5.2.3.3 Inception-ResNet-V2
Inception-ResNet-V2 is developed by the team of Christian Szegedy, Sergey Ioffe,
Alex Alemi, and Vincent Vanhoucke in 2016 (Szegedy et al. 2016).
Inception-ResNet-V2 is a convolutional neural network (CNN) that achieved a
top-1 accuracy of 80.4% and top-5 accuracy of 95.3% in the ILSVRC image
classification. Inception-ResNet-V2 is a version of Inception-V3 network, which
implements some ideas from Microsoft’s ResNet network.
The input image size of the Inception-ResNet-V2 model is 229 × 229 × 3, i.e.,
229 image height × 229 pixel image width × 3 channels (RGB).
Flatten Layer
Fully connected layer with 1 unit and having activation function "sigmoid"
Flatten Layer
Fully connected layer with 1 unit and having activation function "sigmoid"
5.2.3.4 Inception V3
Inception V3 is developed by the collaboration of Zbigniew Wojna, Christian
Szegedy, Sergey Ioffe, Vincent Vanhoucke, and Jonathon Shlens in 2015
(Szegedy et al. 2016).
Inception V3 was the first runner-up for the image classification in the ILSVRC
challenge in 2015 by achieving an accuracy of >78.1% accuracy on the ImageNet
dataset.
The input image size of the Inception-V3 model is 229 × 229 3, i.e., 229 image
height ×
229 pixel image width 3 channels (RGB).
We use Keras application Inception-V3 class to create our transfer learning model
using “ImageNet” weights along with some modifications as described in Fig. 5.4.
We retrained the Inception-V3 model with Adam optimizer along with
exponential learning rate decay and binary cross-entropy loss function (Fig. 5.5).
96 5 Transfer Learning in Biological and Health Care
Inception V3
Flatten Layer
Fully connected layer with 1 unit and having activation function "sigmoid"
Fig. 5.5 Comparison between accuracies on testing dataset generated by retrained transfer learning
models
5.2 Methodology 97
5.2.4 Training
We train our transfer learning models for 1000 epochs wherein step size per epoch
is 3 and regulated with early stopping mechanism which monitors the validation
loss every 50 epochs; if the validation loss does not minimize from the last 50
epochs, then training will stop there, but the model will be restored when the
validation loss is minimum (Fig. 5.6).
5.2.5 Testing
We tested our trained model with the same testing dataset. For benchmarking of
different transfer model, we use different evaluation metrics such as sensitivity,
accuracy, specificity, and area under the receiver operating curve. We found out
that VGG-16 and Inception-ResNet-V2 perform the same and have the highest
accuracies; see Table 5.3.
1.2
0.8
Accuracy
0.6
Sensitivity
0.4 Specificity
AUC
0.2
0
VGG-16
Efficient Inception Inception V3
Net ResNet V2
Fig. 5.6 Comparison between various evaluation parameters such as accuracy, sensitivity, speci-
ficity, and area under the curve on testing dataset generated by retrained transfer learning models
Table 5.3 Evaluation parameter results of various models: we evaluated our transfer learning
models using parameters such as accuracy, sensitivity, specificity, and area under the curve
Model Accuracy Sensitivity Specificity AUC
VGG-16 0.90 1.00 0.80 0.90
EfficientNet 0.80 1.00 0.60 0.80
Inception-ResNet-V2 0.90 1.00 0.80 0.90
Inception V3 0.80 0.80 0.80 0.80
98 5 Transfer Learning in Biological and Health Care
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Visualization and Prediction of COVID-19
Using AI and ML 6
Abstract
The global spread of COVID-19, a syndrome of severe respiratory infections, has
driven the planet into a global crisis. This would influence each zone, such as
the horticultural zone, the agricultural zone, the economic zone, the public
transport market, and so on. We published an analysis that identified the effects
of the global pandemic using next-generation technologies to see how COVID-
19 affected the globe. Prediction is a standard exercise in data science that
assists with anomaly identification, objective setting, and strategic planning in
adminis- tration. We propose a model optimization of interpretable parameters
that can clearly be modeled by experts with dataset domain intuition. We
focus on
international data and conduct complex map simulation of COVID-19’s
interna- tional expansion to date and estimate virus distribution throughout all
regions and
countries. Detailed overview of both region-wise and state-wise recorded
events; forecast of a viral pandemic attack, deaths, and recovered cases; and the
degree to which it is spreading globally are included in this chapter.
Keywords
Artificial intelligence · Machine learning · COVID-19
6.1 Introduction
Currently, we are facing new pandemic globally. Day after day, the condition gets
serious, since conventional treatment strategies do not prevent it. On November
17, 2019, in Wuhan, the sprawling capital of southern China, the first SARS-CoV-
2 pandemic attack was reported. The first case was diagnosed on December 8,
2019, and scientists did not officially accept that there was human-to-human
transmission until January 21. COVID-19s symptoms and premonitions are natural,
and even now
it is difficult to mistake this with another disorder without any corroborative tests.
The clinical introduction is that of a serious appearance of respiratory contamination
that goes from a moderate common cold-like illness to acute viral pneumonia that
induces severe, potentially lethal respiratory distress (Suresh and Jindal 2020).
The prevalent virus spreads basically through beads of salivation or discharge
from the nose if an affected person hacks or sneezes. The flare-up was announced
on January 30, 2020, to be a global public health emergency. Primary risk
factors include
residence/travel to the area, detailing the network’s distribution within 14 days
prior to the onset of symptoms, direct contact with an alleged incident, older age,
hidden well-being, and malignancy (Suresh 2020).
By March 4, the first signs of frenzy that veils and hydroalcoholic gel would be
depleted in quite a while began to bring about open fear about the epidemic.
Consequently, the government demanded disposable masks and gloves, along with
medically approved sanitizers. Conveying that for individuals displaying signs of
disease and for use by health professionals, this type of protective obstruction should
be saved separately. Despite this, the cost of hydroalcoholic disinfectant gel was
impeded to forestall profiteering. Be that as it might, at present, the supply of
covers and hydroalcoholic disinfectant gel is also problematically poor (Ghanchi
2020).
In current situations, systematic mechanisms of testing and recognition (counting
touch following), network measures (counting physical separation), improvement of
human care programmers, and lighting of the general population, and welfare
network can remain a solid focus. To ensure that societies have the flexibility to
continue adhering to these measures, it is important to advance mental prosperity for
individuals living under physical separation measures. Stringent physical
separation steps are especially problematic for society, both economically and
psychologically. Therefore, the zeal for characterizing a sound way to cope with
deceleration is enormous. In any case, until the incidence of exposure is decreased
to an exceed- ingly low level in a given area, transmission can occur until the
maximum of population assurance (Jose et al. 2020) has been achieved.
While focusing on the Indian predicament, the key example of the 2019–2020
coronavirus outbreaks in India was reported from China on January 30, 2020. As
of
April 14, 2020, the Ministry of Health and Family Welfare announced a total of
10,815 predicaments, 1190 rescued, and 353 registered fatalities in the country. As
India’s examination rates are among the lowest in the world, experts suggest the
number of illnesses could be even higher. On March 24, 2020, Dr. Michal Ryan,
the
Executive Director of the World Health Organization’s Health Emergencies pro-
gram, declared that India had a “colossal breaking point” to contend with the
coronavirus eruption and will have a huge effect on the world’s ability to
supervise it as the second-most packed country. On March 24, 2020
(https://en.wikipedia.org/
wiki/2020_coronavirus_pandemic_in_India), the Prime Minister announced a 21-
day shutdown across the nation: the second-most packed region.
A total of 10,815 cases of COVID-19 (including 76 foreign nationals) were
registered in 32 states/union territories according to the Ministry of Health and
Family Welfare. This includes 1189 restored/released, one moved, and 353 deaths.
There is an improvement in the therapeutic separation, monitoring, and home
6.2 Technology for ML and AI in SARS-CoV-2 Treatment 101
Anticipation of the extent of the illness by contact monitoring is the next crucial
phase after an individual is analyzed and confirmed with COVID-19. According to
the WHO, the virus spreads primarily by contact transfer from one person to
another through sweat and running nose (WHO 2020a). Touch monitoring is an
important healthcare method which people use to disrupt the transmission of the
disease chain in order to control the spread of COVID-19 (WHO 2020b). The person
tracing tool is used to classify and handle public newly showing to a tainted
COVID-19 infected people to prevent additional dissemination. Usually the
treatment identifies the infected organism with a 14-days go after the following
exposure. This method would break the COVID-19 chain of the novel corona
virus and reduce the spate by presenting a greater potential for successful helping
and controls to minimize the severity of the recent deadly disease. In order to
create a digital communication monitoring mechanism with the smartphone
application, many infected countries use various technologies such as Global
Positioning System (GPS) network-based API, Bluetooth, contact information,
social graph, and mobile tracking data. The automated tracing procedure can be
real time and easier. These automated technologies are intended to capture data
from individual apps that will be processed by artificial intelligence software to
track an individual. A study has demonstrated the use of artificial intelligence
propelling the pace of contact tracing against COVID-19 diseases (Rorres et al.
2018). After applying the graph theory to data on epidemics of infectious animal
diseases, mainly shipping records between each farm, the consequential pictorial
properties produced by the planned model can be used to allow contact tracing to
be used effectively to improve contact tracing.
Though, presently there are restrictions when resolving situation, anonymity, data
management, and still data safety breaches. Many nations, such as Israel, have
“passed the emergency law on mobile phone records” to fight this disease (BBC n.
d.). In the middle of the worldwide touch tracing applications, some countries apps
have broken the confidentiality act and have been reported risky (MIT n.d.) before
they do the job properly by supplementing the manual tracing process. Nearly
every country, however, has its own touch tracing application, which becomes a
public health emergency as the disease continues to spread across the globe. In
order to battle this disease, we should have a standard contact tracing programmed
to trace any people globally. It is also reported that it is necessary to address
any basic
question: “Is it compulsory or voluntary?” “Is the initiative transparent or translu-
cent?” “Is the collection of information reduced?” “Will the collected information be
demolished as stated?” “Is the host data protected?” “Are there any restrictions or
constraints on the use of the data?.”
6.5 Technology of ML and AI in SARS-CoV-2 Medicines and Vaccine 103
A new model, which forecasts and predicts 1 to 7 days to the front of the generally
infected COVID-19 individuals in Brazilian states, has been suggested to use the
stacking-ensemble with the assist vector regression algorithm on the growing
infected COVID-19 cases of this country results, thereby extending the short-term
prediction loop to advise the professionals to compensate for the disease (Ribeiro
et al. 2020). Using a machine learning classifier named XGBoost on mammographic
factor datasets, recent studies have indicated a new method. After applying the
algorithm, the experts found that some of the distinctiveness of the 74
experimental and blood test samples (lactic dehydrogenase (LDH), lymphocyte,
high-sensitivity C-reactive protein) in estimating and calculating the total number
of COVID-19 patients with extreme mortality rates has a median accuracy of 91%
(Yan et al. 2020). On the other hand, in identifying the majority of patients in need
of intensive medical treatment, the comparatively greater importance of single
lactic dehydroge- nase tends to be a crucial factor, such that of the degree of LDH
involved in various lung illnesses, such as asthma, bronchitis, and pneumonia. The
proposed method used the assessment rule to allow patients to be manageable for
intensive care and to potentially reduce the rate of transience, in order to easily
estimate and forecast infectious people at the greatest risk. Using a deep learning
algorithm for the long term, a Canadian-based forecasting model was developed
using time series. A key factor in predicting the short-term memory network
trajectory was established in the studies, with an end-point prediction of the latest
SARS-CoV-2 outbreak in Canada and around the world (Chimmula and Zhang
2020). For this SARS-CoV-2 outbreak in Canada, the proposed end-point model
estimate will be around June 2020 (JHU 2020); the prediction was likely to be
accurate as newly infected cases dropped rapidly and proved the applicability of
the expert approach to predicting and forecasting the next pandemic/epidemic by
reestablishing key aspects of veiling. In order to combine the accuracy of the
wavelet-based forecasting model with the optimized autoregressive moving
average time series model (Chakraborty and Ghosh 2020), the real-time
forecasting model was proposed. The model solves the problem by designing
short-term SARS-CoV-2 forecasts for various countries as a temporary warning
module for each target country to assist healthcare professionals and policy
makers.
human beings. Taiwanese researchers are designing a new strategy toward increas-
ing the production of a new drug (Ke et al. 2020). The study revealed eight drugs,
i. e., gemcitabine, vismodegib, and clofazimine, using the deep neural network on
eighty-year-old drugs with COVID-19 therapeutic potential after two datasets
were added to the ML and AI technology-based model (one using 3C-like protease
restriction and other data keeping cases of infection with SARS-CoV, SARS-Cov-
2, influenza, and human immunodeficiency virus). Additionally, five other drugs,
such as salinomycin, homoharringtonine, chloroquine, tilorone, and boceprevir,
have also been shown to be operational in the AI laboratory setting.
Researchers from the USA and Korea jointly suggested a novel molecule
transformer-drug target interaction model to address the need for an antiviral drug
that can cure the COVID-19 virus. The report contrasts AutoDock Vina, a free
collaborative screening and molecular docking programmer, to the suggested model,
using a deep learning algorithm on COVID-19 3C-like proteins and approved by
the FDA, with 3410 new drugs available on the market. The findings found that
the best treatment for COVID-19, followed by remdesivir, was a common
antiretroviral medication used to treat HIV called atazanavir (Kd of 94.94 nM)
(Kd of
113.13 nM). In addition, the findings showed that some drugs for viral proteinase
therapy, such as darunavir, ritonavir, and lopinavir, were illuminated. It was also
observed that for the medication of COVID-19 human patients, many antiviral
compounds such as Kaletra may be used.
An antiviral drug was developed by a group of researchers from the USA to
cure the Ebola virus. The study was first made in 2014 (Ekins et al. 2014), beginning
with the ML and AI pharmacophore-based statistical study of the small size of in
vitro infected carriers of Ebola viruses. The study suggested a widely used
amodiaquine and chloroquine complex for the treatment of the malaria virus. In
addition, a blend of numerical screening method with docking application and
machine learning was introduced after finding a decade of drug development
focused on ML and AI technologies to pick supplementary medicine to
investigate SARS-CoV-2 (Ekins et al. 2020). Researchers are looking at the
successful management of Ebola (Ekins et al. 2020) and the experience of the Zika
virus (Ekins et al. 2016), and the same model can also be used to classify COVID-
19 drugs and a potential pandemic of the virus.
It was noted that in combination with the docking application, the use of
machine software was more effective in forecasting the reusability of an existing old
COVID- 19 medication and greatly decreasing the amount of a risk factor in
creating a more cost-effective drug operation. During this emergency, the use of
ML and AI will improve the drug production process by reducing the time slot for
the courier to explore an alternative therapy and remedy by depending on a high
chance of the efficacy, manageability, and clinical knowledge of the current
medicine compound. The finite resources of stable hybrid data and real-life
deployment of the programs were the concerns and problems found in this area.
6.6 Analysis and Forecasting 105
We depend on the daily averages of the three major variables of concern: reported
cases, deaths, and recoveries, which are globally aggregated. The Center for Systems
Science and Engineering (CSSE) at Johns Hopkins University has retrieved these.
These figures are also applied to include the full range of cases spanning the
period from January 22, 2020, to March 11, 2020, on an annual basis. They
contain both
“laboratory-confirmed” and “clinically diagnosed” cases. The significance of recov-
ered cases, which are not as widely mentioned in the media as the cases or deaths
identified, is illustrated. In mid-February, the patterns in both registered cases and
deaths declined, although all the three data trends increased gradually; in late
February and March, a second exponential increase was detected due to a growing
number of cases in South Korea, Iran, and Europe. At around the same time, the
number of cases that have been collected is gradually increasing.
We accept simple time series forecasting techniques to model recorded
COVID- 19 incidents. By using models from the exponential smoothing family
(Hyndman et al. 2002), we generate predictions. Over several predictive
competitions (Makridakis et al. 1982), this family has demonstrated good
prediction accuracy and is especially suited for short series. A number of model
and seasonal forecasting patterns and their variations can be captured by
exponential smoothing techniques. In view of the trends shown in Fig. 6.1, we
restrict our focus to trendy and nonseasonal styles. Notice that a sound path is
being taken in that we want the development to proceed forever in the future. This
methodology opposes other COVID-19 simulation methods, using an S-curve
(logistic curve) model that suggests convergence.
Though statistical methods can be used for model selection (such as knowledge
parameters that determine the optimum probability of a model while penalizing its
complexity), we judgmentally choose a model (Petropoulos et al. 2018) to best
represent the essence of the data. Using multiplicative error and multiplicative
pattern elements, we chose an exponential smoothing model. While in some
situations, taking into account the asymmetric risks involved, an additive trend
model offered lower knowledge criterion values, we chose the multiplicative trend
model because we believe it is simpler to err in the positive direction (Fig. 6.2).
0
0
26/01 05/02 15/02 25/02 06/03 26/01 05/02 15/02 25/02 06/03 26/01 05/02 15/02 25/02 06/03
Fig. 6.2 Highly affected regions for COVID-19 confirmed, active, recovered, and tested cases in
India
We first started at the end of January 30, 2020, and had only ten actual data points
in our hands. We have to make use of the exponential smoothing model of a
multipli- cative pattern. The forecasts were made at the end of January 30. For the
10-day-ahead events reported, the mean estimate (point forecast) was 209,000,
with 91% estimation periods ranging from approximately 39 to 535,000 instances.
The actual cases confirmed were just under 42,000 on February 11, 2020. We
found a significant predicted loss equal to 166,000 instances from the normal
calculation
6.6 Analysis and Forecasting 107
(a cumulative percentage error of 389%), with the figures being highly positive.
However, the individual cases fell behind the prediction intervals.
At the end of February 10, 2020, the chronological sum of our data was then
broadened to include incidents. We made the 10-day-ahead predictions yet again.
For the time between February 12, 2020, and February 21, 2020, it should be
noted that the average estimate is closely followed by the real values. For
February 21, 2020, the estimated error is 5.9 thousand instances. Notwithstanding
the adjust- ment made on February 14, 2020, as opposed to laboratory-proven
instances,
“clinically identified” instances are now included only in terms of how reported
cases are registered. One interesting observation is that this more robust forecast
resulted in a substantial decrease in the slope’s steepness relative to the previous
10-day duration forecast. Another point is that we have already overestimated the
number of confirmed cases at the end of February 21, 2020. Lastly, all the real values
were way above the predicted range of intervals.
We generated a third set of predictions and prediction dates using the data up to
February 21, 2020. The mean estimate for 11 days in advance was 85,000
instances. Again, the slope of the forecasts was lower than that of the previous two
forecast sets, which confirmed a steady decline in the number of cases registered.
We also noted a significant decrease in the corresponding projection volatility
relative to our previous predictions, with the prediction periods becoming
marginally tighter. For 91% of projected periods, the worst-case situation was
almost 700,000 examples, which is half according to the current round of
forecasts. The real cases confirmed were 87,000 at the end of March 02, 2020. We
reported an error of 56,000 instances at the conclusion of this third round of
calculations.
The cumulative estimate for March 12, 2020, was 113,000 confirmed occurrences,
with a comparable volatility rate to the previous round: at the end of March 12, 2020,
there was a 6% probability that they would reach 614,000. The actual confirmed
events reported at the end of this time are about 128,000. At the end of the last
period, the absolute forecast error was 15.5 K, higher in comparison to the
previous forecast series but still well within the forecast intervals. We were
continuously under-forecasting the real events for the second round in a row. This
was attributed to an extraordinary surge in the number of new cases reported,
mostly in Europe, Iran, and the USA, with South Korea being able to decrease the
number of new cases each day significantly.
108 6 Visualization and Prediction of COVID-19 Using AI and ML
Fig. 6.3 COVID-19 confirmed, active, recovered, and tested cases in India
We produced a final set of forecasts and prediction intervals until March 12, 2020,
using the most recent proof. Notice that we have calculated 3 degrees of
uncertainty. Compared to the last two rounds, the trend in our projections is even
higher: for this round, we predict 84,000 new incidents. The associated levels of
volatility are much higher: there is a 26% chance that by the end of March 22,
2020, the overall registered cases will reach 414,000 and a 6% probability that by
the end of March 22, 2020, they will touch 1.18 million (Fig. 6.3).
By segregating the reported confirmed cases into two types—cases within
Main- land China and cases somewhere else—we have tried to build forecasts
since the distinctions between these two classes are different. We developed
exponential
smoothing models separately and then summarized the forecasts. Using this method,
the average estimation is equal to that of all the data considered together, we
remember. The evidence of variation splitting, however, is estimated to be
consider- ably smaller, as recorded cases outside Mainland China are only likely
to have increased dramatically recently.
neural networks that they do not respond to the gradient disappearance or gradient
explosion problem and can only store short-term memory and have only hidden
layer activation functions in the previous step (Hochreiter and Schmidhuber
1997).
It is known that LSTMs are among the most efficient solutions for prediction
operations, and based on the different highlighted features present in the dataset,
they forecast future predictions. With LSTMs, knowledge travels through
elements known as cell states. LSTMs may recall or miss details correctly. The
data obtained over progressive stretches of time is known to be the data from time
series, and LSTMs are typically used as a rigorous means of calculating these data
values. The model converts the previous veiled state to the appropriate stage of the
arrangement in this style of architecture. Long short-term memory cells
(Hochreiter and Schmidhuber 1997) are used for long-term memory retrieval
RNNs, while RNNs can retain only a small amount of information. The problems
of the gradient disappearing and the bursting gradient (Bengio et al. 1994)
plaguing RNN are resolved by LSTMs. LSTM cells are similar to RNN, with
memory blocks replace- able by hidden modules.
The regular LSTM extension we have defined above is stacked LSTM (Graves et
al. 2013), also known as Deep LSTM. There are several hidden layers and several
memory cells on the stacked LSTM. The depth of the neural network is improved
by the stacking of multiple layers, where each layer has some information and
transfers it to the next. The top LSTM layer supplies the previous layer with
sequence information and so on. For each time step, it produces a different output
instead of a single output for all time steps.
Inputs are processed by traditional RNNs in only one direction and ignore the
possible knowledge that they provide. By following the bidirectional topology of
LSTM (Schuster and Paliwal 1997), this issue is solved. By keeping both past and
future information into account, bidirectional LSTM (Bi-LSTM) excludes absolute
temporal time information. Periodic secret RNN neurons are separated into
forward and backward states in which forward state neurons are not bound to
backward states and vice versa. The design without the backward states is identical
to the normal unidirectional RNN. There is no need to provide extra time delays as
used for this process in standard RNN.
110 6 Visualization and Prediction of COVID-19 Using AI and ML
6.8 Conclusion
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Machine Learning Approaches in Detection and
Diagnosis of COVID-19 7
Abstract
Novel coronavirus disease (COVID-19) has hit the world in December, 2019,
with the first case being identified in Wuhan, China. Since then, international
health agencies are making serious efforts to manage the pandemic, exploring
every aspect of therapy development with a special attention on investigating
smart diagnostic tools for rapid and selective detection of COVID-19.
Detection of the disease is mainly through reverse transcription-polymerase
chain reaction (RT-PCR) test, which is complex, expensive, and time-
consuming, making it difficult to scale-up for mass testing. Hence, there is a
need for parallel diagnostic testing procedures that are fast, accurate, and
reliable. In many recent studies, it has been shown that COVID-19 disease
clearly exhibits distinct infection patterns in the lung distinguishable from other
pneumonia-related diseases. Machine learning and artificial intelligence are well-
established methods in image analysis, making them suitable for the analysis of
computerized tomography (CT) chest scans and X-ray images. This provides a
novel class of testing that is noninvasive and can help in point-of-care testing
by the use of portable CXR machines. AI-based medical imaging can help in
quickly and accurately labeling specific abnormal structures, without omission
of even small lesions, making them suitable for the analysis of chest CT scans
and X-ray images. This would alleviate the growing burden on radiologists and
assist them in making accurate diagnosis. In this chapter, we present an
overview of the state-of-the-art deep learning architectures in the detection of
COVID-19 by analysis of chest CT scans and X-ray images.
Keywords
COVID-19 · Deep learning · Chest X-rays · Computerized tomography scans
· Convolutional neural network · ResNet · DenseNet · Inception · Xception
7.1 Introduction
Fig. 7.1 Flowchart of the study by Fang et al. to assess the performance of CT scans for the
detection of COVID-19 comparison to RT-PCR (reproduced from (Fang et al. 2020))
Fig. 7.2 Chest X-ray image on day 3 of a COVID-19 patient (left) clearly indicates right mid and
lower zone consolidation; on day 9 (right) is seen worsening oxygenation with diffuse patchy
airspace consolidation in the mid and lower zones. (Case courtesy of Dr. Derek Smith, Radiopaedia.
org, rID: 75249)
and crazy paving (thickened interlobular lines) are other patterns that are seen in
CT images of the COVID-19 patients (Ng et al. 2020; Awulachew et al. 2020).
The characteristics of the disease is clearly seen in X-ray (Fig. 7.2) and CT scan (Fig.
7.3) images of the chest in COVID-19 patient that help in distinguishing
coronavirus
7.1 Introduction 117
Fig. 7.3 CT scan image performed to assess the degree of lung injury of the patient in Fig. 7.2 on
day 13 (left coronal lung window, right axial lung window). Multifocal regions of consolidation and
ground-glass opacifications with peripheral and basal predominance. (Case courtesy of Dr. Derek
Smith, Radiopaedia.org, rID: 75249)
infection from other pulmonary infections, seen as white patches in CXR and CT
images. Thus, CXR and CT imaging provides a noninvasive diagnostic testing that
can help in point-of-care testing by the use of portable CXR machines. However,
chest radiography image analysis requires the expertise of radiologists, which may
create a bottleneck in the decision-making process during a pandemic situation.
The use of artificial intelligence (AI) models for the diagnosis of COVID-19 using
thoracic images helps in triaging patients and reducing turnaround time, by
automating the decision-making process (Chandra and Verma 2020; Varshni et al.
2019). This has led to the deployment of computer-aided systems using machine
learning (ML) methods in various hospitals globally to help medical staff in faster
triaging of patients.
Deep learning (DL) methods have proven to be the cutting-edge image analysis
tools in most fields. Because of their ability to capture patterns in input images,
DL methods find application in varied tasks, such as face recognition (Mehendale
2020; Nagpal et al. 2019), object identification (Pérez-Hernández et al. 2020; Ren
et al. 2016), applications in natural language processing (Guo et al. 2020), and
medical image analysis (Smailagic et al. 2020; Spanhol et al. 2016). Convolutional
neural network (CNN) is one of the popular architectures of DL models applied in
image analysis. Various CNN architectures, such as ResNet (He et al. 2015),
DenseNet (Huang et al. 2018), Inception (Szegedy et al. 2015), etc., have been
proposed for various tasks based on the data type and application. Here, an
overview of some CNN-based studies is proposed for the diagnostic and
prognostic analysis of chest radiography images of COVID-19 suspects,
including domain knowledge aware
118 7 Machine Learning Approaches in Detection and Diagnosis of COVID-19
Pneumonia is the swelling of air sacs in the lungs due to various reasons, including
viruses, bacteria, fungi, etc., and may result in minor to severe illness in people of all
ages. Common symptoms of pneumonia include cough, fever, shortness of breath,
etc., and diagnosis mainly involves chest X-ray, blood culture, sputum culture, CT
scan, etc. Treatment of pneumonia is based on the type of infection: bacterial,
viral, or fungal. Various viral infections from common flu (influenza) to the deadly
ones, including SARS, MERS, etc., can lead to pneumonia, and death in most such
cases is due to respiratory failure. The CXR and CT scans are the standard
practices for detecting pneumonia, but in pandemic-like situations, the imaging
departments in hospitals may get overwhelmed by the huge number of cases, as
analyzing radiog- raphy images needs expertise and time. Thus, there clearly is a
need for automatic analysis of these images, and AI/ML-based technologies are
well-suited for such tasks. Lung infections typically look as opaque areas in the
images, which can be unclear and difficult to distinguish between various lung
abnormalities, like pneu- mothorax, pleural effusion, pneumonia, pulmonary
tuberculosis, lung scarring, etc., posing a challenge even to radiologists. ML-based
systems can assist radiologists in arriving at the correct decisions as shown by
various studies in detecting pulmonary diseases, like diagnosing pulmonary
tuberculosis (Lakhani and Sundaram 2017), classification of lung nodules for lung
cancer detection (Hua et al. 2015), and detection of various other abnormalities
from radiography images (Islam et al. 2017). By identifying eight statistical
features of the segmented lung areas, Chandra and Verma (2020) were able to
classify CXR images into pneumonia and normal. Deep learning (DL) methods
have proved the best among other ML approaches in the classification tasks for
image data (Antin et al. 2017; Sedik et al. 2020). In fact, application of ML
techniques in medical image diagnosis has proved its ability in reaching human-
level expertise now (Rajpurkar et al. 2017; Jin et al. 2020).
Fig. 7.4 Typical convolutional network framework for classifying COVID-19 cases, which takes
as input CXR images and passes through a series of convolution, pooling, and dense layers and uses
a softmax function to classify an image as COVID-19 infected with probabilistic values between
0 and 1
120 7 Machine Learning Approaches in Detection and Diagnosis of COVID-19
traditional convolution layers are replaced with smaller blocks and have filters of
different sizes to capture patterns at different scales. The architecture of
GoogLeNet applied various parameter optimizations, such as discarding redundant
feature maps, using global average pooling, etc., which helped in limiting the
number of parameters to four million. There are many other variants of CNNs,
which were introduced by making changes to the architecture (not covered here).
A detailed review is given in the study by Khan et al. (2020a). Some of the most
popular architectures applied in the detection of COVID-19 reviewed in this
chapter are given in Table 7.1.
Fig. 7.7 CoroNet architecture. AEH and AEP are the two autoencoders trained independently on
healthy and non-COVID pneumonia subjects, respectively. TFEN is a Feature Pyramid-based
Autoencoder (FPAE) network, with seven layers of convolutional encoder blocks and decoder
blocks, while CIN is a pre-trained ResNet-18 network. (Reproduced from (Khobahi et al. 2020))
7
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ag
Fig. 7.8 COVNet architecture. Features are extracted from each CT scan slice which are combined using max-pooling operation and submitted to a dense layer, no
which generates scores for the three classes. (Reproduced from (Li et al. 2020)) sis
of
C
O
VI
7.3 Application of Deep Learning Approaches in COVID-19 Detection 127
Fig. 7.9 Block diagram of the subsystem (a) performs a 3D analysis of CT scans, for identifying
lung abnormalities, and subsystem (b) that performs a 2D analysis of each slice of CT scans, for
detecting and marking large-sized ground-glass opacities using proposed method (reproduced from
(Gozes et al. 2020))
slice) as normal vs abnormal. The model also outputs a lung abnormality localization
map along with the score to identify areas contributing to the network’s decision,
using Grad-CAM technique (Selvaraju et al. 2017). Using this AI-based system,
eight COVID-19 patients were monitored for a period of 30 days, and the relative
progression of disease among the patients was assessed to allocate to the patients’
required resources accordingly. Thus, AI-enabled diagnostics can help not only in
the detection of but also monitoring the progression of COVID-19 disease.
Recent study by Jin et al. proposed a fast AI system based on deep neural network
for diagnosis of COVID-19, by analyzing chest CT images, which achieved accu-
racy, sensitivity, and specificity close to 95%, and outperformed radiologists by over
two orders of magnitude in diagnosis time (Jin et al. 2020). The study involved a
multitask diagnostic to distinguish between COVID-19, influenza-A/B, non-viral
pneumonia, and non-pneumonia cases. Here, a DL-based model trained on CT
scan images, annotated by radiologists, was able to detect COVID-19 patients
correctly and assist radiologists, by significantly reducing the reading time (Chen
et al. 2020). The model was trained on 46,096 images from a very small set of
106 patients (51 COVID-19, 55 other conditions) retrospectively, and the
prediction results were compared with the diagnosis of the radiologists. The AI
system included five components: (1) a lung segmentation block, (2) COVID-19
diagnosis block, (3) a module for identifying abnormal slices in positive samples,
(4) module for visualizing abnormal regions in the slices, and (5) module for
explaining features of abnormal regions. Input 3D CT volumes were taken slice by
slice and the lung area segmented with DeepLab v1, a 2D semantic segmentation
network (Chen et al. 2016). The segmentation results were used as masks and
concatenated with raw CT slices and fed to COVID diagnosis block, which has
ResNet-152 as a backbone with 152 convolutional layers, pooling and dense (fully
connected) layers using a 2D deep network, after pre-training it on ImageNet.
Output score of this block provides
128 7 Machine Learning Approaches in Detection and Diagnosis of COVID-19
confidence, whether lung-masked slices are COVID-19 positive or negative. The top
three highest scores on 2D slices of a volume are averaged to obtain a 3D volume
score. A block for locating the abnormal slices is the same as the diagnosis block, the
difference being that it was trained only on manually curated COVID-19 positive
images. The workflow of the system is depicted in Fig. 7.10a, and the dataflow in the
AI system is explained in Fig. 7.10b.
Fig. 7.10 (a) Workflow of the AI system data divided into four nonoverlapping cohorts for
training, internal validation, external testing, and expert reader validation. (b) Usage of the AI
system—performs lung segmentation on CT images and diagnosis of COVID-19 and locates
abnormal slices (reproduced from (Jin et al. 2020))
130 7 Machine Learning Approaches in Detection and Diagnosis of COVID-19
Fig. 7.11 Inception V3 architecture has a deeper architecture compared to ResNet (source https://
towardsdatascience.com/illustrated-10-cnn-architectures-95d78ace614d#d27e)
as the initial value that is halved if the validation loss does not increase for three
epochs, called the patience factor. To have more meaningful initial weights, the
network was pre-trained on ImageNet instead of random initialization of weights.
Model was trained on six different combinations of datasets of COVID-19, pneu-
monia, tuberculosis (TB), and healthy samples and validated using tenfold cross
validation.
A deep neural network model, proposed by Khan et al., is based on Xception
architecture, which is basically the extreme version of Inception. It consists of
71 layers deep CNN for classifying the CXR images into binary (COVID-19 and
normal), three class (COVID-19, normal and pneumonia), and four class (COVID,
normal, pneumonia-bacterial, and pneumonia-viral) classifications (Khan et al.
2020b). It uses depth-wise separable convolution layers along with residual
connections, replacing × n n ×n convolutions with × 1 1 k point-wise
convolutions, followed by channel-wise
× n×n spatial convolution operations,
resulting in reducing the number of operations by a factor 1/k. In this case, also
the network was pre-trained on ImageNet and fine-tuned on the task-specific
dataset for 80 epochs in batches of 10. Softmax activation function was applied on
the output of the last connected layer and probability distribution generated for
the
7.3
Ap
pli
cat
ion
of
De
ep
Le
arn
ing
Ap
pr
oa
ch
es
in
C
O
VI
D-
19
De
tec
tio
n
Fig. 7.12 Xception architecture introduced depth-wise separable convolutions (source https://towardsdatascience.com/illustrated-10-cnn-architectures-
95d78ace614d#d27e)
13
1
132 7 Machine Learning Approaches in Detection and Diagnosis of COVID-19
Fig. 7.13 DenseNet architecture connects feature maps of all previous layers to subsequent layers
(source https://towardsdatascience.com/review-densenet-image-classification-b6631a8ef803)
Fig. 7.15 LSTM architecture employs gates to regulate flow of information across layers (source
http://colah.github.io/posts/2015-08-Understanding-LSTMs/)
output classes. Performance of the network was estimated using fourfold cross
validation. To address data imbalance, random under-sampling, was done by ran-
domly deleting samples in majority classes.
The diagnostic analysis on both CXR and CT images using two data augmented
DL models, CNN and convoluted long short-term memory (ConvLSTM), has
been conducted by Sedik et al. (2020). LSTMs have an architecture similar to
ResNets with respect to the cross-layer connectivity. The difference is that in
LSTM, it is done with the help of gates that control the information that is passed over
the layers. For the data augmentation process, a set of simple image
transformations, such as
7.3 Application of Deep Learning Approaches in COVID-19 Detection 133
Convolution Layer Max Pooling Layer Average Pooling Layer Concatenation Layer
Global Average Pooling LayerFully Connected LayerSoftmax layer
Fig. 7.16 @Original Inception Net Architecture (above), truncated Inception Net architecture
(below). (Reproduced from (Das et al. 2020))
scaling, rotation, and flipping resulted in a tenfold increase and was followed by
convolutional generative adversarial networks (CGANs) to address the problem of
limited data. During the learning phase on a given training set, GANs generate
new synthetic data from the existing ones for training. It is composed of generator
and discriminator networks. The generator synthesizes new data from the latent
space of
the input, while the discriminator tries to distinguish reconstructed images from
the input images. The generator’s objective is to increase discriminator’s error
rate. In this study, CGAN consisted of five convolutional transpose layers with
filters of sizes 8, 4, 2, 1, and 1, respectively, in the generator (Fig. 7.17). Input is
given to a
denoising fully connected layer, followed by convolutional transpose layers and
batch normalization layers. At the end of generator, feature maps of input images are
generated. The discriminator consisted of five convolutional layers with filters of
sizes 64, 2, 4, 8, and 1, respectively, followed by Conv2D layers, batch normaliza-
tion layers, and a denoising fully connected layer. All the images were resized before
feature extraction. The two deep learning models, CNN and ConvLSTM, compris-
ing five and one convolution layers, respectively, are followed by max-pooling
and global average pooling (GAP) layers for determining and extracting the
features, which are then fed to the classifier. The performance of classifiers is
carried out with and without data augmentation, to assess its role in diagnosing
COVID-19 using support vector machine and k-nearest neighbor classifiers to
compare with tradi- tional ML techniques. As expected, the DL models exhibited
better performance than SVM and k-NN models.
The study by Brunese et al. proposed a DL model based on VGG-16 (i.e.,
Visual Geometry Group) architecture, a CNN with 16 layers (Brunese et al. 2020).
The model works in three phases: Initially, it tries to distinguish between healthy
and pneumonia-related images. In the next phase, it attempts to differentiate
between COVID-19 images and other pneumonia, and finally, the last phase
identifies regions in the image that are symptomatic of COVID-19 to provide an
explainable system. The architecture used in this study is shown in Fig. 7.18. To
exploit transfer learning,
134 7 Machine Learning Approaches in Detection and Diagnosis of COVID-19
Fig. 7.17 Dataflow in the DL model using data augmentation (reproduced from (Sedik et al.
2020))
224 x 224 x 3
224 x 224 x 64
28 x 28 x 512
14 x 14 x 512
7 x 7 x 512
512
64
2
convolution + ReLU
dense
dropout
max pooling
flatten
Fig. 7.18 Architecture used in the study by (reproduced from (Brunese et al. 2020))
7.3 Application of Deep Learning Approaches in COVID-19 Detection 135
the model has been pre-trained with over 14 million images from ImageNet. To fine-
tune transfer learning, the network is appended with a new fully connected
(FC) layer, after removing the FC layer from pre-trained network, and image resized
to 224 ×224 dimensions, the size of the first convolutional layer. This new FC layer
includes AveragePooling2D (which performs the average pooling operation by
computing the average of every patch in the feature map), Flatten (the input is
flattened by transforming a 2D feature matrix into a vector that is given as an input to
a classifier), Dense (to transform data, in this case to reduce the height of the
vector from 512 to 64 elements), Dropout (to build a network that does not overfit
to training data by randomly selecting neurons not used during training), and
another Dense connection (this dense reduces the height of the vector from
64 to 2, corresponding to the two classes to predict) with softmax function used
for classification (Fig. 7.18). For data generalization, data augmentation was
carried out with a random clockwise or counterclockwise rotation of 15 degrees.
For the explainability feature, gradient-weighted class activation mapping (Grad-
CAM) approach is used here, which results in a heatmap depicting abnormal
regions for each class. The model training, validation, and testing were done on a
dataset with 6523 CXR images, which includes 3520 related to normal class, 2753
related to other pulmonary-related illness, and 250 COVID-19 images, confirmed
by radiologists.
Wang et al. proposed a DL model, COVID-19Net, for diagnostic and
prognostic analysis of CT images (Wang et al. 2020). The unique feature of this
study is using retrospective CT images for pre-training the network, to learn the
lung features, and using follow-up data of 5+ days of 471 COVID-19 patients for
training and validating the model. That is, the transfer learning here is done on
chest CT images, compared to ImageNet database used in most other studies. The
model can identify the patients with high-risk from low-risk group based on follow-
up data, allowing for early interventions and resource management. Through a
prognostic feature selec- tion procedure, three features, namely, age, sex, and
comorbidity, along with a 64 DL model-generated features were combined to
predict a hazard value for each patient using a multivariate Cox proportional
hazard (CPH) model. The median of this cutoff value was used for dividing
patients into low-risk and high-risk groups. The model included three modules for
(1) lung segmentation, (2) non-lung area suppression, and (3) COVID-19
diagnosis and prognosis. The architecture and dataflow in the model are depicted
in Fig. 7.19. Lung segmentation module was build using DenseNet121-FPN, pre-
trained on ImageNet and fine-tuned on VES- SEL12 dataset. Through this
procedure, lung mask in the CT image is obtained, and the lung ROI was extracted
using a bounding box from the CT images. This may include non-lung areas, e.g.,
the heart, spine, etc., which were removed by suppressing the intensities of these
areas. The final lung ROI was standardized using z-score normalization before
being fed to COVID-19Net. The model uses DenseNet-like structure with four
dense blocks, each having multiple stacked convolutional, batch normalization,
and ReLU activation layers. The dense connections in each layer were used to
capture multilevel information from the images. A global average pooling layer
added at the end of convolutional layer
136 7 Machine Learning Approaches in Detection and Diagnosis of COVID-19
batch
COVID-19 normalization
probability
Use CT and gene data of 4106 lung cancer patients to pre-train the COVID-
19Net global average
Fig. 7.19 Illustration of the COVID-19Net model (reproduced from (Wang et al. 2020))
Machine learning models rely on data to learn the patterns in the data. The amount of
data needed depends on how deeply connected are the features in the data. The
nonlinear relationships in the underlying patterns can only be captured by a model, if
it has been trained sufficiently with data possessing all these features. In the case
of DL models, this is a stringent requirement. The major bottleneck in the analysis
of COVID-19 image data has been limited availability of public data compared to
other lung infections, leading to class imbalance problem. To overcome these
challenges, most studies presented here used transfer learning approach.
Transfer learning (TL) is a technique in which model trained on one data is used
for initializing the parameters of another related problem. Given a source domain
and target domain with respective source task and destination task, learning
conditional probability distribution in target domain with insight gained from source
domain is the objective of this approach. This technique has been applied in various
classification tasks, such
as classification of cancer samples (Sevakula et al. 2019), detection/classification
of Alzheimer’s disease (Hon and Khan 2017; Maqsood et al. 2019), etc. The major
advantage of using transfer learning is reduced time for training a neural network
model and may also result in better generalization of the model.
Image analysis models are typically trained on ImageNet dataset, which
consists of over 14 million images organized under more than 100,000
“synonym sets” or
7.3 Application of Deep Learning Approaches in COVID-19 Detection 137
From the recent literature, it is evident that though deep learning models have
attained unparalleled accuracy in the classification and segmentation of images,
their major limitation is interpretability, that is, to identify the features responsible
in decision-making. This is the most important component in model understanding
and model debugging and has limited the acceptance of DL methods, especially in
the medical field. Radiologists, using AI models to assist them in diagnosing various
conditions in a health support system, need to reaffirm the decisions that they
make using these models. This requires the model to help them interpret or
visualize the
features that enabled the model’s decision. In COVID-19 diagnosis using chest
CXR, it is very crucial that model is rightly distinguishing symptomatic COVID-
19 pneumonia from other lung infections. This requires marking on the lung
images the regions that helped in differentiating between different pneumonia-related
cases. Different methods have been proposed in the studies discussed above for
identifying and visualizing the features responsible for prediction. For example,
COVID-Net makes use of GSInquire method, which projects the updated
parameters by the inquisitor to improve the network generated by the generator
into the same subspace as the input x. This helps in visualizing the pixel areas that
contributed for the prediction of the label as shown in red in Fig. 7.20 and helps in
confirming that the algorithm is not making incorrect decisions based on imaging
artifacts, etc. Thus, apart from providing insights into the factors associated with
COVID-19, this would help the clinicians in the screening process with improved
accuracy.
The deep learning model CoroNet (Khobahi et al. 2020) uses attribution map,
which is basically a heatmap, showing the pixels that contributed to the prediction.
These attribution maps are generated using a perturbation-based algorithm and
shown in Fig. 7.21 for three categories: normal, pneumonia, and COVID-19. The
algorithm works by perturbing the input image, such that the target class
probability is minimized. The pixels that minimize the target class probability by a
great extent are highlighted on the heatmaps as the regions contributing to the
correct predictions. It maybe be noted that different regions in the CXR images are
highlighted by the classification model for the three categories considered.
138 7 Machine Learning Approaches in Detection and Diagnosis of COVID-19
Fig. 7.20 Abnormal lung regions identified by GSInquire leveraged from the update parameters
generated by the Inquisitor of the generator-inquisitor pair after probing the response signals
from the generated network with respect to the input signal and target label. (Reproduced from
(Wang and Wong 2020))
Fig. 7.21 Attribution maps for five random patients for the three classifications considered. Yellow regions represent most salient and blue regions the least
salient regions as indicated by the color bar (reproduced from (Khobahi et al. 2020)) 13
9
140 7 Machine Learning Approaches in Detection and Diagnosis of COVID-19
Fig. 7.22 Attention heatmaps generated by GRAD-CAM. The red regions indicate the activation
regions associated with a sample. (Reproduced from (Li et al. 2020))
Fig. 7.23 DL discovered suspicious lung areas learned by COVID-19Net. (Reproduced from
(Wang et al. 2020))
Tp
sensitivity
Tp þ Fn
¼ ð7:2Þ
Tn
specificity
¼
ð7:3Þ
Tn þ Fp
Tp
precision
¼ ð7:4Þ
Tp þ Fp
where Tp is defined as true positive, Tn as true negative, Fp as false positive, and Fn as
false negative.
ðprecision × sensitivityÞ
F1 score 2 ð7:5Þ
¼ × ðprecision þ sensitivityÞ
7.4 Challenges
CNNs have achieved great performances in many challenging tasks, but there are
still grey areas in its performance when it comes to its application in certain areas,
such as medical domain. Data is the backbone of any ML tool, especially for
supervised learning algorithms, and the lack of annotated data is the most
challeng- ing, among other reasons that ML researchers face toward making the
tool confident in assisting the healthcare professionals. The largest available
number of patients CXR or CT images are still very small despite the increase in
number of cases worldwide. For training a ML tool with complex patterns like
ground-glass opacities in case of chest images, the minimum requirement is balanced
training data, which is
142 7 Machine Learning Approaches in Detection and Diagnosis of COVID-19
a far cry from the reality. Deep neural networks are typically considered a black
box when it comes to the explainability of its results. Visualization of results from
DL models, interpreting the predictions with good precision and confidence, is the
need of the hour and needs to be addressed. Further, these technologies have to be
made available in portable devices like smartphones, so that the objectives of the
research are materialized. The training of deep networks requires powerful
computational resources, which makes it challenging to embed them in smaller
portable devices.
7.5 Summary
COVID research is moving at faster than before rates, and thousands of new research
publications have come in the past few months. This chapter has focused on
reviewing few DL-based solutions for diagnosing COVID-19, using chest
radiology images. Most of the studies have exploited the capability of CNNs to
bring out a reliable diagnostic/prognostic tool analyzing CXR or CT scans of the
chest. ResNet, DenseNet, Inception, Xception, VGG, and other customized
models have emerged as forerunners in this task. The performances of all these
models are comparable, and most of them give very high accuracy, sensitivity, and
specificity. The visualization of the results of these models is also presented as
part of the performance of these models. Most studies have used attention
heatmaps to visualize the activation regions in the images that resulted in model
prediction. GRAD-CAM is one such
technology in generating attention heatmaps. Localization of abnormal lung
regions are also addressed that highlight only the lung regions responsible for
model’s decision from the entire image, proving the correctness of the methods.
Though the results from these studies are promising, generalizability of these models
on data from different distributions need to be verified.
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Applications of Machine Learning
Algorithms in Cancer Diagnosis 8
Abstract
Cancer is a deadly disease and is a leading cause of death worldwide. It is a
heterogeneous disease with a number of subtypes. For an effective clinical
management of the cancer patients, the early diagnosis and prognosis is the
need of the hour. The advancing technologies in the field of medicine have led
to the availability of enormous cancer data to the researchers. However, they have
faced a prime challenge of predicting the accurate outcomes of this disease. For
this very purpose, the concept of machine learning (ML) came into existence. The
ML tools and techniques can detect key features from the electronic complex
datasets to model cancer risks or patient outcomes. The ML techniques have been
frequently used by the researchers in the field of bioinformatics and
biomedicine to classify the cancer patients into low- and high-risk groups.
Moreover, there has been an implementation of these techniques in modeling the
progression of the tumor along with its effective treatment. Although the
different ML algorithms have provided an improved understanding of the
tumor condition, a proper validation is required for their applications in
everyday clinical practices. Keeping in mind the growing trend of application
of ML tools in cancer research, we present here a performance analysis of the
three common classifiers: artificial neural networks (ANNs), Naive Bayes, and
support vector machines (SVMs). In this study, the effectiveness and accuracy of
these classifiers have been compared in terms of their sensitivity, specificity,
accuracy, and area under the curve (AUC) using Orange and R programming on
the three different cancer sample datasets (viz., liver, prostate, and breast
cancer).
Keywords
Cancer · Machine learning · ML algorithms · Artificial neural networks (ANN)
· Naive Bayes · Support vector machine (SVM)
8.1 Introduction
Machine learning (ML) has emerged with the innovations in the field of data
sciences as a tool for automated classification. ML comprises a class of techniques
and areas of research that can mimic the learning capacity of humans and enable
the computer to learn and extract/classify patterns. ML is used in a broad range of
applications from forecasting stock market regression to reinforcement learning to
play games, but here we focus on prediction in the sector of healthcare.
The history of the relation between biological science and the field of machine
learning is not new, but it is significant. The applications of ML methods using
biological data are being used for the prediction of genes within and among
species, functional annotation, and system biology and in the analysis of metabolic
pathways. ML approaches are now being applied in medical science for the
detection and classification of different types of tumors.
From the past few decades, healthcare has become one such industry where digital
data has exponentially increased. These data repositories are rich sources of diver-
gent and interesting patterns. Since statistical techniques fall short in analyzing
and extracting these patterns, ML techniques have been evolved to overcome
them, and ML algorithms have a capability to extract, enfold, and transform the
patterns from healthcare data.
The concept of introducing technology to the field of medicine started as a tool
known as expert systems. ML are artificial intelligence (AI)-based techniques that
comprise a variety of algorithms with a capacity to learn from situations and
environment. These algorithms can build models for autonomous prediction and
classification (Ahuja 2019). Similarly, in the past decade, the accuracy rate of cancer
prognosis and diagnosis has not been up to the mark. So, in order to enhance the
decision-making capability of clinicians, the elements of machine learning could
be used to improve the accuracy levels in the pathology system (Sayed 2018). ML
is able to find classes of algorithms that can show a high level of generalization
performance to new datasets to which the machine (computer) is not exposed
during the training.
Past studies were focused on designing of models to predict possible outcomes
of a disease. These models were crafted for classification and prediction using
supervised methods. Result analysis of such studies clearly necessitates the
integra- tion of multidimensional heterogeneous data; feature selection and
classification techniques are favorable tools for cancer prognosis (Kourou et al.
2015). Digitaliza- tion in the field of clinical data handling and simultaneous
popularity of deep neural networks (DNN) is another reason for the inclination
toward ML in healthcare.
ML can detect patterns of certain diseases within patient’s electronic healthcare
records and notify clinicians about any anomalies. Artificial intelligence (AI) in
medical studies usually performs clinical diagnoses and provides suggestions for the
8.1 Introduction 149
Cancer is the second leading cause of death at a global scale. Every year, a large
population suffers due to this deadly disease. In 2018 itself, 9.6 million people
have lost their lives because of cancer. Researchers from different domains are
discover- ing the approaches to counter this disease. Early diagnosis of cancer
helps in saving the life of many. ML-based cancer diagnosis provides better
understanding of disease and preconditions with the level of severity of conditions
of patients (Zhu et al. 2020). This chapter has been devised to describe, compare,
and evaluate the performance of different machine learning techniques for cancer
prediction and prognosis. Specifically the chapter discusses the various machine
learning methods, the types of cancers along with their datasets, and the overall
performance of these ML in early diagnosis and prognosis of cancer.
The literature reveals that a vast number of studies had worked upon the
survival prediction problem using statistical approaches and artificial neural
networks (ANN). However, very few studies related to medical diagnosis using
decision trees (DT) had been conducted. Delen et al. used ANN, DT, and logistic
regression (LR) to design prediction models for breast cancer survival (Delen et al.
2005). Lundin et al. used ANN and logistic regression models for cancer survival
prediction using 5-, 10-, and 15-year breast cancer repositories (Lundin et al. 1999).
Pendharker et al. also used several data mining techniques to unveil new patterns
in breast cancer. The study used the ML algorithms in establishing similarities
between the cancer cases and, thus, helped in proper determination and treatment
of cancer (Pendharkar et al. 1999). These studies are only a few examples of
research that utilize ML to medical fields for prediction of diseases. The
recurrence of breast cancer can also be determined using various data mining
techniques or ML tools.
While the artificial neural networks predominates, a number of other ML strategies
are being used in cancer prediction. The overall performance and predictive accuracy
150 8 Applications of Machine Learning Algorithms in Cancer Diagnosis
The aim of ML algorithms remains to develop a mathematical model that fits the data
(Mitchell 2006). ML study basically deals with the creation and evaluation of
algorithms that facilitate pattern recognition, classification, and prediction, based
on the models derived from existing data. ML algorithm consists of a learning
attribute which is needed to acquire knowledge from data. There are two types of
ML-based problems, one where prior knowledge about data is needed and one where
prior knowledge is not required. Problems based on prior knowledge requirement are
named as prediction and classification. ML designs model for such problems.
During model construction data are supplied to algorithms for learning purpose.
Firstly, ML algorithm is trained from data to constitute a model, and then another
set of data is provided to test the model. In this process, ML uses a learning coefficient
to learn from train data and apply that knowledge on test data. In other problems,
algorithms are directly applied to the final dataset without any training, and
algorithms do not learn anything from data. Based on this learning attribute, ML
algorithms have majorly categorized into four types as shown in Fig. 8.1.
In supervised learning the class membership of new objects is accurately
predicted on the basis of previously available features, whereas in unsupervised
learning there are no such predefined labels for the objects. In such a case,
unsuper- vised algorithms such as clustering explore the data to infer similarities
between objects. The similarities are helpful in defining groups of objects called
clusters. Similarly association algorithms such as Apriori and FP are used to
devise associa- tion between unlabeled dataset. The natural groupings in the data are
easily identified in unsupervised algorithms. Thus, the two learning approaches are
quite opposite to each other. In supervised learning, the data come up with class
labels, and algorithms classify the classes with labeled data; in unsupervised
learning, data are completely unlabeled, and the learning methods works in
defining the labels and classifying objects with them. Semi-supervised algorithms
follow a blended approach of supervised and unsupervised learning. During the
training, the amount of unlabeled data exceeds the labeled data. Self-learning
algorithms, also known as reinforcement learning, are capable enough to learn by
themselves. They gradually learn from labeled data and drive their own logics
and understanding. Figure 8.2 shows different ML algorithms based on their
learning quotient and application.
Generally there are four types of analysis popular in medical diagnostics: descrip-
tive, inferential, predictive, and prescriptive. Machine learning is usually
employed for inferential, predictive, and prescriptive analysis. These algorithms
perform five types of tasks to provide such analysis. Tasks are association,
clustering, dimension reduction, classification, and prediction. The performance of
each task and algorithm is measured by number of metrics. Figure 8.3 illustrates
the tasks and metrics. These
8.2 Machine Learning Techniques 151
metrics are tools to measure the progress of algorithms. They guide researchers to
finalize and verify the ML-based model for their study (Fortunato et al. 2019).
Classification and prediction are generally used for designing the forecasting
model. In classification algorithms, the data item is classified into one of the
predefined class using the learning function. In prediction, the learning function
predicts the value. When a classification or prediction model is developed using
ML techniques, training, testing, and classification or prediction errors are produced.
The former ones are the misclassification errors on the training data, while the
latter ones are the expected errors on testing data. It should be noted that a high-
quality model always fits the training set well and also correctly classifies all the
instances. If the test error rate of a model is high even though the training error
rates are low, then the model suffers with overfitting issues. Overfitting of the
model occurs when data is unbalanced or algorithm is not suitable for the dataset.
While designing a model, factors such as unbalanced class, overfitting, and
underfitting are always essentially considered. These factors influence the
accuracy and precision of a model. Majorly health care studies employ prediction,
dimension reduction, and classification.
The performance of these models can be elevated by taking the right decision
on class balancing and algorithm selection. Metrics are defined to register and
observe the performance of these ML algorithms. Researchers can easily validate
their results
152 8 Applications of Machine Learning Algorithms in Cancer Diagnosis
and derive conclusions using these metrics. Many studies have shown usage of
metrics in cancer prediction assessment (Fortunato et al. 2019).
In recent years, machine learning algorithms are being used for analysis of the
occurrence of disease in several cancer patients. Machine learning provides a more
graceful and effective solution for the classification of cancer patients. The
symptoms of cancer may be misleading, and, in turn, it delays the process of
diagnosis and treatment. Over 100 types of cancers affect humans (Hanahan and
Weinberg 2011). Figure 8.4 shows various applications of ML in cancer study.
For this article we have selected the three most important types of cancers for
the purpose of ML.
Liver Cancer
Hepatocellular carcinoma (HCC) is considered as the prime liver malignancy. It
has even contributed predominantly in the cancer-related deaths worldwide
(Crissien and Frenette 2014). This is also known as primary liver cancer. Other
types of liver
8.3 Machine Learning and Cancer Prediction/Prognosis 153
Prostate Cancer
Prostate is a small walnut-shaped gland in the male reproductive system
responsible for the production of the seminal fluid that nourishes and transports
sperm. Cancer in this gland is one of the most common types of cancer in males.
Most of the prostate cancer grows slowly and remains confined to the prostate gland
only; however, some types of aggressive prostate cancer can spread quickly from
the prostate to other areas of the body, particularly the bones and the lymph nodes.
Though asymptomatic initially, in later stages, it can lead to difficulty in urinating,
blood in the urine, or pain in the pelvis and back. Factors that increase the risk of
prostate cancer include older age, a family history of the disease, and race. The
screening of some biochem- ical parameters can lead to the development of
reliable and specific diagnosis of prostate cancer, which if detected earlier has a
better chance of successful treatment (Barlow et al. 2019).
Breast Cancer
Breast cancer remains the most common invasive cancer among women. It is a
multistep process concerning multiple cell types. Substantial increase in breast
cancer consciousness and research funding has helped to create advances in the
early detection and treatment of breast cancer. In the United States, breast cancer
remains the major cancer among women with approximately 190,000 new cases
annually. Breast cancer incidence rates have increased, but the number of deaths
linked with this disease is progressively declining, largely due to factors such as
earlier detection, a new modified approach to treatment, and a better understanding
of the disease (Baralt and McCormick 2010).
Cancer detection at an early stage has become essential in cancer research for
better clinical management of patients. In this study, three different datasets of
liver, prostate, and breast cancer were examined to screen the budding cancer at an
early stage long before the development of any visible symptoms. Because of the
advance- ment in computational technology and medical science, huge data
repositories of cancer data are generated for clinical research. The bank of datasets
is easily available for cancer analysis and related research (Nagy et al. 2020).
However, the most interesting and challenging task in cancer study is the accurate
prediction of a disease outcome. Various ML techniques can be used for the
classification of cancer
8.3 Machine Learning and Cancer Prediction/Prognosis 155
patients. Different classifiers were used for the analysis purpose, among them are
artificial neural networks (ANN), Naive Bayes classifier, and support vector machine
(SVM) which provide effective models with highly accurate results. Problems such
as determining the class of cancer patients based on their risk (as high or low),
treatment susceptibility, and cancer growth with impacts are analyzed using ML
methods. The ML tools and techniques are being used to predict the precise
progression state and a valid treatment of the cancers. Even though ML methods
have improved the understanding of cancer progression, an appropriate level of
validation is the need of the hour so that these models are adapted easily in
everyday clinical practices (Murali et al. 2020). In this chapter, the predictive
models discussed are based on various supervised ML techniques as well as on
different input features and data samples. Based on the analysis of results, it was
found that these classifiers provide satisfactory performance in terms of accuracy,
recall, precision, specificity, and other parameters. The overall prognosis of
various types of cancer can be improved by the application of ML techniques
(Obaid et al. 2018).
Machine learning algorithms require large amounts of raw datasets for data
explora- tion, data mining, and statistical analysis. Data collection can be done
from various sources after which it is processed to remove missing value and
corrupt data detection imputation. In this chapter, the datasets have been taken
from https:// www.kaggle.com (an online community of data scientists and
machine learners, owned by Google LLC). There are three different datasets about
liver, prostate, and breast cancer, containing important variables such as
occurrence of disease, gene expression, proteins, environmental factors and
diagnosis, and survivability rates. The present study was focused to analyze
cancer based on the following:
– Diagnosis of disease.
– Occurrence of cancer.
– Survivability rate.
Liver cancer dataset: This dataset contained 416 liver patient records and
167 non-liver patient records collected from North East of Andhra Pradesh, India.
The “dataset” column is a class label used to divide groups into liver patient (liver
disease ¼1) or not (no disease ¼ 2). This dataset contains 441 male patient records
and 142 female patient records. Total records are 583.
Any patient whose age exceeded 89 is listed as being of age “90.” Liver dataset
has the following parameters segregated into covariables, factors, and dependent
variable as shown in Table 8.1.
Prostate cancer dataset: There are 12 parameters which were divided into
covariables and dependent variable as shown in Table 8.2.
Breast cancer dataset: Breast cancer dataset has nine parameters which were
divided into covariables, factors, and dependent variable as shown in Table 8.3.
156 8 Applications of Machine Learning Algorithms in Cancer Diagnosis
Figure 8.6 shows a flowchart for cancer prediction using ML in our case study.
After the collection and preprocessing of data, model is framed. If the data is
unlabeled, unsupervised learning algorithm is used for model framing. Labeled
data is the dataset where outcomes are already known. If data is properly labeled,
then dataset is divided into two parts: train and test set, and then model is designed
using semi-supervised or supervised learning algorithms. In this study, we have
labeled datasets. Cross-validation is another important step used for validation of
results. In such case data can be divided into three sets instead of two: train, test,
and validation set, respectively.
There are different tools in the market for ML designing. Python and R are
popular languages for ML coding. The tool selection depends upon a user’s
understanding of coding and comfort of usage. There are some tools that provide a
smooth interface to apply ML in any dataset. These tools are very useful in the
initial stage of research.
They help researchers gain basic understanding of ML process without the burden of
coding. Also, they provide clear and effective visualization of results. In this chapter,
Orange tool and RStudio have been discussed. Research needs to learn R program-
ming to use RStudio. In the case of Orange, users can simply drag and design their
model.
Orange
Orange is an open source tool with component-based visualization facilities for
data visualization, machine learning, and data analysis. It is a data mining tool
frequently used in biomedicine, bioinformatics, genomic research, and teaching. It
also provides a python coding interface for python library plug-in. Orange
components are termed as widgets that include simple data visualization, subset
selection and preprocessing, and empirical evaluation of learning algorithms and
modeling. Workflows can be created by linking predefined or user-designed
widgets. Widgets can also be edited using python coding.
RStudio
RStudio is an integrated development environment (IDE) for R. R is an easy but
extensive programming language for data manipulation, analysis, and
visualization. It is popular among data scientists for its effective data handling and
storage facilities. RStudio includes a console, syntax-highlighting editor that
supports direct code execution, as well as tools for plotting, history, debugging,
and workspace management. A GNU package, source code for the R software
environment, is written primarily in C. It includes a large number of libraries to
support medical and bioinformatics analysis.
8.3 Machine Learning and Cancer Prediction/Prognosis 159
Methodology
The first step requires data collection. In this study, we have collected a dataset
from an online data repository. Dataset comprises population characteristics, age,
gender, and factors responsible for predicting survival rate. Dataset involving
breast, liver, and prostate cancer was considered. The final dataset for the cancer
patients was developed after the implementation of data cleansing and
preprocessing strategies. The dataset is then split into two sets: train and test. In
the next stage, an algorithm was selected after reviewing literature, and then the
model is framed from train and test data. Figure 8.6 describes the methodology
flowchart for the current study.
The current study of cancer has three predicted purposes: (1) the evaluation risk
assessment or susceptibility of the cancer under observation, (2) the evaluation of
occurrence/reoccurrence or local control of the developing cancer, and (3) the
evaluation of the survival rates. In the first two cases, there is a chance of
developing or redeveloping a type of cancer after complete or partial remission. In
the last case, the prime objective is to predict the disease-specific survival rate or
the overall survival rate after the development of cancer. The prediction of cancer
patient outcome usually deals with life expectancy, survivability, progression,
treatment, and diagnosis. For this purpose, Orange and R programming are used.
These algorithms are used to extract instances from large datasets, to create
statistical software, graphics, and data analysis. Both these tools are also an open
source data mining tool and allow a user to perform ample of data mining
algorithms, which involve collection of tools for data classification, regression,
clustering, association rules, and visualization.
Fig. 8.9 The flow diagram of Naive Bayes in machine learning (Source: https://i.stack.imgur.com)
Naive Bayes
Naive Bayes is another ML algorithm for classification problems. It is working based
on Bayes’ probability theorem. It is used to resolve problems associated with text
and web classification, which deals with HD training datasets. It is the first algorithm
that is designed to resolve text classification problems. Figure 8.9 is a flow graph
of Naive Bayes.
• Train time ¼More time the model takes; it will predict the best accuracy.
• AUC (area under the curve)¼A measure of how well a parameter can distinguish
between occurrence and nonoccurrence of cancer. The higher the AUC, the better
the model is predicting. It gives an overall performance of a classification
model. The area under the ROC curve depicts the measure of separability. The
value of AUC ranges from 0 to 1. AUC below 0.5 shows a failed test model. A
perfect test has an area of 1.00. It has zero false positives and zero false negatives.
So, in order to yield correct results, the test should have an area between these two
values. The area is reported as a fraction even if the results are plotted as
percentages. Figure 8.10 shows the ROC curve.
• CA (cumulative accuracy) ¼ It observes average accuracy of all the models.
• F1 ¼Harmonic mean of precision and recall.
• Sensitivity ¼The fraction of people with the disease that the test correctly
identifies as positive. The formula is Sensitivity True¼Positives/(True
Positives + False Negatives).
• Specificity: The fraction of people without the disease that the test correctly
identifies as negative. The formula is Specificity¼ True Negatives/(True
Negatives + False Positives).
• ROC curve ¼ The ROC (receiver operating characteristic) curve is a promising
tool used to predict the probability of a binary outcome. The graph is plotted
for a number of different candidate threshold values between 0.0 and 1.0 while
keeping
162 8 Applications of Machine Learning Algorithms in Cancer Diagnosis
the false positive rate on the x-axis and the true positive rate on the y-axis. The
prime utilization of the ROC curve is in deciding where to draw the line
between “normal” and “not normal.” The decision will become easier if all the
control values exceed or are lower than all the patient values. However, in
reality, these
two distributions overlap, and hence the decision-making process is not that easy.
If the threshold value is increased, those who do not have the disease would not be
mistakenly diagnosed, but there are chances that some of the diseased people
are missed. If the threshold value is lowered, there will be a correct
identification of almost all diseased people, but at the same time there are
chances of diagnosing the disease in more people than the actual ones.
The aim of the study was to get the highest accuracy and specificity for the
various classifiers. Furthermore, the accuracy of the three classifiers is compared
in order to recognize which classifier works better for the classification of different
kinds of cancer. All classifiers with their types are rated based on these standards, the
overall accuracy, the specificity, and the time taken to construct the model.
8.4 Results and Analysis 163
Patients with liver cancer have been continuously increasing. The prime reasons
behind this could be periodic and excessive consumption of alcohol, exposure to
harmful gases, and consumption of contaminated food, pickles, and drugs. The
prediction algorithm was evaluated using the liver cancer dataset, reducing the
overall burden on the doctors. Our aim was to use this patient record to determine
which patients have developed liver cancer and which do not. Figure 8.11 shows
the flowchart in Orange tool for designing ML models.
Figure 8.12 shows the comparative table of SVM, NN, and Naive Bayes for
liver cancer data.
The model was constructed using tenfold cross-validation with 50% training
dataset. The performance of each model is compared using the area under the
curve (AUC); cumulative accuracy (CA); F1 score, which is a weighted harmonic
mean of precision and recall; precision; and recall. According to the results, NN
has the highest CA, i.e., 78%, recall (78%), and precision (77%) with F1 score of
76%. F1 score is good when it is near to 100%. It refers model performance in
combination of precision and recall. Overall NN is constructing a better model.
Figures 8.13a, 8.13b, and 8.13c shows the confusion matrices of all the three
algorithms. The dataset size was 583, out of which 167 cases belong to class 2 and
416 cases belong to class 1.
Figure 8.13a shows SVM confusion matrix for liver dataset.
The results are as follows:
Fig. 8.13a Confusion matrix for liver cancer dataset using SVM
• There are 124 cases which actually belong to class 1 and predicted also 1.
• There are 292 cases which actually belong to class 1 but predicted as 2.
• There are 42 cases which actually belong to class 2 but predicted as 1.
• There are 125 cases which actually belong to class 2 and correctly predicted as 2.
8.4 Results and Analysis 165
Fig. 8.13c Confusion matrix for liver cancer dataset using Naive Bayes
Therefore, out of 416 liver patients, SVM is able to predict only 124 cases, and
out of 167 non-liver patients, SVM is able to predict only 125 cases accurately.
Figure 8.13b provides neural networks confusion matrix for liver
dataset. The following are the results:
• There are 382 cases which actually belong to class 1 and predicted also 1.
• There are 34 cases which actually belong to class 1 but predicted as 2.
166 8 Applications of Machine Learning Algorithms in Cancer Diagnosis
Hence, out of 416 liver patients, NN is able to predict only 382 cases, and out
of 167 non-liver patients, NN is able to predict only 74 cases accurately.
Figure 8.13c illustrates Naive Bayes confusion matrix for liver
dataset. The results are as follows:
• There are 275 cases which actually belong to class 1 and predicted also 1.
• There are 141 cases which actually belong to class 1 but predicted as 2.
• There are 48 cases which actually belong to class 2 but predicted as 1.
• There are 119 cases which actually belong to class 2 and correctly predicted as 2.
Thus, out of 416 liver patients, Naive Bayes is able to predict only 275 cases,
and out of 167 non-liver patients, Naive Bayes is able to predict only 48 cases
accurately.
From the confusion matrices, it could be concluded that NN is able to predict liver
patients more precisely, whereas non-liver patients are predicted better by SVM.
The trade-off between the true positive rate and false positive rate is
summarized using the ROC curves for a predictive model using different
probability thresholds. The quantification of the overall ability of the test to
discriminate between the diseased individuals and those without the disease is
done by determining the area under the ROC curve. Figures 8.14a and 8.14b
shows the ROC of all the three models.
AUC is referred further for inference. The TPR and FPR for every possible
threshold value of the classifier are obtained, and then the graph is plotted between
0 and 1. A perfect test has an area of 1.00. In the given model AUC are:
8.4 Results and Analysis 167
Commands for R
>nn.results<- compute(nn, temp_test)
>results<- data.frame(actual = testset$Disease, prediction
=nn.results$net.result)
>roundedresults<-sapply(results,round,digits=0)
>roundedresultsdf =data.frame(roundedresults)
>attach(roundedresultsdf)
>table(actual,prediction)
>prediction
168 8 Applications of Machine Learning Algorithms in Cancer Diagnosis
The dataset was divided into 20–80 for test/train. The R commands produced
confusion matrix. Here 0 is the liver cancer patients, and 1 is the case without liver
cancer as shown in Table 8.4.
In this, NN performance has increased as 396 cases are correctly discovered out
of 416 infected cases. Similarly 82 cases are correctly identified out of 168 as
noninfected cases.
Our dataset includes back pain symptoms that are classified as abnormal or
normal. Prostate cancer is a disease in which malignant (cancer) cells form in the
tissues of the prostate. Our dataset contains prostate cells that are classified as
good or bad and are appropriate for the use of predictive models. This dataset
includes 12 variables. Our aim was to use this patient record to determine which
patients have diagnosed with disease and which do not. Orange and R language
tools were used to determine the best accuracy model and better performance.
Figure 8.16 illustrates the perfor- mance of all the models on the prostate cancer
dataset.
8.4 Results and Analysis 169
Fig. 8.16 Predictive model using the Orange tool on prostate cancer dataset
After a thorough analysis of the results of the different classifier models, these
results were compared with each other. From Fig. 8.16, it can be concluded that
NN alone performed the best in terms of specificity (94.4%), precision (95.4%),
recall (95.4%), and accuracy (94.4%). SVM is also equally good and better than
Naive Bayes.
Figure 8.17a shows SVM confusion matrix for the prostate cancer
dataset. The results are as follows:
• There are 594 cases which actually belong to class B and predicted also B.
• There are 16 cases which actually belong to class B but predicted as M.
• There are 28 cases which actually belong to class M but predicted as B.
• There are 332 cases which actually belong to class M and correctly predicted
as M.
Therefore, out of 610 patients with benign cancer, SVM is able to predict only
594 cases, and out of 360 with malignant cancer, SVM is able to predict only
332 cases accurately.
Figure 8.17b shows Naive Bayes confusion matrix for the prostate cancer dataset.
The results are as follows:
170 8 Applications of Machine Learning Algorithms in Cancer Diagnosis
Fig. 8.17a Confusion matrix for prostate cancer dataset using SVM
Fig. 8.17b Confusion matrix for prostate cancer dataset using Naive Bayes
• There are 581 cases which actually belong to class B and predicted also B.
• There are 29 cases which actually belong to class B but predicted as M.
• There are 41 cases which actually belong to class M but predicted as B.
• There are 319 cases which actually belong to class M and correctly predicted
as M.
Therefore, out of 610 patients with benign tumor, Naive Bayes is able to
predict only 581 cases, and out of 360 with malignant cancer, Naive Bayes is able
to predict only 319 cases accurately.
8.4 Results and Analysis 171
Fig. 8.17c Confusion matrix for prostate cancer dataset using neural networks
• There are 590 cases which actually belong to class B and predicted also B.
• There are 20 cases which actually belong to class B but predicted as M.
• There are 25 cases which actually belong to class M but predicted as B.
• There are 335 cases which actually belong to class M and correctly predicted
as M.
Therefore, out of 610 patients with benign tumor, NN is able to predict only
590 cases, and out of 360 with malignant cancer, NN is able to predict only 335 cases
accurately.
Figure 8.18 illustrates the ROC curve for prostate cancer.
The curve shows the receiver operating characteristics and summarizes the
trade- off between the true positive and false positive rates for a predictive model:
The datasets were trained using the three methods: ANN, SVM, and Naive Bayes,
followed by the development of the classifier model. After this, different perfor-
mance metrics were used to observe their respective results. The maximum value
of
172 8 Applications of Machine Learning Algorithms in Cancer Diagnosis
Fig. 8.18 Curve of receiver operating characteristics for prostate cancer dataset
the area under the curve (AUC) was observed in the neural networks, that is,
0.990, as compared to Naive Bayes. Neural networks (NN) is the best prediction
model for the prostate cancer dataset. The three layers of neurons are visible here.
The AUC of NN is higher than other classification models; as a result, NN is
sufficient for clinical diagnosis.
Figure 8.19 shows the three-layer neural networks, which involves an inner
layer containing independent parameters, a middle layer which has been processed,
and an output layer which is also called diagnostic output containing dependent
variables.
In Fig. 8.20, NN performance has been evaluated using 50–50 split and 70–30
split. This time the size of the test data in the 50–50 split was 284. In 285, 67 were
of class B (shown as 0 in Fig. 8.20), and 218 were of class M (shown as 1 in Fig.
8.20).
Briefly, the NN performed at 98% accuracy.
Similarly, in the case of 70–30 split, the size of the test dataset was 200, where
132 were of class M and 39 was of class B. NN accuracy was 99%.
8.4 Results and Analysis 173
In breast cancer, malignant cell growth occurs in the breast. The cancer has a
potential to spread to other parts of the body, if left untreated. This cancer is the
most common type of cancer in women of the United States. In every three
cancers diagnosed, one case is of breast cancer. Our aim was to use this patient record
data to determine the survivability rate of patients suffering from breast cancer.
Orange and R language tools were used to determine the best accuracy model and
better performance. Figure 8.21 provides the performance analysis generated by
Orange using the breast cancer dataset.
The model was constructed using fivefold cross-validation with 66% training
dataset. The performance of each model is compared using the area under curve
(AUC); cumulative accuracy (CA); F1 score, which is a weighted harmonic mean
of precision and recall; precision; and recall. According to the results, NN has the
highest CA, i.e., 71%, recall (77.2%), and precision (75%) with F1 score of 75%.
F1 score is good when it is near to 100%. It refers model performance in combination
of precision and recall. Overall NN is constructing a better model.
Figures 8.22a, 8.22b and 8.22c shows the confusion matrices of all the three
algorithms. The dataset size was 290, out of which 55 cases belong to class 0 (No,
not infected), and 235 cases belong to class 1 (Yes, infected).
Figure 8.22a shows the following results of SVM model:
• There are 4 cases which actually belong to class No and predicted also No.
• There are 51 cases which actually belong to class No but predicted as Yes.
• There are 9 cases which actually belong to class Yes but predicted as No.
Fig. 8.21 Performance comparison of machine learning models for breast cancer dataset
8.4 Results and Analysis 175
Fig. 8.22a Confusion matrix for breast cancer dataset using SVM
• There are 226 cases which actually belong to class Yes and correctly predicted
as Yes.
Therefore, out of 55 non-patients, SVM is able to predict only four cases, and
out of 235 patients, SVM is able to predict only 226 cases accurately.
Figure 8.22b shows NN confusion matrix for the breast cancer dataset. The
results are as follows:
• There are 15 cases which actually belong to class No and predicted also No.
• There are 40 cases which actually belong to class No but predicted as Yes.
• There are 26 cases which actually belong to class Yes but predicted as No.
176 8 Applications of Machine Learning Algorithms in Cancer Diagnosis
Fig. 8.22c Confusion matrix for breast cancer dataset using Naive Bayes
• There are 209 cases which actually belong to class Yes and correctly predicted
as Yes.
Therefore, out of 235 patients, NN is able to predict only 209 cases, and out of
55 non-patients, NN is able to predict only 15 cases accurately.
Figure 8.22c shows the following results:
• There are 26 cases which actually belong to class No and predicted also No.
• There are 29 cases which actually belong to class No but predicted as Yes.
• There are 41 cases which actually belong to class Yes but predicted as No.
• There are 194 cases which actually belong to class Yes and correctly predicted
as Yes.
Therefore, out of 235 patients, naive Bayes are able to predict only 194 cases, and
out of 55 non-patients, naive Bayes is able to predict only 26 cases accurately.
These matrices reveal that NN and SVM are both appropriate models for breast
cancer prediction.
Figure 8.23 shows the ROC curve, and the trade-off between the true positive and
false positive rates are summarized for a predictive model.
– AUC of SVM is 0.500.
– AUC of Naive Bayes is 0.507.
– AUC of NN is 0.512.
The average value of the area under the curve (AUC) was observed in all the
classification models, that is, neural networks (0.512), SVM (0.50), and Naive Bayes
(0.507). Still, neural networks (NN) is a good prediction model for the breast
cancer dataset.
8.4 Results and Analysis 177
Further, using the RStudio, NN model was designed to show the three layers of
neurons as shown in Fig. 8.24. This time, to check the model precision and accuracy,
we take a random sample of 168 data from 290 dataset.
In Fig. 8.25, NN performance has been evaluated using 50–50 split and 70–30
split. This time the size of the test data in the 50–50 split was 84 (as the complete
dataset was 168). In 84, four were of class No (shown as 0 in Fig. 8.25) and 58
were
of class Yes (shown as 1 in Fig. 8.25). Briefly, the NN performed at 96% accuracy.
Similarly in the case of 70–30 split, the size of the test dataset was 52, where
two were of class No and 39 was of class Yes. NN accuracy was 95%.
In short, the following observations were registered:
• Neural networks outperforms in all the three datasets. Its accuracy was high in
comparison to SVM and Naive Bayes.
• SVM precision was better in all the results.
178 8 Applications of Machine Learning Algorithms in Cancer Diagnosis
• Also the dataset suffers from unbalanced class problem. In each dataset patients
or infected number was much higher than noninfected cases. The results will
definitely change when balanced data is supplied to these models.
• Cross-validation is another important aspect in verifying the results. In this study,
fivefold and tenfold validations are taken, from which the best results were
selected for discussion.
8.6 Future Possibilities and Challenges in Cancer Prognosis 179
• Orange tool has provided clear visualization of the curve and confusion
matrices. It has helped to understand the performances of each model.
The present study has the future potential to apply ML models in other data with
different features, related to survival prognosis of the patients. Machine learning
algorithms have become a significant technique for a variety of applications in
astronomy, social media, medical diagnostics, online trading, smart devices,
online education, etc. (Mitchell 1997; Duda et al. 2001). The ML algorithms are
powerful from the traditional problem-solving algorithms with the ability to learn
from the data without being explicitly programmed. With the advent of cloud
computing, the data management and storage issues can be handled with greater ease
and flexibility, while the data analytics part can be well addressed by the use of
machine learning algorithms. Medical science has exponential dataset and finds
ML very useful for early diagnostic or prescriptive analysis (Islam et al. 2020).
The future possibility of ML in cancer prognosis is:
• Precision medicine.
• Gene-based analysis for cancer generation.
• Emotional aspect of human and cancer susceptibility.
• Drug-target interaction and identification of natural drugs for cancer.
• Recommendation systems for symptom analysis, disease detection, and treatment
prescription.
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Abstract
Tuberculosis (TB) and leprosy (caused by mycobacterial pathogens) are two
age-old infections, which we are facing even today. India is a major contributor
to the global burden of leprosy and tuberculosis, which adversely affects the
diverse communities as well as having a prevalence in different parts of the
country. Timely diagnostics and effective treatment are very challenging, and
the emergence of drug resistance has further complicated the management of
these mycobacterial diseases. Various lineages of these mycobacterial
pathogens show varying phenotypes in terms of clinical presentations and
treatment outcomes. Altogether these factors make it further difficult to
understand the full genetic diversity and pathogenicity of these pathogens using
the conventional genomic and proteomic approaches. However, thanks to the
recent technological advances in the genomics and proteomics field, many of
these constraints have been suitably addressed. While it is relatively simpler to
produce the omics data in a high-throughput manner, the bottleneck now is the
pace to assimilate this large data into some useful information to reach a
relevant, meaningful conclusion in a timely manner to assist the clinician in
making a judgment.
In India, genetic diversity of different strains has been widely studied using
approaches based on Next-generation sequencing (NGS), metagenomics,
spoligotyping, and PCR. But there are still gaps in predicting phenotypes accu-
rately from genotypic data, in particular for certain drugs. Recently, Machine
learning (ML) methods were successfully used to develop predictive classifica-
tion models and to identify compounds based on their biological activities.
Artificial Intelligence- (AI) based ML learns from known data characteristics
and makes predictions. Machine learning approaches can find statistical
dependencies in the data and also take into account the non-linear and feature-
interaction effects. In this way, new knowledge can be unleashed and data has
been proven to be useful that can provide clinically actionable
recommendations
Fig. 9.1 The picture displays the interconnected gene expression domains, from genome to
metabolite. Using microarrays, sequencing, and Mass spectrometry at each stage reveals to get
multi-level gene and protein expression, these techniques delivered a multidimensional view of
both natural and pathological processes
WHO Global Report 2018 claims that 27% of new cases of tuberculosis (TB) are
from India, which is the highest number among countries with high TB burdens,
followed by China with 9% of new cases (World Health Organization 2018).
While the number of new cases worldwide was lower than those reported in the 2017
study, only a small shift was observed in the number of new cases coming from India.
India also has the second highest incidence of cases of multidrug resistance
(MDR), with the highest mortality rate (Lohiya et al. 2020). While the drug-
susceptible cases had a higher rate of cure, the treatment success rate for MDR and
XDR TB cases was just 54% and 30%, respectively. Moreover, the 2016 WHO
global TB report estimated the prevalence of Rifampicin resistant TB (RR-TB)
cases to be 4.1% in the new cases and 19% in the previously treated cases. Despite
an increase in the number of testing for Rifampicin resistance, an estimated
240,000 people died from RR-TB (Chatterjee et al. 2018). In India, too, the
number of cases of rifampicin resistant TB (RR-TB) is alarmingly high (Singh et
al. 2020). Given the high cases of RR-TB in
186 9 Use of Artificial Intelligence in Research and Clinical Decision Making.. .
India, there are only three major studies to date that focused on MTB’s genetic
diversity using a WGS-based approach to whole genome sequencing (Manson et
al.
2017; Chatterjee et al. 2017; Advani et al. 2019). The majority of clinical isolates
were drug-sensitive in the first two studies that restricted the detection of
resistance mutations. But both studies emphasize the need for a diagnostic
approach based on next-generation sequencing (Manson et al. 2017; Chatterjee et
al. 2017). The third study conducted by ICMR-JALMA focused on MDR TB
samples and discovered over 300 SNPs in 38 genes associated with drug
resistance that are not used in diagnostic research (Advani et al. 2019). The study
also found that bedaquiline- resistant mutations were present in seven MDR
samples, including three from the Manson dataset. Other than these studies, there
are several separate reports from
clinical isolates with 2–3 TB WGS representing special cases, such as severe drug
resistance (Rufai and Singh 2019; Kalo et al. 2015). However, to date, there are no
such programs from India to compile all available data sets and provide the Indian
environment with actionable therapeutic and diagnostic insights.
However, worldwide, numerous studies have comprehensively analyzed the
perturbations in many tuberculosis virulent strains at the transcriptome and proteome
level, such as identification of non-coding and micro RNAs, gene expression
profiling of reference and mutant strains, and transcriptional start site mapping of
clinical isolates (Tagliani et al. 2021; Wan et al. 2020; Romanowski et al. 2020).
High throughput transcriptomic techniques such as microarrays and RNA
sequence (RNA-seq) can assess the transcriptional response to the changes in
mycobacterial genomes, such as nutrient starvation, antibiotic exposure,
insufficient oxygen, etc. (Peng et al. 2020; Kwan et al. 2020; Hu et al. 2020; Liu
et al. 2020a).
In a longitudinal study, a predictive signature for active TB disease had
recently been applied with the objective of transcriptomic profiling. For two years,
Zak and his colleagues have tracked healthy teenagers from South Africa, taking
blood samples every six months (Zak et al. 2016). Forty-six people were finally
diagnosed with TB from a total of thousand participants in the study.
Transcriptomic profiles were collected from the blood samples of these individuals
and compared with profiles of the individuals who remained healthy during this
study prior to their time of diagnosis of TB and they were able to differentiate
between the two groups with the Statistical significance.
In several studies, microRNA profile variations between TB patients and
healthy controls, either from RNA derived from peripheral blood cells or from
freely circulating microRNA present in patient serum or plasma samples, were
examined (Wu et al. 2012; Chakrabarty et al. 2019; Spinelli et al. 2013; Yi et al.
2012; Qi et al. 2012). Nevertheless, it is still difficult to accurately interpret clearly
lists of identifiers from biological features, because of our unfinished awareness of
microRNA functions. Computational and experimental evaluation of biomarkers
candidates shows that micro RNAs may play an important role in controlling
immune response, for example, by affecting neutrophil mobilization in the lung
(Dorhoi et al. 2013).
Proteomic analysis generally, has been performed with liquid-chromatographic
tandem mass spectrometry (LC-MS) of cellular and secreted fractions, accompanied
9.1 Introduction of Technological Advancements and High Throughput Data in.. . 187
>60% of the total cases reported globally indicating an active transmission (Rao and
Suneetha 2018). Leprosy diagnosis is mostly based on clinical presentations, and
there is a great need of a suitable, field-friendly laboratory tool for assisting in its
early and differential diagnosis. Repetitive loci (called RLEP, is present in 37
copies in M. leprae genome) is a preferred target for specific and sensitive
detection of
M. leprae DNA in clinical samples (Cole et al. 2001). In addition, appropriate
tools for molecular epidemiology of leprosy are lacking. M. leprae strains from around
the world have been classified on the basis of four SNP types (branches 1–4)
and
16 SNP subtypes (1A–1D, 2E–2H, 3I–3 M, and 4 N–4P) based on comparative
genomic analysis of four different M. leprae strains from India, Brazil, Thailand, and
the United States which require PCR-sequencing of several genomic loci, making
it very challenging due to limited amount of genomic DNA of the pathogen from
the clinical samples (Monot et al. 2009). Genotyping a large panel of M. leprae
strains has revealed its strong geographical association, thereby suggesting
possible routes of dissemination worldwide. However, there is a very limited
genomic information currently available about M. leprae strains present in India
(Benjak et al. 2018).
Previous high throughput SNP typing studies of M. leprae from various
endemic regions in India have shown that the SNP subtype 1D is the most
prevalent genotype in India (present in ~76% of the cases), while other SNP types
are 1B, 1C, 2E, 2H, and 2G (Monot et al. 2009; Lavania et al. 2015). The
emergence of multidrug- resistant in M. leprae is also a major concern (Lavania et
al. 2018; Matsuoka 2010). The molecular epidemiology of leprosy is challenging
as it requires PCR-Sequencing of multiple loci (Scollard et al. 2006).
Whole Genome Sequencing was also recognized as an effective genotyping
method, as it allows for a finer resolution of the genetic diversity of each isolate
and offers the best dataset for population-based research (Monot et al. 2009; Lavania
et al. 2015). In 2009, there were only four complete genomes of leprosy, but this
small quantity of strains led to a good typing method and astounding data on strain
variations and genetic evolution. Since 2009, along with 16 subtypes, new
subtypes have increasingly been reported, for example, a study reported the new
genotype called 1B-Bangladesh (Tio-Coma et al. 2020).
In 2011, M. leprae was reported to be entirely re-sequenced from a wild armadillo
and three patients with leprosy in the US. Comparative genomic analysis between
Asian and Brazilian strains revealed 51 SNPs and 11-bp insertion-deletion. The
M. leprae genotype of foreign exposure patients usually represented their country
of origin or history of travel. In 28 out of the 33 wild armadillos and 25 out of the 39
US patients who were living in areas of armadillo-borne M. leprae, a single and
previously not reported M. leprae genotype (3I-2-v1) was found (Truman et al.
2011).
Similarly, in 2013, the M. leprae genome was sequenced from five Medieval
skeletons from UK, Sweden, and Denmark using the DNA array capture
(Schuenemann et al. 2013). The old M. leprae sequences were compared with
11 contemporary strains of different genotypes and geographical origins.
Comparisons revealed that over the past thousand years the conservation was
remarkable, that leprosy is European in the Americas, and that the M.
Leprae
9.1 Introduction of Technological Advancements and High Throughput Data in.. . 189
genotype in medieval Europe is common with the Middle East, which has
produced a significant impact on the study of palaeomicrobiology and evolution of
human pathogens.
Consequently, in 2015, a thorough evaluation was made with the use of micro-
arrays of DNA chip, covering the entire spectrum of the disease together with its
reactional states, of human mRNA for leprosy skin lesions. Sixty-six leprotic (10TT,
10BT, 10BB, 10BL, 5LL, 14R1 and 10R2) samples and nine safe skin biopsies
containing healthy males and females were used as controls. In this study, 1580
mRNA were found to be differentially expressed in diseased lesions versus
healthy controls. Also, several genes have been found in all leprotic cases,
whereas other
genes were found in reactional states only, such as Type “1”: GPNMB, IL1B,
MICAL2, FOXQ1; type “2,” AKR1B10, FAM180B, FOXQ1, NNMT, NR1D1,
PTX3, TNFRSF25 (Belone et al. 2015). The role of these mRNAs have been
explored in developing new diagnostic markers and therapeutic targets for leprosy
as these mRNAs are known to be involved in various pathophysiological and
signaling processes and in several other diseases (Mehta and Liu 2014).
Another important study in 2015, using deep sequencing, illustrates that the
genomic sequence of M. lepromatosis present in a skin biopsy was linked with
M. leprae that has undergone an extensive reduction. The genomes show broad
synthesis and close in size (~ 3.27 Mb). Protein coding genes share the identity of
93% nucleotide sequence, and pseudogenes were 82% the same. Phylogenetic
comparisons and the Bayesian dating analysis suggested that the two leprosy
bacilli are remarkably preserved despite their ancient separations and still have
similar pathologies (Singh et al. 2015).
With increased high throughput screening in the field of tuberculosis, it was
demonstrated that strain variations modulate virulence, immune phenotypes, and
play a crucial role in antibiotic susceptibilities with differential drug resistance and
adaptation. The advancement in molecular leprosy research with the advancement of
genome sequencing types has strengthened and established a similar pattern.
Recently, some hypermutated genes were identified by the comparative genomics
of the 150 leprae genomes of different geographical areas and presumed to play a
role in the drug resistance, pathogenesis, or host adaptation of the bacterium (Benjak
et al. 2018). Although mutations in a resistant rpoB, folP1 and gyrA area were
present as a characteristic hallmark for drug resistance, authors identified three
highly muted genes (ribD, fadD9 and nth) in drug vs. susceptible strains that indicate
their direct involvement in medication resistance or compensatory mechanisms.
However, few genes have been strongly mutated, independent from the genotype
of drug resistance, for example, ml0411, a serine-rich antigen belongs to the PPE
family (Benjak et al. 2018). This summarizes that the problem of traditional typing
systems for leprae could be easily addressed by an entire genome approach. The
technological difficulties, price, and lengthy downstream analyses, however
limited their use.
A variety of studies have been carried out over the years to describe the leprae
proteome (Parkash and Singh 2012). A high-throughput proteomic approach was
undertaken in 2008 that resulted in identification of nearly 250 new proteins for
190 9 Use of Artificial Intelligence in Research and Clinical Decision Making.. .
M. leprae. One hundred and four proteins were detected in the cell wall, 98
proteins in the membrane fraction and 60 proteins were identified in the
soluble/cytosol fraction (Marques et al. 2008). In a 2009 report, 1046 proteins
were identified, including five proteins encoded with previously forecast
pseudogenes, using Gel-LC-MS/MS, using a linear quadruple ion trap-Orbitrap
mass spectrometer (de Souza et al. 2009). Metabolic profiles extracted from urine
were calculated and it was found that the urinary metabolome could be used to
distinguish endemic controls from untreated mycobacterial disease patients, as
regulation in the urine of patients with RR before RR initiation was also different
from RR-Diagnose.
Few literature studies on M. leprae mRNA expression are also reported.
Bleharski and colleagues assessed the genes’ expression of leprosy patients having
polar forms of skin lesions (Bleharski et al. 2003). They found many up-regulated
mRNAs linked to antigen processing as well as presentation in leprosy. A compre-
hensive assessment of leprosy lesions with microarrays was conducted for
differen- tially expressed miRNAs. As the levels of RNA expression were
modulated by MDT, the assessment of the RNA pattern of expression may be a
good predictor for leprosy treatment. Of the 1605 M. leprae genes, 315 suggested
twofold higher signal intensity, which includes the family of metabolic Acyl-CoA
enzymes and medicinal metabolic enzymes possibly linked to M. leprae virulence.
Diana et al. published a study that tells about the expression of pseudogenes in M.
leprae and which were showing regulated expression in different conditions
(Williams et al. 2009). A similar study has been conducted to identify the
microRNAs of leprae and showed the regulation in different disease condition,
like reactions, drug resistance, and according to RJ classification (Akama et al.
2009).
As M. leprae cannot be cultured, therefore scientists are facing the daunting
task of assigning molecular and cellular roles to thousands of newly predicted
gene products. With the advent of high throughput screening, now M. leprae
reference genome has about 2699 annotated active genes, and at least 2041
proteins are predicted to be produced by it which were 1604 previously, with now
lesser number of pseudogenes, i.e., 607, which was previously thought to be
1155. Despite considerable progress, the identification of many more promising
proteins still needs to be performed. The investigators are looking forward to
developing new methodologies for preventing nerve damage, effective leprosy
treatment, and diag- nosis of M. leprae.
The discovery of drugs and medicines at the end of the twentieth century mostly
focused on target methods (Zuniga et al. 2015). In order to identify potential drug
targets, the identification of the mycobacterial whole genomic sequences and their
strains has played a crucial role (Ioerger et al. 2013). Several compound groups have
been identified by high-performance target-based screening. Some of them are still
9.1 Introduction of Technological Advancements and High Throughput Data in.. . 191
being established at the leading stage. For example, Targets include PanC, FtsZ,
FadD32, gyrA, rpoB, folP LeuRS, InhA for M. tuberculosis and M. leprae (Chetty
et al. 2017; Islam et al. 2017; Uddin et al. 2016; Waman et al. 2019). Once
structural knowledge is available, virtual screening has become more common, 3D
objectives can be used to test possible inhibitors (Gimeno et al. 2019). This
approach provides the advantage of limited laboratory work and the opportunity to
scan very large libraries of compounds. For example, M. tuberculosis drug target
DprE1 (Zhang et al. 2018a). A large scale virtual screening was done and from
around four million compounds, 41 compounds were classified as likely inhibitors
(Wilsey et al. 2013). Six of the compounds were active against M. smegmatis,
indicating that the method is useful. Recently, it was believed that it is necessary
not only to concentrate on novel bioactive compounds but also to repurpose
existing compounds to a new molecular target in an attempt to discover new
inhibitors (Singh et al. 2019; Štular et al. 2016; Nagpal et al. 2020; Pushkaran et
al. 2019; Rani et al. 2020). It would be significantly less intensive effort and
enormous financial burden on traditional drug development procedures to
repurpose a known bioactive compound, especially with its proven
pharmacological properties (Pan et al. 2014). InhA is an isoniazid target and
remains of interest to many groups (Štular et al. 2016; Pauli et al. 2013). The 3D
pharmaceutical model was developed based on 36 InhA crystal structures,
including wild InhA and drug-resistant mutants InhA, apo InhA, and complex
InhA, with either NADH, substratum, or ligand. Parallel to the quest for ligands,
four docking programs and almost one million compounds have been screened; 19
molecules have been identified as possible noncytotoxic inhibitors. The enzyme was
tested with six molecules and three inhibiting InhA purified molecules, though data
have not yet been documented against living bacteria (Pauli et al. 2013).
The use of drug screens against individual patient isolates is an alternate approach
to finding successful therapeutics against multidrug-resistant bacterial infections.
It takes around 10–12 years on average with sufficient resources for the creation of
a new antibiotic (Jackson et al. 2018) (Fig. 9.2).
For example, promising antibiotics have been found against MDR Mycobacte-
rium tuberculosis, Acinetobacter baumannii, and Borrelia burgdorferi by
recycling existing medicines (Sun et al. 2016; Silva et al. 2018). There are also
thousands of additional approved antibiotics for illnesses other than infections that
can be administered against MDR bacteria or can potentially resensitize MDR
bacteria to
standard care antibiotics by overcoming a specific medical resistance mechanism.
Reports have identified <200 approved antibiotics available to clinicians to
choose treatments. Current antitubercular therapy suffers from a longer-term
disadvantage that presents a significant challenge to the growth of patient non-
compliance and resistance. The current situation needs alternative approaches,
which can reduce care
time so that improved health results can be achieved. For example, drug repurposing
and medications, namely, statins, metformin, Bevacizumab, Zileuton, ibuprofen,
aspirin, Valproic acid, Adalimumab, and Vitamin D3, have shown promising
results in clinical outcomes in TB patients during preliminary examination
(Mishra et al. 2020). The key benefit of this drug repurposing screening strategy is
to recognize and apply licensed drugs with a new identity. Antimicrobial
compounds may pass
192 9 Use of Artificial Intelligence in Research and Clinical Decision Making.. .
~6.5 ~7 ~1.5
~1-2
~0-2 ~1-6 ~1-2
Repurposing Drug
Fig. 9.2 Schematic representation of the steps involved in traditional drug discovery process vs. AI
based drug repurposing with the salient features of both the processes
With the emergence of the genomic era, the use of high-throughput genomics have
started to generate biological data at an exponential pace (Chance et al. 2004;
Esfandyarpour et al. 2013; Lebrigand et al. 2020; Sarnaik et al. 2020). The
scientific field of -omics provides vast volumes of data primarily on the basis of
advances in genomics and biotechnology (Oliveira 2019; Jiang and He 2020).
High-throughput systems that calculate the expression of thousands of genes or non-
coding transcripts (e.g., miRNAs), genotyping methods and next-generation
sequencing (NGS) technologies, whole genome-wide interaction studies (GWAS)
that produce quanti- tative gene expression profiles (e.g., RNA-seq), identification
of a significant num- ber of gene variants (SNPs, Indels); are some of the major
applications (Koumakis 2020; Zhang et al. 2017; Qin 2019). The vast volume of
data creates unprecedented
9.2 High Volume Data and the Bottleneck in Data Analysis 193
possibilities for research at the genomic or systemic level, which opens the door
for new biological findings (Fig. 9.3).
However, this modern paradigm faces severe challenges, like data accuracy,
which must be monitored on the scale of the genome because analysis of data sets
polluted with erroneous data is likely to lead to erroneous conclusions. For
example, manual curation has been shown that MTB TlyA was involved in
ribosomal biogenesis and the functional annotation were incorrect, not only in
microbial and plant genomes but also in M. tuberculosis (Arenas et al. 2011).
Similarly, in 2020, it was shown that in all the mycobacterial family, the protein
annotated as HemN could not exhibit coproporphyrinogen III dehydrogenase
(CPDH) activity and has been mis-annotated as HemN and therefore highlights
the need to correct the present annotation to heme chaperone HemW in various
bioinformatics databases (unpub- lished data). The main reason behind is a
presence of a variety of protein sequence databases which appears to be polluted
with incorrect/incomplete sequences. The reason behind lacking of proper scrutiny
is the growing proportion of protein sequences derived from huge genome
sequencing data, but since few genomes have been completely sequenced so far,
researchers are annotating the sequences through comparative approaches,
depending on sequence alignments (Prada and Boore 2019). However, in the case
of genome design, sequencing errors, sequence gaps, and misassemblies result in
an excessive rate of misannotations (Nobre et al. 2016; Wakeling et al. 2019). One
significant cause of this error is that, in genomes, the apparent number of genes
can be divided into several contigs that leads to the increase in the number of
incorrect genes (Denton et al. 2014). Secondly, despite the completion of proper
genome sequences and genome assemblies, the issue of protein coding genes
prediction errors has emerged. In the case of intron-rich genomes, the ENCODE
Genome Annotation Evaluation Project has shown clearly that the pre- diction of
the correct structure of protein coding genes remains a difficult job (Guigó et al.
2006). Various approaches provided different predictions, but the most reliable were
typically forecasting methods based on experimentally determined mRNA and
protein sequences. Nevertheless, it was shown that the prediction of only about
~60% of the genes has an identical genomic structure of the protein-coding genes
(Harrow et al. 2009). Most recently, a tool for exhaustive all-against-all sequence
comparison called “Contaminator” has been described, which detected contamina-
tion in >2 million sequences (and 6795 species) in GenBank database, >114,000
sequences (in 2767 species) in the NCBI Reference Sequence Database (RefSeq),
and 14,132 protein sequences the non-redundant (NR) protein database. These could
be due to mislabeled/incorrectly labeled reference samples, contamination, or due
to the presence of more than one species in some samples. As the sequence
volume keeps on increasing, it is important to identify such sources which can
cause false interpretations and resultant false interpretations (Steinegger and
Salzberg 2020).
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d
Cli
nic
al
Fig. 9.3 Data accumulation at EMBL-EBI by data resource over time. The y-axis shows total bytes for a single copy of the data resource over time. Resources De
shown are the BioImage Archive, Proteomics IDEntifications (PRIDE), European Genome-Phenome Archive (EGA), ArrayExpress, European Nucleotide cis
Archive (ENA), Protein Data Bank in Europe and MetaboLights. The y-axis for both charts is logarithmic, so not only are most data types growing, but the ion
rate of growth is also increasing. For all data resources shown here, growth rates are predicted to continue increasing. From Cook et al., NAR, 2020 Ma
kin
g..
.
9.2 High Volume Data and the Bottleneck in Data Analysis 195
One of the advantages of NGS is to analyze hundreds and thousands or even millions
of goals simultaneously. The clinical NGS in mycobacterial investigations is not
only a diagnostic program but it is also widely used in the identification of
mutation targets for the treatment of certain tuberculosis and leprosy and the
identification of a high risk population (Qin 2019). In recent years, various drugs
have been created to target molecules and more will be available. This capability
provides NGS tremen- dous potential for clinical application. For example, any
tumor can have multiple mutations in cancer patient treatment, any disease can
have a number of SNPs involved and a number of pathways involved in the
progression of the disease (Di Resta et al. 2018). In these clinical environments,
typical molecular tests require multiple tests for many mutations. For these
multiple tests, a larger amount of tissue may be required. Those targets can be
challenged in a single test using NGS technology (Mokrousov et al. 2016; Eloit
2014). Therefore, less tissue is needed and tested results are obtained from dozens
and hundreds of DNA targets. The number of mutations in different diseases has
increased in recent years in scientific research. For example, numerous mutations
were found in Mycobacterium tubercu- losis and Mycobacterium leprae that lead
to drug resistance, loss of function, pseudogene formation, loss of protein-protein
interaction, etc. (Singh et al. 2020; Chatterjee et al. 2017; Wan et al. 2020; Benjak
et al. 2018; Matsuoka et al. 2007; Singh and Cole 2011) These results also indicate
that diagnostic and follow-up molecular trials should be conducted for multiple
mutations. The burden of mutation has become a significant parameter to be
evaluated with the introduction of immu- notherapy (Kim et al. 2020). Numerous
mutations in a TB and leprosy sample need to be investigated again. Typical
molecular research procedures for these needs are not useful (Grossman et al.
2013). For certain tasks of patient care, NGS technology is therefore appropriate.
In the current medical practice, more details on mutation must also be derived
from biopsy samples (Hodgson et al. 2012). Since biopsy samples are very small,
traditional molecular tests are often not possible to meet such requirements. In order
to meet these needs, NGS was developed. NGS technology can test several
samples and multiple targets simultaneously by massive parallel sequencing. This,
therefore, increases molecular test processing time (Yohe and Thyagarajan 2017).
In personalized precision medicine, it has become clear that NGS technology is an
important tool. It offers information for the classification of disease conditions,
therapeutic selection, and prognostic assessment. The use of NGS in clinical
settings, however, entails difficulties (Bacher et al. 2018). For example, several
reports have been made using NGS technology to disclose profiles of drug
resistance in MTB. In prior studies, only one or more MTB drugs, which were
resistant and without susceptible strains, were usually used. Nevertheless, it is
extremely doubtful that this condition will arise in clinical practice. Without prior
information on the resistor status, clinicians need to use checks, which mean that
they need details about the relationship or non-relation of the variant found in
196 9 Use of Artificial Intelligence in Research and Clinical Decision Making.. .
clinical specimens. In this context, the distribution of each gene and healthy
polymorphisms not linked to the drug resistance should be considered when
evaluating NGS results (Kumar and Abubakar 2015).
Researchers are able to generate and interpret a large deal of omics data with the
advancement of biotechnology and the advent of high-performance sequencing.
Because, a high number of High-throughput data, sometimes known as “big” data,
is generated, most of the algorithms in bioinformatics are focused on master learning
and, recently (Lyko et al. 2016), on deep learning to recognize trends, predict the
course of treatment of disease, and model it. Machine learning advances have created
unprecedented momentum in biomedical computer science and have led to new
fields of biological information and computational biology research (Camacho et
al. 2018). Machine learning is an artificial intelligence division that focuses on
algorithms and strategies for learning by examples by gathering characteristics of
interest depending on the underlying distribution of probabilities (Rajkomar et al.
2019). It has the same idea as the expert system; it can mimic a human expert’s
capabilities. It can make an automated decision based on the knowledgebase the
domain expert has entered. Since human expertise is not always accessible or
sufficient to meet the community’s needs, diagnostic software using machine
learning can be used as a replacement for human expertise (Allam 2020).
It is evident that in specific tasks in omics data, machine learning models can have
greater accuracy than state-of-the-art approaches (Lane et al. 2018). The
increasing trend in deep learning architectures in genomic research, deep learning, and
machine learning, particularly for multiscale and multimodal data analysis for
precision
media, is anticipating accelerated changes in genomics (Libbrecht and Noble
2015; Zou et al. 2019). Owing to huge data generation, the era known as “big”
data, deep learning methods have shown to be an efficient discipline of ML. Machine
learning techniques have successfully been used to develop predictive
classification models, including compound recognition, based on their
biological behaviors,
predictions for side effects, new gene predictions associated with diseases, micro-
array data processing, and drug development (Liu et al. 2013). AI-based ML
learns from known data characteristics and then makes blind data predictions. In
order to
identify single nucleotide variants (SNV’s) as immune or TB prone, Artificial
Intelligence and ML algorithms have already been used to determine new
mutation-supported resistance (Oliveira 2019).
There are various benefits of various ML algorithms. To that end, four algorithms
have been predicted by supervised users, namely, naïve Bayes (NB), k next-door
neighbor (kNN), artificial neural network (ANN), and sequential minimization
(SMO) algorithm, based on Support Vector Machine (SVM) (Deepika and Seema
9.3 Advent of Artificial Intelligence (AI) & Machine Learning (ML) 197
mutant protein and anti-TB drug complexes to validate the phenotype observed
(Priya Doss et al. 2014).
The repurposing of already present drug substances for various indications can
significantly reduce the time and cost needed to develop new medicinal products
(Pushpakom et al. 2019; Oprea and Mestres 2012). While this field has graduated
with a range of software tools from the discovery to the purposeful assessment,
artificial intelligence progress is expected to dramatically improve predictive capa-
bility (Paranjpe et al. 2019). Taking advantage of the thousands of approved drugs
and more than 4000 compounds abandoned during phase II production in new
drug development activities is especially useful when aimed at neglected diseases
like leprosy (Parvathaneni et al. 2019). Likewise, since many current antituber
medications cause major side effects as well as promote resistance, it is very
tempting to repurpose non-resistant agents with limited side effects into TB
medicines (Passi et al. 2018). Advances in methods of drug repurposing and
access to genomic data also allow the systematic development of personalized,
repurposed options. Through machine learning models, computational drugs
repurpose has moved to modern methods for analyzing drug effects using
conventional biological approaches focused on determining chemical similarities
and molecular dockings (Kinnings et al. 2011). Examples include gene expression
and functional strategies focused on the genomics, such as corresponding drug
indications by disease-specific response profiles on the basis of gene expression and
mRNA expression. Another example includes identification of new possible
protein target indications through genome-wide association studies (GWAS),
generation of genetic variation-based approaches to find out Single nucleotide
variations as a result of drug are some of the solutions provided by AI to find out the
overall effect of drug in the system (Schneider 2018). These approaches are based
on disease-networks that relate knowledge on diseases scrapped from different
public resources to create multi- level networks (e.g., reactomes, KEGG text-
mining pathways) or a disease graph based on gene expression profiles and protein
networks. Due to the rapid accumula- tion and growing accessibility and
standardization of chemical and genomic data alongside pharmacological and
phenotypic knowledge, drug repurposing is becom- ing an excellent case study for
proponents of the implementation of AI technologies
in the pharmaceutical field (Mak and Pichika 2019). The question plays with AI’s
strengths in collecting insightful features from noisy, incomplete, and high-
performance data. Different AI-based methods were suggested for identifying
potential drug exploiting opportunities through the integration of diverse heteroge-
neous data sources information; examples include PREDICT, SLAMS, NetLapRLS,
and DTINet (Yang et al. 2019). In field design, AI is implemented via the
generation of the learning prediction model and performs a quick virtual screening
to show the output accurately. Moreover, AI can easily identify drugs and can
combat new diseases, including leprosy and tuberculosis, through a drug
repurposing strategy.
9.3 Advent of Artificial Intelligence (AI) & Machine Learning (ML) 199
One of the advantages of NGS is to analyze hundreds and thousands or even millions
of goals simultaneously (Hodkinson and Grice 2015). The clinical NGS is not only a
diagnostic program. It’s also widely used in the identification of mutation targets
for the treatment of certain tuberculosis and leprosy and the identification of a high
risk population (Advani et al. 2019; McNerney et al. 2018; Monot et al. 2009). In
recent
years, various drugs have been created to target molecules and more will be
available. This capability provides NGS tremendous potential for clinical applica-
tion. Any tumor can have multiple mutations in cancer patient treatment, for
example. In these clinical environments, typical molecular tests require multiple
tests for many mutations. For these multiple tests, a larger amount of tissue may
be required. Those targets can be challenged in a single test using NGS technology
(Papadopoulou et al. 2019). Therefore, less tissue is needed and tested results are
obtained from dozens and hundreds of DNA targets (Buyuksimsek et al. 2019).
The number of mutations in different diseases has increased in recent years in
scientific research. For example, numerous mutations were found in
Mycobacterium tubercu- losis and Mycobacterium leprae that lead to drug
resistance, loss of function, pseudogene formation, loss of protein-protein
interaction, etc. These results also indicate that diagnostic and follow-up
molecular trials should be conducted for multiple mutations. NGS technology can
test several samples and multiple targets simultaneously by massive parallel
sequencing. This, therefore, increases molecular test processing time. In
personalized precision medicine, it has become clear that NGS technology is an
important tool. It offers information for the classification of disease conditions,
therapeutic selection, and prognostic assessment. The use of NGS in clinical
settings, however, entails difficulties. For example, several reports have been
made using NGS technology to disclose profiles of drug resistance in MTB. In
prior studies, only one or more MTB drugs, which were resistant and without
susceptible strains, were usually used. Nevertheless, it is extremely doubtful that this
condition will arise in clinical practice. Without prior information on the resistor
status, clinicians need to use checks, which mean that they need details about the
relationship or non-relation of variant found in clinical specimens. In this context,
the distribution of each gene and healthy polymorphisms not linked to the drug
resistance should be considered when evaluating NGS results.
200 9 Use of Artificial Intelligence in Research and Clinical Decision Making.. .
The spread of COVID-19 produced a catastrophe, and the rapid treatment of this
disease is a preventive medication with a history of patients recovered in the
present pandemic (Fauci et al. 2020). In the COVID-19 scenario, the use of AI-
enabled medication can be beneficial with technological advances in Artificial
Intelligence (AI), together with increased computational resources (Vaishya et al.
2020). The pharmaceutical industry also seeks new and state-of-the-art technology
in this respect to map, control, and limit the spread of COVID-19 disease
(Swayamsiddha and Mohanty 2020; Ting et al. 2020). AI research models can be built
to predict drug structures that can theoretically handle COVID-19 (Alimadadi et al.
2020). AI and machine learning can help the approach by quickly realizing that
drugs have a sufficiency with COVID-19, and thus overcoming any barrier
between a large number of drugs. A lot of information is available in open phases
from various health services and organizations. A number of groups have started
to use this advancement to increase the exposure of COVID-19 medicines and
better under- stand the battle against infection by the resistant frame (Mohanty et
al. 2020). GlaxoSmithKline (GSK) and Vir Biotechnology pharmaceutical
companies joined forces to advance coronavirus treatment using computerized
reasoning and CRISPR by early April. In addition, Harvard University was
recently united with the Human Vaccines Project called Human Immunomics
Initiative, which uses human-made thinking models to quicken antibodies to a
wide range of infections, including COVID-19 (Mohanty et al. 2020). A
knowledge representation system that uses
GPS data to show users’ locations of known COVID-19 cases has been lately
developed by a team from Southern Illinois University (SIU). Google and Apple
have worked to create a link with the Bluetooth software program (Mohanty et al.
2020). These methods can be very efficient and accurate in the collection of data.
Organizations are carrying out research on various pathways in effectively
accepted medicines, having identified human well-being profiles, based on a
simple under- standing of the infection (Shi et al. 2020). With regard to COVID-
19, the two most popular instances of this are hydroxychloroquine (endorsed to
treat malaria), remdesivir (Ebola). Therefore, an AI model can be modeled well by
giving the input from the data set to find out the efficacy of these medicines
(Mohanty et al. 2020). Likewise, groups of work started to look at artificial
intelligence (AI) as a method to read and analyze XR and CT scans, and these
forms of COVID-19 AI-based methods may be broadened to include all kinds of
respiratory diseases. For example, Deep learning detects COVID-19 and separates
it from pneumonia using chest CT, which means that AI could help turn a standard
CT or X-ray scan into a versatile tool for prompt diagnosis, which would not only
be useful for detecting COVID-19 but also other respiratory diseases (Li et al.
2020). In order to speed up potential COVID-19 case recognition, the use of ML
algorithm via a mobile web-based survey was proposed that will reduce the
dissemination of the
9.4 Illustrations of Machine Learning in Different Research Fields 201
Data Collection
COVID-19 Data
Manag
ement
PreventionTherapeu and
tics Artificial Machine Proces
Intelligence Learning sing
Deep Learning
Hospital Operation
Diagnosis
b. AI
and ML in
mycobacterial
research
Fig. 9.5 The image depicts diverse applications of artificial intelligence in healthcare. The ability
of AI to learn and rewrite its own rules, through Machine Learning and Deep Learning, offers
not only benefits for today but also yet unseen capabilities for tomorrow
et al. 2008). Work on the use of ML models for in vitro MTB datasets has
contributed to the modeling of large MTB datasets, which have been made
available for various classes (Lane et al. 2018). These models can be used to rate
and filter similarly large numbers of molecules associated with pharmacophore
methods before in vitro research. For example, in 2004, for media optimization,
AI was used in the production of Rifamycin B via Amycolatopsis mediterranei S699
barbital insensitive mutant strain (Bapat and Wangikar 2004). Rifamycin B was
considered to be an effective tuberculosis and leprosy antibiotic. To improve the
medium composition, ML approaches were explored, such as genetic algorithm
(GA), neighborhood analysis (NA), and decision tree technology. These medium
combinations have increased Rifamycin B productivity by more than 600%,
indicating that Genetic algorithms have become amazing at optimizing the
fermenting medium and have qualitatively exposed the relationships between the
media-media interaction in the form of collection of high, medium, and low
produc- tivity levels (Bapat and Wangikar 2004). Similarly, Bayesian models were
used to predict several anti-tuber compounds. In 2014, by filtering the library
of over
150,000 compounds, Bayesian models picked 48 compounds that can be tested
in vitro; 11 were working with MIC values ranging from 0.4μM to 10.2μM, with
high hit rate. These include five quinolones, three molecules with long aliphatic
bonds and three singletons and, among these, were ciprofloxacin, a drug used to treat
leprosy and tuberculosis (Ekins et al. 2014). A second validation of this method
tested 550 molecules and 124 molecules were found active. A third example tested
48 compounds with an independent group and 11 were labeled as successful. A
validation used a range of 1924 molecules as a comparison with the various ML
models to demonstrate the enrichment rates which were in some cases greater than
tenfold. Several experiments often analyze how MTB data sets are integrated and
models of data reported by different groups are evaluated. For example, in 2018, a
convolutional neural network-(CNN) based model was created to explicitly recog-
nize the TB bacillus called TB-AI. Two hundred and one samples (108 positive cases
and 93 negative cases) were gathered as the test set following the training of the
neural network model to investigate TB-AI. TB-AI obtained a sensitivity of
97.94% and specificity of 83.65% against double confirmed diagnosis both by
microscopes and digital slides by pathologists (Xiong et al. 2018). These
combined efforts demonstrated the significance of several MTB models and also
indicated important
molecular characteristics for the active agents that recently reported the development
of new antibacterial β-lactam with MTB activity. ThyX and Topoisomerase I have
further established machine learning models for individual drug discovery targets
(Djaout et al. 2016). In order to precisely diagnose and predict new cases of
leprosy, Brazilian scientists recently have developed combined molecular and
serological
methods research using AI based random forest (RF) algorithms. All the
asymptom- atic SSS samples were obtained for 16SrRNA qPCR and the ELISA
tests for LID-1 and ND-O-LID antigens. Statistical analysis showed anti-LID-1
sensitivity (63.2%), ND-O-LID (57.9%), qPCR SSS (36.8%) and microscopic
diffraction (30.2%). But the use of RF suggests a strong increase in the sensitivity of
MB leprosy (90.5%), PB leprosy (70.6%) with a 92.5% specificity (Gama et al.
2019). Early diagnosis of
9.4 Illustrations of Machine Learning in Different Research Fields 203
Dermatology is the branch of medicine that treats the skin and its disorders. The
causes of skin disorders include fungal, bacterial, allergic, and even insect bite
disorders (Burns et al. 2008). They can also occur due to other diseases or because
of the environment. Genetic factors also play a major role in the onset of a skin
condition. Warts, Insect Bites, Psoriasis, Eczema, Meningitis, Measles, Ichthyosis,
Acne, Scarlet Fever, and Stings are some examples of skin diseases (Hay et al.
2006). Erythematoscuamous class is one of the groups of skin diseases showing
symptoms like the redness of the skin (erythema) is characterized by cell loss
(squamous) (Azar et al. 2013). Psoriasis, seborrheic dermatitis, pityriasis rosea,
chronic dermatitis, and lichen planus are some of the diseases that fall under the
category of Erythematoscuamous class. It is very difficult to find out the specific
illnesses that occur in a patient while diagnosing a skin disease, particularly of the
groups of erythemato-scuamous diseases, the most common diseases in dermatol-
ogy. Many researchers have tried to build automated systems that can predict this
field. The artificial intelligence domain includes various algorithms, which are suited
to developing diagnostic systems for skin diseases. Various examples are given
204 9 Use of Artificial Intelligence in Research and Clinical Decision Making.. .
hereby. In 2017, Esteva et al. published a seminal study in Nature that was
notewor- thy for being the first to compare the performance of a neural network
with dermatologists in diagnosing skin cancer (Esteva et al. 2017). They used pre-
trained GoogLeNet Inception v3 architecture and fine-tuned the network by using
a dataset of 127,463 clinical and dermoscopic skin lesion images. Two hundred
and sixty-five clinical images and 111 dermoscopic images of a
‘keratinocytic’ or ‘melanocytic’ type were provided to dermatologists and asked if
they would: (1) prescribe biopsy or further care, or (2) reassure the patient. As a
result, the average dermatologist was adequately recommending at a level below
the CNN. Recently, the deep neural network algorithm was used by researchers
for classifying dermoscopic images of four different skin diseases. The accuracy
of Dataset A (1067 images) is 87.25 2.24% and the accuracy of dataset B (528
simi- larly distributed) is 86.63% 5.78%. These four cutaneous diseases were Basal
Cell Carcinoma (BCC), melanocytic nevus, sebourrheic keratosis (SK), and
psoriasis (Zhang et al. 2018b). It is worth noting that the treatment of these
diseases are completely different and, incorrect or delayed diagnosis may result in
inappropriate care, delayed treatment, and even leads to death. It is also important
for doctors to diagnose correctly in due course. After these four diseases
automatically can be identified using the Artificial Intelligence System, clinicians
can surely support patients by better and accurate diagnosis. In another report,
16,114 de-identified cases (photographs and clinical data) were used as differential
diagnosis of skin conditions using a Deep learning for teledermatology practices.
The DL differentiates between 26 common conditions of the skin, representing
80% of primary health cases and also claasifies 419 conditions of the skin. F 963
cases tested, the DL algorithm was not inferior to six other dermatologists and was
higher than the six primary care physicians (PCPs) and six nurses (NPs) in the
rotary panel of three board certified dermatologists (Liu et al. 2020b). In another
landmark research, images from various websites related to different skin diseases
have been collected. The database formed contains 80 photos of three diseases (20
Regular photographs, 20 photos of Melanoma, 20 images of eczema, and 20
images of psoriasis), and the method of detection was established with a
pretrained, convolutionary neural system (AlexNet) and SVM that with 100%
accuracy, the device successfully detects three different forms of skin disease. This
approach takes a digital picture of the skin region of the disease effect, then uses
image analyses to classify the disease type. It is easy and needs no costly
equipment but a camera and a computer (ALEnezi and Method 2019). Skin
disease identification constitutes a key step in reducing death rates, disease
transmission, and skin disease growth. At present, treatment of these diseases are
very costly and processed through a time- consuming clinical procedures.
Artificial intelligence enables the development of automated dermatological
screening techniques at an initial level, by focusing on image extraction, which is
an important factor in the classification of skin diseases.
9.5 Limitations of AI and ML 205
The development of AI algorithms, the emergence of big data systems and the
specialization of architectural hardware have contributed to the rapid growth of AI
technology, especially in terms of the ML and DL approaches, alongside the
development of the architectural hardware specialization, such as CPU, GPU,
TPU, as well as large scale parallel computing (Yang et al. 2019). In several ways,
AI has outpaced performance-related human experts. Therefore it is not shocking but
exciting to use AI in drug research in a market along with a conservative approach
(Miller and Brown 2018). AI is now coupled into the majority of pharmaceutical
drug discovery phase, including problem recognition, hit/lead analysis, lead
optimi- zation, pharmacokinetic properties, toxicology, and clinical trial protocols
(Fleming 2018). In spite of high boom during its inception, many obstacles are
maintaining a calm head for AI applications in drug development. The collection
of appropriate, high-quality, problem-specific data in particular remains a major
challenge for the development of AI-assisted medicines (Yang et al. 2019;
Fleming 2018). This is, sadly, simply not the case in the field of drug
research, and there are many explanations why the standard or the quantity of
data is not great. For one, confi- dence in the etiquette of data points depends
highly on experimental circumstances, because of the extremely complicated
biological structures under which medicines work (Yang et al. 2019). Various
experimental conditions typically yield different or even contradictory effects. In
contrast to the large amount of knowledge available to us, the amount of data
available to us in the field of drug development is very limited (Jackson et al.
2018). Thus, the world needs not only the revolution in the process but also a
revolution in the AI-assisted field of drug discovery (Fleming 2018; Sellwood et
al. 2018; Zhong et al. 2018; Zhu 2020). A computer screening that is powered by
machine learning is the next important constraint. Due to the difference of positive
and negative results, current high-performance statistical approaches have the
same issue as their theoretical equivalent (Gimeno et al. 2019). Moreover, in
addition to the acceptance into clinical practice, interpretative performance is
critical for revealing the information discovered by AI systems and for the identifi-
cation of biases which may result in inappropriate behavior. In order to distinguish
between bias, AI systems must be carefully implemented (Oliveira 2019; Fleming
2018; Dias and Torkamani 2019). When medical AI systems are not checked for
distortion, they can function as disparity propagators. For example, DeepGestalt,
an AI program for the study of facial dysmorphology, showed low precision in
individuals of African versus European ancestry in defining the Down syndrome
(36.8% vs. 80%, respectively) (Lumaka et al. 2017). The retraining of the Down
syndrome model for African origin individuals has raised the Down syndrome
diagnosis to 94.7%. Risk estimation in different population groups is also vulnerable
to unequal output as training data under-representation (Martin et al. 2019). None-
theless, tools are being developed which contribute to resolving the machine bias,
which could not only help to overcome machine bias problems but also lead to
diagnostic systems free of human bias (Chen et al. 2019). Profound learning can
make maximum use of receptor, ligand information and their known interactions
to
206 9 Use of Artificial Intelligence in Research and Clinical Decision Making.. .
help share knowledge from several studies and multiple targets to enhance our target
performance. Researchers are expecting the huge boom in advancement of virtual
screening technologies in the coming years to substitute or enhance the conventional
high-performance screening process to increase the screening speed and success rate
as the FDA has licensed growing numbers of AI algorithms (Topol 2019).
However, these algorithms present a range of legal and ethical issues relating to
data collection and privacy in the design and generalization of algorithms; for
example, the legal procedure for updating this algorithms with new data and the
responsibility of the prediction mistakes have not been touched yet (Topol 2019;
Vayena et al. 2018). Providing an open source of AI models including the source
codes, metagraphs, etc. to improve transparency could benefit the scientific and
medical community (Dias and Torkamani 2019).
strength lies in the question of achieving true artificial intelligence: that it can’t
learn like a human. Human intelligence functions naturally and by incorporating
various
cognitive mechanisms to make up a certain view. Artificial intelligence, on the
other hand, creates a model that can comfort like people, which seems unlikely,
because nothing can replace a person with an artificial object. Biologically, for
various reasons, the brain easily maintains the current intelligence lead on
machines (Strukov et al. 2019). First of all, the information can be stored and
processed within the same units, neurons and synapses. Secondly, in addition to
superior architectural design, if neurons are taken for the comparative function, the
brain has the advantage in cores number. Up to ten million cores are provided in
advanced supercomputers, while the brain has almost 100 billion neurons (Oprea
2020). Nonetheless, the AI
technique that currently drives virtually every area is linked to people’s lives. In
certain fields of study and education, AI is unavoidable. The rate of that is just
picking up. This transition needs to be adapted and embraced by the human
population.
Acknowledgments The authors thank Dr. Aparup Das, Director, ICMR-National Institute of
Research in Tribal Health, Jabalpur for the encouragement and kind support. The manuscript has
been approved by the Publication Screening Committee of ICMR-NIRTH, Jabalpur and assigned
with the number ICMR-NIRTH/PSC/51/2020.
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Abstract
Data intensive technologies using medical big data, analysed by machine learning
algorithms, play a key role in revolutionising healthcare. However, results from
several findings show that these algorithms have potential to gain negative impact
on healthcare system as compared to the existing primitive healthcare systems
which involve physicians. Current algorithms are accused of these deficiencies
resulting from biased training data bearing numerous missing values, errors,
and biased inputs. This is due to under- or over-representation of certain groups
of data, trivial data curation methods, etc. In this chapter, we describe
Perceptive Bias, Processing Bias, and the ways to compute bias for Medical
Big Data analysis.
Keywords
Artificial intelligence · Machine learning · Medical big data · Big data analytics
· Algorithms · Bias · mHealth
10.1 Introduction
generate a huge quantum of data through sensors, just like humans, and process it
using computational intelligence (Skilling and Gull 1985). This huge quantity of
data can be termed as Big data.
Big data can be defined as datasets which are so diverse and complex in scale
that it cannot be managed and analysed by existing data base management systems
and thus requires new architectural framework, algorithms for its management
(Lee and Yoon 2017). Although Big data is characterised by its V’s, i.e. Volume,
Velocity, and Variety, which in itself represents its gigantic size and the
tremendous values
and knowledge hidden in it which could significantly benefit the Big data
shareholders (Arora 2018). Smartphone’s. Big data lately came into prominence
because of data intensive technologies, as we are residing in the world which
utilises enough amounts of data.
Big Data is basically categorised into three major types that is structured, semi-
structured, and unstructured data. Structured-data concerns all data which is stored in
the database in tabular form. Structured data represent only 5–10% of all informatics
data. For example, relational data. Semi-Structured data is information that does
not
inhabit in a relational database but that does have some organisational properties that
make it easier to analyse. For example, CSV sttructured and XML, JSON documents
are semi structured documents, NoSQL databases, considered as Semi-Structured
and Unstructured data, represent around 80% of data. Unstructured data is every-
where. In fact, most individuals and organisations achieve their lives around free
data. For example, video-graphic documents, word-processing documents, photo-
graphic documents, presentations, webpages, and many other kinds of business
documents, audio files, Electronic-mails, Word files, PDF’s, Text’s, Media
Logs,... (Cirillo and Valencia 2019).
Big Data infrastructure is a framework which covers important components,
including Hadoop (hadoop.apache.org), NoSQL databases, massively parallel
processing (MPP), and others, that are used for storing, processing, and analysing
Big Data. Big Data analytics covers collection, manipulation, and analyses of
massive, diverse datasets that contain a variety of data types, including genomic
data and EHRs to reveal hidden patterns, cryptic correlations, and other intuitions on
a Big Data infrastructure (He et al. 2017).
In this chapter, we discuss about the sources of medical big data, machine
learning, and artificial intelligence algorithms used to analyse the medical big data
and the potential reasons of bias in the data which raise a question about use of
machines without human intervention in healthcare. The most common reasons for
bias during data curation could be corruption of data, redundant or missing
records, missing values, etc., which, cumulatively, increases over the process of
structuring, processing, and analysing which could result in false predictions.
10.3 Analysis of Medical Big Data 219
There are various sources of medical Big data not limiting to medical health
records, electronic healthcare records, clinical registries, diagnostic reports,
biometrics, patient reported data (mHealth), data over internet, diagnostic and
medical imaging, genetic/molecular bio-markers, data from coherent studies, data
from clinical trials, routine check-ups, and smart phone generated data in real time
(He et al. 2017; Saxena and Saxena 2020; Savage 2012).
Integration of this medical big data from various sources cause complements
the dimension of the data, which amplifies itself to multiple folds, thus
becomes complex and incorporates redundancy, incompleteness, incongruence
resulting in bias with cumulative increase over the successive levels. Medical big
data (MBD) varies from Big Data from other disciples thus its generally hard to
analyse and extract knowledge for most investigators, making practice of open
datascience or medical Big Data Analytics (BDA) less popular due to ethical
concerns, risk of misuse of data by third parties and unavailability of open source
reliable data in public domain (Jensen 2018).
MBD is relatively new. Thus it is usually curated and collected using pre-
defined protocol in fixed forms, thus they are relatively more structured than big
data from other disciplines. This is mainly due to the well-structured data
extraction process that simplifies the raw data (He et al. 2017; Denny et al. 2018).
Curation of MBD is expensive due to involvement of skilled man-power,
expensive instrumentation (diagnostic and imaging platforms, sensors, etc.), and
especially due to involvement of human population as subjects (e.g., Clinical
trials). Thus availability of MBD is relatively limited and is usually collected in
non-reproducible situation, affected by various sources of uncertainty at each level
(due to human involvement), such as missing data, measurement errors, technical
collapses, etc. (Ntoutsi et al. 2020).
Potential applications of MBD can be found in personalised medicine, clinical
decision support system, diagnostic and treatment decision to support patient’s
behaviour using mobile device, population health analysis, fraud detection and
prevention, etc. (Denny et al. 2018; Ntoutsi et al. 2020) Based on these
applications,
Data analytics for MBD could be used in various healthcare sectors to improve
quality of healthcare, including predictive modelling (for the optimum use of
resources and accessing risks), management of population, surveillance of medical
device safety and drugs, monitoring heterogeneity in treatment and disease,
clinical decision support and personalised medicine, performance measurement,
thus improving quality of care, monitoring public health and research applications
(Rumsfeld et al. 2016).
Data science algorithms enable machines to perform tasks skilfully, using artificial
intelligence. They require data to learn, thus they require datasets to train themselves
before predictive models can be obtained (Skilling and Gull 1985). There are several
220 10 Bias in Medical Big Data and Machine Learning Algorithms
ML algorithms used to analyse and predict MBD, such as Decision Tree (DT), Naïve
Bayes (NB) classifiers, k-nearest neighbours (k-NN), Support Vector Machine
(SVM), Artificial Neural Network (ANN), Deep Learning (DL), etc.
In Decision Tree (Ramírez et al. 2019), a simple algorithm creates mutually
exclusive classes by answering questions in a predefined order. Naïve Bayes
(NB) classifiers, output probabilistic dependencies among variables. In k-nearest
neighbours, a feature classified according to its closest neighbour in the dataset,
are used for classification and regression. Support Vector Machine uses a trained
model which will classify new data into categories. It can find complex patterns by
choosing kernels which perform transformation of data and choose support
vectors.
Artificial Neural Network is used to approximate functions. They have several layers
of neuron resembling human. Each “neuron” has a weight that determines its
importance. Each layer receives data from the previous layer, calculates a score,
and passes the output to the next layer. It is considered supervised machine
learning. Deep Learning uses a variant of ANNs, where multiple layers of neurons
are used. It
can perform both supervised or unsupervised learning (Tang et al. 2019; Bibault
et al. 2016).
10.4 Bias
Bias is not a new problem, rather “Bias is as old as human civilization” and “it is
human nature for members of the dominant majority to be oblivious to the
experiences of other groups” (Jensen 2018; Saxena et al. 2021). Artificial Intelli-
gence (supervised or unsupervised learning) algorithms are significantly employed
in public and private domains to make decisions which are beyond the capabilities of
human, which have long term impact on mankind and society. However, these
algorithms may cumulatively amplify the pre-existing bias in MBD which, con-
sciously or unconsciously, incurred during data curation and analysis thus
evolving new criteria and classification with tremendous potential for new bias.
This had led to increasing concern among data scientists and curators to reconsider
the artificially intelligent system and its associated algorithms towards new
approaches which efficiently solves the purpose with sensitivity addressing the
fairness of the decision thus reducing the chances of bias.
For the ease of categorisation in this chapter, Bias is divided into three different
classes (Fig. 10.1).
• Perceptive Bias
These are the approaches which understand the origin or creation of bias in the
society followed by its entry into the social and technical systems and
ultimately manifestation or fairness of data used by AI algorithms, which can
be defined formally and modelled to give a knowledgeable outcome.
• Processing Bias
As the name suggests, this approach deals with the bias which pioneers during
different stages of decision-making by AI algorithms primarily focusing on input
10.4 Bias 221
However, as the AI algorithms and AI technology crawls deep into the society, it
is important for data scientists and algorithm creators to be aware of conscious,
subconscious or unconscious discrimination or bias due to any past incident in life
to ensure the responsible usage of technology, keeping in mind that “a
technological
approach on its own is not a panacea for all sort of bias and AI problems” (Ntoutsi
et al. 2020).
Bias is a primitive notion for Machine Learning and AI algorithms, which was
trivially referred to assumptions or educated guesses made by specific model or
curator themselves (Mitchell 1997). Stab et al. in their survey studied about “incli-
nation or prejudice of a decision made by an AI system which is for or against one
person or group, especially in a way considered to be unfair” (Ntoutsi et al. 2020).
This survey supports our assumption about how bias enters the data analytics system
and how it is incorporated as the part of data which serves as input data to AI
algorithms. Further, we discuss various aspects of perceptive bias and their definition
with example of mhealth- or smartphone-generated medical data.
222 10 Bias in Medical Big Data and Machine Learning Algorithms
resting, at work, in stress, and normal control condition) to obtain the unbiased
data, which is often difficult due to obvious reasons, including shortage of
subjects, human intervention, manipulation, and missing values. Admit all these
factors, un-conscious bias could potentially occur as the developer who designed
the algo- rithm or the protocol for study had certain perception to things which at
some point of time was misinterpreted by the user or the curator who is making
the entry in the dataset could introduce bias in the dataset. Thus fairness of data
will always be a question whether it is a large dataset or small, where large
datasets might have underrepresentation of certain groups, while small datasets might
fail to represent the entire group of data.
10.4.2.1 Pre-Processing
MBD is the pioneer source of bias, which is introduced to balance the missing values
in dataset to balance it before using it to train an algorithm. The notion behind this
logic is that “more fair the training data, more reliable the predictive model will
be” thus reducing the chances of discrimination and bias in the lineage process.
Thus, to
achieve this, the data science curators modify the original data by manipulating the
class labels for selected observations close to the decision-making factors by using
heuristic aiming to carefully balance unprotected and protected groups in training
datasets (with loosely controlled effect). Calmon et al. proposed a problematic
fairness-aware framework which alters the distribution of data towards fairness,
while controlling pre-instance distortion by preventing data utility for learning
(Calmon et al. 2017).
10.4.2.2 In-Processing
In-processing approach re-introduces the problem of classification by unambigu-
ously incorporating the discrimination behaviour of model in function via regulation
by training on potential target labels. Most of the approaches known so far are true
for supervised learning case, which impose equal refurbishment errors for both
unprotected and protected groups. Thus selection of right model with appropriate
accuracy on large dataset with reduced bias is important to minimise cumulative
increase in bias.
224 10 Bias in Medical Big Data and Machine Learning Algorithms
10.4.3.3 AI Decisions
Every factor of data annotates something and several factors in a group can lead to an
interpretation about that particular situation. Alike AI and ML algorithms interpret
10.5 Conclusion 225
the huge MBD datasets to extract knowledge out of them to generate meaningful
notions. Generally these decisions are made using specific models and approaches,
like black box model, rule based decision sets, model and optimal classification
trees, deep neural networks, etc.
Just like every coin has two faces, so are different sides of the outcome. Thus,
in upcoming research, we need to develop statistical relational learning to take
per- spective of knowledge reasoning and accounting, while developing the AI
models on more logical grounds.
10.5 Conclusion
actions are taken upon false predictions (especially on incidental finding). For
instance, the information stored in e-Health records is observed data rather than
experimental data. Thus, they have a high level of by-systematic bias. Other
associated problems for objective nature of Big data, including the fact that
interpretations, methods, and inputs are value-driven making it easy to ignore bias,
technical quality making unbounded use of data easily justified. Moreover, as the
bias is introduced during every stage right from data curation to processing and
also algorithm designing and training of algorithm, it cumulatively increases at
every stage and adds up to infer completely different outcomes in comparison to
actual situation. More research needs to be done on accessing the bias, thus
identifying the bias and better predict the outcomes.
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