Computational Biology and Chemistry 102 (2023) 107788

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Computational Biology and Chemistry

journal homepage: www.elsevier.com/locate/cbac

Early diagnosis of Parkinson’s disease: A combined method using deep

learning and neuro-fuzzy techniques
Mehrbakhsh Nilashi a, b, *, Rabab Ali Abumalloh c, Salma Yasmin Mohd Yusuf d, Ha
Hang Thi e, f, **, Mohammad Alsulami g, Hamad Abosaq g, Sultan Alyami g, Abdullah Alghamdi g
a
UCSI Graduate Business School, UCSI University, No. 1 Jalan Menara Gading, UCSI Heights, 56000 Cheras, Kuala Lumpur, Malaysia
b
Centre for Global Sustainability Studies (CGSS), Universiti Sains Malaysia, 11800, USM Penang, Malaysia
c
Computer Department, Applied College, Imam Abdulrahman Bin Faisal University, P.O. Box. 1982, Dammam, Saudi Arabia
d
Primary Care Medicine Department, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh 47000, Selangor, Malaysia
e
Institute of Research and Development, Duy Tan University, Da Nang, VietNam
f
International School, Duy Tan University, Da Nang, VietNam
g
Computer Science Dept., College of Computer Science and Information Systems, Najran University, Najran, Saudi Arabia

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

Keywords: Predicting Unified Parkinson’s Disease Rating Scale (UPDRS) in Total- UPDRS and Motor-UPDRS clinical scales is
Computational intelligence an important part of controlling PD. Computational intelligence approaches have been used effectively in the
Parkinson’s disease early diagnosis of PD by predicting UPDRS. In this research, we target to present a combined approach for PD
UPDRS
diagnosis using an ensemble learning approach with the ability of online learning from clinical large datasets.
Diagnosis
Accuracy
The method is developed using Deep Belief Network (DBN) and Neuro-Fuzzy approaches. A clustering approach,
Time complexity Expectation-Maximization (EM), is used to handle large datasets. The Principle Component Analysis (PCA)
technique is employed for noise removal from the data. The UPDRS prediction models are constructed for PD
diagnosis. To handle the missing data, K-NN is used in the proposed method. We use incremental machine
learning approaches to improve the efficiency of the proposed method. We assess our approach on a real-world
PD dataset and the findings are assessed compared to other PD diagnosis approaches developed by machine
learning techniques. The findings revealed that the approach can improve the UPDRS prediction accuracy and
the time complexity of previous methods in handling large datasets.

1. Introduction as the PD develops (Sapir et al., 1999). PD includes non-motor symptoms

Parkinson’s Disease (PD) is a progressive neurodegenerative disorder
(Kim et al., 2020) triggered by polygenic and environmental factors
(Krohn et al., 2020). PD mostly affects people over 60 years (Razali and
Ahmad, 2011). Parkinson’s symptoms and the rate of progression vary
among individuals. PD symptoms entail muscle rigidity, delay of
movement, walking problems, tremor of the limbs, balance and coor­
dination, cognition, vocal impairment, eating and swallowing problems,
and mood disturbances (Eskidere et al., 2012; Sakar and Kursun, 2010).
Voice impairments such as dysphonia and dysarthria have been indi­
cated in approximately 90% of PD patients (Eskidere et al., 2012; Little
et al., 2008). Parkinson’s patients often experience dysphonia (Majdi­
nasab et al., 2012), which is distinguished by a breathy and harsh voice
and motor symptoms (see Fig. 1). In most cases, medical tests are not
available for definitive detection of the disease so an accurate diagnosis
can be difficult. Parkinson’s disease can impact both men and women.
The disease affects approximately 50% more men than women.
Currently, there are no laboratory tests for the diagnosis of non-genetic
causes of PD. Accurate detection depends on the neurological history of
a person with PD. While PD is not cured, some symptoms are frequently
alleviated with medications, surgical treatment, or other therapies.
Usually, Unified Parkinson’s Disease Rating Scale (UPDRS) is used to
track PD symptom progression (Eskidere et al., 2012; Nilashi et al.,
2020b, 2016; Tsanas et al., 2009). UPDRS displays the existence and
intensity of symptoms (Eskidere et al., 2012; Prashanth and Roy, 2018a)
which is widely used as a medical rating scale for PD (Disease, 2003;

* Corresponding author at: UCSI Graduate Business School, UCSI University, No. 1 Jalan Menara Gading, UCSI Heights, 56000 Cheras, Kuala Lumpur, Malaysia.
** Corresponding author at: Institute of Research and Development, Duy Tan University, Da Nang, Vietnam.
E-mail addresses: nilashidotnet@hotmail.com (M. Nilashi), hntha@duytan.edu.vn (H.H. Thi).

https://doi.org/10.1016/j.compbiolchem.2022.107788
Received 3 June 2022; Received in revised form 28 October 2022; Accepted 8 November 2022
Available online 10 November 2022
1476-9271/© 2022 Elsevier Ltd. All rights reserved.
M. Nilashi et al.
Eskidere et al., 2012; Nilashi et al., 2020b, 2016; Prashanth and Roy,
2018b; Tsanas et al., 2009). Both motor impairment and motor disability
are assessed by this scale.
Many research have utilized up-to-date approaches based on ma­
chine learning techniques to inspect and present insights from medical
data. Disease diagnosis using machine learning techniques has been a
center of interest of researchers in both medical and artificial intelli­
gence fields. Machine learning algorithms are being utilized widely for
disease detection in the healthcare sector (Arji et al., 2019; Kishore et al.,
2020; Nilashi et al., 2018b; Senturk, 2020; Sharma et al., 2020). These
algorithms have been found to be effective in PD diagnosis through a set
of real-world datasets. While these techniques have provided robust
outcomes to inspect different data sets in the context of PD (Ferreira
et al., 2022; Valla et al., 2022), the majority of research has utilized
supervised approaches that do not utilize incremental learning ap­
proaches. In fact, both accuracy and real-time prediction are important
criteria that must be considered in the development of disease diagnosis
systems. Incremental learning can help avoid the re-computation pro­
cess to develop prediction models. The re-computation process can
impact the prediction time of the model. Incremental learning enables
fast computation of the data (Guo et al., 2014). It can overcome
large-scale problems. In contrary to conventional approaches, it presents
promising outcomes in real applications (Li et al., 2021). Based on that,
it has been utilized and integrated with different approaches such as
continual algorithms (Wiwatcharakoses and Berrar, 2021), extreme
learning machines (Li et al., 2021), generative rehearsal strategy (Lee
et al., 2021), and transfer learning (Koivu et al., 2021). Still, although
incremental learning has gained the interest of researchers, the
deployment of incremental learning in disease diagnosis and prediction,
particularly PD detection, is fairly unexplored. In addition, for large
datasets, the sole use of supervised learning methods may not be an
efficient way to predict the disease as the prediction models may not be
appropriately constructed from the input and output variables of the
dataset. In fact, the use of unsupervised and incremental learning
Fig. 1. Proposed method.
2
Computational Biology and Chemistry 102 (2023) 107788
techniques can significantly reduce both processing time and memory
consumption. Hence, the use of unsupervised and incremental machine
learning techniques must be taken into account in the development of
disease diagnosis algorithms and systems.
In this research, a novel approach using deep learning and neuro-
fuzzy techniques is presented to track PD progression from a real-
world dataset. Specifically, we employ Deep Belief Network (DBN)
(Hinton, 2009) combined with Adaptive Neuro-Fuzzy Inference System
(ANFIS) (Jang, 1993) in constructing UPDRS prediction models. The
fuzzy logic proposed by (Zadeh, 1965) has been an effective approach
for modeling systems for disease diagnosis (Chen et al., 2013; Ganji and
Abadeh, 2011). The mathematical model of fuzzy logic expresses the
degree of uncertainty in terms of the distribution of possibilities (For­
oughi et al., 2023; Nilashi et al., 2020a; Yadegaridehkordi et al., 2020).
In this study, the combination of fuzzy logic with the neural network
approach (neuro-fuzzy) aims to provide an efficient way of predicting
UPDRS. In addition, the DBN can examine the data’s essential charac­
teristics in depth. It minimizes the influence of human factors and
significantly enhances neural network training outcomes. The approach
also applies Expectation-Maximization (EM) to segment the data. To
overcome the computation time issue, we develop the proposed method
for incremental learning. Through several experiments, we will
demonstrate that the use of incremental approaches is efficient for
real-time PD diagnosis. The approach is assessed using real-world PD
data and the outcomes are evaluated and compared with other PD
detection approaches.
The remainder of this work is organized as follows. In Section 2, we
provide the related work for PD diagnosis using machine learning
techniques. In Section 3, we present the proposed methodology. In
Section 4, we present the dataset for method evaluation. In Section 5, the
results of the method evaluation on the dataset are provided. Finally, we
conclude this research in Section 6. A list of abbreviations utilized in this
research is shown in Table 1.
M. Nilashi et al. Computational Biology and Chemistry 102 (2023) 107788

Table 1 tracking of the severity or progress of PD (El Maachi et al., 2020; Grover
List of abbreviations utilized in this research. et al., 2018). In Table 2, we present a summary of the approaches that
Abbreviation Description were used in PD diagnosis, classification, and tracking in previous
literature.
ANFIS Adaptive Neuro-Fuzzy Inference System
CD Contrastive Divergence In a study presented by Das (2010), a comparison between several
CML Conventional Machine Learning PD diagnosis approaches was elaborated. The method utilized in the
CNN Convolutional Neural Networks study aimed to effectively identify healthy people. Four classification
DBN Deep Belief Network patterns (NNs, Regression, DMneural, and DT) were deployed and
DL Deep Learning
DNN Deep Neural Network
comparative research was applied. Several assessment approaches were
DR Deep Ranking carried out for measuring the outcome score of the utilized patterns. The
DT Decision Tree outcome of the study highlighted that NNs presented better classifica­
ELM Extreme Learning Machines tion outcomes against the regression, DMneural, and decision tree
ET Essential Tremor
(92.9% classification accuracy). Additionally, the outcomes were
GBRM Gaussian– Restricted Boltzmann Machine
GMM Gaussian Mixture Model assessed compared to KSVM and presented encouraging outcomes.
HC Healthy Control SVM is a nonlinear pattern classification algorithm. SVM maps input
HOSVD Higher-Order Singular Value Decomposition data into a high-dimensional feature space, where it uses a nonlinear
K-NN K-Nearest Neighbour kernel function to construct an optimal discriminant hyperplane. SVM
KSVM Kernel Support Vector Machines
NMS-MRI Neuromelanin Sensitive Magnetic Resonance Imaging
was deployed in several studies in PD classification and diagnosis
LR Logistic Regression (Bhattacharya and Bhatia, 2010; Chen et al., 2013; Eskidere et al., 2012;
LSTM Long Short-Term Memory Ozcift, 2012). For example, along with DT and LR, SVM was used by
ML Machine Learning (Yadav et al., 2012) for PD detection. The outcome of the research was
MSA Multiple System Atrophy
assessed compared to other techniques. The authors concentrated on the
NNs Neural Networks
PCA Principle Component Analysis speech pronunciation complexity signs among PD-impacted individuals
PD Parkinson’s Disease and attempted to frame the model by utilizing three data mining ap­
PT Parkinsonian Tremor proaches from various perspectives. The outcomes of the deployed ap­
RBM Restricted Boltzmann Machine proaches were assessed regarding three main aspects of accuracy,
SOM Self-Organizing Map
specificity, and sensitivity. The findings of the research indicated that,
SVD Singular Value Decomposition
SVM Support Vector Machine regarding accuracy and sensitivity, SVM presented the best outcome. On
SVR Support Vector Regression the other hand, in terms of specificity, LR presented the best results.
UPDRS Unified Parkinson’s Disease Rating Scale Exarchos et al. (2012) used the DT module and association rules for
PD diagnosis. The designed approach was a portion of the PERFORM
system, which was utilized for PD controlling and therapy. In the sug­
2. Related work
gested approach, a PD patient carried out some primary assessments and
the system generated the upcoming incident of the signs depending on
Several researchers have explored PD in terms of the detection and
the primary tests and therapy. Following that, a particular therapy will
diagnosis of the disease (Camps et al., 2018; Nilashi et al., 2020b; Ortiz
be specified for the PD patient. The experts can explain the predictions
et al., 2019). Other approaches have focused primarily on the remote
by displaying the conditions. This approach was assessed using
real-world data. Furthermore, the outcomes presented an encouraging
Table 2 prediction accuracy (57.1–77.4%). As stated by the authors, the research
Previous Literature on PD Diagnosis. has one limitation concerning the lack of real-world data.
Deep Learning (DL) techniques, and specifically, CNN has presented
Method References
encouraging outcomes in many artificial intelligence applications
SVM (Bhattacharya and Bhatia, 2010; Ozcift, 2012; Eskidere et al.,
regarding its robust pattern recognition capabilities (Afonso et al., 2019;
2012; Chen et al., 2013; Behroozi and Sami, 2016; Nilashi et al.,
2018b ;Nilashi et al., 2018a;Asgari and Shafran, 2010;Yadav et al.,
Pereira et al., 2018; Shinde et al., 2019). Afonso et al. (2019) adopted
2012) CNN for modeling signals in PD diagnosis. The authors assessed the
KNN (Polat, 2012;Chen et al., 2013;Jain and Shetty, 2016;Behroozi and designed approach under multiple contexts and indicated the enhance­
Sami, 2016;Wan et al., 2018) ment in the classification accuracy compared to their proceeding
NN (Das, 2010; Afonso et al., 2019; Pereira et al., 2018; Shinde et al.,
research. Pereira et al. (2018) adopted CNN to extract the features from
2019; Eskidere et al., 2012; Babu and Suresh, 2013; Hariharan
et al., 2014; Khan et al., 2016; Buza and Varga, 2016; Al-Fatlawi handwritten dynamic photos. The researchers have also presented a
et al., 2016; Jain and Shetty, 2016; Grover et al., 2018) dataset that contains signals of PD patients and healthy individuals for
ANFIS (Nilashi et al., 2019; Polat, 2012; Nilashi et al., 2018a) the research community. Additionally, Shinde et al. (2019) developed a
Fuzzy Logic (Li et al., 2011; Polat, 2012; Chen et al., 2013) computerized technology to analyze the dataset that was collected from
K-Means (Polat, 2012)
GP (Guo et al., 2010; Khan et al., 2016; Avci and Dogantekin, 2016)
100 individuals with various conditions and used CNN to establish
EM (Guo et al., 2010; Nilashi et al., 2017a; Nilashi et al., 2019; biological indicators to classify PD patients from NMS-MRI. The result of
Hariharan et al., 2014; Nilashi et al., 2018a) the research provided an accuracy of 80% and enabled determining the
PCA (Nilashi et al., 2017a; Chen et al., 2013; Hariharan et al., 2014; most discriminative parts of the neuromelanin contrast.
Nilashi et al., 2018a)
Few researchers have adopted DBN in PD diagnosis and identifica­
Random Forest (Peterek et al., 2013)
LDA (Hariharan et al., 2014; Wan et al., 2018) tion. In a similar context to this research, Nilashi et al. (2020b) used DBN
DT (Nilashi et al., 2017a; Froelich et al., 2015; Yadav et al., 2012; and SVR to measure UPDRS. The authors utilized the
Exarchos et al., 2012) Self-Organizing-Map (SOM) technique in the clustering process to
Association (Jain and Shetty, 2016) enhance the accuracy of the outcome. The approach was assessed using
Rule
NB (Naranjo et al., 2016; Behroozi and Sami, 2016; Abdar and
a real-world dataset. Nine segments were indicated, and a DBN was
Zomorodi-Moghadam, 2018) designed for each segment. The outcomes of the DBN prediction models
Regression (Wan et al., 2018; Yadav et al., 2012) were incorporated by the SVR approach. Additionally, the findings were
Deep Learning (Grover et al., 2018; Gunduz, 2019; Wan et al., 2018; Johri and assessed compared to other approaches (SVR, Neuro-Fuzzy techniques,
Tripathi, 2019; Nilashi et al., 2020c)
and supervised learning techniques). The findings indicated that

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M. Nilashi et al. Computational Biology and Chemistry 102 (2023) 107788

integrating the clustering, DBN, and SVR presented improved UPDRS 4. Mathematical background of EM and DBN
predictions compared to other approaches.
Additionally, various approaches have been advanced for remote In the following sub-sections, we present the mathematical back­
monitoring of PD progress. Many other researchers have concentrated ground of the EM and DBN techniques used in the proposed method.
on the detection of the degree of the disease or the prediction of the
severity (Grover et al., 2018; Kim et al., 2018). Several studies have used 4.1. Gaussian mixture model (GMM)
feature extraction approaches using speak signals as input data to
determine the intensity of the disease (Asgari and Shafran, 2010; Galaz As a probabilistic method, clustering with GMM allows modeling
et al., 2016; Grover et al., 2018). For example, Grover et al. (2018) each cluster by a parametric Gaussian distribution (Bouman et al.,
designed a new approach for PD severity identification using NNs. The 1997). EM has been an effective clustering technique for different ap­
outcomes of the research presented good accuracy (81.66%) compared plications (Ambroise et al., 1997; Garriga et al., 2016; Ramirez-Rozo
to other approaches. et al., 2012).
A one-dimensional superposition of Gaussian parts represents the
3. Methodology distribution of the full data f(x) as follows:
( )
The main goal of the study is to develop a new approach for PD T ∑
− 1
1
exp − 2(x − μj ) (x − μj )
diagnosis using an ensemble learning approach with the ability of online ∑J
( ) ∑ J
j
f (X) = pj f X|μj , Ʃj = pj (1)
learning using a large clinical dataset (see Fig. 1). Basically, the Deep j=1 j=1
d
(2п)2 |Ʃj |2
1

Belief Network and Neuro-Fuzzy approaches are used to achieve the goal
( )
of the study. First, a clustering approach, Expectation-Maximization, is ∑J ∫
where j=1 pj = 1 and x f X|μj , Ʃj dx = 1.
applied to handle the large dataset. Second, Principal Component
Analysis (PCA) was used for data noise removal by solving the multi- The function f(x) is formed using J distributions, with probability
collinearity issue (Alin, 2010; Graham, 2003; Mansfield and Helms, values pj , j = 1, 2, …, J. Each value x can be mapped based on
1982) within the PD data. Third, the DBN-ANFIS prediction is per­ any of the J model distributions. The approach of maximum-likelihood
{
formed. This will accordingly increase the accuracy of the prediction of may be adopted for the calculation of missing variables, Ɵ = μj , Ʃ j ,
UPDRS in the PD data. We assess our approach on a real-world PD }
J
dataset and the findings are evaluated compared to other PD diagnosis Pj j = 1 by optimizing the log-likelihood formula referring to the
approaches developed by machine learning techniques. The proposed group of possible training inputs {Xk } NK = 1, as follows:
DBN-ANFIS is presented in Fig. 2. ( )
The proposed method entails two steps to handle the missing data ∑ ∑
N J
( )
L= log pj f X k |μj , Ʃj (2)
and perform online learning. In the case of missing data, we have k=1 j=1
considered K-NN in the proposed method. The method is further
developed for incremental learning through Incremental PCA (IPCA) EM calculations can be used to solve the problem of an inadequate
and Incremental DBN-ANFIS. Finally, if new data is available, the dataset. The need for data regarding the labels of the data used in the
method will be able to train the new data and update the previous training step raises the issue of training data samples. To calculate GMM
prediction models through incremental approaches of the techniques. parameters, the EM formula is used by following the next stages:
This procedure is provided to refine the computation time of UPDRS
prediction through the features provided in the PD dataset. 1. Determine the initial values pj (0), μj(0), Σj(0), j = 1, 2,
…J and calculate the primary log-likelihood.

Fig. 2. A general structure of DBN-ANFIS.

4
M. Nilashi et al. Computational Biology and Chemistry 102 (2023) 107788

( )
∑
N ∑
J
( ) 4.2. Rule of a DBN
L(0) = log pj(0) f Xk |μj (0), Ʃj (0) (3)
4.2.1. RBM
k=1 j=1

RBM is a stochastic Neural Network (NN) (Shao et al., 2016; Wang

and Shang, 2014). Fig. 3 presents the structure of RBM, in which dual
2. Expectation-stage: calculate
layers, a visible layer v = { vi |i = 1, 2, 3, …, n}, and an invisible layer
( ) { ⃒ }
pj (t)f xk | μj (t), Ʃj (t) h = hj ⃒j = 1, 2, 3, …, n , construct the NN. The links between the
p (j|xk , Ɵ(t) ) = j
∑
J binary nodes in both layers are confined in the RBM. Additionally, all
Pl (t)f (xk | μl (t), Ʃl (t) )
l=1 nodes in both layers are completely linked. Still, in the h layer or the v
= 1, 2, …, J, k = 1, 2, 3, …, N (4) layer, the nodes are not linked.
As an energy-based method, the energy equation of the RBM is
represented by weights and biases as follows:
3. Find the new values in the maximization stage. ∑
n ∑
m ∑
m ∑
n
E(v, h) = − wij hj vi − ai vi − bj hj (7)
1 ∑N
j=1 i=1 i=1 j=1
pj (t + 1) = p(j|xk , Ɵ(t) )
N k=1
In the v layer, vj is the visible node i, whereas, in the hidden layer h,
hj is the hidden node j. The weight among vj and hj is repre­
∑
N
xk p(j|xk , Ɵ(t) ) sented by wij . ai and bj are the bias values of the vj and the hj ,
μj (t + 1) = k=1
respectively. The equation implies that the joint distribution of vj and
∑N
p(j|xk , Ɵ(t) ) hj is described as follows:
k=1
exp( − E(v, h) )
( )( )T p(v, h) = (8)
∑
N
Z
∑ p(j|xk , Ɵ(t)) xk − μj (t + 1) xk − μj (t + 1)
k=1
(t +1) =
∑
N Z is the normalizing variable which is measured using the following
equation:
j p(j|xk , Ɵ(t))
k=1
∑∑
(5) Z= exp( − E(v, h) ) (9)
v h

In any of the h layer or the v layer, the nodes are not linked, hence,
4. Calculate the new log-likelihood values in the convergence check
the conditional probabilities of vj and hj are separated and can be
stage.
( ( )) calculated as follows:
∑
N ∑
J ∑ ( )
L(t + 1) = log pj (t + 1)f xk |μj (t + 1), (t + 1) (6) ( ⃒ ) ∑m

k=1 j=1 j p hj = 1⃒v = sigmoid wij vi + bj

i=1

( )
5. Go back to the second stage if |L(t + 1) − L(t) |〉 δ for a pre­ ∑
n
p(vi = 1|h) = sigmoid wij hj + ai (10)
defined threshold δ; else terminate. j=1

The sigmoid function is calculated using the following equation:

Sigmoid(x) = 1/(1 + exp( − x) ) (11)
To calculate the variables’ boundaries {w, a, b}, conjugate
gradient descent is particularly used to increase the logarithmic likeli­
hood of the data used to train the NN. The variables {w, a, b} can
be measured as follows:
∂lnP(v) (〈 〉 〈 〉 )
Δwij = ≈ η vi hj data − vi hj rec
∂wij

∂lnP(v) ( )
Δai = ≈ η 〈vi 〉data − 〈vi 〉rec
∂ai

∂lnP(v) (〈 〉 〈 〉 )
Δbj = ≈ η hj data − hj rec (12)
∂bj

η is the ratio of the learning process; 〈〉data indicates the anticipation of

the input data distribution; 〈〉rec is the anticipation of the reconstructed
input data distribution (Yu and Yan, 2019). Still, the expectation
〈〉rec cannot be calculated flexibly (Hinton and Salakhutdinov, 2007).
To conduct RBM training effectively, the CD formula is used to update
the variables (Hinton, 2002). The conditions for {w, a, b} can be
calculated from the following equations:
(〈 〉 〈 〉 )
Δwij ≈ η vi hj data − vi hj k

Fig. 3. Restricted Boltzmann Machine.

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M. Nilashi et al. Computational Biology and Chemistry 102 (2023) 107788

( )
Δai ≈ η 〈vi 〉data − 〈vi 〉k
σ i n+1 = σ i n + Δσ i n + mΔσi n− 1
(18)
(〈 〉 〈 〉 )
Δbj ≈ η hj data − hj k (13) RBM and GRBM differ in the method of producing the re­
constructions and the energy function.
where 〈〉k represents the allocation of samples following Gibbs sam­
4.2.3. DBN architecture
pling for stage k. In general, a single full-step Gibbs sampler uses the CD
The DBN technique is considered a probabilistic generative model
algorithm to reconstruct the data (Hinton and Salakhutdinov, 2007).
with a deep structure (Hinton et al., 2006). This technique is trained
The initial training input is partitioned into mini-groups during the
through greedy layer-wise algorithms in two main stages (Hua et al.,
implementation step. This can enhance the effectiveness of the imple­
2015), pre-training and fine-tuning (see Fig. 4). Before the training
mentation process. The update formulas of RBM variables may be rep­
stage, RBMs are trained sequentially from below to above. The v layer of
resented as:
RBM1 processes the continuous data, the CD algorithm changes the
wij n+1 = wij n + Δwij n + mΔwij n− 1
weights and biases. Weights and biases should be settled after the
training stage, and the outcome of the h layer in RBM1 will be processed
ai n+1 = ai n + Δai n + mΔai n− 1
by the v layer in RBM2. The remaining RBMs are trained similarly and
the training procedure is continued till the final RBM. This stage follows
bj n+1 = bj n + Δbj n + mΔbj n− 1
(14) the unsupervised pattern. Weights and biases are initiated following the
pre-training step of each RBM. As a supervised pattern, the back­
n is the existing training group; m expresses the momentum that is propagation (BP) technique is deployed to change all the weights to
adopted to enhance the learning rate (Hinton, 2012). enhance the resulting accuracy by utilizing the target and DBN outputs.
This process continues to reach the greatest era.
4.2.2. GRBM
Gaussian RBM can be used to present a closed-form depiction of the 5. Dataset
distribution of the training data (Fischer and Igel, 2014). Besides, GRBM
can be utilized to represent high-dimensional real-valued data. Several This research utilized a real-world data set to assess the proposed
studies have deployed GRBM in several contexts of digit recognition hybrid approach. This dataset is widely used for machine learning ap­
(Bengio, 2009) and image recognition (Hinton and Salakhutdinov, proaches developed for PD diagnosis (Eskidere et al., 2012; Nilashi et al.,
2006). In this study, the nodes in the v layer and h layer are binary and 2018b; Tsanas et al., 2009). The dataset consists of 5875 records with 16
stochastic. In GRBM, the binary value is changed through independent features and two outputs, around 200 records per patient for 28 males
Gaussian noise. GRBM algorithm of energy is expressed as: and 14 females (Tsanas et al., 2009). The features are HNR, NHR, RPDE,
∑
n ∑ ∑ ∑ DFA, PPE, MDVP:Jitter (Abs), Shimmer:DDA, MDVP:Jitter:PPQ5,
m
wij hj vi m
(vi − ai )2 n
E(v, h) = − − − bj hj (15) MDVP:Shimmer, MDVP:Jitter:RAP, Jitter:DDP, MDVP:Shimmer (dB),
σi 2σ i 2
j=1 i=1 i=1 j=1 Shimmer:APQ3, Shimmer:APQ5, Shimmer:APQ11 and MDVP:Jitter
(%). The outputs of this dataset are Total-UPDRS and Motor-UPDRS
where σi and ai are respectively the standard deviation and mean of which are aimed to be predicted by the proposed method. In Fig. 5,
Gaussian noise added to the data for inputs. Accordingly, in GRBM, the the histogram with a normal distribution fit for Motor- and Total-UPDRS
condition distributions of v and h layers are transformed to: is presented.
( )
( ⃒ ) ∑m
wij vi
p hj = 1⃒v = sigmoid + bj 6. Results
i=1
σi
( ) The method was implemented in MATLAB R2013b. The EM clus­
∑
n
p(vi = 1|h) = N σi wij hj + ai , σi 2 (16) tering was applied to PD datasets. The selection of the correct count of
j=1 clusters is critical in any clustering technique. The likelihood needs to be
optimized in the EM clustering with the Gaussian mixture model. Thus,
( )
where x indicates the real measure of the input data; N μ, σ2 in­ the best cluster number is chosen for this optimization by assessing
dicates Gaussian distribution with σ2 (variance) and μ (mean). The value different measures for the count of clusters. It is important to note that
σ 2 is considered as a training value that enables the best result of σ 2 . The we applied information theoretical criteria like the Akaike Information
update rules for {w, a, b, σ} can be expressed as: Criterion (AIC) (Akaike, 1974) to determine the optimum cluster value,
(〈 〉 〈 〉 ) according to Pelleg and Moore (Pelleg and Moore, 2000). We have
Δwij =
∂lnP(v)
≈η
vi hj
−
vi hj therefore used the re-substitution AIC estimate and have evaluated the
∂wij σi data σi k data for the optimum number of clusters. Furthermore, we used 10-fold
(〈 〉 〈 〉 ) cross-validation in the clustering process to achieve unbiased outcomes.
Δai =
∂lnP(v)
≈η
vi
−
vi Finally, the best clustering results were obtained for EM with 13 clusters,
∂ai σi 2 data σi 2 k the optimal criterion value (275755.9052) was obtained when EM
(〈 〉 generated 13 segments from PD data. The results of EM are visualized for
∂lnP(v) 〈 〉 )
Δbj = ≈ η hj data − hj k 13 clusters in Fig. 6. In this figure, the distribution of Total-UPDRS and
∂bj Motor-UPDRS in 13 clusters of EM is visualized using PC1 generated by
PCA. For ease of visualization, a part of the results for the PD features is
∂lnP(v) presented in Fig. 7 using PC1 and PC2.
Δσ i =
∂σ i We advanced supervised learning for DBN after data clustering
(〈 〉 〈 〉 )
(vi − ai )2 ∑ (vi − ai )2 ∑ through EM to forecast Total- and Motor-UPDRS. The DBN predictive
n n
wij hj vi wij hj vi
≈η − − − (17)
σi 3 j=1
σi σi 3 j=1
σi models were trained for each EM cluster. Another number of training
epochs was considered in each cluster. In each cluster, we tried 100
data k

In the same way, updating conditions for biases { a, b} and weights DBNs with several epochs ranging from 100 to 1000 and a step size of
w stay the same and the update condition for variance σ is: 100. In every DBN’s hidden layer, the number of neurons is set to 100. In

6
M. Nilashi et al. Computational Biology and Chemistry 102 (2023) 107788

Fig. 4. Architecture of DBN.

addition, in the DBN’s input layer 16 neurons were used. In ELM there PC1 = 0.777, PC2 = 0.786 and PC3 = 0.0522, the value of 31.5 is ob­
were 100 hidden layers. The data were divided into training and test tained for Motor-UPDRS. In addition, if PC1 = 0.352, PC2 = 0.663, and
data in each cluster. In an interval (0, 1), the data was first normalized PC3 = − 0.208, the value of 32.1 is obtained by Total-UPDRS. Note that
using Eq. [19]. the prediction of Motor-UPDRS and Total-UPDRS can be performed
through all PCs generated from the dataset. However, in the results, as
X − min (X)
(19) shown in Fig. 10, only 3 PCs have been considered.
′
X =
Max (X) − min(X)
Choosing the appropriate number of components for PCA is a crucial
The feature extracted by DBN in each cluster was used as the input of issue. The rule proposed by (Cattell, 1966) was used to determine the
the ANFIS model for prediction, and a hybrid method with different most important PCs in the PCA analysis. According to this rule, the
fuzzy membership functions was employed in the ANFIS network to chosen PCs in each cluster are listed in Table 3.
improve the prediction accuracy. For ANFIS, we have considered The proposed method is evaluated using two evaluation metrics,
Gaussian membership functions (Ahani et al., 2021; Kurtulus and Flipo, R2adjusted (adjusted coefficient of determination) and RMSE (Root Mean
2012; Mardani et al., 2018; Nilashi et al., 2017b, 2015). In each cluster, Square Error) as respectively shown in Eq. (20) and Eq. (21). Consid­
the DBN-ANFIS was implemented with these membership functions. For ering Pi as real outputs for Motor- and Total-UPDRS, Ak for predicted
each input, three linguistic variables (Low, Moderate, and High) were Motor- and Total-UPDRS, Pm as the mean value of predicted output and
considered (see Fig. 8). Am as actual mean value with m independent variables, RMSE and
We present the results of DBN-ANFIS in Fig. 9 for different segments.
R2adjusted are computed for N samples as follows:
To visualize the results, 3D plots in the ANFIS are generated for every
√̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅
two inputs versus the outputs of the models, Motor-UPDRS and Total- 1 ∑N
UPDRS. These plots show the behavior of the ANFIS models to predict RMSE = (Pi − Ak )2 (20)
N i=1
Motor-UPDRS and Total-UPDRS through the PD features which have
⎛ ⎞
been transformed into the PCs vectors. ∑
N
In Fig. 10, we present the prediction result of Total- and Motor- ⎜
⎜
(Ai − Am )(Pi − Pm ) ⎟(
⎟
)
N− 1
UPDRS based on 3 PCs out of 16 PCs generated by the PCA technique.
i=1
R2adjusted = 1 − ⎜
⎜1 − √̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅ √̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅
⎟
⎟ N− m− 1
These PCs are used instead of the main variables. Similar to the main ⎝ ∑ ⎠
N
(Ai − Am )2 × (Pi − Pm )2
variables, each PC includes membership functions based on three lin­ i=1
( )
guistic variables in ANFIS modelling. Based on the values of PCs the ( )2 N− 1
Motor-UPDRS and Total-UPDRS are predicted through two fuzzy rules = 1− 1− R
N− m− 1
constructed by training the ANFIS models. It is found that if (21)

7
M. Nilashi et al. Computational Biology and Chemistry 102 (2023) 107788

Fig. 5. Visualizing (a) histogram with a normal distribution fit for Total-UPDRS and Motor-UPDRS and (b) distribution of Total-UPDRS and Motor-UPDRS by PCA.

Fig. 6. Visualizing the EM clustering results for PD dataset.

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M. Nilashi et al. Computational Biology and Chemistry 102 (2023) 107788

Fig. 7. PD features in EM clusters.

Fig. 8. Membership functions used in ANFIS models.

Fig. 9. The prediction results in 3D plots in ANFIS.

The results of predicting Motor- and Total-UPDRS are presented for
two clusters of EM by DBN-ANFIS in Fig. 11. According to the results, it
is found that DBN-ANFIS has accurately predicted the Motor- and Total-
UPDRS in the clusters.
In Fig. 12, RMSE in 40 epochs for 13 clusters is displayed. In Table 4
and Table 5, we present the results of the proposed method, EM +
DBN + ANFIS, along with the other prediction methods, DBN + ANFIS,
SVR, and ANFIS. The training was performed for 100 epochs in ANFIS.
The hybrid approach was used to train the data. In this experimental
evaluation, we have selected the RBF kernel for SVR with the best C and
( )
γ values C = 23 , γ = 2− 2 obtained by an exhaustive search method.
The results are presented for RMSE and R2adjusted for each training and
test set. The results are presented for max, min, and mean values. Note
that the average values of R2 and RMSE are considered for all clusters
in these tables. In the case of Motor-UPDRS, the results demonstrate that
EM + DBN + ANFIS(RMSE = 0.537; R2 = 0.893) outperforms other
prediction machine learning techniques, DBN + ANFIS(RMSE =
( )
0.894; R2 = 0.866), DBN +SVR RMSE = 0.875; R2 = 0.886 ,
SVR(RMSE = 1.313; R2 = 0.761) and ANFIS(RMSE = 1.584; R2 =
0.702). In the case of Total-UPDRS, it is found that
EM +DBN +ANFIS(RMSE = 0.513; R2 = 0.913) provides more accu­
rate results compared to DBN + ANFIS(RMSE = 0.880; R2 = 0.880),

9
M. Nilashi et al. Computational Biology and Chemistry 102 (2023) 107788

Fig. 10. Prediction result of Motor-UPDRS and Total-UPDRS based on 3 PCs.

Table 3
Chosen PCs in each cluster.
Cluster No. PCs

PC1 PC2 PC3 PC4 PC5 PC6 PC7 PC8 PC9 PC10 PC11 PC12 PC13 PC14 PC15 PC16

Cluster 1 √ √ √ √ √ √ √ √ √
Cluster 2 √ √ √ √ √
Cluster 3 √ √ √ √ √ √ √ √
Cluster 4 √ √ √ √ √
Cluster 5 √ √ √ √ √ √ √ √
Cluster 6 √ √ √ √ √ √
Cluster 7 √ √ √ √ √ √ √
Cluster 8 √ √ √ √ √ √ √
Cluster 9 √ √ √ √ √ √ √ √
Cluster 10 √ √ √ √ √
Cluster 11 √ √ √ √ √ √ √ √
Cluster 12 √ √ √ √ √
Cluster 13 √ √ √ √ √ √ √ √ √

( )
DBN +SVR RMSE = 0.870; R2 = 0.892 and SVR(RMSE = 1.297; R2
( )
= 0.784) and ANFIS RMSE = 1.568; R2 = 0.722 . We also compare
the RMSE of the proposed method with the method proposed by (Zhao
et al., 2015). In their method, HSLSSVR, the authors evaluated the
method on the PD dataset used in this study and provided the RMSE
results for Motor-UPDRS and Total-UPDRS. It is found that the RMSE
values obtained by HSLSSVR are respectively 0.8158 and 0.8004 for
Motor-UPDRS and Total-UPDRS which is higher than the RMSE values
of our method.
We also extended our data analysis in terms of the computation time

10
M. Nilashi et al.
Fig. 11. Motor- and Total-UPDRS prediction results in two clusters.
of the methods. We tried to compare the computation time of the in­
cremental learning technique with the non-incremental technique. The
incremental EM+DBN+ANFIS is compared with the non-incremental
EM+DBN+ANFIS, DBN+SVR and DBN+ANFIS on the same dataset.
The results are presented in Fig. 13. The plots are provided as a function
of the incremental data ratio for computation time. It is found that the
incremental EM+DBN+ANFIS method has been effective in minimizing
the computation time concerning the non-incremental
EM+DBN+ANFIS, DBN+SVR and DBN+ANFIS methods. The plots in
Fig. 13 for both incremental and non-incremental approaches show that
the increase of data has less impact on the computation time of the in­
cremental approach. This is because the method which can learn online
from the available data does not need to rerun the model for whole data.
In fact, the incremental approach can update the previous prediction
model with newly added data.
7. Conclusion
Machine learning has been effectively utilized in the diagnosis of PD.
Accurate prediction of UPDRS is important in the diagnosis of PD.
Multiple researchers have concentrated on the development of algo­
rithms to accurately predict the scales of UPDRS, Total-UPDRS, and
Motor-UPDRS. In this research, we proposed a novel approach through
11
Computational Biology and Chemistry 102 (2023) 107788
machine learning techniques for UPDRS prediction. The method was
developed using Expectation-Maximization (EM), Deep Learning (DL),
and ANFIS techniques. DBN was used to predict UPDRS from the clusters
discovered by EM. The method was assessed using real-world PD input
data and the outcomes were evaluated and compared with previous PD
diagnosis approaches. It was found that this approach was effective in
improving the accuracy of UPDRS prediction as well as the time
complexity compared to previous approaches that utilize huge input
data. The use of the clustering technique was effective in the improve­
ment of the computation time with the aid of an incremental approach.
In addition, incorporating the DBN and ANFIS led to accurate prediction
of UPDRS concerning the other approaches, SVR and ANFIS, measured
by the RMSE and adjusted coefficient of determination metrics. The
method proposed in this research has proved to be effective in accurate
UPDRS prediction. However, it is recommended that future studies
should further investigate the use of deep learning and clustering tech­
niques for PD diagnosis approaches. In addition, as the majority of
previous works have focused on non-incremental approaches, the
development of online learning approaches is valuable to be investi­
gated on the large PD datasets. Accordingly, in a future study on PD
diagnosis, we aim to refine the accuracy and computation time of the
method through optimization and incremental deep learning techniques
for large datasets.
M. Nilashi et al. Computational Biology and Chemistry 102 (2023) 107788

Fig. 12. RMSE in 40 epochs for 13 clusters.

Table 4
Motor-UPDRS and R2 and RMSE results.
Metrics EM+DBN+ANFIS Method DBN+ANFIS Method SVR Method ANFIS Method DBN+SVR Method

Train Test Train Test Train Test Train Test Train Test

RMSE Max 0.520 0.544 0.875 0.905 1.243 1.368 1.654 1.731 0.862 0.891
Min 0.512 0.520 0.872 0.882 1.136 1.259 1.356 1.438 0.850 0.859
Mean 0.516 0.537 0.871 0.894 0.932 1.313 1.505 1.584 0.856 0.875
R2adjusted Max 0.931 0.914 0.897 0.875 0.881 0.792 0.811 0.765 0.913 0.898
Min 0.907 0.879 0.869 0.853 0.805 0.731 0.665 0.639 0.891 0.875
Mean 0.922 0.893 0.877 0.866 0.843 0.761 0.738 0.702 0.902 0.886

Table 5
Total-UPDRS and R2 and RMSE results.
Metrics EM+DBN+ANFIS Method DBN+ANFIS Method SVR Method ANFIS Method DBN+SVR Method

Train Test Train Test Train Test Train Test Train Test

RMSE Max 0.512 0.521 0.874 0.886 1.229 1.353 1.641 1.715 0.864 0.869
Min 0.495 0.512 0.865 0.876 1.121 1.241 1.341 1.421 0.862 0.871
Mean 0.506 0.513 0.866 0.880 1.175 1.297 1.491 1.568 0.863 0.870
R2adjusted Max 0.943 0.928 0.915 0.897 0.889 0.815 0.834 0.785 0.921 0.912
Min 0.925 0.894 0.891 0.861 0.827 0.753 0.687 0.659 0.909 0.872
Mean 0.937 0.913 0.909 0.880 0.858 0.784 0.761 0.722 0.915 0.892

CRediT authorship contribution statement
Mehrbakhsh Nilashi: Supervision, Conceptualization, Methodol­
ogy, Investigation, Software, Data curation, Formal analysis, Writing –
original draft, Writing – review & editing, Validation. Rabab Ali Abu­
malloh: Conceptualization, Methodology, Investigation, Software, Data
curation, Formal analysis, Writing – original draft, Writing – review &
editing, Validation. Salma Yasmin Mohd Yusuf: Investigation, Writing
– original draft, Writing – review & editing, Validation. Ha Hang Thi:
Conceptualization, Writing – review & editing, Validation. Mohammad
Alsulami: Investigation, Writing – review & editing, Visualization.
Hamad Abosaq: Investigation, Writing – review & editing, Visualiza­
tion. Sultan Alyami: Investigation, Writing – review & editing, Visu­
alization. Abdullah Alghamdi: Investigation, Writing – review &
editing, Visualization.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.

12
M. Nilashi et al.
Fig. 13. Computation time for incremental and non-incremental approaches.
Data Availability
Data will be made available on request.
Acknowledgements
The authors are thankful to the Deanship of Scientific Research at
Najran University for funding this work under the Research Collabora­
tion Funding program grant code NU/RC/SERC/11/13.
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