Artificial Intelligence In Medicine 103 (2020) 101807

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Artificial Intelligence In Medicine

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Prognostic factors of Rapid symptoms progression in patients with newly T

diagnosed parkinson’s disease
Kostas M. Tsiourisa,b, Spiros Konitsiotisc, Dimitrios D. Koutsourisa, Dimitrios I. Fotiadisb,d,*
a
Biomedical Engineering Laboratory, School of Electrical and Computer Engineering, National Technical University of Athens, GR15773, Athens, Greece
b
Unit of Medical Technology and Intelligent Information Systems, Dept. of Material Science and Engineering, University of Ioannina, GR45110, Ioannina, Greece
c
Dept. of Neurology, Medical School, University of Ioannina, GR45110, Ioannina, Greece
d
Dept. of Biomedical Research, Institute of Molecular Biology and Biotechnology, FORTH, GR45110, Ioannina, Greece

ARTICLE INFO ABSTRACT

Keywords: Tracking symptoms progression in the early stages of Parkinson’s disease (PD) is a laborious endeavor as the
Parkinson’s disease disease can be expressed with vastly different phenotypes, forcing clinicians to follow a multi-parametric ap-
Rapid progression proach in patient evaluation, looking for not only motor symptomatology but also non-motor complications,
Prognostic factors including cognitive decline, sleep problems and mood disturbances. Being neurodegenerative in nature, PD is
Machine learning
expected to inflict a continuous degradation in patients’ condition over time. The rate of symptoms progression,
however, is found to be even more chaotic than the vastly different phenotypes that can be expressed in the
initial stages of PD. In this work, an analysis of baseline PD characteristics is performed using machine learning
techniques, to identify prognostic factors for early rapid progression of PD symptoms. Using open data from the
Parkinson’s Progression Markers Initiative (PPMI) study, an extensive set of baseline patient evaluation out-
comes is examined to isolate determinants of rapid progression within the first two and four years of PD. The rate
of symptoms progression is estimated by tracking the change of the Movement Disorder Society-Unified
Parkinson's Disease Rating Scale (MDS‐UPDRS) total score over the corresponding follow-up period. Patients are
ranked according to their progression rates and those who expressed the highest rates of MDS-UPDRS total score
increase per year of follow-up period are assigned into the rapid progression class, using 5- and 10-quantiles
partition. Classification performance against the rapid progression class was evaluated in a per quantile partition
analysis scheme and in quantile-independent approach, respectively. The results shown a more accurate patient
discrimination with quantile partitioning, however, a much more compact subset of baseline factors is extracted
in the latter, making a more suitable for actual interventions in practice. Classification accuracy improved in all
cases when using the longer 4-year follow-up period to estimate PD progression, suggesting that a prolonged
patient evaluation can provide better outcomes in identifying rapid progression phenotype. Non-motor symp-
toms are found to be the main determinants of rapid symptoms progression in both follow-up periods, with
autonomic dysfunction, mood impairment, anxiety, REM sleep behavior disorders, cognitive decline and
memory impairment being alarming signs at baseline evaluation, along with rigidity symptoms, certain la-
boratory blood test results and genetic mutations.

1. Introduction
Parkinson’s disease (PD) is the second most common neurological
disorder affecting an estimated 0.3 % of the global population [1].
Population-based studies have shown that the prevalence of PD in-
creases significantly with age as disease diagnosis is rare in individuals
below 50 years old, while the number of patients per 100,000 people
doubles for each age decade above 60 years old, with males being
slightly more prone. Some geographical variations have also been found
with the prevalence of PD being highest in South America and sig-
nificantly lower in Asia with prevalence in populations from Europe,
North America and Australia in between [2]. Although the neurophy-
siology of molecular pathways and pathological consequences of the
disease have been studied at neuron-level scale as well as wider brain
connectivity networks [3–5], the exact causes leading to PD remain
elusive. On a genetic level, the list of gene mutations associated with PD

⁎
Corresponding author at: Unit of Medical Technology and Intelligent Information Systems, Dept. of Materials Science and Engineering, University Campus of
Ioannina, GR 45110, Ioannina, Greece.
E-mail address: fotiadis@cc.uoi.gr (D.I. Fotiadis).

https://doi.org/10.1016/j.artmed.2020.101807
Received 26 February 2019; Received in revised form 7 January 2020; Accepted 13 January 2020
0933-3657/ © 2020 Elsevier B.V. All rights reserved.

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K.M. Tsiouris, et al.
continues to grow in size suggesting the existence of a partially inherent
etiology [6,7], while environmental and lifestyle conditions have also
been suggested as potential risk factors for PD diagnosis as well [8].
PD is predominately characterized as a movement disorder due to
its motor clinical symptomatology, leading to disabilities as motor
symptoms spread from the initial onset location and progress in se-
verity. Motor symptoms are caused by the brain’s inability to adjust the
levels of dopamine production and release, a neurotransmitter that is
crucial in between neurons communication and movement control, due
to the impairment of dopaminergic neurons [9]. However, the non-
motor symptomatology of the disease has equally important compli-
cations in patient’s condition, with recent studies showing that PD pa-
tients have increased risk of experiencing cognitive decline, dementia,
sleep disorders, depression and psychosis [10–12]. This great variation
in PD symptoms expression can be seen in almost every aspect of pa-
tient’s condition, from distinctive tremor-dominant and gait dis-
turbances-dominant motor symptoms patient groups [13], to cognitive
impairment versus non-impaired and presence of sleep disorders versus
non-sleep disturbances groups in the non-motor symptoms front [14].
To make matters worse, previous studies have shown that these dif-
ferences in PD phenotype can affect significantly the overall disease
progression rate [15,16].
A phenotype that is also caused by the heterogeneous nature of PD
and is not so often studied is that of atypical rapid disease progression.
In general, progression of PD can vary significantly from patient to
patient, with differences in motor symptoms progression in particular
being among the most notable in clinical environment. However, since
there is not official guideline regarding what should be considered as
(atypically) rapid progression of PD [17], the term is used rather va-
guely and usually describes qualitative changes in patient’s condition
when reaching certain milestones of the typical PD progression
pathway prematurely. Leaving definition difficulties aside, early rapid
progression risk stratification is an important unmet need in the initial
post-diagnosis PD patient evaluation, as it can have a positive impact in
multiple levels by: (a) alerting physicians to follow a more precise
disease management plan, as these patients would require increased
attention to copy with the aggressive phenotype of their condition, (b)
improving the screening process for inclusion of PD patients in clinical
studies, in order to evaluate their clinical outcomes under more chal-
lenging disease conditions. For example, the expected impact of a new
treatment can be better validated in a medication-placebo group trial if
the enlisted patients have a natural predisposition in developing a se-
vere symptomatology faster, in time, for the relatively limited duration
of the study.
In the research for prognostic factors, most of the previous studies
relied on univariate and, to a lesser extent, multivariate statistical
analysis in their search for baseline determinants of rapid progression in
PD [18–21]. Data mining and machine learning algorithms are viable
alternatives to statistical analysis, as they can perform multi-parametric
evaluations of a wide range of features and symptoms to discover
hidden dependencies among them, offering a significant advantage over
univariate statistical analysis. However, machine learning has not
gained too much attention in this field and only recently such methods
are starting to emerge in PD progression analysis, partially because of
increasing data availability, as big cohort studies such as PPMI are now
providing access to large-scale, longitudinal data with clinical evalua-
tions over several years [22]. In the era prior to such initiatives open
datasets were scarce, limiting independent research and even most
private cohorts consisted of about a couple of hundred patients [23],
which restricted the use of machine learning techniques, as data volume
is key to increase the robustness of the analysis and its outcomes.
In this study, a machine learning-based methodology is proposed to
isolate baseline features that are indicative of early rapid progression in
PD. The change in the total score of the Movement Disorder
Society‐sponsored revision of the Unified Parkinson's Disease Rating
Scale (MDS‐UPDRS) [24] is used to track progression of PD in a cohort
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Artificial Intelligence In Medicine 103 (2020) 101807
of newly diagnosed patients from the PPMI dataset. Patients are split
into groups according to their progression rate using quantiles parti-
tion, with the ones experiencing the fastest progression within the
follow-up period, considered as the rapid progression class. An ex-
tensive search is then performed in the available feature space, using
every baseline evaluation outcome from the PPMI dataset (i.e. clinical,
imaging and laboratory examinations), to identify the most informative
baseline features in relation to symptoms progression. To the best of our
knowledge, this is the first time that such an extensive baseline feature
vector is used in a machine learning-based analysis to detect potential
prognostic factors of rapid PD symptoms progression and eminent
functional decline in newly diagnosed patients. In addition, prognostic
factors are evaluated in two different timelines, assessing PD progres-
sion at the 2- and 4-year follow-up interval independently.
2. Markers of disease progression
With official guidelines lacking, one of the most debatable aspects in
the evaluation of PD progression is the core definition of the disease
progression marker itself: How do we accurately track and measure
progression in PD? According to the literature, there is no definitive
answer due to the complexity of the disease and its wide range of
phenotypes with vastly different symptomatology. A wide variety of
potential disease progression markers have been studied in the past,
including blood, serum and urine analysis, cerebrospinal fluid (CSF)
analysis, brain imaging (i.e. MRI, SPECT, DaTscans), clinical outcomes
and neurophysiological biomarkers. However, a systematic revision of
such studies by McGhee et al. concluded that they were generally of
poor quality, with small numbers of participants, excessive inclusion/
exclusion criteria and potentially flawed methodologies with simplistic
statistical analysis being conducted; even in longitudinal ones. Based on
their search, the authors suggested that currently there is not sufficient
evidence and cross-study agreement in the literature to recommend the
use of any biomarker to effectively track progression of PD [25].
Using clinical evaluations, PD progression can be estimated in a
qualitative or quantitative manner. A qualitative approach relies on
tracking the time required for each patient to reach major milestones in
the disease progression pathway in search for atypically early onset. For
example, changing stages in the Hoehn and Yahr scale [26] has been
proposed as a viable way to track such important milestones to pro-
gression of PD symptoms and disability in [27], while PD patients have
been considered as rapidly progressed when a lower than expected time
interval is required to reach stages 3 and above in the scale, as these
stages declare severe functional disability [28]. A downside of this
approach is that the scale is mostly dependent on symptom locality to
track PD progression as they expand from lateral to bilateral and axial
and does not consider symptom severity per stage. In addition, quali-
tative analyses are rather a condition-based triggered assignment of PD
patients as rapidly progressed cases and do not provide a way to
quantify or measure the rate of progression over any time interval (e.g.
progression per month/year/visit).
Therefore, to obtain a more accurate estimation of PD progression
rate quantitative progression analysis have been proposed instead. In
quantitative approaches, the MDS-UPDRS is the most frequently used
scale to evaluate progression of functional decline and disability due to
PD symptoms, as it is currently considered the golden standard for
motor symptoms evaluation and their effects in patient’s daily living in
both motor and non-motor experiences [29–31]. Despite being pre-
dominately skewed towards motor symptoms evaluation, the first parts
of the scale evaluate a wide variety of non-motor aspects of PD, in-
cluding mental cognition decline, psychosis, depression, sleep problems
and daytime sleepiness, etc., making the MDS-UPDRS the most multi-
parametric PD evaluation scale. The non-motor symptoms evaluation
parts of MDS-UPDRS may lack the level of detail found on other scales
targeting non-motor aspects specifically (e.g. MoCA, RBD, SCOPA,
STAI) to be able to provide an equally comprehensive non-motor
K.M. Tsiouris, et al.
Fig. 1. Schematic representation of the proposed methodology for the identification of prognostic factors for rapid PD progression at baseline evaluation.
symptoms assessment, but the total MDS-UPDRS score was able to
outperform these scales and other biological markers, by showing lower
variance in discriminating disease severity in the early stages of PD in a
recent study estimating evolution trajectories using data from the PPMI
dataset [21]. In addition, the motor evaluation part of the scale was
found to have a strong correlation with neuronal loss in the substantia
nigra, with neuronal density decreasing linearly with every point of
increased total MDS-UPDRS part III score [32]. Thus, despite having far
from perfect balance between motor and non-motor symptoms, MDS-
UPDRS is nonetheless as best it can get when considering the range of
PD symptoms that are covered in a single evaluation scale.
A potential downfall of using the MDS-UPDRS scale for quantitative
measuring of PD progression is not accounting for the effects of in-
itiating symptomatic therapy [33]. Observed symptoms are expected to
reduce in severity interfering with an accurate representation of the
true rate of PD progression. A solution is to estimate a function that
describes the bounded benefit of symptomatic treatment and adjust the
rater’s scoring values. However, as depicted in a recent review of such
models with medication-adjusted estimations of MDS-UPDRS scores,
these models were empirically developed, lacking mechanistic ap-
proaches to consider systems biology and pharmacology modeling [34].
Thus, despite being promising, there is not enough evidence and clin-
ical trials to validate these findings. Regardless, in our case study this is
less of an issue since patients who continue to experience a severe
downfall in their observed symptomatology despite medication treat-
ment consist the targeted PD population of our analysis. Considering
the high standards in patient management under the supervision of the
PPMI study protocols, patients ranking continuously higher MDS-
UPDRS scores during the study can be confidently considered as cases
of rapid PD progression. Furthermore, to minimize the confounding
effects of dopaminergic medication, the analysis of the motor MDS-
UPDRS part III in this study is restricted to scores recorded only in the
OFF state, with a minimum of 6 h between the last dose and the MDS-
UPDRS evaluation.
3. Materials and methods
3.1. PPMI dataset
The Parkinson’s Progression Markers Initiative (PPMI) is a pro-
spective observational, multi-center study with 34 clinical partners
around the world, aiming to develop the largest collection of open data,
providing longitudinal evaluations of PD patients with clinical evalua-
tions, imaging results and biologic specimens. The PPMI cohort aimed
to promote independent research in identifying potential markers of PD
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Artificial Intelligence In Medicine 103 (2020) 101807
progression, in order to expand our understanding regarding the evo-
lution of PD symptoms in the early stages of the disease. The study is
still ongoing, collecting data according to the initial follow-up visits
schedule, with plans to extend patient evaluation with annual visits
until 2023, in an attempt to offer long-term evaluation outcomes with
observational data from subjects monitored for 5–13 years (depending
on the cohort). In this study we focus on the De Novo cohort as it is the
only one tracking the progression of PD in newly diagnosed and un-
treated patients. This cohort includes 423 patients (i.e. 65.5 % males
and 34.5 % females), with a mean age of 61.6 years (i.e. 34–85 years
old) at baseline evaluation, with an average total UPDRS score of
32.35 ± 13.14 points. Resting tremor was present at diagnosis in 331
patients (i.e. 78.25 %), rigidity in 320 patients (i.e. 75.65 %), brady-
kinesia in 348 patients (i.e. 82.27 %) and postural instability in 29
patients (i.e. 6.86 %). Patient monitoring included four follow-up visits
in the first year after enrolment (i.e. in the 3rd, 6th, 9th and 12th
month), followed by two annual visits in six months intervals for every
year of follow-up afterwards.
3.2. Rapid PD progression and early functional decline
An outline of the proposed methodology for identifying prognostic
factors of rapid symptoms progression in patients with PD using ma-
chine learning algorithms is shown in Fig. 1. The proposed metho-
dology consists of four primary modules: (a) extraction of the baseline
features for each patient, (b) estimation of the progression rate based on
the change of the total MDS-UPDRS score, (c) patient segregation in
quantiles according to progression rate (i.e. 5-quantiles and 10-quan-
tiles, respectively) with the patients in the top upper quantile reporting
the most rapid progression, and (d) an extensive search in the baseline
feature space to isolate the features that can most accurately dis-
criminate the rapid progression class of patients from the rest; who have
reported slower progression rates. Each module is presented in more
detail in the following subsections.
3.2.1. Baseline feature extraction
A wide range of baseline features are included in this study, by
gathering every patient evaluation outcome that is available in the
Clinical Data files of the PPMI dataset, covering every aspect of PD with
motor and non-motor clinical symptoms evaluation, brain imaging re-
sults, blood/serum/CSF laboratory results, genetics, general neurolo-
gical and physical examination, etc. The extracted feature vector in-
cludes in total 601 baseline feature values for every patient in the De
Novo cohort. The complete list of the baseline features that are used in
our analysis is shown in Table 1. If a baseline feature is missing from a
K.M. Tsiouris, et al. Artificial Intelligence In Medicine 103 (2020) 101807

Table 1
The complete list of the baseline features that are available in the PPMI clinical dataset.
Group of features Evaluation scales/Clinical examinations/Imaging/Laboratory results at baseline Number of features

Neurological Exams Cranial Nerves 9

General neurological exam 18

Physical Exams General physical exam 11

Vital signs 10

General patient information Demographics 14

Family history 25

Socio-Economics 2

MRI/DatScan – SPECT Imaging DatScan – SPECT results 5

Brain Region 4

MRI results 5

Lab Exams Blood Chemistry and Hematology 44

Biomarker analysis 55

Biospecimen analysis results 4

Motor symptoms MDS-UPDRS part II 14

MDS-UPDRS part III 37

MDS-UPDRS total score 1

Modified Schwab and England ADL 1

PASE Household Activity 9

Genetics SNCA multiplication and Genetic Risk Score 2

NeuroX Genotyping Selected SNPs 33

Non-motor symptoms MDS-UPDRS part I 15

MDS-UPDRS part I total score 1

Benton Judgment of Line Orientation 35

Cognitive Categorization 5

Epworth Sleepiness Scale, ESS 10

Geriatric Depression Scale (short), GDS 17

Hopkins Verbal Learning Test, HVLT 14

Letter-Number Sequencing, LNS 24

Montreal Cognitive Assessment, MoCA 35

Questionnaire for Impulsive-Compulsive disorders, QUIP 14

REM Sleep Behavior Disorder Questionnaire, RBDSQ 23

Scale for Outcomes in Parkinson’s disease for Autonomic Symptoms, SCOPA-AUT 39

Lexical and Semantic Fluency 6

State-Trait Anxiety Inventory, STAI 43

Symbol Digit Modalities, SDM 5

University of Pennsylvania Smell ID Test, UPSIT 5

PD features Symptoms present at diagnosis 7

Total: 601

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K.M. Tsiouris, et al.
patient’s record, the respective screening value for that particular fea-
ture is obtained instead (if available) in order to minimize missing
values, as the two visits are about one month apart. In addition, some
evaluations were solely performed during the screening visit, so their
corresponding features are recovered from the screening visit instead of
the baseline as well.
3.2.2. PD progression rate estimation
Progression of PD is estimated using the total score of the MDS-
UPDRS. However, since the patients in the De Novo PPMI cohort were
newly diagnosed and had to be medication-free in order to be eligible
for participation in the study, the vast majority did not developed motor
fluctuations and therefore part IV was not assessed and, thus, these
values are not reported in the respective files. Consequently, part IV of
the MDS-UPDRS is not used in the estimation of the total score for each
visit and the progression rate is estimated using the respective values of
parts I-III (i.e. Part I: Non-Motor Aspects of Experiences of Daily Living,
Part II: Motor Aspects of Experiences of Daily Living and Part III: Motor
Examination). As it was mentioned in Section 2, if there are both “ON”
and “OFF” evaluations of the MDS-UPDRS motor examination part III,
the results from the evaluation at “OFF” state are used in the estimation
of the total score, to minimize the effect of medication on the observed
symptoms severity. For clarity, we denote the total MDS-UPDRS score
used in this study as total MDS-UPDRS parts I-III score in the rest of the
manuscript.
The total MDS-UPDRS parts I-III score is extracted from the PPMI
records of each patient for the baseline and the subsequent follow-up
evaluations up to four years later (i.e. months 3, 6, 9, 12, 18, 24, 30, 36,
42 and 48). Then, depending on the duration of the follow-up evalua-
tion period (i.e. 2 or 4 years), a 2-D data points matrix is formed con-
taining the discrete visit time intervals and the respective value of the
total MDS-UPDRS parts I-III score for each visit. The baseline score is
also included as the starting point in the estimation of the progression
rate, resulting in 7 and 11 discrete evaluation visits for the 2 and 4 year
follow-up periods, respectively. A simple polynomial curve fitting
model is then used to extract a function that best describes the pro-
gression of total MDS-UPDRS parts I-III score per visit with a linear
polynomial, as follows:
y = ax + b.
The curve fitting model proposes a solution for a , b that best fits the 2-D
data matrix by minimizing the sum of squared deviation (least-squares
fitting) using a recursive analysis:
y1 x1 1
y2 a x2 1
= ,
b early withdraw. The rapid progression classes within the same follow-
yn xn 1
where a is the slope, b is the y-intercept, x1,2, ..., n is the time interval of
baseline and follow-up visits in months, and y1,2, ..., n is the total MDS-
UPDRS parts I-III score per visit.
In order to estimate their PD progression rate, patients need to have
a total MDS-UPDRS parts I-III score available for their baseline or
screening visit, the last visit of the follow up period (i.e. at month 24 or
48 for the 2-year and 4-year follow-up, respectively) and at least one
evaluation score per year in between the baseline and the final visit.
Since no imputation for missing values is performed, patients lacking
this minimum number of MDS-UPDRS evaluation scores were excluded,
reducing the number of available patients to 358 for the 2-year follow-
up period and 212 for the 4-year follow-up period, respectively. The
more simplistic linear progression fitting model was selected to cope
with the restricted time resolution in follow-up visits and the presence
of missing values, as it can provide an accurate-enough estimation of
the overall trend of PD progression for each patient, and not to indicate
that a linear progression of PD symptoms is actually expressed in real
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Artificial Intelligence In Medicine 103 (2020) 101807
life. Positive linear slope values declare symptoms worsening, negative
values declare a mitigation of symptoms (e.g. due to treatment initia-
tion) and close to zero slope values denote a steady, overall, course of
symptomatology over the follow-up period, respectively.
3.2.3. Rapid progression class
Once the progression rate has been extracted for every patient in
each follow-up period, it is possible to sort and split patients into sub-
groups according to their estimated progression values. The quantiles
partition approach is used to separate patients into groups of equal size,
moving from slower progression rates at the lower end, to higher pro-
gression rates towards the top. The quantile-splitting is a viable alter-
native considering that there is no official guidelines or thresholds to
signify rapid progression. Thus, in order to avoid using empirical
thresholds, we opted to implement a 5 and 10-quantiles partition split
of the patient population for each follow-up period of 2 and 4 years. As
it is shown in Fig. 2, the upper quantile in both splits contains the pa-
tients who experienced the highest rates of symptoms progression and
they are assigned into the rapid progression class (i.e. top 20 % of cases
compared to top 10 %, respectively). The number of patients and the
mean progression rate of each quantile is shown in Fig. 2 as well.
Testing with both 5 and 10-quantiles partition will allow us to in-
vestigate the existence of a potential data-oriented threshold in defining
rapid progression, should a notable difference in the discrimination
accuracy between the two is observed.
An advantage of using quantile partition to split PD patients into
subgroups of advancing progression rates, is that it allows us to eval-
uate if there are different prognostic baseline features depending on the
estimated progression rate trend, by comparing the rapid progression
class with varying levels of slower progression rates. Thus, as it is
shown in Fig. 2, the rapid progression class (i.e. “RP class”) is evaluated
for significant differences in patients’ baseline features against each
lower quantile separately, to obtain clinical information in the type of
baseline factors depending on progression rate. In addition, the pro-
posed methodology will be also evaluated in a quantile partition-in-
dependent classification scheme, with the rapid progression class being
tested against all the remaining patients, who are assigned into a single
lower progression class (i.e. green bar in Fig. 2) for this analysis, dis-
regarding their respective variance in progression rate per quantile. It
(1) should be noted that each one of the 4 rapid progression classes across
the respective evaluation splits shown in Fig. 2 is different, as each one
consists of different patients. For example, from the 358 patients in the
2 year follow-up only 212 remain at 4 years, so not all patients who
were considered as rapidly progressed at 2 years will also progress after
4 years. Thus, it is very likely that patients have switched classes
compared to their 2 year evaluation or are completely missing due to
up period are also different due to using the 5- and 10-quantiles par-
(2)
tition to obtain the top 20 % and 10 % of most rapidly advanced pa-
tients (i.e. the top 20 % consists of the same top 10 % and another 10 %
of patients below them).
3.2.4. Baseline feature selection and classification
A preprocessing step is initially performed to remove features with
many missing values, exceeding a predefined threshold of 0.3 in rela-
tion to the total number of instances. In addition, features containing a
single unique category of values are also removed as they have no
discriminative potential with respect to the classification outcome (e.g.
all instances have “Male” as gender). Our goal is to perform a complete
evaluation analysis for potential baseline prognostic factors and, hence,
every baseline feature remaining after preprocessing is considered in
the feature selection process, in order to identify the most informative
baseline features. Feature selection allows for not only improved clas-
sification performance, but it also enhances the robustness of the clas-
sifier, since the number of available baseline features remaining is
larger than the number of available instances (i.e. curse of
K.M. Tsiouris, et al. Artificial Intelligence In Medicine 103 (2020) 101807

Fig. 2. Class partition scheme of the PPMI De Novo cohort per follow-up period, with and without quantile-specific evaluation. The values on the left of each quantile
denote the mean rate of change in MDS-UPDRS parts I-III score in points/year. N = total number of patients, n1-n10=number of patients per quantile.

dimensionality). To avoid such issues, we implemented a non-greedy,
best-first feature selection algorithm which performs an exhaustive
search in the entire feature space, to extract the most comprehensive
and compact subset of features that can still provide high classification
accuracy.
The feature selection process is schematically depicted in Fig. 3. We
initially set a starting node consisting of two different features from the
baseline feature vector Fi and Fj , with i [1,2, …, N ], j [1,2, …, N ],
i j and N denoting the total number of baseline features available.
Using only the 2 features [Fi , Fj] we evaluate their potential classifi-
cation performance by fitting the selected classification algorithm in the
training proportion of the dataset. If the fit provides both a sensitivity
and specificity above 0.5 in respect to the rapid progression class, the
feature selection process will continue by adding more features to
further improve classification performance, otherwise the starting node
is discarded and another starting node, with a different set of features
[Fi , Fj ] that has not been previously tested, is selected for evaluation
instead.
Let us denote Fk with k [1,2, …, N ] and k i j , a third feature to
be added in the initial subset of features [Fi , Fj] of a starting node that
provided sensitivity and specificity higher than 0.5. Using only the 3-
feature subset [Fi , Fj, Fk ], their potential classification performance is
evaluated again by fitting the classification algorithm in the training
data. If the fit provides an increase in classification accuracy of at least
0.01 compared to [Fi , Fj], the 3-feature subset is stored along with its
classification performance, otherwise the 3-feature subset [Fi , Fj, Fk ] is
discarded. Then, a different subset of 3 features is selected and eval-
uated by changing Fk , let us denote it as [Fi , Fj, Fk ] with
k k i j , in an iterative process, until every possible 3-feature
combination has been evaluated (i.e. N 2 iterations required in total
to evaluate all potential 3-feature subsets). In each iteration, a unique 3-
feature subset is being evaluated and it is either stored if its classifi-
cation accuracy improved that of [Fi , Fj] by at least 0.01, or discarded if
no improvement could be obtained, as described in the case of subset
[Fi , Fj, Fk ] above.
Once all iterations are completed, the stored 3-feature subsets,
which improved the classification accuracy of the starting node [Fi , Fj],
are further expanded into 4-feature subsets (i.e. [Fi , Fj, Fk, Fl] with
l [1,2, …, N ]), by adding a different fourth baseline feature (i.e.
l k i j ) into each stored 3-feature subset following a similar
iterative process as before. Each unique subset of [Fi , Fj, Fk, Fl] is
evaluated using the classification algorithm and the training data and is
either stored for further expansion into 5-feature subsets if its classifi-
cation accuracy improved that of its preceding [Fi , Fj, Fk ] subset by at
least 0.01 or discarded otherwise as before, respectively. The repetitive
process of adding extra features is eventually terminated when the

Fig. 3. Baseline feature selection and classification. Starting nodes of two features are expanded to their full potential during training. The best subset of features is
then used for the evaluation with the testing set.

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Table 2
Classification performance results for the rapid progression class at the 2-year follow-up without considering quantile
partition.

MDS-UPDRS=Movement Disorder Society‐Unified Parkinson's Disease Rating Scale, STAI=State-Trait Anxiety Inventory,
MoCA=Montreal Cognitive Assessment, GDS=Geriatric Depression Scale, RBDSQ=REM Sleep Behavior Disorder
Questionnaire, ESS=Epworth Sleepiness Scale, SDM=Symbol Digit Modalities, LNS=Letter-Number Sequencing,
rsXXXXXX=Single Nucleotide Polymorphisms (SNPs).
*p ≤ 0.05; indicate significant prognostic value at baseline.

accuracy of the last (n)-sized feature subset can no longer improve by
more than 0.01 in the following (n+1)-sized feature subsets. At this
point the initial starting node [Fi , Fj] has been evaluated to its full
potential and a new starting node is set for evaluation, using a different
set of features [Fi , Fj ] which has not been tested before. The total
number of unique combinations of 2-feature starting nodes (SNs) that
have to be fully expanded and evaluated depends on the size of the
baseline feature vector and can be estimated as:
targeted group of users consists of non-machine learning experts, such
as the medical personnel in this work. The proposed methodology was
developed in Python 3.6 using the python-weka-wrapper3 package [35],
which offers complete access to the WEKA API and its extensive toolkit
of open libraries [36], directly from within Python.
4. Results

N!
SNs = , For a more complete evaluation, two different follow-up periods are
(N 2)! (3) tested, considering the first 2 and 4 years of follow-up visits in-
dependently, and two distinct rapid progression classes per follow-up
where N is the total number of available baseline features.
period, respectively, consisting of the top 20 % and 10 % of the patients
When the search within the entire feature space is completed and all
with the fastest progression. In addition, two classification schemes are
possible SN combinations have been evaluated, the stored classification
evaluated: a) quantile partition-independent analysis in Section 4.1,
performance results from each n-feature subset are compared to find
where the rapid progression class is compared against all the remaining
the subset that provided the best classification accuracy, overall during
patients who are assigned to a single slower progression class, dis-
training. This subset will be selected for the final evaluation with the
regarding their individual progression rates, and b) a more detailed
testing proportion of the dataset. In case of identical classification
analysis between the rapid progression class and each corresponding
performance between subsets with different number of features, the
partition of patients with slower progression rates as independent
subset with the smaller number of features is selected (e.g. choose a 4-
classes in Section 4.2, in order to investigate the connection between
feature subset over a 5-feature). Finally, in case of identical classifica-
the various progression rates (i.e. from slower to faster) and the ob-
tion performance between subsets with the same feature count (e.g. two
served baseline clinical symptomatology and whether different phe-
4-feature subsets), the respective unique features are selected for
notypes are expressed. The classification performance is estimated with
testing.
RIPPER and Naïve Bayes algorithms. Statistically significant differences
Two different classifiers are selected as classification algorithms for
between the two classes were estimated for each selected baseline
evaluation, namely the Naive Bayes and the Repeated Incremental
feature using one-way ANOVA or Mann-Whitney U tests (depending on
Pruning to Produce Error Reduction (RIPPER) algorithms. Both algo-
criteria such as normal distribution, homogeneity of variances).
rithms are widely used in biomedical applications and medical data
The classification performance results for all classification experi-
analysis since they offer easier interpretation, the first in terms of
ments below are estimated using 5-fold cross-validation to minimize the
probability estimates demonstrating feature significance, the latter in
potential risk of overfitting due to the relatively low volume of samples
terms of classifications rules providing insights in decision making in
compared to the number of baseline features. Classification accuracy is
natural language (e.g. “IF (MDS-UPDRS part III score > = 19) AND
estimated as (TP + TN)/(TP + TN + FP + FN), sensitivity is estimated
(age > 67) AND (…) THEN Class = Rapid progression”). The ease of
as TP/(TP + FN) and specificity as TN/(TN + FP), where:
interpretation of the extracted results is very important since the

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Table 3
Classification performance results for the rapid progression class at the 4-year follow-up without considering quantile
partition.

MDS-UPDRS=Movement Disorder Society‐Unified Parkinson's Disease Rating Scale, STAI=State-Trait Anxiety Inventory,
SCOPA-AUT=Scale for Outcomes in Parkinson’s disease for Autonomic Symptoms, GDS=Geriatric Depression Scale,
RBDSQ=REM Sleep Behavior Disorder Questionnaire, MoCA=Montreal Cognitive Assessment, LNS=Letter-Number
Sequencing, rsXXXXX=Single Nucleotide Polymorphisms (SNPs).
*p ≤ 0.05; indicate significant prognostic value at baseline.

• True Positives (TP) denote the patients correctly classified as rapidly
progressed.
• True Negatives (TN) denote the patients correctly classified as
slower progressed.
• False Positives (FP) denote the patients incorrectly classified as ra-
pidly progressed.
• False Negatives (FN) denote the patients incorrectly classified as
slower progressed.
4.1. Evaluation without quantile partition split
In this classification scheme, the top 20 % and 10 % of the PD pa-
tients with the most rapid progression are evaluated against all the
remaining patient population in a 2-class classification output (i.e.
rapid vs slower progression class). To overcome classification perfor-
mance limitations due to the high class imbalance without excluding
any cases from the evaluation, the patients from the slower progression
class are randomly split into 4 equal subgroups for the classification
with the top 20 % of patients and into 9 equal subgroups with the top
10 %, respectively. Each subgroup is independently evaluated against
the rapid progression class and the mean value of all the respective
performance metrics (i.e. accuracy, sensitivity and specificity) that are
estimated per subgroup is reported.
The classification performance results for the 2-year follow-up
period are presented in Table 2. Restricting the number of patients in
the rapid progression class to the top 10 % of the most rapidly advanced
cases resulted in higher classification performance, with the mean
classification accuracy being 11.36 % higher using the RIPPER algo-
rithm (i.e. 82.84 % compared to 71.48 %) and 11.53 % using the Naïve
Bayes algorithm (i.e. from 84.76 % compared to 73.23 %), respectively.
The number of features selected per classification run with each random
split (i.e. features selected per subgroup) is shown in Table 2 along with
the total number of selected features from all subgroups. The results
show a slight advantage of the Naïve Bayes algorithm over RIPPER (less
than 2 %), however, it also required up to more than double the number
of baseline features to achieve this, which is not an ideal trade-off.
Thus, we opted to select the more compact feature subset of the RIPPER
algorithm as the better outcome from this evaluation and include the
selected features in Table 2 along with the corresponding p-values from
statistical analysis. The exact baseline features that were selected using
the Naïve Bayes algorithm and their respective p-values are provided in
Supplementary Table 1.
The corresponding analysis results for the 4-year follow-up period
are presented in Table 3. The increased duration of the follow-up period
resulted in a 10.32 % and 5.84 % increase in accuracy (i.e. 81.80 % and
88.68 % compared to 71.48 % and 82.84 %) for the RIPPER algorithm
compared to the 2-year follow-up period, with similar levels of increase
for the Naïve Bayes algorithm, respectively (i.e. 82.38 % and 91.12 %
compared to 73.23 % and 84.76 %). Thus, an advantage of tracking PD
progression rates over longer periods can be observed based on these
results. As in the 2-year follow-up, classification performance improved
when only the top 10 % of the most rapidly advanced cases were as-
signed to rapid progression class, with mean accuracy increasing from
81.80%–88.68 % and from 82.38%–91.12 % for the RIPPER and Naïve
Bayes algorithms, respectively. As shown by the total number of fea-
tures and the features selected per subgroup, feature selection with
Naïve Bayes is again less optimal with substantially more features re-
quired for only a slight increase in classification performance, thus, the
RIPPER algorithm is preferred and its selected features are presented in
Table 3 along with the corresponding p-values from statistical analysis.
Due to size limitations, the baseline features selected using Naïve Bayes
are provided in Supplementary Table 2 along with their respective p-
values. The small number of features selected per evaluation subgroup
in Tables 2 and 3 using RIPPER (i.e. 2–5 features) showcases the im-
portance of feature selection in minimizing the effects of overfitting.
Commonly selected features across the different classification experi-
ments in Tables 2 and 3 are highlighted for convenience. Although
perfect overlap between selected features is not expected considering

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Table 4
Classification performance results for the rapid progression class per follow-up period, using 5 and 10-quantiles partition.

Table 5
Baseline factors for rapid progression selected using RIPPER algorithm per follow-up period using 5-quantiles partition.
5-quantiles Baseline features selected
partition
100-80 % 2 years follow-up 4 years follow-up

vs 80-60 % MDS-UPDRS: Speech, rs11158026, STAI: Some unimportant thought is MDS-UPDRS: Leg agility, rs11060180, Semantic Fluency: Animal score,
bothering, Blood test: Serum chloride, Number of full siblings, STAI: STAI: Not feeling calm cool and collected, RBDSQ: Sudden limb
Worrying over possible misfortunes, GDS: Good spirits most of time, STAI: movements, STAI: Not feeling steady, rs199347, SCOPA-AUT: Feel full very
Have disturbing thoughts quickly during meal

vs 60-40 % Blood test: Serum glucose, Semantic Fluency: Total number of vegetables, SCOPA-AUT: Been impotent, STAI: Feel strained, SCOPA-AUT: Trouble
STAI: High state subscore, RBDSQ: Disturbed sleep, STAI: Some tolerating heat, Blood test: Urea nitrogen, rs11060180, LNS: Trial 4a,
unimportant thought bothering SCOPA-AUT: Pass urine again within 2 hours, Number of half siblings,
Blood test: Eosinophils, SCOPA-AUT: Saliva dribbled out of mouth

vs 40-20 % MDS-UPDRS: Anxious mood, Blood test: Total protein, MDS-UPDRS: Rest MDS-UPDRS: Urinary problems, Benton Test: Item 9, RBDSQ: Aggressive/
tremor amplitude upper extremity, Height (taller), Rigidity present at Action packed dreams, MDS-UPDRS: Toe tapping, HVLT: Immediate recall
diagnosis, Brain region: Left putamen trial 2, SCOPA-AUT: Difficulty retaining urine, rs11158026, rs115462410,
rs11724635, rs118117788, rs17649553, rs8192591

vs 20-0 % Neurological Exam: Plantar reflex, MDS-UPDRS: Toe tapping, RBDSQ:
Speaking in sleep, HVLT: Immediate recall trial 1, HVLT: Immediate recall
trial 3, rs12637471, SCOPA-AUT: Saliva dribbled out of mouth, RBDSQ:
Aggressive/Action packed dreams, rs118117788, RBDSQ: Hurt bed
partner, Semantic Fluency: Animal score, Postural Instability present at
diagnosis
MDS-UPDRS: Urinary problems, Neurological Exam: Plantar reflex,
MDS-UPDRS: Toe tapping, RBDSQ: Disturbed sleep, SCOPA-AUT: Pass
urine at night, RBDSQ: Sudden limb movements, STAI: Worry too much
over something that really doesn’t matter, rs11158026, MoCA: Delayed
recall red, LNS: Questions 1-7 score, rs14235

MDS-UPDRS=Movement Disorder Society‐Unified Parkinson's Disease Rating Scale, STAI=State-Trait Anxiety Inventory, SCOPA-AUT=Scale for Outcomes in
Parkinson’s disease for Autonomic Symptoms, GDS=Geriatric Depression Scale, RBDSQ=REM Sleep Disorder Questionnaire, HVLT=Hopkins Verbal Learning Test,
MoCA=Montreal Cognitive Assessment, LNS=Letter-Number Sequencing, Benton Test=Benton Judgment of Line Orientation, rsXXXXXX=Single Nucleotide
Polymorphisms (SNPs).

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Table 6
Baseline factors for rapid progression selected using RIPPER algorithm per follow-up period using 10-quantiles partition.
10-quantiles Baseline features selected
partition
100-90 % 2 years follow-up 4 years follow-up

vs 90-80 % MDS-UPDRS: Hygiene, MoCA: Delayed recall subscore, RBDSQ: MDS-UPDRS: Gait, STAI: Not being content, MDS-UPDRS: Total score,
Parkinsonism, Benton Test: Item 19, STAI: Feel confused, rs12637471 Number of full siblings, Side predominately affected at onset

vs 80-70 % rs11060180, rs71628662, MoCA: Delayed recall subscore, MDS-UPDRS: STAI: Some unimportant thought bothering, RBDSQ: Speaking in sleep,
Finger tapping, MDS-UPDRS: Constipation problems, Neurological Exam: RBDSQ: Aggressive/Action packed dreams, Standing blood pressure
Reflex arm systolic, Blood test: Basophils, RBDSQ: Vivid dreams, Height (taller),
Benton Test: Item 27

vs 70-60 % MDS-UPDRS: Pain and other sensations, Benton Test: Item 27, STAI: Feel Age (older), STAI: Not feeling pleasant, STAI: Worry too much over
rested, MoCA: Abstraction, MDS-UPDRS: Turning in bed, SCOPA-AUT: something that really doesn’t matter, HVLT: Derived retention total score
Difficulty retaining urine

vs 60-50 % ESS: Being sleepy, STAI: Being jittery, Age (older), Blood test: Serum
bicarbonate, MDS-UPDRS: Constipation problems, MDS-UPDRS: Eating
tasks, MDS-UPDRS: Leg agility, MDS-UPDRS: Postural tremor, MoCA:
Delayed recall face
MDS-UPDRS: Urinary problems, Semantic Fluency: Total number of
vegetables, Standing heart rate, Age (older), Supine blood pressure, Number
of half siblings, STAI: Worry too much over something that really
doesn’t matter, Depression category, QUIP: Summary score, SCOPA-AUT:
Feel full very quickly during meal, MDS-UPDRS: Rest tremor amplitude
lower extremity, rs11724635, rs12456492

vs 50-40 % Cranial Nerve VIII, Blood Test: Serum uric acid, MoCA: Language subscore,
RBDSQ: Speaking in sleep, UPSIT: Score booklet #4, STAI: Feel satisfied
about self, MDS-UPDRS: Rigidity neck, MDS-UPDRS: Facial expression,
RBDSQ: Hurt bed partner, SCOPA-AUT: Having difficulty swallowing or
choked, ESS: Fall asleep while sitting/reading, LNS: Trial 4a
SCOPA-AUT: Constipation problems, SCOPA-AUT: 1-21 score, STAI: Feel
strained, Blood test: Serum chloride, Blood test: Serum IGF-1, Blood test:
Basophils, MoCA: Verbal Fluency number of words, Brain Region: Right
putamen, HVLT: Recognition, UPSIT: Score booklet #1, Semantic
Fluency: Animal score

vs 40-30 % Blood test: Serum chloride, HVLT: Recognition, UPSIT: Score booklet #3, Blood test: ALT(SGPT), MDS-UPDRS: Urinary problems, RBDSQ:
SCOPA-AUT: 1-21 score, Blood test: Eosinophils, Identify self as Asian/ Aggressive/Action packed dreams, MoCA: Attention serial 7 sec, Number
Black-African American/Indian/Alaska Native of full siblings

vs 30-20 % MDS-UPDRS: Hand movements, HVLT: Immediate recall trial 1, RBDSQ: MDS-UPDRS: Rigidity upper extremity, RBDSQ: Have aggressive/action
Depression, MDS-UPDRS: Constipation problems, LNS: Derived scaled packed dreams, STAI: Not feeling satisfied, STAI: Not feeling at ease
score, Biological father with PD

vs 20-10 % MDS-UPDRS: Eating tasks, MoCA: Total score, RBDSQ: Summary score, GDS: Being afraid of something bad happening, Number of paternal aunts/
Number of children, STAI: Not feeling satisfied, SCOPA-AUT: 24-25 score uncles, STAI: Worry too much over something that really doesn’t matter,
MDS-UPDRS: Rigidity lower extremity, Height (taller)

vs 10-0 % MDS-UPDRS: Eating tasks, RBDSQ: Speaking in sleep, SCOPA-AUT: 22-23 MDS-UPDRS: Body bradykinesia, Benton Test: Item 1, STAI: Not Feeling
score, MDS-UPDRS: Toe tapping, MDS-UPDRS: Leg agility, UPSIT: Score pleasant, STAI: Not being content
booklet #1, Blood test: Basophils, MoCA: Delayed recall subscore

*MDS-UPDRS=Movement Disorder Society‐Unified Parkinson's Disease Rating Scale, STAI=State-Trait Anxiety Inventory, SCOPA-AUT=Scale for Outcomes in
Parkinson’s disease for Autonomic Symptoms, GDS=Geriatric Depression Scale, RBDSQ=REM Sleep Disorder Questionnaire, HVLT=Hopkins Verbal Learning Test,
MoCA=Montreal Cognitive Assessment, UPSIT=University of Pennsylvania Smell ID Test, LNS=Letter-Number Sequencing, Benton Test=Benton Judgment of Line
Orientation, ESS=Epworth Sleepiness Scale, QUIP=Questionnaire for Impulsive-Compulsive disorders, rsXXXXXX=Single Nucleotide Polymorphisms (SNPs).

that the classes across the four evaluation experiments are different, the
majority of the selected baseline features are repeatedly found between
the evaluation experiments in Tables 2 and 3, while the contextual si-
milarities of others that do not overlap makes them practically identical
(e.g. “STAI: Worry too much over something that really does not matter”
and “STAI: Some unimportant thought bothering”, “SCOPA-AUT: Weak
urine stream in past month” and “MDS-UPDRS: Urinary problems”).
4.2. Evaluation per quantile partition split
In this classification scheme, the rapid progression class is evaluated
against the corresponding lower quantiles, which are consider as in-
dependent classes. Classification performance is estimated for both
follow-up periods, using RIPPER and Naïve Bayes algorithms as before.
The results for all classification experiments are presented in Table 4,
including the number of selected features per classification algorithm.
Regarding the effect of the follow-up period, the results show an in-
crease in classification accuracy for the RIPPER algorithm when moving
to the 4-year follow-up by 11.16 % on average (1.03–17.99 %) for the
5-quantiles and by 7.56 % on average (2.37–10.42 %) for the 10-
quantiles partition, respectively. Almost identical margins of improve-
ment are noted for Naïve Bayes as well. As expected, the 10-quantiles
partition provided higher classification performance for both algo-
rithms compare to 5-quantiles partition. The RIPPER algorithm utilizes
again a more compact subset of selected features offering similar clas-
sification performance as Naïve Bayes with fewer baseline features. In
fact, there are only two instances where Naïve Bayes required less
features (i.e. partitions 60-50 % and 50-40 %, 4-year follow-up). A
multiclass classification approach is not evaluated due to relatively high
number of individual classes, especially when considering the 10-
quantile partition split.
The most informative baseline features per classification quantile
and follow-up period for the 5-quantiles partition are presented in
Table 5. The baselines features of each quantile classification are pre-
sented in order of selection from the best-first search algorithm. The
majority of the selected baseline features come from non-motor eva-
luation outcomes including urinary and speech problems, saliva
drooling, signs of cognitive decline and memory impairment (i.e.
MoCA, LNS, Benton Test, HVLT and Lexical and Semantic fluency
scales), patient in depressed mood and with higher levels of anxiety as
captured by STAI scale, autonomic dysfunction captured with SCOPA-
AUT scale and presence of sleep disorders (i.e. RBDSQ scale). Multiple
single nucleotide polymorphisms (SNPs) are also found in the rapid
progression class along with variations in the concentration of some

10

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K.M. Tsiouris, et al.
Fig. 4. Comparison of the proposed methodology with our preliminary study
showcasing the improvement in classification performance by extending the
baseline features included in feature selection.
components found in the blood test laboratory results. Finally, motor
symptoms are substantially fewer and are primarily found to be origi-
nating from the lower extremities including agility and toe tapping,
with minor signs of postural instability at baseline. In order to retain the
size of Table 5, the results from the statistical analysis for all baseline
features selected by the RIPPER algorithm are shown in detail in Sup-
plementary Table 3. The baseline features that were selected using
Naïve Bayes are provided in Supplementary Table 5 along with their
respective p-values, respectively.
The respective baseline features per follow-up period for the 10-
quantiles partition are presented in Table 6. The results suggest again
that the majority of baseline features originate from non-motor symp-
toms, including sleep-related problems and daytime sleepiness (i.e.
RBDSQ and ESS scale), autonomic dysfunctions with urinary problems
(i.e. SCOPA-AUT, MDS-UPDRS scales), impaired cognition and memory
(i.e. MoCA, Benton test, HVLT, LNS and Lexical and Semantic Fluency
scales), depressed mood and anxiety (i.e. GDS, STAI scales) and genetic
mutations. Combined with the above, laboratory findings from blood
test analysis are also helpful. In this higher tier of most rapidly pro-
gressed patients, however, there are some features that were not pre-
viously reported using the 5-quantiles partition, including olfactory
dysfunction detected with the University of Pennsylvania smell identi-
fication test (UPSIT), age at baseline evaluation and constipation pro-
blems. Motor-oriented features are also limited in the top 10 % of pa-
tients, with the identification of symptoms at lower extremities
including leg agility and toe tapping along with signs of rigidity, pos-
tural and rest tremor at hands. Commonly selected features across
different partitions and/or classification experiments within Tables 5
and 6 are highlighted in bold for convenience. Statistical analysis is also
performed for all baseline features selected by RIPPER and the results
are shown in Supplementary Table 6 due to size limitations, while the
corresponding baseline features using the Naïve Bayes algorithm are
provided in Supplementary Table 6 along with their respective p-va-
lues.
5. Discussion
This study aimed to demonstrate a different approach in the re-
search for early prognostic factors of rapid PD progression and func-
tional decline, proposing a machine learning-based alternative in a field
that is traditionally dominated by statistical analysis and regression-
based modeling. The proposed methodology can extract baseline factors
of rapid progression by performing multi-parametric evaluations over
an extensive feature space of about 430 features (i.e. after
11
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Artificial Intelligence In Medicine 103 (2020) 101807
preprocessing), while previous studies were often limited to fewer
features and univariate feature analyses, which is not ideal considering
the heterogeneous nature of PD. The change of MDS-UPDRS score over
time was used to estimate the trend of progression rate for each patient
and two different classification schemes were evaluated over two dis-
tinct follow-up patient monitoring periods.
5.1. Rapid progression classification performance
The Naïve Bayes and RIPPER classification algorithms were tested
in this study to compare their ability to successfully extract the most
informative baseline features during training and provide accurate
patient classification when validating with the testing data. The two
algorithms provided, overall, similar levels of classification perfor-
mance during testing, with Naïve Bayes being marginally better; be-
tween 1–5 % in some cases. This slightly better classification perfor-
mance, however, came with the added drawback of requiring more
baseline features, which would frequently reach more than 2 times the
amount of features selected by RIPPER for the same classification task.
This trade-off in feature selection density was not favorable and, thus,
going with the more compact feature subsets that were extracted using
RIPPER in the vast majority of the experiments was weighted as a better
alternative.
The results of the evaluation with the De Novo cohort of the PPMI
dataset revealed an improvement when a longer follow-up period is
considered in the estimation of the progression rate. Moving from 2 to
4 years the classification accuracy increased in all cases tested, with and
without quantile partitions, suggesting a better outcome in identifying
rapid progression phenotype. As expected, judging on the rate of pro-
gression in the first couple of years is not ideal as progression can be
affected by not inherent factors such as delayed treatment initiation.
Most of these issues are gradually smoothed out over time with ap-
propriate patient management strategies, leaving a more clear depic-
tion of the patients who have an inherent predisposition for rapid
progression and usually show poor response to medication.
Performance is also affected by the number of patients assigned to the
rapid progression class, with classification results improving in both
classification schemes in Sections 4.1 and 4.2, when using only the
upper 10th quantile. The results from Tables 2 and 3 show that the
mean sensitivity of RIPPER algorithm increased by 6.17 % and 11.23 %
for both the 2- and 4-year follow-up period, respectively, when using
only the patients from upper 10-quantile in the rapid progression class.
Specificity gains show greater variance as its mean value reached a
significant 13.23 % improvement in the 2-year follow-up, while only an
increase of 2.71 % was obtained at the 4-year follow-up. In addition,
similar improvements can be noted in the results of Table 4 from the
quantile-dependent evaluation, as sensitivity and specificity increased
from 77.14 to 85.71% and 73.61-83.33%–79.41-91.18 % and 80.56-
100 % in the 2-year follow-up, and from 85.37 to 97.56% and
80.95–97.67 % to 95–100 % and 90.48–100 % in the 4-year follow-up,
respectively.
Discrimination of the rapid progression class has also improved by
considering a wider range of baseline features in the search for poten-
tial prognostic factors. Compared to our preliminary results in [37],
where a smaller subset of only 139 baseline features were used to
classify the same cohort of the De Novo PPMI patients within a 2-year
follow-up period, the total classification accuracy has increased sig-
nificantly for both 5 and 10-quantiles partitions. The reduced baseline
feature evaluation in [37] provided a lower mean classification accu-
racy of 76.6 % compared to 88.4 % in this study for the 10-quantiles
partition and 70.5 % compared to 79.54 % for the 5-quantiles partition,
respectively, while extending the follow-up period to four years pro-
vided even better results regardless the size of quantiles partition. The
classification accuracy across all cases is shown in Fig. 4. Regarding
similar methodologies in the literature using machine learning techni-
ques, Faghri et al. [38] proposed a model for rapid progression
K.M. Tsiouris, et al.
Fig. 5. ROC curves for classification performance across all evaluation experiments using RIPPER algorithm.
prognosis based on baseline features consisting of 140 clinical para-
meters to discriminate between slow, moderate and fast disease pro-
gression. Selecting 52 features as the most significant determinants, the
evaluation results with the De Novo PPMI cohort reported a 4-year
progression prognosis with an average AUC of 0.93. The proposed
methodology provided an average AUC of 0.82 and 0.87 for the top 20
% and 10 % in the quantile-independent analysis using significantly
fewer baseline features (i.e. 13 and 14, respectively). Using the 10-
quantile evaluation, the proposed methodology provided an average
AUC of 0.96 using 59 baseline features and the RIPPER algorithm in the
same 4-year follow-up evaluation period. The corresponding ROC
curves are shown in Fig. 5.
5.2. Baseline prognostic factors analysis
The majority of the baseline features selected in both classification
schemes evaluated in this study (i.e. Sections 4.1 and 4.2) consists
predominately of non-motor symptoms, including signs of autonomic
dysfunction, sleep disorders, signs of cognitive decline, memory im-
pairment, emotional disturbances with signs of depression and anxiety,
higher age at baseline evaluation and genetic risk factors due to SNPs.
Despite the wide range of the specific baseline features that are re-
ported in Tables 2–6, broader categories of alarming early symptoms
can be easily identified by aggregating the selected baseline features
according to the general class of symptoms and conditions that they are
used to evaluate patients for, as it is shown in Table 7. The contextual
similarities of the different selected baseline features in each class of
symptoms presented in Table 7, highlights the relevance of the under-
lying non-motor symptomatology even in a more abstract way. Fur-
thermore, this aggregated level of prognostic symptoms can also be
more useful in the everyday clinical environment as it easier to re-
member and look for. The prevalence of non-motor baseline symptoms
as prognostic factors is evident in Table 7 and, as shown by the detailed
evaluation results in Tables 5 and 6, is consistent and unaffected by the
different rates of progression expressed in each quantile partition. Fi-
nally, the transition from 5- to 10-quantiles partition, where fewer of
the most advanced cases are assigned into the rapid progression class,
revealed the high prognostic value of early smell dysfunction, daytime
sleepiness and advancing age for rapid progression of PD.
Our findings are in agreement with previously reported
12
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Artificial Intelligence In Medicine 103 (2020) 101807
determinants for faster progression of PD symptoms and increased
disability. Older age of patients during either the diagnosis of the dis-
ease or the baseline evaluation has been previously suggested as one of
the most valid factors for rapid progression and shorter survival time in
many studies [23,29,39–44]. Cognitive impairment at baseline eva-
luation is another feature that has been widely correlated with faster
worsening of motor function and disability in PD [29,41,42] and has
been even suggested to increase risk of mortality [44] and early de-
velopment of dementia [45]. In fact, diagnosis of dementia at baseline
evaluation is also highly indicative of faster functional decline with
patients requiring home nursing much sooner [20,39]. Then, the se-
lection of features declaring early urinary, constipation and eating
problems, signifies the commonly reported prognostic value of auto-
nomic symptoms for rapid progression phenotyping [46–48]. Further-
more, urinary, gastrointestinal, cardiovascular and thermoregulatory
dysfunction has been reported to greatly impact PD patients’ quality of
life [49,50]. Smell dysfunction is also very common in PD and the ap-
pearance of low UPSIT scale scores in the top 10 % of patients with
faster progression, shows its usefulness as a prognostic factor for rapid
progression as well [51].
REM Sleep Behavior Disorders (RBD) and excessive daytime slee-
piness have been known to impact most neurodegenerative diseases and
PD in particular [52,53]. The expression of both conditions is highly
correlated with more rapid disease progression [54–56], earlier onset
and increased severity of non-motor PD symptoms affecting patients’
quality of life [57,58]. RBD and excessive daytime sleepiness at baseline
evaluation were also reported as potential risk factors for later emo-
tional disorders, including depression and anxiety [12]. Depressed pa-
tients have also been shown to express significant decline in cognition,
memory, activities of daily living and a more rapid progression of dis-
ability by advancing faster through the Hoehn and Yahr stages
[23,59,60]. Presence of anxiety, which is commonly coexisting with
depression and other mood disturbances, is also correlated with severe
non-motor phenotypes [61,62] and more rapid progression [63,64].
Most common symptoms of anxiety include distress, worries and fear,
which are usually accompanied by social withdrawal due to the em-
barrassment of the PD symptoms expression [65]. In accordance with
the literature, symptoms of anxiety and depression are also found in-
dicative of rapid PD progression in this study.
Based on our results, neuron degeneration and brain atrophy is also
K.M. Tsiouris, et al. Artificial Intelligence In Medicine 103 (2020) 101807

Table 7
Categorization of the most prominent selected baseline features into their relevant class of symptoms and related conditions.
Broad category Class of symptoms Relevant baseline features selected

Autonomic dysfunction [46–50] Urinary problems MDS-UPDRS: Urinary problems, SCOPA-AUT: Weak urine stream, Difficulty retaining urine, Pass urine again
within 2 hours, Pass urine at night

Digestive difficulties MDS-UPDRS: Constipation problems, SCOPA-AUT: Constipation problems, Feel full very quickly during meal,
Having difficulty swallowing or choked

Other SCOPA-AUT: 1–21 score, Saliva dribbled out of mouth

Sleep Problems [12,54–58] REM sleep RBDSQ: Move arms/legs during sleep, Sudden limb movements, Aggressive/Action packed dreams, Speaking
in sleep, Hurt bed partner, Disturbed sleep

Daytime Sleepiness ESS: Fall asleep while watching TV, Fall asleep while sitting/reading, Being sleepy

Cognitive dysfunction [29,39,41–45] Cognitive impairment Semantic Fluency: Animal score, Total number of vegetables, MoCA: Verbal fluency, Visuospatial/Executive
subscore, Language subscore, Total score, LNS: 5a/5c/4a, Derived scaled score, Benton Test: Multiple items

Memory problems MoCA: Delayed recall subscore, HVLT: Immediate recall, Recognition, GDS: More memory problems than
most

Emotional disorders [23,59–64] Mood impairment GDS: Feel situation is hopeless, Being afraid of something bad happening, Depression category, RBDSQ:
Depression, MDS-UPDRS: Apathy

Anxiety disorders STAI: Some unimportant thought is bothering, Worry too much over something that really doesn’t matter,
Feel strained, Not feeling/being content, Not feeling satisfied, Not feeling pleasant, MDS-UPDRS: Anxious
mood

Lab exams [74–76] Blood tests Basophils, Serum chloride, APTT-QT, Eosinophils, Serum glucose

Clinical Evaluation [20,23,41,77–79] Motor MDS-UPDRS: Rigidity upper/lower extremities & neck, Leg agility, Toe tapping

Activities of daily living MDS-UPDRS: Eating tasks, Speech, Hygiene, Part I summary score

Neurological Plantar reflex, Cranial Nerves

Genetics [69–73] SNPs rs823118, rs329648, rs11060180, rs118117788, rs11158026, rs11724635, rs12637471

Other [23,51,66–68] UPSIT: Booklet scores, Age, MDS-UPDRS: Pain and other sensations, Brain region: Left/Right putamen,
Height, Number of siblings

*MDS-UPDRS=Movement Disorder Society‐Unified Parkinson's Disease Rating Scale, STAI=State-Trait Anxiety Inventory, SCOPA-AUT=Scale for Outcomes in
Parkinson’s disease for Autonomic Symptoms, GDS=Geriatric Depression Scale, RBDSQ=REM Sleep Disorder Questionnaire, HVLT=Hopkins Verbal Learning Test,
MoCA=Montreal Cognitive Assessment, UPSIT=University of Pennsylvania Smell ID Test, LNS=Letter-Number Sequencing, Benton Test=Benton Judgment of Line
Orientation, ESS=Epworth Sleepiness Scale, rsXXXXXX=Single Nucleotide Polymorphisms (SNPs).

found to be indicative of rapid symptoms progression in PD, enhancing
previous findings reported in [66] for the faster overall progression
subgroup of PPMI patients when analyzing PD-specific brain networks
for deformations using MRI data. A connection between structural
changes in the putamen brain region and sleep disorders, was reported
by Boucetta et al. with patients scoring higher in the RBD scale than
matching controls [67], while an inverse correlation between depres-
sion and anxiety symptoms severity and basal ganglia DAT availability,
especially in the left anterior putamen region, was shown in [68]. Re-
garding genetic analysis, as it is shown by the selected SNPs in Table 7,
patients from the rapid progression class carried various genetic mu-
tations, which are among the most frequent SNPs found in PD patients
[69] and were also previously associated as risk factors [70,71] and
determinants of faster motor symptoms progression [72,73]. The con-
centration of eosinophils and basophils from blood test results showcase
the impact of inflammation in PD phenotyping and as a pathogenic
factor for the progression of the disease [74,75], while reduced levels of
glucose have been reported to increase the risk of early cognitive de-
cline [76].
Motor symptoms, in contrast, are found to be less informative as
determinants of rapid progression. Presence of rigidity and impaired
movement of lower extremities, including reduced leg agility and toe
tapping potential, were among the few motor symptoms that were se-
lected as prognostic factors. The rigidity-bradykinesia phenotype has
been also reported in the literature [23,41], while reduced leg
movement and strength and peripheral sensation in PD patients have
been associated with increased risk of fall [77,78]. Early impairment in
activities of daily living has been found to be indicative of rapid motor
symptoms progression [20] and a potential marker for PD progression
overall [79]. Finally, some of the selected features that were not pre-
viously reported in the literature include patient’s height, family history
dependencies with close relatives with and without PD and number of
siblings. It should be noted, however, that these features were usually
among the last to be added in the subset of selected baseline features
suggesting that their prognostic value might be comparably smaller.
Gender did not seem to impact the rate of symptoms progression.
A limitation of this study lies within the framework of the evalua-
tion process as, in the absence of official guidelines, the quantiles
partition split resulted in a relatively high number of individual classes,
preventing the effective evaluation of multi-class approaches and
leading to high variance in the selected features in Tables 5 and 6. This
issue was mitigated in this work by using a quantile-independent ana-
lysis, which resulted in much more compact set of prognostic baseline
features (i.e. Tables 2 and 3). Towards this direction, the reduction of
the number of quantiles considered as in [80] or a phenotype-specific
partitioning approach, turning the variation in the expressed sympto-
matology from patient to patient into an advantage, could be viable
alternatives and potential solutions to overcome such limitations and
are planned for our future work.

13

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K.M. Tsiouris, et al.
6. Conclusions
Patient stratification for rapid symptoms progression and early
functional decline in newly diagnosed PD patients has the potential to
completely change our perspective regarding patient management in
the early stages of the disease, leading to better and more precise in-
terventions. In this study, a wide variety of baseline features were as-
sessed for their ability to signal higher risk of rapid progression, using
machine learning techniques. The results suggest that there are sig-
nificant variations in the observed non-motor symptomatology and
mental condition of PD patients at baseline, which should alarm clin-
icians that an aggressive phenotype of PD might be present. Early signs
of autonomic dysfunction, sleep disorders, affected mood and anxiety,
cognitive or memory decline along with advanced age, olfactory im-
pairment, presence of genetic mutations and rigidity are found to be
useful prognostic factors for rapid progression within the first 2 and
4 years of follow-up, while a slower progression is expected when such
symptoms do not appear at diagnosis.
Funding
This work was supported by the PD_Manager project, funded within
the EU Framework Programme for Research and Innovation Horizon
2020, under grant number 643706.
Declaration of Competing Interest
The authors declare that there is no conflict of interest regarding the
publication of this work.
Acknowledgements
Data used in the preparation of this article were obtained from the
Parkinson’s Progression Markers Initiative (PPMI) database (www.
ppmi-info.org/data). For up-to-date information on the study, visit
www.ppmi-info.org. PPMI is a public-private partnership funded by the
Michael J. Fox Foundation for Parkinson’s Research and funding part-
ners. The list with full names of all of the PPMI funding partners found
at www.ppmi-info.org/fundingpartners.
Appendix A. Supplementary data
Supplementary material related to this article can be found, in the
online version, at doi:https://doi.org/10.1016/j.artmed.2020.101807.
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