i An update to this article is included at the end

Informatics in Medicine Unlocked 19 (2020) 100339

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Informatics in Medicine Unlocked

journal homepage: http://www.elsevier.com/locate/imu

A machine learning algorithm to improve patient-centric pediatric

cardiopulmonary resuscitation
Dieter Bender a, *, Vinay M. Nadkarni b, C. Nataraj c
a
Villanova Center for Analytics of Dynamic Systems, Villanova University, USA
b
Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia, USA
c
Moritz Endowed Chair Professor in Engineered Systems, Villanova Center for Analytics of Dynamic Systems, Villanova University, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Several studies suggest that the outcome of pediatric cardiopul-monary resuscitation depends
Electrocardiography strongly on timely recognition of the underlying cause for cardiac arrest, the prominent ones being primary
Wavelet transform ventricular fibril-lation and secondary asphyxia-associated ventricular fibrillation. If the cause could be deter­
Support vector machine
mined within the first minute of cardiopulmonary resuscitation, the administration could be appropriately
Cardiac arrest
Cardiopulmonary resuscitation
modified in order to achieve optimal outcome. However, distinguishing the two causes has been a difficult
Ventricular fibrillation challenge.
Asphyxia Objective: To derive a robust algorithm with acceptable accuracy that distinguishes primary ventricular fibril­
lation and secondary asphyxia-associated ventricular fibrillation within the first minute of starting cardiopul­
monary resus-citation.
Methods: We address this problem with MACWAVE, a new computa-tional technique integrating advanced signal
processing and machine learning. MACWAVE is an algorithm that uses wavelet transforms with electrocardiog-
raphy data to identify the most differentiating characteristics of the signal and uses them as features to develop a
support vector machine classification model.
Results: The developed algorithm shows an average classification accuracy of 85%, this being the first result ever
achieved for this critical pediatric problem.
Conclusion: Being the first research effort to ever analyze this critical pediatric problem, the MACWAVE method
can improve patient-centric cardiopulmonary resuscitation treatment and significantly increase positive out­
comes for pediatric cardiac arrest.

1. Introduction
While it is difficult to determine the exact numbers, cardiac arrest
(CA), also known as sudden cardiac arrest (SCA), accounts for millions of
deaths every year globally, and over 300,000 in the United States alone
[1–4]. An estimated number of 200,000 patients per year receive
in-hospital cardiopulmonary resus-citation (IH-CPR) [5–8]. More
detailed reports point out that 59% of adults and 93% of children have
their in-hospital cardiac arrest in ICUs or PI- CUs [7,9–11]. However,
despite highly equipped medical environment and continuous upgrades
of the CPR guidelines and standards, frequently issued by the American
Heart Association (AHA), only 25% of adults and 50% of children sur­
vive to hospital discharge after receiving IH-CPR [1,6,7,11–14].
Multiple studies suggest that oftentimes the main reason for an
adverse outcome in pediatric CPR is the unknown pathogenesis of CA in
children [4,7,11,15]. Ventricular fibrillation (VF), characterized as
rapid, disorganized contractions of the heart with complex electrocar­
diogram (ECG) is uncommon, but not rare during out-of-hospital pedi­
atric cardiac arrests’ [9,16]. In fact, it is reportedly the initial rhythm in
19%–24% of such cardiac arrest cases [4,17]. In adults, when prompt
defibrillation is provided soon after onset of VF, the attained outcomes
tend to be positive. For example, in a cardiac catheteriza-tion labora­
tory, the rates of survival have been reported to approach 100% [4].
“When automated external defibrillators are used within 3 min of wit­
nessed VF in casinos, long-term survival has been shown to be 75%” [4].
However, most pediatric cardiac arrests occur in critically ill children

* Corresponding author.
E-mail address: dbender2@villanova.edu (D. Bender).
URL: http://www.vcads.org (D. Bender).

https://doi.org/10.1016/j.imu.2020.100339
Received 23 January 2020; Received in revised form 20 April 2020; Accepted 29 April 2020
Available online 18 May 2020
2352-9148/Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
D. Bender et al.
with underlying respiratory failure or circulatory shock and are gener­
ally preceded by asphyxia [18,19].
Treatment of choice is prompt CPR through chest compressions and
initial assisted ventilation, providing adequate oxygen delivery to meet
metabolic de-mand and removal of carbon dioxide [4]. As a result, the
ECG examination for primary VF or subsequently developed secondary
asphyxia-associated VF is underemphasized [4,20,21]. In many cases,
the delayed recognition of VF and not delivering timely defibrillation to
restore shockable heart rhythm, is the cause for negative pediatric CPR
outcome. Thus, an immediate recognition of the underlying cause for CA
in children is crucial. It has been generally recognized that if the path­
ological cause is determined within the first minute of CPR, more pos­
itive results can be achieved by performing an appropriately modified
administration (i.e., CPR vs. medications vs. prompt defibrillation) [4,8,
Fig. 1. An overview of the designed MACWAVE algorithm.
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Informatics in Medicine Unlocked 19 (2020) 100339
22–24]. Hence, the chief goal of our study is to derive a classification
algorithm for distinguishing primary VF and secondary
asphyxia-associated VF at the beginning of intervention, in order to
improve patient-centric CPR procedures.
Computational intelligence (CI) techniques have helped to address
many biomedical problems. Many such problems can be characterized
as pattern recognition or classification tasks and are fit for a subfield of
CI known as ma-chine learning (ML). Nowadays, there is widespread
belief that quantity of the data and high computational power drive the
performance of the ML algorithms.
when dealing with dynamic systems such as the one at hand. How­
ever, we be-lieve and have shown in a preliminary version of this work
[25] that meticulous analysis and detection of significant but often
hidden characteristics in the raw data, while utilizing ML algorithms
D. Bender et al.
more in the form of computational tool, would be a more effective
approach. Moreover, such an approach can lead to additional insight
into the underlying physiological mechanisms. This study, re-sulting in a
new algorithm (MACWAVE), solidifies this claim and shows not just
accurate classification results, but also answers the question why such
accuracy was achieved, providing a basis for further improvement.
2. Methodology
2.1. Overview
The structure of an ML algorithm is typically portrayed by three main
prin-ciples: input data, learning algorithm and model. An overview
shown in Fig. 1 illustrates how, through a learning process, input data is
utilized to construct the correct model to carry out the defined task.
The raw data in our domain consists of ECG signals. The input data
can essentially be described here as characteristics, or as features, of the
signals that are mathematically mapped from the signal domain into the
feature domain. The defined features drive the learning algorithm and
ultimately build the ML model; thus, the performance of the ML model is
decided by the quality of the features, making the mathematical map­
ping functions pivotal for the accuracy of any ML utilization. Nowadays,
advancement in computational intelligence
field has made most of the ML algorithms somewhat ‘ready to use
products’, making the feature extraction process the limiting, and
therefore, the most critical step in the development of the ML algorithm.
This section describes a novel interdependent machine learning and
wavelet transform analysis, that was designed with particular focus i) to
find the desired mapping function to identify unknown features, as well
as ii) to optimize the feature extraction step of the developed MACWAVE
(MAChine Learning With WAVelet Transforms) algorithm.
2.2. Data
The raw data was taken from 36 healthy 3-month-old domestic fe­
male swine with two different ventricular fibrillation types induced
during the experiment.
- Group I: primary VF (n ¼ 20) and Group II: asphyxia-associated VF
(n ¼ 16).
In both groups, the animals were anesthetized and mechanically
ventilated using Datex Ohmeda anesthesia machine (Modulus SE) on a
mixture of room air and titrated isoflurane (1.0–2.5%) with a tidal
volume of 10–12 ml/kg, positive-end expiratory pressure of 60 mm H2O,
and titration of rate to sustain end-tidal carbon dioxide (EtCO2) at
38–42 mmHg [7,11]. The primary VF injury was simulated through the
induction of electrical pacing to the heart. Once VF was confirmed, the
animal was left untreated for 7 min. In the asphyxia-associated VF
group, the injury was fabricated by endotracheal tube clamping for 7
min, at the end of which the VF was induced and confirmed. Fol-lowing
the injury period of 7 min, CPR was provided for both groups with a
target rate of 100 chest compressions min 1 and ventilations at 6 min 1
with 100% oxygen. Due to the nature of original experiments [7,11],
half of the animals from each group randomly received either blood
pressure-targeted care (BP-care), consisting of compression depth
titrated to a target systolic blood pressure of 100 mmHg; or optimal
American Heart Association Guideline
care (Guideline-care), consisting of target depth of 51 mm [26].
However, no intravenous vasopressors were administered in BP-care nor
the Guideline-care in the first 2 min of provided CPR. Thus, to eradicate
potential impact on the data introduced through different CPR se­
quences after t9 ¼ 9 min, only the data obtained amid the initial 2 min of
the resuscitation period in the interval between t7 ¼ 7 min and t9 ¼ 9 min
was selected for this study. The ECG and the EtCO2 data used in this
study were measured with a sampling frequency of 100Hz with an ICU
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Informatics in Medicine Unlocked 19 (2020) 100339
monitor: model HP66 (Hewlett Packard, Palo Alto, CA) and NICO
(Novametrix Medical Systems Inc., Wallingford, CT), re-spectively. The
PowerLab data acquisition system recorded the ECG and the EtCO2 data
with their measured sampling frequency. The experimental proto-col,
explained in more detail in Ref. [7,11], was approved by The Chil­
dren’s Hospital of Philadelphia Institutional Animal Care and Use
Committee and the Univer-sity of Pennsylvania Institutional Animal
Care and Use Committee (IACUC). As described in Ref. [7,11], the
collected data is first of its kind, targeting specific resuscitation prob­
lems, including the one presented in this study.
Since the beginning of data-logging (tl) was at random times (Δt ¼ t0
tl) before t0 as shown in Fig. 2 and considering that the main task of
this study was.
to classify VF type promptly after its occurrence, the beginning of the
injury period and resuscitation period, respectively, were identified
using a wavelet transform (WT) of the EtCO2 signal. The background of
WT is provided in Appendix A; however, Fig. 2 illustrates this pre­
processing step graphically through transients shown in the WT plot
with respect to the original EtCO2 signal, and highlights the detected
first 2 min of CPR. Using the identified time-interval, the correlated ECG
signal from each sample was retained for further analysis. As was found
later, the first minute of the retained ECG was itself sufficient to conduct
further analysis; thus, the rest of the paper refers to only the first
retained minute of the ECG signals as the raw or the original signal. It
should be noted here that the goal of this investigation was to classify
primary VF and secondary asphyxia-associated VF at the beginning of
the resuscitation. Thus, the only relevant ECG data for this study is
during the time-window at t7, directly following the injury period.
During the CPR-detection-step, it was found that some of the original
signals were corrupt or had missing periods. Thus, the number of raw
data was reduced to 33 samples (20 primary VF and 13 asphyxia-
associated VF).
2.3. Feature extraction and signal examination
Literature shows that wavelet transform has proven itself to be an
indis-pensable addition to the signal processing field. Moreover, it is
validated signal analysis tool of choice when it comes to examining ECG
signals [27–29] and is a suitable technique to quantify desired charac­
teristics of the ECG signal, permitting to construct a decisive set of
features for ML applications [30,31]. Its principal ideas are briefly
explained in Appendix A and its strong points are demonstrated through
our analysis.
As shown through previous studies [29,32], WT provides extraor­
dinary in-sights regarding frequencies and their attributes often hidden
in the raw ECG signal with respect to their temporal locations. However,
when dealing with ECG signals from groups both having pathological
conditions, such as primary VF or asphyxia-associated VF, the well
known and typical P-QRS-T sinus pat-tern is no longer present. For
instance Fig. 3 shows VF ECG segments of both sample groups, with
imposed normal P-QRS-T waveform. In both sample groups, the signal
appears similarly sporadic and disordered, making conven-tionally
established WT examinations of ECG signals infeasible for this problem.
We began a coarse WT analysis of the ECG signals of the given
waveforms in order to identify the relevant and general signal charac­
teristics. Next, the observed results were analyzed using a more tailored
WT analysis, in an in-terdependent ML combination, to ultimately
obtain the most relevant signal characteristics to refine the final classi­
fication model.
As suggested by Addison in Ref. [27], a Morlet function, see Eq. (1),
was used as the mother wavelet with initial scales s ¼ [1–128] and a
wavelet transform was performed on the preprocessed 1-min-ECG-seg­
ments. Fig. 4 illustrates these steps graphically, showing the trans­
formation from the original ECG signal to the obtained WT coefficient
spectrum W {f (1–128, μ)}. To quantify WT coefficient spectrum of the
ECG segment as defined by Eq. (2), the energy E was calculated with
D. Bender et al. Informatics in Medicine Unlocked 19 (2020) 100339

Fig. 2. a) Protocol design: tl start of data recording, t0 start of asphyxia or VF in-jury, t7 start of manual cardiopulmonary resuscitation, t9 titration is performed
differently for BP-Care and Guideline-Care VF samples. The experiment is conducted until Return of Spontaneous Circulation (ROSC) or t27 b) EtCO2 Signal c)
Wavelet transform of the EtCO2 signal to detect transients.

respect to s according to Eq. (3). Repeating the process for all 33 sam­
1
ples, each of the original ECG signals was characterized interim in the
t2
ΨðtÞ ¼ 1 ejω0 t e 2 (1)
form of an energy metric. π4

4
D. Bender et al.
Fig. 3. Imposed normal ECG sinus rhythm on the ECG waveform of a) primary VF sample and b) secondary asphyxia-associated VF sample.
2.4. Feature selection
The dimensionality of the input data was reduced to its principal
features. This process is often introduced to avoid the effects of the curse
of dimension-ality [33] and consequently, overfitting of the classifica­
tion model. Through a feature-filtering step implementing a mutual
information (MI) process described in Appendix B, the dimensionality
reduction, or in other words, feature selec-tion, was used to remove
multi-collinearity in the feature set and insignificant energy values
across the samples. The obtained MI rank revealed that the most rele­
vant energy values stem from the interval of the WT coefficient spectrum
with s ¼ [50–75] or in other words, from the decomposed frequency
aspects.
Described by W {f (50–75, μ)} (see Table 1). It should be noted here
that, despite the fact that this finding seems obvious through visual
examination of the plots shown in Fig. 4c, and can be seen in asphyxia as
well as in the VF sample, this was not the case for most samples. From
Eq. (3), where n ¼ 26, the established 26 energy values were used as a
26-dimensional feature set of each sample to train and evaluate a binary
ML classifier.
Z ∞
�t μ�
Wff ðs; μÞg ¼ f ; Ψs;μ ¼ f ðtÞΨ* dt (2)
t¼ ∞ s statistical features.
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Informatics in Medicine Unlocked 19 (2020) 100339
� n
� �o
EðsÞj ¼ �W f sj ; μ j2 (3)
where j ¼ 1, 2, …n and n ¼ number of scales.
2.5. Machine learning
A linear support vector machine (SVM) classifier was chosen as the
ML algorithm to build the desired classification model for reasons that
are explained in Appendix C. Utilizing the support vectors of the ob­
tained SVM model, the least-separable samples were identified and their
WT spectrum examined in more detail.
It was found that the trends of the most dominant frequencies of the
least-separable samples seem to differ. Thus, the scattering of peking
magnitudes in the WT coefficient spectrum W {f (50–75, μ)} with respect
to translational parameter μ and scale s, were summarized statistically.
Calculating variance (VAR), standard deviation (SD), median absolute
deviation (MAD), first and second order central moment (CMn), range of
values (RoV) and interquartile range (IQR) of the dominant magnitudes,
a 7-dimensional feature set was ob-tained for each sample. As was done
previously, a linear SVM classifier was trained and evaluated using these
An important step when working with ML is to make sure that the
D. Bender et al. Informatics in Medicine Unlocked 19 (2020) 100339

Fig. 4. I. primary VF sample and II. secondary asphyxia-associated VF sample; a) orig-inal ECG waveform, b) coefficient spectrum W {f (1–128, μ)} of the ECG
wavelet trans-form, c) most significant interval of the ECG wavelet transform coefficient spectrum W {f (50–75, μ)}.

important characteristic when dealing with dynamic patient physio­

Table 1
logical data [35]. In many cases, as in the biomedical field, the data sets
Ranked features.
are limited, and a widely used holdout-validation approach that parti­
Rank ECG Energy ECG Statistical Most Valuable (all sets) tions the data into exactly two subsets for training and testing [36],
1 s¼ 63 CM2 CM2 might not be an option. A commonly used method to resolve this chal­
2 s¼ 50 VAR VAR lenge is cross-validation [34,37].
3 s¼ 62 MAD s ¼ 63
Giving that this is a medical problem with a small sample size and
4 s¼ 64 SD MAD
5 s¼ 65 RoV SD unknown inter-patient distribution, we have decided to rely on error
6 s¼ 59 IQR RoV minimization and generalization optimization with the given samples,
7 s¼ 55 CM1 s ¼ 50 instead of expanding the data set through synthetic representatives [38,
8 s¼ 68 – s ¼ 64 39]. Thus, to address the limited number of samples in our investigation,
9 s¼ 61 IQR
we have employed a popular k fold (k ¼ 8) cross-validation method in
–
10 s¼ 60 – –
11 s¼ 66 – – the learning phase of the ML algorithm [39]. Please note that this is a
12 s¼ 67 – – method that a considerable number of ML studies employ, because, on
Note: ECG Energy calculated with respect to s: scale, CMn: central moment of nth average, it decreases the bias and variance of the predic-tions on unseen
order, VAR: variance, MAD: median absolute deviation, SD: standard deviation, data and the cross-validation error estimates nearly agree with the true
RoV: range of values, IQR: interquartile range. error of the final classification model [37,38,40,41]. In this method, the
available data is partitioned into k randomly chosen subsets of approx­
obtained classification model is not biased to the training data, i.e., the imately equal size, and k rounds of learning are performed. On each
model is not overfitting and most importantly assures high generaliza­ round, 1/k of the data is held out for testing, and the remaining exam­
tion capability [34]. Generalization capability refers to how well the ples are used for training, such that each subset is used exactly once for
developed classification model performs with unseen testing data, an validation. As a result, the average estimated error from the loss

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D. Bender et al. Informatics in Medicine Unlocked 19 (2020) 100339

functions during the training of k rounds as shown in Eq. (4), assures less Table 2
overfitting, high retention of generalization ability and is a closer esti­ Summary of results.
mate of the true error of the model. Feature Set Accuracy [%] AUCROC

1 X
K
K X Energy 73 0.82
CVðDÞ ¼ LðAðDk Þðxi ; yi ÞÞ (4) ECG Statistical 79 0.91
K k¼1
n Most Valuable (all sets) 85 0.88
ðxi ;yi Þe2eTk

where D: Data Set, Tk: kth Training Set, n: Number of Samples, K:

Number of k-folds, L: Loss Function, A: Algorithm, (xi, yi): Samplei and
Targeti

3. Results

The performance of the developed SVM classifier is summarized in

Table 2 with respect to each constructed feature set. The ranking of each
individual feature set is shown in Table 1.
As one can see, the best results were obtained when all features,
ranked and identified as valuable, were combined together. The best
algorithm accuracy was achieved by eliminating features one by one
according to MI rank, starting with the least important one, until the
accuracy could not be improved further.
For comparison among the algorithms, the performance was evalu­
ated using the overall accuracy and the Area Under the Receiver Oper­
ating Characteristic Curve (AUCROC) that summarizes the classification
threshold. The final linear SVM classifier performed with an overall
accuracy of 85% and AUCROC value of 0.88. The confusion matrix in
Fig. 5. Confusion matrix exemplifying output accuracy of final SVM model.
Fig. 5 shows the outcome of the best SVM classification model.

(at t7).
4. Discussion
The limiting attribute of this study was the underpowered data set.
Al- though the generalization of the classifier was addressed through the
Through a codependent wavelet transform and interactive SVM al­
8 fold cross-validation and the SVM algorithm having the ability to
gorithm, we were able to utilize techniques that are often used in a signal
retain high infer-ence (AUCROC ¼ 0.88) from a small sample set (Ap­
processing and machine learning field, in a novel way. The approach led
pendix C), a larger data set would have allowed for a more extensive
to new and previously unknown ECG waveform characteristics to
investigation, strengthening the results. On the other hand, the high-
separate the VF types. For example, it was detected that the most sig­
quality data and the promising results of this study could naturally
nificant frequencies embedded in the ECG signal were between 2Hz and
lead to large data sets of human data, since the characteristics of swine
16Hz (derived from the identified scales 50–75) and yielded the most
CPR models are highly comparable with human CPR models [48–50].
decisive class separation. Several studies analyzing the VF waveform
The novelty of the MACWAVE method is that the classification
Have reported that the relevant frequencies in ECG are observed
accuracy.
within 2Hz–48Hz range, which could explain the relevance of discov­
Of 85% was achieved using only noninvasive signals. Such nonin­
ered major frequencies in this study [17,42,43]. In addition, studies [42,
vasive approach has obvious advantages: no trauma to nerves, tissues,
44,45] have pointed out that VF ECG patterns change with the duration
and organs, no taxing on the overall circulatory system and almost
of CPR due to correlation with coronary perfusion pressure. This might
instant signal availability with no preparation time. An additional
explain the relevant changes in dominant frequency trends that were
captured through detailed examination of the WT frequency spectrum. achievement of our research was to provide fast access of the developed
method in a way that it could utilize the technology already available in
However, none of the mentioned studies showed what particular attri­
butes in the bandwidth 2Hz–16Hz can be used as distin-guishing fea­ every ICU.
tures to classify the investigated VF types during CPR, something that we
were able to identify through interactive ML algorithm and MI feature 5. Conclusion
reduction, as listed in Table 1, in the “Most Valuable (all sets)” column.
A novel methodology for classification of two important pediatric
The significance of identified features suggests that further investigation
ventricular fibrillation types was developed achieving a classification
exploring the frequency trends with respect to time might result in a
accuracy of 85% and.
much faster VF classification, needing a shorter ECG time window.
AUCROC of 0.88. The constructed MACWAVE algorithm demon­
Although 85% classification accuracy signifies a reliable identifica­
strated and validated the superiority of ML approach, over more
tion of car-diac arrest’s pathology, the results suggest additional inter­
simplistic statistical anal-ysis, by identifying previously unknown class
pretation as well. Several studies have shown that initial primary VF
decisive characteristics of the VF waveforms, such as frequency trends.
waveform and prolonged primary VF waveform are characteristically
The significance of gained knowledge can expand the underlying
different [42,46,47]. These observations might imply that the achieved
physical and medical meaning of the arrest type. Most importantly it
classification in this study can be the result of waveform differences
should be noted that this is the first research effort to ever ana-lyze this
between prolonged primary VF and initial secondary
critical pediatric problem, the significance of which could lead to more
asphyxia-associated VF. It should be noted here that the goal of this
successful patient-centric pediatric cardiopulmonary resuscitation
study was to classify CA injury promptly after the beginning of CPR.
treatment.
Hence, future studies will seek additional understanding of the knowl­
edge gained through this study, in particular examining beginning of
primary VF (at t0) and beginning of secondary asphyxia-associated VF

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D. Bender et al. Informatics in Medicine Unlocked 19 (2020) 100339

Acknowledgments R. Morgan for stimulating discussions and medical insights.

On a problem of this nature, clearly we had to work closely with
medical researchers and the work was performed in close association
with The Children’s Hospital of Philadelphia. We thank Dr. T. Kilbaugh
for generously providing the data, as well as Drs. R. Sutton, R. Berg and
We are also immensely grateful to Villanova University for funding
this research through a University Graduate Assistantship.
The authors wish to thank the anonymous reviewers for their critical
reviews and insightful suggestions, which substantially improved the
paper.

Appendix A. Wavelet Transform

Signal processing theory separates majority of the signals into four classes: deterministic (periodic and transient) and nondeterministic (stationary
and non-stationary). Despite this clear classification, most of the real-world signals, and especially human data, may contain a few or all of such
attributes. Subsequently this creates a need for a signal processing tool equipped to uncover aspects such as time specific discontinuities and
breakdown points, as well as trends and transients.
Short-time Fourier transform (STFT) and wavelet transform (WT) allow for such analyses. However, the drawback of STFT is that there exists a
trade-off between the time resolution and frequency resolution. In other words, the time resolution and bandwidth of STFT can not be selected to be
small simul-taneously [30,51]. In contrast to this, the wavelet transform addresses these limitations and provides an elegant solution to the drawbacks
of STFT [30].
Mathematically, the wavelet transform of a continuous signal f (x) is defined by Eq. (A.1), where Ψ is the selected wavelet function. The trans­
formation can also be interpreted as a cross-correlation of a continuous signal f (x) and a set of wavelets Ψ s,μ with different widths at different temporal
locations. The widths, or dilation and contraction of the wavelet is governed by the scaling parameter s and is responsible for the resolution of the
transform. The temporal location, or the movement of the wavelet along the time axis is governed by the translational parameter μ.
Z ∞ �t μ�
Wff ðs; μÞg ¼ f ; Ψs;μ ¼ f ðtÞΨ* dt (A.1)
t¼ ∞ s
Fundamentally, the wavelet transform measures the similarity between the analyzed signal f (x) and modified base wavelets Ψ s,μ. Thus, the wavelet
trans-form is a set of WT coefficients W (WT coefficient spectrum W {f (s, μ)}), where the magnitude of W {f (s, μ)}) represents how close the wavelet
function Ψ s,μ is correlated with the windowed segment of the analyzed signal f (t) [30,51,52]. In non-technical terms, wavelet transform can be
thought of as a ‘mathematical microscope’ [27], where the scale s is the magnification parameter at an explored temporal location μ. The illustrations
in Fig. 4 show a graphical and more in-tuitive representation of this idea applied to our data. The temporal position of the transform is represented by
the x-axis, while the y-axis represents the scale s of the base wavelet Ψ , and the color intensity, the magnitude of the wavelet coefficient Wx,y.

Appendix B. Mutual Information

Mutual information (MI) is a commonly used filtering method to select a subset from a given feature set, independent of the subsequent ML al­
gorithm [53,54]. It is relatively robust against overfitting, and yields the minimum gen-eralization error and therefore, is the preferred feature ranking
approach for training sets with small sample sizes [55]. In general, MI is a measure of depen-dency between a random variable X and a random
variable Y. Mathematically it is defined as
XX pðx; yÞ
IðX; YÞ ffi pðx; yÞ log (B.1.)
x2X y2Y
pðxÞepðyÞ

where p(x, y) is the joint probability mass function and p(x) and p(y) are the marginal probabilities [53,56]. If X and Y are entirely independent, their
mutual information I(X, Y) has a minimum value of zero. Consequently, the features whose MI with the class variable are the largest, are considered
the most important ones; thus, in the established MI rank (Table 1) the features are in descending order with respect to their MI value.

Appendix C. Support Vector Machines

The support vector machine (SVM) classifier was chosen as the machine learning algorithm to build the desired classification mode for several
reasons. Foremost, an SVM classifier is suitable for small data sets, as is the case here. The algorithm can be trained to construct an accurate clas­
sification model with limited or unbalanced data samples without sacrificing the generalization property for future unseen data. The framework of
SVM is based on sound optimization theory, governed by a mathematical objective function, Eq. (C.1).

1 X
N
� � �
hðw; b; αÞ ¼ jjwjj2 αe yi wT xi þ b 1 ; (C.1.)
2 i¼1

where h(w, b, α) ¼ separating hyper plane, w ¼ separating vector b ¼ bias, α ¼ Lagrange multiplier, xi ¼ sample i, and yi ¼ class of sample i.
The geometric interpretation of ||w||, is that it is the width of the margin be-tween the two classes and in its simple geometric interpretation
provides helpful insight for further investigation of the data [57]. Least separable samples (xi, when 1 is small or when xi is a Support Vector) can be
easily identified and lead to better understanding of relevant features. Consequently, that leads to the most relevant traits of the relevant signals and a
better understanding of the most optimal feature space [58]. Further, since the SVM learning algorithm considers all samples (i ¼ 1 …, N), the effect of
the obtained model on the classi-fication accuracy due to the optimized feature space can be easily evaluated with all N samples. This process can be
carried out repeatedly resulting not solely in a better accuracy of the classifier, but as in our case, a better understanding of significant raw signal
characteristics and their physical meaning.

8
D. Bender et al. Informatics in Medicine Unlocked 19 (2020) 100339

Appendix D. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.imu.2020.100339.

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1. The relationship between retinal vessel geometrical changes to
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