Journal Pre-proof

Prognostic Factors of Rapid Symptoms Progression in Patients with

Newly Diagnosed Parkinson’s Disease

Kostas M. Tsiouris, Spiros Konitsiotis, Dimitrios D. Koutsouris,

Dimitrios I. Fotiadis

PII: S0933-3657(19)30132-0
DOI: https://doi.org/10.1016/j.artmed.2020.101807
Reference: ARTMED 101807

To appear in: Artificial Intelligence In Medicine

Received Date: 26 February 2019

Revised Date: 7 January 2020
Accepted Date: 13 January 2020

Please cite this article as: Tsiouris KM, Konitsiotis S, Koutsouris DD, Fotiadis DI, Prognostic
Factors of Rapid Symptoms Progression in Patients with Newly Diagnosed Parkinson’s
Disease, Artificial Intelligence In Medicine (2020),
doi: https://doi.org/10.1016/j.artmed.2020.101807

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© 2020 Published by Elsevier.

Prognostic Factors of Rapid Symptoms Progression in Patients with
Newly Diagnosed Parkinson’s Disease

Kostas M. Tsiouris1,2, Spiros Konitsiotis3, Dimitrios D. Koutsouris1 and Dimitrios I. Fotiadis2,4

1
Biomedical Engineering Laboratory, School of Electrical and Computer Engineering, National
Technical University of Athens, GR15773, Athens, Greece.
2
Unit of Medical Technology and Intelligent Information Systems, Dept. of Material Science and
Engineering, University of Ioannina, GR45110, Ioannina, Greece.

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3
Dept. of Neurology, Medical School, University of Ioannina, GR45110, Ioannina, Greece.
4
Dept. of Biomedical Research, Institute of Molecular Biology and Biotechnology, FORTH, GR45110,
Ioannina, Greece.

Corresponding author: Dimitrios I. Fotiadis.

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Address: Unit of Medical Technology and Intelligent Information Systems, Dept. of Materials Science
and Engineering, University Campus of Ioannina, GR 45110, Ioannina, Greece.
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Tel: +302651009006

Fax: +302651005588
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E-mail: fotiadis@cc.uoi.gr
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Highlights

 Introducing machine learning techniques in the search for prognostic factors of rapid
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progression in PD
 Evaluate a comprehensive set of 601 baseline features as potential early prognostic
factors
 Assess PD symptoms progression rate at 2 and 4 years after baseline evaluation
 Quantile partition analysis and quantile-independent classification frameworks are
tested

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  Non-motor symptoms at early stages of PD are the main determinants for rapid
progression

Abstract-

Tracking symptoms progression in the early stages of Parkinson’s disease (PD) is a laborious endeavor
as the disease can be expressed with vastly different phenotypes, forcing clinicians to follow a multi-
parametric approach in patient evaluation, looking for not only motor symptomatology but also non-
motor complications, including cognitive decline, sleep problems and mood disturbances. Being

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neurodegenerative in nature, PD is 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

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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

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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 outcomes is examined
to isolate determinants of rapid progression within the first two and four years of PD. The rate of
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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.
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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
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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
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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
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evaluation can provide better outcomes in identifying rapid progression phenotype. Non-motor
symptoms 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 laboratory blood test results and genetic mutations.

Keywords: Parkinson’s disease; Rapid progression; Prognostic factors; Machine learning

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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
increases 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 significantly lower in Asia with prevalence in populations from
Europe, North America and Australia in between [2]. Although the neurophysiology 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 continues to grow in size suggesting the

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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,

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leading to disabilities as motor symptoms spread from the initial onset location and progress in
severity. Motor symptoms are caused by the brain’s inability to adjust the levels of dopamine
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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
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symptomatology of the disease has equally important complications in patient’s condition, with recent
studies showing that PD patients have increased risk of experiencing cognitive decline, dementia,
sleep disorders, depression and psychosis [10-12]. This great variation in PD symptoms expression can
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be seen in almost every aspect of patient’s condition, from distinctive tremor-dominant and gait
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disturbances-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 differences in
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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
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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 vaguely 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

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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 challenging 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 severe
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

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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

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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,
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longitudinal data with clinical evaluations 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
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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.
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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
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to track progression of PD in a cohort of newly diagnosed patients from the PPMI dataset. Patients are
split into groups according to their progression rate using quantiles partition, with the ones
experiencing the fastest progression within the follow-up period, considered as the rapid progression
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class. An extensive 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
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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 progression at the 2- and 4-year follow-up interval
independently.

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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

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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].

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Using clinical evaluations, PD progression can be estimated in a qualitative or quantitative manner. A
quantitative approach relies on tracking the time required for each patient to reach major milestones
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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
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to progression 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
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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, qualitative
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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).
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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
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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 predominately
skewed towards motor symptoms evaluation, the first parts of the scale evaluate a wide variety of
non-motor aspects of PD, including 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

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scales targeting non-motor aspects specifically (e.g. MoCA, RBD, SCOPA, STAI) to be able to provide
an equally comprehensive non-motor 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

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not accounting for the effects of initiating symptomatic therapy [33]. Observed symptoms are

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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

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models with medication-adjusted estimations of MDS-UPDRS scores, these models were empirically
developed, lacking mechanistic approaches to consider systems biology and pharmacology modeling
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[34]. Thus, despite being promising, there is not enough evidence and clinical trials to validate these
findings. Regardless, in our case study this is less of an issue since patients who continue to experience
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a severe downfall in their observed symptomatology despite medication treatment 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
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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 hours
between the last dose and the MDS-UPDRS evaluation.
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3. Materials and Methods

3.1 PPMI dataset

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The Parkinson’s Progression Markers Initiative (PPMI) is a prospective 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 evaluations, imaging results and biologic
specimens. The PPMI cohort aimed to promote independent research in identifying potential markers
of PD progression, in order to expand our understanding regarding the evolution 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

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Figure 1. Schematic representation of the proposed methodology for the identification of prognostic factors for

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rapid PD progression at baseline evaluation.

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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

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tracking the progression of PD in newly diagnosed and untreated 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
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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%), bradykinesia in
348 patients (i.e. 82.27%) and postural instability in 29 patients (i.e. 6.86%). Patient monitoring
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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

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An outline of the proposed methodology for identifying prognostic factors of rapid symptoms
progression in patients with PD using machine learning algorithms is shown in Fig. 1. The proposed
methodology consists of four primary modules: (a) extraction of the baseline features for each patient,
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(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-quantiles, respectively)
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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 discriminate 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

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 Table I. The complete list of the baseline features that are available in the PPMI clinical dataset.

Group of features Evaluation scales/Clinical examinations/Imaging/ Number

Laboratory results at baseline of features
Neurological Cranial Nerves 9
Exams General neurological exam 18
General physical exam 11
Physical Exams
Vital signs 10
Demographics 14
General patient
Family history 25
information
Socio-Economics 2
DatScan – SPECT results 5
MRI/DatScan –
Brain Region 4
SPECT Imaging
MRI results 5
Blood Chemistry and Hematology 44
Lab Exams Biomarker analysis 55
Biospecimen analysis results 4
MDS-UPDRS part II 14
MDS-UPDRS part III 37

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Motor symptoms MDS-UPDRS total score 1

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Modified Schwab and England ADL 1
PASE Household Activity 9
SNCA multiplication and Genetic Risk Score 2
Genetics
NeuroX Genotyping Selected SNPs 33
MDS-UPDRS part I 15

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MDS-UPDRS part I total score
Benton Judgment of Line Orientation
Cognitive Categorization
Epworth Sleepiness Scale, ESS
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35
5
10
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Geriatric Depression Scale (short), GDS 17
Hopkins Verbal Learning Test, HVLT 14
Letter-Number Sequencing, LNS 24
Non-motor Montreal Cognitive Assessment, MoCA 35
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symptoms Questionnaire for Impulsive-Compulsive

disorders, QUIP 14
REM Sleep Behavior Disorder Questionnaire, RBDSQ 23
Scale for Outcomes in Parkinson’s disease for
39
Autonomic Symptoms, SCOPA-AUT
Lexical and Semantic Fluency 6
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State-Trait Anxiety Inventory, STAI 43

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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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with motor and non-motor clinical symptoms evaluation, brain imaging results, blood/serum/CSF
laboratory results, genetics, general neurological and physical examination, etc. The extracted feature
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vector includes 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 I. If a baseline
feature is missing from a patient’s record, the respective screening value for that particular feature 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

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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

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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,

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24, 30, 36, 42 and 48). Then, depending on the duration of the follow-up evaluation period (i.e. 2 or 4
years), a 2-D data points matrix is formed containing the discrete visit time intervals and the respective
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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 9 and 11 discrete evaluation visits
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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 progression of total MDS-UPDRS parts I-III score per
visit with a linear polynomial, as follows:
y  a x  b, (1)
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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:
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 y1   x1 1 
   x 1
 y2    a   2 , (2)
  b   
     
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 y n   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

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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 life. Positive linear slope
values declare symptoms worsening, negative values declare a mitigation of symptoms (e.g. due to
treatment initiation) and close to zero slope values denote a steady, overall, course of
symptomatology over the follow-up period, respectively.

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3.2.3 Rapid progression class

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Once the progression rate has been extracted for every patient in each follow-up period, it is possible
to sort and split patients into subgroups according to their estimated progression values. The quantiles
partition approach is used to separate patients into groups of equal size, moving from slower

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progression rates at the lower end, to higher progression rates towards the top. The quantile-splitting
is a viable alternative considering that there is no official guidelines or thresholds to signify rapid
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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
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shown in Fig. 2, the upper quantile in both splits contains the patients 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
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investigate 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.
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Figure 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.

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An advantage of using quantile partition to split PD patients into subgroups of advancing progression
rates, is that it allows us to evaluate 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 proposed methodology will be also evaluated in a quantile partition-independent
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,
disregarding their respective variance in progression rate per quantile. It should be noted that each
one of the 4 rapid progression classes across the respective evaluation splits shown in Fig. 2 is

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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

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compared to their 2 year evaluation or are completely missing due to early withdraw. The rapid
progression classes within the same follow-up period are also different due to using the 5- and 10-
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quantiles partition to obtain the top 20% and 10% of most rapidly advanced patients (i.e. the top 20%
consists of the same top 10% and another 10% of patients below them).
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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 relation to the total number of instances. In addition, features
containing a single unique category of values are also removed as they have no discriminative
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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
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order to identify the most informative baseline features. Feature selection allows for not only
improved classification performance, but it also enhances the robustness of the classifier, since the
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number of available baseline features remaining is larger than the number of available instances (i.e.
course of 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

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Figure 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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2 features [𝐹𝑖, 𝐹𝑗] we evaluate their potential classification performance by fitting the selected
classification algorithm in the training proportion of the dataset. If the fit provides both a sensitivity
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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
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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
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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
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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 evaluated by changing 𝐹𝑘, let us denote it as [𝐹𝑖, 𝐹𝑗, 𝐹𝑘′] with
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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 classification 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

12
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 classification 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 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 (SN) that have to be fully

of
expanded and evaluated depends on the size of the baseline feature vector and can be estimated as:

ro
𝑁!
𝑆𝑁𝑐𝑜𝑚𝑏𝑖𝑛𝑎𝑡𝑖𝑜𝑛𝑠 = , (3)
(𝑁 − 2)!

where 𝑁 is the total number of available baseline features. -p

When the search within the entire feature space is completed and all possible SN combinations have
re
been evaluated, the stored classification performance results from each n-feature subset are
compared to find the subset that provided the best classification accuracy, overall during training. This
lP

subset will be selected for the final evaluation with the testing proportion of the dataset. In case of
identical classification performance between subsets with different number of features, the subset
with the smaller number of features is selected (e.g. choose one 4-feature subset over a 5-feature).
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Finally, in case of identical classification performance between subsets with the same feature count
(e.g. two 4-feature subsets), the respective unique features are selected for testing.

Two different classifiers are selected as classification algorithms for evaluation, namely the Naive
ur

Bayes and the Repeated Incremental Pruning to Produce Error Reduction (RIPPER) algorithms. Both
algorithms are widely used in biomedical applications and medical data analysis since they offer the
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first in terms of probability estimates demonstrating feature significance, the latter in terms of
classifications rules providing insights in decision making in natural language (e.g. “IF (MDS-UPDRS
part III score >= 19) AND (age > 67) AND (…) THEN Class=Rapid progression”). The ease of
interpretation of the extracted results is very significant when the 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.

13
4. Results
For a more complete evaluation, two different follow-up periods are tested, considering the first 2
and 4 years of follow-up visits independently, and two distinct rapid progression classes per follow-up
period, respectively, consisting of the top 20% and 10% of the patients with the fastest progression.
In addition, two classification schemes are evaluated: a) quantile partition-independent analysis in
Section 4.1, where the rapid progression class is compared against all the remaining patients who are
assigned to a single slower progression class, disregarding their individual progression rates, and b) a
more detailed analysis between the rapid progression class and each corresponding partition of
patients with slower progression rates as independent classes in Section 4.2, in order to investigate
the connection between the various progression rates (i.e. from slower to faster) and the observed
baseline clinical symptomatology and whether different phenotypes are expressed. The classification

of
performance is estimated with RIPPER and Naïve Bayes algorithms. Statistically significant differences
between the two classes were estimated for each selected baseline feature using one-way ANOVA or

ro
Mann-Whitney U tests (depending on criteria such as normal distribution, homogeneity of variances).

The classification performance results for all classification experiments below are estimated using 5-
-p
fold cross-validation to minimize the potential risk of overfitting due to the relatively low volume of
samples compared to the number of baseline features. For Tables II-IV, accuracy is estimated as
re
(TP+TN)/(TP+TN+FP+FN), sensitivity is estimated as TP/(TP+FN) and specificity as TN/(TN+FP), where:
 True Positives (TP) denote the patients correctly classified as rapidly progressed,
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 True Negatives (TN) denote the patients correctly classified as slower progressed.
 False Positives (FP) denote the patients incorrectly classified as rapidly progressed.
 False Negatives (FN) denote the patients incorrectly classified as slower progressed.
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4.1 Evaluation without quantile partition split

In this classification scheme, the top 20% and 10% of the PD patients with the most rapid progression
ur

are evaluated against all the remaining patient population in a 2-class classification output (i.e. rapid
vs slower progression class). To overcome classification performance limitations due to the high class
imbalance without excluding any cases from the evaluation, the patients from the slower progression
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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 II.
Restricting the number of patients in the rapid progression class to the top 10% of the most rapidly

14
Table II. Classification performance results for the rapid progression class at the 2-year follow-up without
considering quantile partition. Acc=Accuracy, Sens=Sensitivity, Spec=Specificity.
2-year follow-up period
Rapid progression (top 20%) VS Rapid progression (top 10%) VS
Slower progression (Rest) Slower progression (Rest)
Total Features Acc Sens Spec Total Features Acc Sens Spec
features selected per features selected per
selected subgroup (%) (%) (%) selected subgroup (%) (%) (%)
RIPPER 11 3-4 71.48 70.36 72.57 15 2-5 82.84 76.53 85.82
Naïve
Bayes 16 5-6 73.23 71.42 75.00 31 3-9 84.76 82.35 87.03
Selected baseline features (RIPPER) p-values Selected baseline features (RIPPER) p-values
MDS-UPDRS: Pain & other sensations 0.291 MDS-UPDRS: Pain & other sensations 0.014*
ESS: Fall asleep watching TV 0.043* MDS-UPDRS: Urinary problems 0.003*
MoCA: Delayed recall subscore 0.041* MDS-UPDRS: Rigidity upper extremity 0.047*
RBDSQ: Move arms/legs during sleep 0.012* Any paternal aunts/uncles with PD 0.057
RBDSQ: Sudden limb movements 0.008* SDM: Derived Symbol Digit 0.174
GDS: More memory problems than most 0.227 MoCA: Delayed recall subscore 0.004*

f
Blood test: Eosinophils (%) 0.294 MoCA: Total score 0.011*

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LNS: Trial 5a/5c 0.006* RBDSQ: Speaking in sleep 0.004*
STAI: Some unimportant thought bothering 0.037* RBDSQ: Sudden limb movements 0.008*
rs823118 0.415 STAI: Feel content 0.213
rs329648 0.191 Blood test: Serum glucose (mg/dL) 0.018*
Blood test: APTT-QT (sec) 0.065

rs823118
pr
LNS: Trial 5a/5c
rs11060180
0.017*
0.001*
0.042*
MDS-UPDRS=Movement Disorder Society‐Unified Parkinson's Disease Rating Scale, STAI=State-Trait Anxiety Inventory, MoCA=Montreal
e-
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.

advanced cases resulted in higher classification performance, with the mean classification accuracy
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being 11.36% higher using the RIPPER algorithm (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
l
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shown in Table II 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
ur

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 II along with the
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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 I.

The corresponding analysis results for the 4-year follow-up period are presented in Table III. 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

15
Table III. Classification performance results for the rapid progression class at the 4-year follow-up without
considering quantile partition. Acc=Accuracy, Sens=Sensitivity, Spec=Specificity.
4-year follow-up period
Rapid progression (top 20%) VS Rapid progression (top 10%) VS
Slower progression (Rest) Slower progression (Rest)
Total Features Acc Sens Spec Total Features Acc Sens Spec
features selected per features selected per
selected subgroup (%) (%) (%) selected subgroup (%) (%) (%)
RIPPER 13 3-5 81.80 79.88 83.65 14 3-4 88.68 91.11 86.36
Naïve
Bayes 21 4-8 82.38 75.61 88.92 29 4-7 91.12 92.78 89.56
Selected baseline features (RIPPER) p-values Selected baseline features (RIPPER) p-values
MDS-UPDRS: Rigidity upper extremity 0.021* MDS-UPDRS: Apathy 0.033*
MDS-UPDRS: Summary score of part I 0.038* MDS-UPDRS: Urinary problems 0.004*
MoCA: Visuospatial/Executive subscore 0.096 MDS-UPDRS: Rigidity neck 0.048*
SCOPA-AUT: Weak urine stream in past month 0.049* Cranial Nerve V 0.294
SCOPA-AUT: 1-21 score 0.044* SCOPA-AUT: 1-21 score 0.004*
RBDSQ: Sudden limb movements 0.002* Blood test: Basophils (%) 0.101

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RBDSQ: Move arms/legs during sleep 0.002* Blood test: APTT-QT (sec) 0.097

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Blood test: Eosinophils (%) 0.388 Number of children 0.006*
Blood test: APTT-QT (sec) 0.016* STAI: Feel self-confident 0.042*
GDS: More memory problems than most 0.528 STAI: Feel content 0.209
STAI: Worry too much over something that
GDS: Feel situation is hopeless 0.014* 0.011*
really does not matter

pr
rs329648 0.373 LNS: Trial 5a/5c 0.008*
rs118117788 0.150 rs11060180 0.044*
rs823118 0.026*
MDS-UPDRS=Movement Disorder Society‐Unified Parkinson's Disease Rating Scale, STAI=State-Trait Anxiety Inventory, SCOPA-AUT= Scale
e-
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.

rates over longer periods can be observed based on these results. As in the 2-year follow-up,
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classification performance improved when only the top 10% of the most rapidly advanced cases were
assigned to rapid progression class, with mean accuracy increasing from 81.80% to 88.68% and from
82.38% to 91.12% for the RIPPER and Naïve Bayes algorithms, respectively. As shown by the total
l

number of features and the features selected per subgroup, feature selection with Naïve Bayes is again
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less optimal with substantially more features required for only a slight increase in classification
performance, thus, the RIPPER algorithm is preferred and its selected features are presented in Table
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III 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 II along with their respective
p-values. The small number of features selected per evaluation subgroup in Tables II and III using
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RIPPER (i.e. 2-5 features) showcases the importance of feature selection in minimizing the effects of
overfitting. Commonly selected features across the different classification experiments in Tables II and
III are highlighted for convenience. Although perfect overlap between selected features is not
expected considering 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 II-III, while the contextual similarities 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

16
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 independent 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 IV, including the number of selected features per classification
algorithm. Regarding the effect of the follow-up period, the results show an increase 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,

f
respectively. Almost identical margins of improvement are noted for Naïve Bayes as well. As expected,

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the 10-quantiles partition provided higher classification performance for both algorithms compare to
5-quantiles partition. The RIPPER algorithm utilizes again a more compact subset of selected features

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Table IV. Classification performance results for the rapid progression class per follow-up period, using 5 and 10-
quantiles partition. Acc=Accuracy, Sens=Sensitivity, Spec=Specificity.
Quantiles partition 2-year follow-up 4-year follow up
e-
5-quantiles Features Acc Sens Spec Features Acc Sens Spec
Classifier
100-80% selected (%) (%) (%) selected (%) (%) (%)
RIPPER 8 80.28 77.14 83.33 8 94.05 92.68 95.35
vs 80-60%
Naïve Bayes 16 80.28 87.14 73.61 14 90.47 90.24 90.69
Pr

RIPPER 5 76.06 78.57 73.61 10 94.05 90.24 97.67

vs 60-40%
Naïve Bayes 8 76.76 72.85 80.55 13 91.67 90.24 93.02
RIPPER 6 77.30 80.00 74.65 12 89.16 97.56 80.95
vs 40-20%
Naïve Bayes 13 80.85 80.00 81.69 14 92.77 90.24 95.23
RIPPER 12 84.51 85.71 83.33 11 85.54 85.37 85.71
vs 20-0%
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Naïve Bayes 11 83.10 87.14 79.16 20 92.77 87.80 97.61

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10-quantiles
Features Acc Sens Spec Features Acc Sens Spec
100-90% Classifier
selected (%) (%) (%) selected (%) (%) (%)
RIPPER 6 85.71 79.41 91.67 5 95.24 95.00 95.45
vs 90-80%
Naïve Bayes 10 88.57 85.29 91.67 12 95.24 100 90.91
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RIPPER 6 85.71 85.29 86.11 8 95.24 100 90.91

vs 80-70%
Naïve Bayes 11 95.71 91.17 100 14 97.61 95.00 100
RIPPER 6 88.57 88.24 88.89 4 95.12 100 90.48
vs 70-60%
Naïve Bayes 9 88.57 82.35 94.44 9 95.12 100 90.48
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RIPPER 9 87.14 79.41 94.44 13 97.56 95.00 100

vs 60-50%
Naïve Bayes 10 87.14 82.35 91.67 10 97.56 95.00 100
RIPPER 12 85.71 91.18 80.56 11 95.12 100 90.48
vs 50-40%
Naïve Bayes 14 87.14 91.17 83.33 8 100 100 100
RIPPER 8 87.14 85.29 88.89 5 95.12 95.00 95.24
vs 40-30%
Naïve Bayes 14 88.57 88.23 88.89 15 97.56 95.00 100
RIPPER 6 92.75 91.18 94.29 4 95.12 100 90.48
vs 30-20%
Naïve Bayes 13 94.20 94.11 94.28 12 97.56 95.00 100
RIPPER 6 88.57 85.29 91.67 5 95.12 100 90.48
vs 20-10%
Naïve Bayes 10 90.00 91.17 88.89 20 100 100 100
RIPPER 8 94.29 88.24 100 4 100 100 100
vs 10-0%
Naïve Bayes 15 91.42 94.11 88.89 28 100 100 100

17
offering similar classification 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 V. The baselines features of each quantile classification are
presented in order of selection from the best-first search algorithm. The majority of the selected
baseline features come from non-motor evaluation 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

f
as captured by STAI scale, autonomic dysfunction captured with SCOPA-AUT scale and presence of

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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 components found in

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

MDS-UPDRS: Speech, rs11158026, STAI: Some MDS-UPDRS: Leg agility, rs11060180, Semantic
unimportant thought is bothering, Blood test: Fluency: Animal score, STAI: Not feeling calm cool
Pr

vs 80-60% Serum chloride, Number of full siblings, STAI: and collected, RBDSQ: Sudden limb movements,
Worrying over possible misfortunes, GDS: Good STAI: Not feeling steady, rs199347, SCOPA-AUT:
spirits most of time, STAI: Have disturbing thoughts Feel full very quickly during meal

SCOPA-AUT: Been impotent, STAI: Feel strained,

Blood test: Serum glucose, Semantic Fluency: Total SCOPA-AUT: Trouble tolerating heat, Blood test:
l

number of vegetables, STAI: High state subscore, Urea nitrogen, rs11060180, LNS: Trial 4a, SCOPA-
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vs 60-40%
RBDSQ: Disturbed sleep, STAI: Some unimportant AUT: Pass urine again within 2 hours, Number of
thought bothering half siblings, Blood test: Eosinophils, SCOPA-AUT:
Saliva dribbled out of mouth

MDS-UPDRS: Urinary problems, Benton Test: Item

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

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

18
the blood test laboratory results. Finally, motor symptoms are substantially fewer and are primarily
found to be originating 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 V, the results from the statistical
analysis for all baseline features selected by the RIPPER algorithm are shown in detail in
Supplementary Table III. The baseline features that were selected using Naïve Bayes are provided in
Supplementary Table V along with their respective p-values, respectively.

The respective baseline features per follow-up period for the 10-quantiles partition are presented in
Table VI. The results suggest again that the majority of baseline features originate from non-motor
symptoms, 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

of
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,

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laboratory findings from blood test analysis are also helpful. In this higher tier of most rapidly
progressed patients, however, there are some features that were not previously reported using the
5-quantiles partition, including olfactory dysfunction detected with the University of Pennsylvania
-p
smell identification test (UPSIT), age at baseline evaluation and constipation problems. Motor-
oriented features are also limited in the top 10% of patients, with the identification of symptoms at
re
lower extremities including leg agility and toe tapping along with signs of rigidity, postural and rest
tremor at hands. Commonly selected features across different partitions and/or classification
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experiments within Tables V and VI 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 IV due to size limitations, while the corresponding baseline features using the Naïve Bayes
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algorithm are provided in Supplementary Table VI along with their respective p-values.

5. Discussion
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This study aimed to demonstrate a different approach in the research for early prognostic factors of
rapid PD progression and functional decline, proposing a machine learning-based alternative in a field
that is traditionally dominated by statistical analysis and regression-based modeling. The proposed
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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 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 distinct follow-up patient monitoring periods.

19
Table VI. Baseline factors for rapid progression selected using RIPPER algorithm per follow-up period using 10-
quantiles partition.
10-quantiles
Baseline features selected
partiotion
100-90% 2 years follow-up 4 years follow-up
MDS-UPDRS: Hygiene, MoCA: Delayed recall MDS-UPDRS: Gait, STAI: Not being content, MDS-
vs 90-80% subscore, RBDSQ: Parkinsonism, Benton Test: UPDRS: Total score, Number of full siblings, Side
Item 19, STAI: Feel confused, rs12637471 predominately affected at onset
STAI: Some unimportant thought bothering,
rs11060180, rs71628662, MoCA: Delayed
RBDSQ: Speaking in sleep, RBDSQ:
recall subscore, MDS-UPDRS: Finger tapping,
vs 80-70% Aggressive/Action packed dreams, Standing blood
MDS-UPDRS: Constipation problems,
pressure systolic, Blood test: Basophils, RBDSQ:
Neurological Exam: Reflex arm
Vivid dreams, Height (taller), Benton Test: Item 27
MDS-UPDRS: Pain and other sensations,
Age (older), STAI: Not feeling pleasant, STAI: Worry
Benton Test: Item 27, STAI: Feel rested, MoCA:
vs 70-60% too much over something that really doesn’t
Abstraction, MDS-UPDRS: Turning in bed,
matter, HVLT: Derived retention total score

f
SCOPA-AUT: Difficulty retaining urine

ESS: Being sleepy, STAI: Being jittery, Age
(older), Blood test: Serum bicarbonate, MDS-
UPDRS: Constipation problems, MDS-UPDRS:
vs 60-50%
Eating tasks, MDS-UPDRS: Leg agility, MDS-
UPDRS: Postural tremor, MoCA: Delayed recall
face
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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:

Cranial Nerve VIII, Blood Test: Serum uric acid, pr

Summary score, SCOPA-AUT: Feel full very quickly
during meal, MDS-UPDRS: Rest tremor amplitude
lower extremity, rs11724635, rs12456492

SCOPA-AUT: Constipation problems, SCOPA-AUT:

e-
MoCA: Language subscore, RBDSQ: Speaking in
1-21 score, STAI: Feel strained, Blood test: Serum
sleep, UPSIT: Score booklet #4, STAI: Feel
chloride, Blood test: Serum IGF-1, Blood test:
satisfied about self, MDS-UPDRS: Rigidity neck,
vs 50-40% Basophils, MoCA: Verbal Fluency number of words,
MDS-UPDRS: Facial expression, RBDSQ: Hurt
Brain Region: Right putamen, HVLT: Recognition,
Pr

bed partner, SCOPA-AUT: Having difficulty

UPSIT: Score booklet #1, Semantic Fluency: Animal
swallowing or choked, ESS: Fall asleep while
score
sitting/reading, LNS: Trial 4a
Blood test: Serum chloride, HVLT: Recognition,
Blood test: ALT(SGPT), MDS-UPDRS: Urinary
UPSIT: Score booklet #3, SCOPA-AUT: 1-21
problems, RBDSQ: Aggressive/Action packed
vs 40-30% score, Blood test: Eosinophils, Identify self as
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dreams, MoCA: Attention serial 7 sec, Number of

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

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

score MDS-UPDRS: Rigidity lower extremity, Height (taller)

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

20
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 performance during testing, with Naïve Bayes being marginally better;
between 1-5% in some cases. This slightly better classification performance, 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.

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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

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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 progression in the first couple of years is not ideal as progression can be affected
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by not inherent factors such as delayed treatment initiation. Most of these issues are gradually
smoothed out over time with appropriate patient management strategies, leaving a more clear
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depiction 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
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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 II and III show that the
mean sensitivity of RIPPER algorithm increased by 6.17% and 11.23% for both the 2- and 4-year follow-
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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
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follow-up. In addition, similar improvements can be noted in the results of Table IV from the quantile-
dependent evaluation, as sensitivity and specificity increased from 77.14-85.71% and 73.61-83.33%
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to 79.41-91.18% and 80.56-100% in the 2-year follow-up, and from 85.37-97.56% 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 potential 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 significantly for both 5 and 10-quantiles partitions. The reduced baseline feature evaluation

21
Figure 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.

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in [37] provided a lower mean classification accuracy of 76.6% compared to 88.4% in this study for the

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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 provided even better results regardless the size of
quantiles partition. The classification accuracy across all cases is shown in Fig. 4. Regarding similar

pr
methodologies in the literature using machine learning techniques, Faghri et al. [38] proposed a model
for rapid progression prognosis based on baseline features consisting of 140 clinical parameters to
e-
discriminate between slow, moderate and fast disease progression. Selecting 52 features as the most
significant determinants, the evaluation results with the De Novo PPMI cohort reported a 4-year
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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
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Figure 5. ROC curves for classification performance across all evaluation experiments using RIPPER algorithm.

22
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 impairment, 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 reported in
Tables II-VI, 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

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used to evaluate patients for, as it is shown in Table VII. The contextual similarities of the different
selected baseline features in each class of symptoms presented in Table VII, highlights the relevance

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of the underlying non-motor symptomatology even in a more abstract way. Furthermore, this
aggregated level of prognostic symptoms can also be more useful in the everyday clinical environment
as it easier to remember and look for. The prevalence of non-motor baseline symptoms as prognostic
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factors is evident in Table VII and, as shown by the detailed evaluation results in Tables V and VI, is
consistent and unaffected by the different rates of progression expressed in each quantile partition.
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Finally, 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
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dysfunction, daytime sleepiness and advancing age for rapid progression of PD.

Our findings are in agreement with previously reported determinants for faster progression of PD
symptoms and increased disability. Older age of patients during either the diagnosis of the disease or
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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
evaluation is another feature that has been widely correlated with faster worsening of motor function
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and disability in PD [29, 41, 42] and has been even suggested to increase risk of mortality [44] and
early development of dementia [45]. In fact, diagnosis of dementia at baseline evaluation is also highly
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indicative of faster functional decline with patients requiring home nursing much sooner [20, 39].
Then, the selection of features declaring early urinary, constipation and eating problems, signifies the
commonly reported prognostic value of autonomic symptoms for rapid progression phenotyping [46-
48]. Furthermore, 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 appearance 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].

23
Table VII. Categorization of the most prominent selected baseline features into their relevant class of symptoms
and related conditions.
Class of
Broad category Relevant baseline features selected
symptoms
Urinary MDS-UPDRS: Urinary problems, SCOPA-AUT: Weak urine stream, Difficulty retaining
Autonomic problems urine, Pass urine again within 2 hours, Pass urine at night
dysfunction Digestive MDS-UPDRS: Constipation problems, SCOPA-AUT: Constipation problems, Feel full
[46-50] difficulties very quickly during meal, Having difficulty swallowing or choked
Other SCOPA-AUT: 1-21 score, Saliva dribbled out of mouth
RBDSQ: Move arms/legs during sleep, Sudden limb movements, Aggressive/Action
Sleep REM sleep
packed dreams, Speaking in sleep, Hurt bed partner, Disturbed sleep
problems
[12, 54-58] Daytime
ESS: Fall asleep while watching TV, Fall asleep while sitting/reading, Being sleepy
Sleepiness
Semantic Fluency: Animal score, Total number of vegetables, MoCA: Verbal fluency,
Cognitive
Cognitive Visuospatial/Executive subscore, Language subscore, Total score, LNS: 5a/5c/4a,
impairment
dysfunction Derived scaled score, Benton Test: Multiple items
[29, 39, 41-45] Memory MoCA: Delayed recall subscore, HVLT: Immediate recall, Recognition, GDS: More
problems memory problems than most

f
Mood GDS: Feel situation is hopeless, Being afraid of something bad happening, Depression

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Emotional impairment category, RBDSQ: Depression, MDS-UPDRS: Apathy
disorders STAI: Some unimportant thought is bothering, Worry too much over something that
[23, 59-64] Anxiety
really doesn’t matter, Feel strained, Not feeling/being content, Not feeling satisfied,
disorders
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
Activities of
daily living
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MDS-UPDRS: Rigidity upper/lower extremities & neck, Leg agility, Toe tapping

MDS-UPDRS: Eating tasks, Speech, Hygiene, Part I summary score

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Neurological Plantar reflex, Cranial Nerves
Genetics [69-73] SNPs rs823118, rs329648, rs11060180, rs118117788, rs11158026, rs11724635, rs12637471
Other UPSIT: Booklet scores, Age, MDS-UPDRS: Pain and other sensations, Brain region:
[23, 51, 66-68] Left/Right putamen, Height, Number of siblings
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* 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).
l

REM Sleep Behavior Disorders (RBD) and excessive daytime sleepiness have been known to impact
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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
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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 emotional
disorders, including depression and anxiety [12]. Depressed patients have also been shown to express
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significant decline in cognition, memory, activities of daily living and a more rapid progression of
disability 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 embarrassment of the PD symptoms expression [65]. In accordance with the literature,
symptoms of anxiety and depression are also found indicative of rapid PD progression in this study.

24
Based on our results, neuron degeneration and brain atrophy is also 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 depression and anxiety symptoms severity and
basal ganglia DAT availability, especially in the left anterior putamen region, was shown in [68].
Regarding genetic analysis, as it is shown by the selected SNPs in Table VII, patients from the rapid
progression class carried various genetic mutations, 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 concentration of eosinophils and basophils from

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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

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increase the risk of early cognitive decline [76].

Motor symptoms, in contrast, are found to be less informative as determinants of rapid progression.
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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 selected as prognostic factors.
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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
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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 previously reported in the literature include
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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
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smaller. Gender did not seem to impact the rate of symptoms progression.

A limitation of this study lies within the framework of the evaluation process as, in the absence of
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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 V-VI. This issue was mitigated in this work by using a quantile-independent
analysis, which resulted in much more compact set of prognostic baseline features (i.e. Tables II-III).
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 symptomatology from patient to
patient into an advantage, could be viable alternatives and potential solutions to overcome such

25
limitations and are planned for our future work.

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 interventions. In this study, a wide
variety of baseline features were assessed for their ability to signal higher risk of rapid progression,
using machine learning techniques. The results suggest that there are significant variations in the
observed non-motor symptomatology and mental condition of PD patients at baseline, which should
alarm clinicians 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

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advanced age, olfactory impairment, 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

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progression is expected when such symptoms do not appear at diagnosis.

Conflict_of_interest_statement
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The authors declare that there is no conflict of interest regarding the publication of this work.
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Acknowledgements
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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
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Parkinson’s Research and funding partners. The list with full names of all of the PPMI funding partners
found at www.ppmi-info.org/fundingpartners.
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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.
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26
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