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. 2020 Dec 2;15(12):e0243051. doi: 10.1371/journal.pone.0243051

Impact of disease stage and age at Parkinson’s onset on patients’ primary concerns: Insights for targeted management

Roongroj Bhidayasiri 1,2,*, Thanatat Boonmongkol 1, Yuwadee Thongchuam 1, Saisamorn Phumphid 1, Nitinan Kantachadvanich 1, Pattamon Panyakaew 1, Priya Jagota 1, Rachaneewan Plengsri 3, Marisa Chokpatcharavate 3, Onanong Phokaewvarangkul 1
Editor: Mathias Toft4
PMCID: PMC7710032  PMID: 33264321

Abstract

Background

The concerns of people with Parkinson’s disease (PD) about their disease are often different from the objective clinical picture and subject to various influencing factors, including disease progression. Currently our understanding of these concerns is limited, particularly in Asian countries.

Methods

A 50-item survey on Parkinson’s Disease Patients’ Concerns (PDPC Survey) was developed by a multidisciplinary care team. The subjective greatest concerns (most commonly concerning symptoms) of patients at a specialist centre in Bangkok, Thailand, were explored and categorised according to disease stage and age at onset of PD.

Results

Data for 222 patients showed concerns varied widely. Motor symptoms giving the greatest concern were problems with walking and/or balance (40.5% of patients), while the most commonly concerning non-motor symptom (NMS) was constipation (41.0%). Patterns were observed amongst different patient subgroups. Early PD patients (H&Y stage 1) were more concerned about NMS than motor symptoms, while the reverse was true for advanced PD patients. Young-onset PD patients showed significantly greater concerns than typical-onset patients about motor symptoms relating to social functioning, working and stigmatisation, such as speech (p = 0.003).

Conclusions

This study, in an Asian patient cohort, provides an assessment of a wide range of PD patients’ concerns, encompassing not only motor symptoms and NMS, but also treatment-related adverse events, care in the advanced stage, and the need for assistive devices. Identifying the concerns of individual PD patients and implementing a patient-centred approach to care is critical to their wellbeing and optimal outcomes. The PDPC survey can help healthcare teams build a more accurate picture of patients’ experiences to inform clinical management.

Introduction

The underlying concerns of people with Parkinson’s (PD) about their condition can often be different from the objective clinical symptoms they present to the healthcare team. In a broad sense, concerns reflect what we believe or perceive and, in the setting of PD, could be current problems, future worries, both, or even something in between. Moreover, patients’ concerns may change or fluctuate, depending on a range of influencing factors, including age at onset of PD, disease severity, disease progression, prevailing social or cultural circumstances, and their personal subjective experiences [1–6]. Nowadays, it is common for patients to seek information from websites and social media, which can also influence their perceptions and understanding of PD and its treatment. How specific factors contribute to each patient’s view is likely to be complex and will vary according to individual circumstances. In addition, knowledge gaps or the level and accuracy of patients’ understanding of their disease may influence their attitudes and opinions [7]. Patients’ concerns about possible stigmatisation can also alter their view of their condition and its treatment, and even lead to social isolation [8, 9].

Various centres have undertaken surveys of PD patients perceptions and what might influence them but, overall, data are limited. Studies report a wide diversity of patient experiences and note the significant impact of non-motor symptoms (NMS), in addition to motor issues [1, 2]. In some cases a disconnect between physicians’ and patients’ perceptions of their disease and its treatment has been noted [10], highlighting the need for a deeper understanding of patients’ experiences. The group ‘Parkinson Inside Out’ includes healthcare professionals and researchers who have been diagnosed with PD [11, 12] and are therefore in the unique position of understanding what the disease looks like from a clinical standpoint as well as what it feels like to live with PD every day. They highlighted pain, sleep disturbances, and impulse-control disorders as key issues. Cultural differences in PD patients’ perceptions of treatment have been reported, for example between the USA and Japan [6] however specific studies in Asian countries are lacking. A small study from Taiwan found common themes in the patients’ experiences, namely a lack of knowledge about of symptoms, feeling a loss of control, gradual deterioration, and a deep sense of helplessness [13]. A larger survey from Thailand found significant knowledge gaps amongst PD patents across three domains: diagnosis, therapeutic options, and disease course, suggesting the need for education [7].

The challenge for healthcare providers is that the types of concerns expressed by PD patients are often subjective aspects of the disease experience that are not captured with traditional diagnostic tools used in the clinic. While standard rating scales, such as the Movement Disorders Society’s Unified Parkinson’s Disease Rating Scale [14], are valuable clinical tools, they can lack the granularity to detect the individual variations in disease manifestation and the more subjective aspects of a patient’s disease experience.

Patient-reported outcomes (PROs) relating to symptoms and health-related quality of life (HRQoL) are a direct reflection of the patient’s perceived health status and their overall wellbeing. PROs can therefore provide important additional information to help build a more accurate clinical picture. It is important that physicians are aware of the patient’s perspective of their symptoms and understand their impact on that person so they can fully engage, and communicate well with them, their family and caregivers, as well as being able to target the right strategy to address their concerns [5].

Efforts have been made to develop patient-centred measures of symptom severity in PD using self-rating scales to assess the patient’s condition, which have shown good correlation with some existing clinical scales [15]. However, most investigations have focused on motor and non-motor aspects of the disease and lack information about other dimensions that may also influence HRQoL. Therefore, our study aimed to explore patient’s greatest concerns about a range of factors, such as their overall feeling of happiness, the impact of adverse events, and issues regarding palliative care and assistive devices, in addition to motor symptoms and NMS. Variations in these concerns amongst different groups of patients–according to their stage of disease and age of onset of PD–were also evaluated with the aim of providing information to enable healthcare providers to target the most suitable PD care and management strategy to each group of patients.

Methods

Survey development and steps of validation

A multidisciplinary care team at Chulalongkorn Centre of Excellence for Parkinson’s Disease and Related Disorders (ChulaPD, www.chulapd.org), comprising movement disorder neurologists, PD Nurse Specialists, physical therapists, social workers, occupational therapists, representatives from a PD support group (both patients and caregivers), worked in collaboration to determine the process of constructing a new survey related to patients’ concerns in English language. All members were bilingual and all healthcare professionals had extensive experience, of at least 5 years, in the care of PD patients. All members were requested to review key publications and scales to determine PD-specific themes that are related to the following domains: 1) motor symptoms; 2) non-motor symptoms (NMS); 3) symptoms of fluctuations; 4) adverse events; 5) care in the advanced stage; and 6) assistive devices as well as happiness level [14, 16–28]. In addition, one-on-one and group interviews were also conducted with patients and caregivers attending a local PD support group. These interviews were structured and unscripted. The information from these sources guided the development of PD-specific items, which finally generate 50 items for the survey on Parkinson’s Disease Patients’ Concerns (PDPC Survey) covering these six domains and happiness level (S1 Table). Each item was assigned an ordinal response based on a severity scale from 0 (not concerned) to 10 (most concerned). It includes questions on subjective happiness (1 item), motor symptoms (12 items), NMS (13 items), symptoms of fluctuations (wearing off and dyskinesia; 9 items), adverse events (AEs) related to treatment (6 items), care in the advanced stage (7 items), and the use of assistive devices (2 items), and takes approximately 15–30 minutes to complete.

Comprehension of all items were tested for content validity by another expert panel who were not involved with item generation. The index of item-objective congruence (IOC) was conducted on all questionnaire items, demonstrating a positive content validation of all IOC index of at least 0.6 on all items (S1 Data). The PDPC Survey was then translated, according to the translation standards, into Thai (PDPC Survey-Thai version) and back-translated into English, with modifications of the Thai wordings where necessary. The consistencies of both Thai and English versions were then approved by two independent bilingual movement disorder neurologists who were not involved in the PDPC Survey development. Other aspects of survey development and validation were not performed.

Administration of the survey on Parkinson’s disease patients’ concerns

Between March and June 2019, the PDPC Survey-Thai version was administered by one of the healthcare team to PD patients attending outpatient clinics of the ChulaPD, which is a main tertiary referral centre for PD, affiliated with Chulalongkorn University Hospital and the Thai Red Cross society. Patients with cognitive impairment (Mini Mental State Examination score <23) were excluded. Patients were asked to rate their concerns for each item on a severity scale from 0 (not concerned) to 10 (most concerned) based on their experience during the past month. The severity was further classified as ‘Some concern’ for the rating between 0 and 6 and ‘Most concerning’ for the rating between 7 and 10. The distinction between ‘Some concern’ and ‘Most concerning’ was determined by the consensus of the Chulalongkorn Parkinson Patients’ Support Group, represented by two authors (RP and MC), who perceived that the severity for ‘Most concerning’ should reflect the 30% end of the severity spectrum. Results were reported in a form of most commonly concerning symptoms, referring to what the most patients rated these symptoms as highly concerning. Disease stage was assessed using the Hoehn and Yahr (HY) scale [29]. The presence of caregiver in this study refers to a stable main caregiver, which is defined as any person who, without being a professional or belonging to a social support network, usually lives with the patient and, in some way, is directly implicated in the patient’s care or is directly affected by the patient’s health problem [30]. Since there is no consensus on the definition of early and advanced stages of PD, we adopted the traditional classification of early and advanced stages according to the HY scale where bilateral segmental involvement with postural and gait impairment (HY stage > 3), which also marks a clinical milestone, classifies advanced stage whereas early stage refers to those with HY stage 1–2 [31]. The study was approved by the Human Ethics Committee of the Faculty of Medicine, Chulalongkorn University (IRB. No. 134/62). All participants gave informed written consent before entering the study in accordance with the Declaration of Helsinki. Data were collected in Excel files, encrypted, anonymised, and stored on ChulaPD’s secure data server for analysis.

Statistical analysis

Patient demographics and baseline characteristics were summarised using either means and standard deviations (SD) or frequencies and percentages, as appropriate. Chi-squared tests were used to compare the differences for categorical variables between three subgroups: (1) PD patients with or without caregivers, (2) early (HY 1–2) or advanced stage of PD (HY ≥3), and (3) young-onset (onset of symptoms at <50 years of age) or typical-onset PD. An unpaired t-test was used to compare the differences for continuous variables where the data were fit to a normal distribution for the comparison of the above three subgroups where data was fitted to a normal distribution. In addition, an effect size for mean differences of the PDPC survey scores of PD patients with and without caregivers was calculated for Cohen’s d.

To identify predictors of having a caregiver, binary logistic regression analysis was performed in which the presence of caregiver need was a dependent variable and twenty participant-related variables were selected to run into the logistic model as independent variables, including problems with walking and/or balance, getting out of bed, freezing of gait, constipation, daytime sleepiness, pain and/or aching, slow movement, muscle cramping, difficulty performing fine finger movements, any stiffness, marked decline in physical ability, cognitive difficulties (part of NMS), bedridden wheelchair bound, difficulty swallowing, cognitive difficulties (part of symptoms of the advance stage), age, gender, presence of postural instability, and presenting symptoms of bradykinesia. Goodness-of-fit statistics using the Hosmer–Lemeshow test helped to determine whether the model adequately described the data and indicated a poor fit if the significance value was <0.05. The logistic model was undertaken with Forward (Wald) stepwise technique in order to select the most predicable variables to determine caregiver need in PD patients. The predictors were reported as odds ratio (OR) with a p-value of <0.05 (2-tailed) considered statistically significant. All statistical analyses were performed using SPSS version 23.0 software.

Results

The PDPC Survey was completed by 222 PD patients. Patients included in the analysis had a mean age of 68 years and a mean H&Y scale score of 2.76; half of the patients (50.5%) had stable caregivers (Table 1).

Table 1. Demographics of the 222 PD patients who completed the Parkinson’s disease patients' concerns survey.

Item Results
Age 67.69 ± 10.84
Male gender 125 (56.3%)
Disease duration 10.40 ± 6.58
Presenting symptoms at the time of diagnosis:
 ■ Bradykinesia

  1. (61.7%)
 ■ Tremor

  1. (48.6%)
 ■ Rigidity

  1. (41.9%)
 ■ Gait difficulty 87 (39.2%)
Mean HY Score (all patients) 2.76 ± 0.91
Number at each HY stage:
 ■ Stage 1

  1. (2.7%)
 ■ Stage 2

  1. (43.7%)
 ■ Stage 3

  1. (32.9%)
 ■ Stage 4

  1. (16.2%)
 ■ Stage 5 10 (4.5%)
Presence of postural instability 119 (53.6%)
Presence of caregivers 112 (50.5%)
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Categorical data are reported as number and percentage; continuous data are reported as mean ± standard deviation. HY: Hoehn & Yahr stage.

Total patient cohort

Overall, the subjective happiness rating on a scale from 0 (very unhappy) to 10 (very happy) was a mean (SD) of 6.41 (2.23). Responses regarding motor symptoms showed those rated as giving the most commonly concern were problems with walking and/or balance (40.5%), getting out of bed (39.6%), and freezing of gait (36.5%) (Table 2). For NMS, constipation represented the symptom that gave the most commonly concern (41.0%) (Table 2). For symptom fluctuations, slow movement (41.4%; an OFF-period symptom) was the symptom that gave the most commonly concern, followed by muscle cramping (36.5%) and any stiffness (34.7%) (Table 2). Drug-induced dyskinesia was not rated by patients as a symptom of most commonly concern.

Table 2.

PD patients’ greatest concerns regarding (a) motor symptoms, (b) non-motor symptoms, (c) symptoms fluctuations, (d) adverse events, and (e) palliative care (n = 222).

Most commonly concerning symptoms Percentage of patients reporting most commonly concerning symptoms Overall severity
a. Motor symptoms
 Problems with walking and/or balance 40.5% 5.45 ± 2.93
 Getting out of bed 39.6% 5.10 ± 3.07
 Freezing of gait 36.5% 4.92 ± 3.39
b. Non-motor symptoms
 Constipation 41.0% 5.16 ± 3.39
 Fatigue 31.1% 4.40 ± 2.98
 Urinary problems 27.5% 4.15 ± 3.15
c. Symptom fluctuations
 Slow movement 41.4% 5.21 ± 3.06
 Muscle cramping 36.5% 4.80 ± 3.11
 Any stiffness 34.7% 4.61 ± 3.17
d. Adverse events
 Gastrointestinal symptoms 31.5% 4.51 ± 3.22
 Urinary symptoms 23.9% 3.96 ± 3.27
 Neuropsychiatric symptoms 16.7% 3.05 ± 2.96
e. Care in the advanced stage
 Marked decline in physical ability 40.5% 5.42 ± 3.22
 Bedridden/wheelchair bound 35.1% 4.47 ± 3.88
 Cognitive difficulties 30.2% 4.22 ± 3.29
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Severity scores are reported as mean ± standard deviation. Symptoms were classified as ‘most concerning’ for patient’s ratings of 7 and beyond.

In terms of possible treatment-related AEs, symptoms that were rated as the most commonly concerning were GI (31.5%), urinary (23.9%) and neuropsychiatric (16.7%) (Table 2).

Concerns in advanced stage

For symptoms related to the care in the advanced stage, the three symptoms that rated as the most commonly concerning were a marked decline in physical ability (40.5%), becoming bed- or wheelchair-bound (35.1%), and cognitive difficulties (30.2%). The predominant concerns in the advanced stage were factors found to be associated with having a caregiver, namely chewing and swallowing, and getting out of bed, both of which had statistically significant odds ratios (Tables 3 and S2). The presence of caregivers was significantly higher amongst those with advanced PD compared with early PD patients (p<0.01). In a comparison of PDPC Survey scores between patients with caregivers and those without, a similar pattern was observed with factors such as difficulty chewing and swallowing, getting out of bed, and problems with walking and/or balance, rated as having a significantly higher severity by those with caregivers (S2 Table).

Table 3. Factors associated with presence of a caregiver.

Predictive factor Model: Odds ratios/Exp(B)
Difficulty chewing and swallowing 2.455*
Getting out of bed 3.751*
Hosmer–Lemeshow test 0.936
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*Statistically significant using the binary logistic model.

Analysis by Hoehn & Yahr stage

When patients’ greatest concerns about motor symptoms and NMS were analysed according to their HY stage, it was found that patients at HY stage 1 generally did not report great concern about motor symptoms whilst patients at more advanced HY stages described symptoms of greatest concern relating to problems with walking and/or balance, freezing of gait, and getting out of bed (Table 4). On the other hand, patients at HY stage 1 reported greatest concern about NMS such as constipation, lack of interest or enthusiasm, or urinary problems. Overall, constipation was rated as the most commonly concerning NMS. While patients at HY stage 1 did not report great concerns about motor symptoms, they shared some concerns on problems with walking and/or balance in 66% of patients, followed by difficulty speaking and shaking both in half of patients.

Table 4.

Top three symptoms of most commonly concern on (a) motor symptoms and (b) non-motor symptoms according to Hoehn and Yahr stage (n = 222).

Stage 1 Stage 2 Stage 3 Stage 4 Stage 5
 a. Motor symptoms
None Getting out of bed (35.1%) Problems with walking and/or balance (46.6%) Problems with walking and/or balance (58.3%) Freezing of gait (80.0%); Getting out of bed (80.0%); Turning in bed (80.0%)
None Problems with walking and/or balance (28.9%) Freezing of gait (37.0%) Freezing of gait (55.6%); Getting out of bed (55.6%) Problems with walking and/or balance (70.0%)
None Freezing of gait (26.8%) Getting out of bed (35.6%) Turning in bed (44.4%) Difficulty speaking (60.0%); Saliva and drooling (60.0%); Social activities (60.0%)
 b. Non-motor symptoms
Constipation (16.7%) Constipation (36.1%) Constipation (49.3%) Constipation (41.7%); Insomnia (41.7%) Urinary problems (70.0%)
Lack of interest or enthusiasm (16.7%) Daytime sleepiness (29.9%) Urinary problems (31.5%) Fatigue (36.1%) Fatigue (60.0%)
Urinary problems (16.7%) Fatigue (28.9%) Fatigue (30.1%) Pain and other sensation (33.3%) Constipation (40.0%); Daytime sleepiness (40.0%); Hallucination and delusions (40.0%); Lack of self-control (40.0%)
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Data were categorised according to number and percentage. No additional items were included in the 2nd and 3rd ranking for NMS under HY stage 1 patients due to equal scoring of top three symptoms in the 1st ranking.

Analysis by age of onset of PD

When comparing the greatest concerns of young-onset PD patients with those of typical-onset PD patients, our study found that young-onset patients rated freezing of gait as the most commonly concerning motor symptom (46.3%), whereas for typical-onset PD it was getting out of bed, and problems with walking and/or balance (both 39.5% of patients) with freezing of gait ranked second (33.5%) (Table 5). Constipation was rated as the most commonly concerning NMS by both patient cohorts. In terms of symptom fluctuations, the highest ranking most commonly concerning symptoms in young-onset PD patients were slow movement (57.4%), difficulty performing fine finger movements (53.7%), any stiffness (50.0%), and muscle cramping (50.0%), possibly because these are factors that relate to social functioning, working and stigmatisation. A similar profile of symptoms was observed in the typical-onset PD group, however there was a trend to lower numbers of patients reporting them, and with numerically lower severity ratings.

Table 5.

Comparison of the most commonly concerning symptoms between young-onset and typical-onset PD patients on (a) motor symptoms, (b) non-motor symptoms, (c) symptom fluctuations, (d) adverse events, and (e) care in the advanced stage (n = 222).

Young-onset PD Typical-onset PD
Symptom (%) Overall severity Symptom (%) Overall severity
 a. Motor symptoms
Freezing of gait (46.3%) 5.37 ± 3.40 Getting out of bed (39.5%) 5.04 ± 3.10
Problems with walking and/or balance (39.5%) 5.31 ± 2.94
Problems with walking and/or balance (44.4%) 5.87 ± 2.91 Freezing of gait (33.5%) 4.77 ± 3.39
Difficulty speaking (42.6%) 5.65 ± 2.99 Turning in bed (29.3%) 3.33
 b. Non-motor symptoms
Constipation (48.1%) 5.67 ± 3.19 Constipation (38.9%) 4.99 ± 3.46
Fatigue (31.5%) 4.81 ± 3.03 Fatigue (31.1%) 4.26 ± 2.97
Daytime sleepiness (27.8%) 4.22 ± 2.75 Urinary problems (29.9%) 4.25 ± 3.22
Anxiety and/or panic attacks (27.8%) 4.81 ± 2.50
 c. Symptom fluctuations
Slow movement (57.4%) 6.46 ± 2.62 Slow movement (36.5%) 4.80 ± 3.10
Difficulty performing fine finger movements (53.7%) 6.26 ± 2.72 Muscle cramping (31.7%) 4.41 ± 3.13
Pain and/or aching (31.7%) 4.66 ± 2.89
Any stiffness (50.0%) 5.76 ± 3.05 Any stiffness (29.3%) 4.23 ± 3.13
Muscle cramping (50.0%) 5.96 ± 2.75
 d. Adverse events
Gastrointestinal symptoms (37%) 4.72 ± 3.40 Gastrointestinal symptoms (29.9%) 4.47 ± 3.17
Urinary symptoms (31.5%) 4.35 ± 3.41 Urinary symptoms (21.6%) 3.84 ± 3.23
General symptoms (16.7%) 3.44 ± 2.85 Neuropsychiatric symptoms (16.8%) 2.95 ± 2.98
Neuropsychiatric symptoms (16.7%) 3.33 ± 2.91
 e. Care in the advanced stage
Marked decline in physical ability (53.7%) 6.63 ± 2.84 Marked decline in physical ability (35.9%) 5.01 ± 3.24
Bedridden/wheelchair bound (44.4%) 5.26 ± 4.05 Bedridden/wheelchair bound (31.7%) 4.18 ± 3.78
Difficulty swallowing (42.6%) 4.67 ± 3.61 Cognitive difficulties (28.1%) 3.95 ± 3.29
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Severity scores are reported as mean ± standard deviation.

Even though drug-induced dyskinesia was not rated amongst the top three most commonly concerning symptoms by either group of patients, young-onset PD patients reported drug-induced dyskinesia as a most commonly concerning symptom significantly more than typical-onset PD patients (33.3% vs 9%, p < 0.001).

The predominant treatment-related AEs of greatest concern were GI and urinary symptoms in both patient groups. The top two ranked most commonly concerning symptoms regarding care in the advanced stage in both groups were a marked decline in physical ability and being bedridden/wheelchair bound, however higher numbers on the young-onset PD group reported these and there was a trend to higher rankings of severity than in the typical-onset PD group.

S3 Table shows a comparison of the severity of different concerns of young-onset versus typical PD patients regarding motor symptoms, NMS, and symptom fluctuations. Patients with young-onset PD reported significantly more concerns about a number of motor symptoms and symptom fluctuations, including difficulty speaking (p = 0.003), eating tasks (p = 0.003), washing and bathing (p = 0.04), shaking (p = 0.005), and dyskinesia (p = 0.001) and a number of NMS, including low and/or depressed mood (p = 0.01) and anxiety and/or panic attacks (p<0.001) when compared to typical-onset PD patients.

Need for assistive devices

Analysis of responses for the total patient cohort regarding concerns about the need for assistive devices found that a shower chair (38.3%) was considered as the most needed device amongst, followed by a walking stick (36.5%) and anti-slip mat (34.7%) (Table 6). When results were analysed according to whether patients had early-stage or advanced-stage PD, advanced-stage patients reported a significantly greater need for a walking stick (p = 0.01), a wheelchair (p<0.001), and an anti-choking cup (p = 0.03) than early-stage patients (Table 6).

Table 6. Patients’ concerns regarding the need for assistive devices: Comparison of patients with early-stage versus advanced-stage PD.

Item All participants (n = 222) Early-stage PD (n = 103) Advanced-stage PD (n = 119) p-value
Walking stick 81 (36.5%) 29 (28.2%) 52 (43.7%) 0.016*
Laser-guided walking stick providing visual cues 42 (18.9%) 19 (18.4%) 23 (19.3%) 0.867
Walker 40 (18.0%) 14 (13.6%) 26 (21.8%) 0.110
Wheelchair 57 (25.7%) 14 (13.6%) 43 (36.1%) <0.001*
Electric adjustable bed 44 (19.8%) 19 (18.4%) 25 (21.0%) 0.633
Wearables for fall detection 30 (13.5%) 13 (12.6%) 17 (14.3%) 0.718
Tremor suppression spoon 17 (7.6%) 5 (4.9%) 12 (10.1%) 0.144
Tremor suppression gloves 16 (7.2%) 4 (3.9%) 12 (10.1%) 0.075
Bed rails 41 (18.5%) 19 (18.4%) 22 (18.5%) 0.994
Home rails 71 (31.9%) 29 (28.2%) 42 (35.3%) 0.255
Bed support rails 62 (27.9%) 23 (22.3%) 39 (32.8%) 0.084
Anti-slip mat 77 (34.7%) 39 (37.9%) 38 (31.9%) 0.354
Cushioned fall mat 37 (16.7%) 14 (13.6%) 23 (19.3%) 0.253
Horizontal lines on the floor as visual cues 15 (6.7%) 9 (8.7%) 6 (5.0%) 0.274
Button-up device 10 (4.5%) 5 (4.9%) 5 (4.2%) 0.815
Shower chair 85 (38.3%) 33 (32.0%) 52 (43.7%) 0.075
Commode 49 (22.1%) 19 (18.4%) 30 (25.2%) 0.226
Anti-choking cup 26 (11.7%) 7 (6.8%) 19 (16.0%) 0.034*
Fall alarm 61 (27.5%) 29 (28.2%) 32 (26.9%) 0.833
Electric home ladder 11 (4.9%) 4 (3.9%) 7 (5.9%) 0.494
Suction device 10 (4.5%) 3 (2.9%) 7 (5.9%) 0.287
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All statistics were performed using the Chi-squared test for categorical units and an unpaired t-test for continuous units. A p-value less than 0.05 was considered statistically significant.

Discussion

Our study using the PDPC survey found that patients’ concerns about their symptoms vary widely and depend on how they perceive their motor symptoms, NMS, fluctuations, and overall treatment experience, at different disease stages, which also reflects in the results of previous studies [1, 2]. However, although symptoms in PD are individualised, we also observed a pattern of concerns amongst different subgroup of PD patients (young-onset PD versus typical onset PD and early versus advanced PD).

Some patients’ greatest concerns reflect their current symptoms whilst others relate more to worries of what will happen to them in the future, as shown when results were analysed according to patients’ HY stage. In our study, those at HY stage 2 were concerned about getting out of bed, gait/balance, and freezing, which are generally not the symptoms that manifest at this stage, and suggests that they may be worrying about developing these disabilities in the future. A previous study undertaken to assess the level of PD severity associated with disability and to identify the sequence of loss of independence in common daily activities found that disability with loss of independent function was found at HY stages 2–3 [32]. Difficulty with daily activities, without loss of independent function was reported earlier, at HY stages 1–2, so transition from HY stage 2–3 seems to be milestone in relation to gait-dependent activities and has also been found to be an index of disease progression [33].

There are several possibilities to explain our observation that patients expressed concerns about future symptoms. Firstly, they may have subtle symptoms which are not markedly manifest during an examination. It is possible that patients may actually feel these subtle symptoms developing and some patients may be even more sensitive than others to the presence of these small changes. This is similar to the finding that PD patients can have measurable subclinical tremor before visible tremor is apparent [34]. Subjective assessment of the patient’s experience may therefore provide an additional advantage in helping quantify subclinical symptoms. Secondly, patients may be more concerned about future symptoms based on what they observe in other patients, for example at the clinic or of they participate in patient support groups. They may also have seen information about PD on the internet or social media, however as has been shown from a study in Korea, this material can be unreliable and even misleading [35]. Another possibility is belief in the common myth that their disease will eventually take control of them and they will become wheelchair- or bed-bound. For patients who express their concerns about future symptoms it may be of value for the physicians to explore with them why they feel this way and target management accordingly.

It is interesting to observe that none of patients at HY stage 1 reported their greatest concerns about motor symptoms, their greatest concerns related to constipation, lack of interest, and urinary problems. However, patients at HY stage 1 did share some concerns (but not greatest concerns) on a range of motor symptoms, including problems with walking and balance, difficulty speaking, and shaking but with lesser severity. It is possible that these HY stage 1 patients, who were relatively new to the diagnosis, were focusing on their most current troublesome NMS, rather than the less troublesome motor symptoms, which might have responded well to current dopaminergic medications. As far as we are aware, there is no previous information on patients’ concerns in different HY stages. The closest study that we could identify reported patient’s perspectives in early PD patients from the UK with up to 6 years of disease duration of which motor symptoms, including tremor, slowness, and stiffness, were rated as the most troublesome symptoms but bowel problems were also included within the top 10 most bothersome symptoms in this study [1]. Different results may reflect different study group populations. These findings should be further explored in a larger group of patients to determine a range of significant concerns that may be targets for treatment in early stage patients.

Sub-analysis by age of onset of PD found that higher concern rankings were reported by young-onset PD patients compared with typical-onset PD patients for factors that would be likely to impact on their social functioning (e.g. shaking, drug-induced dyskinesia) and ability to work, such as slow movement and difficulty performing fine finger movements. In addition, drug-induced dyskinesia was not found to be the most commonly concerning symptom in the patients surveyed in this study except for a group of young-onset PD patients who identified drug-induced dyskinesia as the most commonly concerning symptom significantly more than typical-onset patients although they did not rate it within the top three most commonly concerning symptoms related to fluctuation. This finding is similar to two previous studies involving patients from Japan and North America which reported that dyskinesia was not a concern with PD treatment in either group, whereas wearing off was a common concern in the North American patients while developing hallucinations was a common concern amongst Japanese patients [4, 6]. When an impact of dyskinesia on activities of daily living (ADLs) was evaluated, the percentage of patients reporting severe impact on ADLs by dyskinesia was less than 5%. Moderate impact was less than 30% whereas the majority reported mild or even no impact from dyskinesia [36]. Nevertheless, dyskinesia is the visible sign that might lead to social embarrassment or stigmatisation and continue to be a matter of debate on its impact on different subgroups of PD patients. Whilst the prevalence of troublesome dyskinesia is falling in a number of recent studies, the presence of dyskinesia is still a matter of concern, particularly those with troublesome or disabling dyskinesia, or at-risk PD populations (e.g. young-onset patients) [37, 38].

Knowledge about the likely concerns of different patient subgroups is critical when managing different group of patients. In busy clinical practice, it is likely that physicians do not have sufficient time to administer a full rating scales or questionnaires. Therefore, a focused interview based on physician’s understanding of the concerns of patient subgroups might have benefits for individual patients. For example, neurologists should ask patients about the presence of NMS, e.g. constipation, even when their examination shows that patient’s motor symptoms are well under control. On the other hand, if a patient expresses concerns about gait and balance even though their examinations demonstrate minimal findings, this should be explored further since gait/balance symptoms are an indicator of disease progression and are strongly associated with disabilities.

Treatment-related adverse events are important as they can have an impact on PD symptoms and ultimately on a patient’s quality of life, physical functioning, or disability. For example, neuropsychiatric adverse events can affect sleep, nausea and vomiting can affect absorption of medications, while orthostatic hypotension can affect balance and contribute to falls. In terms of adverse events in our study, GI issues were the most significant worry amongst all patients. GI problems are known to be common in PD patients, can affect the whole GI tract, and are likely to get worse as the disease progress, so it is important that physicians ask about such symptoms.

Results regarding the need for assistive devices showed relatively low scores for most devices and minimal differences between the subgroups analysed. None of the assistive device items included in our questionnaire was rated as a required item by more than half of the survey participants. It is possible that patients’ knowledge of particular assistive devices was limited or lacking, especially regarding specialised devices such as tremor suppression spoons or gloves. This highlights the need for the timely referral of patients to appropriate occupational and physical therapists to discuss the available options. As patients rated this section based on their needs for assistive devices, the interpretation of their responses as ‘needed’ could have different meanings. For example, patients may indicate their needs for assistive devices based on either current symptoms or their worries for future symptoms. Likewise, patients may not express their needs for these devices as they may perceive these devices as a symbol of disability. Current evidence shows that on average only 9% of PD patients are referred to these specialities or to therapists who have the training and skills needed to undertake home safety assessments [39].

In our study, factors that predicted when patients were likely to have caregiver were difficulties with chewing and swallowing, and difficulties getting out of bed. In clinical practice, if these concerns become apparent in a patient who does not have a caregiver present, then this should signal to the healthcare team that further discussion is needed as part of their ongoing care plan to determine how they could best be supported. The presence of these kinds of functional difficulties should be explored and regularly reviewed by neurologists to assess the ability of the patient to manage independently as well as their impact on other related ADLs. It is possible that the presence of these types of concerns are early signs towards the development of complications, e.g. aspiration pneumonia in the case of swallowing difficulties. The support of caregivers for PD patients is important and valuable, and may delay or prevent such complications. There are data to show that home-based occupational therapy interventions can be beneficial when PD patients and caregivers participate together [40].

A balanced clinical judgement is critical when managing PD patients. By focusing on the particular symptoms, patients express concerns about does not mean that we should ignore other symptoms. It is possible that patients do not report their symptoms because of their own lack of knowledge or misunderstanding. Indeed, a recent study identified barriers in communications about OFF periods between healthcare providers and PD patients who often perceived that their OFF periods were part of the disease, so could not be improved by physician’s intervention [41].

In light of the growing interest in the use of patient-centred digital outcome (PCDO) measures in PD, it is likely that in the future there will be greater use of mobile technologies to capture data on patient perceptions [42, 43]. Recently, a roadmap for implementation of PDCOs measure has been proposed to facilitate the adoption of such mobile health technologies in PD to help inform clinical management [43].

By using this 50-item survey, this study provides an assessment of various aspects of PD patients’ concerns, not limited to motor symptoms and NMS, but also including aspects such as treatment-related AEs, care for the advanced stage, and the need for assistive devices. It explores subjective aspects of the disease experience (e.g. level of happiness) as well as objective aspects (e.g. gait, tremor). Importantly, it reports data for an Asian PD cohort, which is currently lacking in the published literature. Previous literature on NMS suggests that cultural and ethnic background can indeed influence symptom perception [44]. Limitations of the study relate to its single-centre design and cross-sectional assessment which limits the possibility to see how these concerns may have evolved as disease progresses. Moreover, the validation of this survey is still preliminary as demonstrated by content validation, but still lacks a complete process of reliability and external validity assessment. It is also possible that certain items of the survey could be misinterpreted by patients. For example, “shaking” can be interpreted by patients as either tremor or dyskinesia. As the majority of PD patients will experience dementia, the exclusion of this patient group from the study may limit the generalisability of results. Identifying particular concerns of individual patients and then implementing an individualised approach to their PD care is critical to their wellbeing and optimal outcomes. Instruments such as the PDPC survey can help healthcare teams develop a more accurate picture of patients’ perceptions of, and concerns about, their disease which will aid discussion about their ongoing management to allay any fears and help fulfil their individual desires and goals.

Supporting information

S1 Table. The Parkinson’s Disease Patients’ Concerns Survey (PDPC Survey).

(DOCX)

Click here for additional data file. (29KB, docx)
S2 Table. Comparison of the characteristics and PDPC Survey of patients with caregivers and those without.

(DOCX)

Click here for additional data file. (27.1KB, docx)
S3 Table. Patients’ concerns on motor and non-motor symptoms: comparison between young-onset and typical-onset PD patients.

(DOCX)

Click here for additional data file. (34KB, docx)
S1 Data. Development and validation of the Parkinson’s Disease Patients’ Concerns Survey (PDPC Survey).

(DOCX)

Click here for additional data file. (37.1KB, docx)

Acknowledgments

Data checking and reviewed was provided by Dr Karen Wolstencroft, Bluewolf Communication Limited, UK.

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

RB is supported by Senior Research Scholar Grant (RTA6280016) of the Thailand Science Research and Innovation (TSRI), International Research Network Grant of the Thailand Research Fund (IRN59W0005), and Center of Excellence grant of Chulalongkorn University (GCE 6100930004-1).

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Decision Letter 0

Mathias Toft

29 Jul 2020

PONE-D-20-18129

Impact of disease stage and age at Parkinson’s onset on patients’ primary concerns: Insights for targeted management

PLOS ONE

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Reviewer #1: Overall, this is a well written paper on patients' concerns in Parkinson's disease, an area increasingly recognized in clinical medicine to be important to delivery of good patient-centred care.

However, there are a number of points I would like the authors to address.

MAJOR COMMENTS

1. It is stated that items in the PDPCQ were rated "from 0 (not concerned) to 10 (most concerned)", but it is unclear (e.g., in Table 2) how items were ranked. The meaning and distinction between the columns "Some concerns" and "Most concerns" in Table 2 is not explained. Why was fatigue, for example, which had a mean score of 4.40 in the "Some concerns" column, ranked higher than constipation which had a mean score of 5.16? (also I note that the mean/SD figures for Fatigue and Constipation look like exact mirror images of each other and I would ask the authors to verify that this is not an error?). In Table 4, I don't understand how/why no motor symptom achieved a ranking for HYI patients - does this mean that all 6 patients with HYI rated all 12 motor symptoms as 0 ("not concerned")? This would seem highly unusual to me.

2. Similarly, regarding the statement in the Results: "Drug-induced dyskinesia was not rated by patients as a concerning symptom", does this mean that no patient gave this item a rating of at least 1/10? This seems to be at odds with the authors' statement that young-onset PD patients were concerned about drug-induced dyskinesia. This important (and perhaps controversial) point regarding dyskinesias not being an issue of patient concern was again mentioned in the Discussion and the authors should present the data in the manuscript text itself to substantiate this point.

3. I would probably tone down claims that the PDPCQ was "validated" (e.g., 1st sentence of the Discussion: "Our study using the validated PDPCQ …"), since it appears that only content validation/IOC was performed - and many other validation tests/metrics were not performed (e.g., can say "preliminary" validation was conducted. A brief inspection of the instrument reveals a number of areas that will need to be improved e.g., for future use: (i) "Shaking" without further clarification, to (presumably) denote "Tremor" (however, it is well known that patients not uncommonly say "Shaking" to describe dyskinesias); (ii) I am not sure why "Social activities" - which will commonly be influenced by many issues including non-motor features such as anxiety - should be categorized as a "motor" concern; (iii) Although it is true that "Weight loss" is more common in advanced PD, studies have shown that this is often also an early feature of PD; (iv) I am doubtful that the dichotomous choice of "Need" vs. "No need" really captures "concerns" about assistive devices, e.g., stigma associated with the use of walking aids; (v) In the "Adverse events" section, I have concerns about how patients are meant to interpret e.g., "General symptoms" or "Cardiovascular symptoms" (postural giddiness??). It is of course too late to alter the questionnaire for the purposes of publishing this paper, but some of these issues should at least be discussed as study limitations.

4. The authors should not report that a result is "statistically significant" without specifying the actual values/effect size at the same time, e.g., in the Results: "…, both of which had statistically significant odds ratios". The latter are arguably more important than statistical significance. Please rectify this elsewhere in the manuscript too.

5. For Table 3, it is unclear how many/what factors were considered for entry into the model, prior to the 2 items ("Difficulty chewing/swallowing" and "Getting out of bed") emerging as predictive factors.

MINOR COMMENTS

1. In the Results, the meaning of the statement "half of the patients … had support from caregivers". Do the authors mean that half the patients needed help from caregivers? In Table 1, I think the same thing is phrased as "Presence of caregiver" which could mean something else, e.g., that a caregiver was present during the administration of the questionnaire. The "presence of caregivers was significantly higher …" is again mentioned in the Results section, with unclear meaning.

2. In Table 1, bracket signs in the table are inverted, please correct.

3. In Table 1, the meaning of "Presenting symptoms" is unclear. Do the authors mean symptoms endorsed by the patient to be present at the time when the questionnaire was done? Or symptoms occurring at the time of initial disease presentation?

4. I am not sure that I agree with the statement: "Trying to fine-tune dopaminergic medications … to improve motor symptoms … is likely to worsen a patient's constipation". On what basis do the authors make this statement? I am not aware of good evidence indicating that levodopa worsens constipation, nor dopamine agonists except those with anticholinergic activity such as piribedil.

Reviewer #2: This is an important topic and overall the authors have done a laudable job. My main concern is with the "development and validation" of their scale which is not provided in sufficient detail and would probably be its own manuscript if done with reliable item selection and other psychometric methods. Other concerns are mainly to do with clarity. Comments by section:

ABSTRACT

- In methods it states this scale was developed and validated. It is not clear here whether this was done and previously published or if this was part of the current paper. If the goal of the current paper more details are needed.

- Unclear how a cross-sectional study could be "randomized", nor how this relatively small study of a single new scale be called "comprehensive".

INTRO

- 2nd sentence in first paragraph should have references

- If a goal of this paper is to develop and validate a new scale this should be clearly stated. If this scale was previously validated, this should be referenced.

METHODS

- What is ChulaPD?

- As I understand it, the questionnaire was developed by a movement team coming up with 50 questions to cover several areas of interest. I am not a scale development expert but this does not seem adequate - most scales go through several iterations of item development, including work with the population of interest to make sure items are representative, understandable and clinimetrically sound. It may be more fair to say you performed a cross-sectional survey and present those results than developed and validated a scale.

- Do we know how patients interpreted the term "concerns" - e.g. current problems vs. future worries vs. both, or perhaps variable between people?

- It is unclear what the domain "palliative care" means. It seems that this is used to describe advanced disease.

- It is unclear what it means that the survey was "randomly" distributed. I assume this is simply a convenience sample and that there was no sampling strategy.

RESULTS

- parentheses are backwards in Table 1

- It is unclear how "given the most concern" was determined. Was this simply scores = 10? The highest score? Using some cut-point? Whatever the method, it should be clearly described and justified.

- the "Caregiver Support" section is confusing. How was "palliative care stage" defined? The statement on "factors predictive of need for caregiver support" is misleading. As I understand it these are simply factors associated with having a caregiver.

- I find it hard to believe that HY I really had no concerns about motor symptoms. They ranked everything as 0? Perhaps this is an issue with the survey although I would believe that nonvoter concerns might outweigh motor concerns.

- Table 4 (and related text) is confusing. How was "rated 1st" determined? Most common (and if so is this simply a score above 1)? Highest mean score? Highest mean score amongst those reporting the symptoms? How is it possible that some categories have multiple items ranked 1st? Did they have exactly the same score?

- For the subgroup analyses (e.g. by age of onset) do we know if the differences between groups were statistically significant? Some of the differences mentioned seem small.

- How is early and advanced stage PD defined? How is it that over 13% of early stage PD need wheelchairs?

- In the

DISCUSSION

- This section starts by stating "the validated PDPCQ". A reference is needed. I do not think this paper is adequate to claim this is a validated scale.

- Second paragraph calls into question how patients are interpreting questions and whether most interpret them in the same way. If we do not know this basic question, or if the term in the survey is vague or could have multiple meanings it calls into question findings.

- Another big concern is the exclusion of persons with MCI and dementia in a study that claims to be "comprehensive". 75% of people with PD will develop dementia - excluding such persons limits conclusions and statements around people with advanced disease.

**********

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Reviewer #2: No

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PLoS One. 2020 Dec 2;15(12):e0243051. doi: 10.1371/journal.pone.0243051.r002

Author response to Decision Letter 0

8 Oct 2020

6 October 2020

Mathias Toft, MD., PhD.

Academic Editor

PLoS One

Dear Prof. Toft,

Re: Manuscript # PONE-D-20-18129: Impact of disease stage and age at Parkinson’s onset on patients’ primary concerns: Insights for targeted management

Thank you very much for your letter of the 30th of July 2020. We found the editor’s and reviewer’s comments very helpful and respond to them as follows:

Reviewer #1: Overall, this is a well-written paper on patients’ concerns in Parkinson’s disease, an area increasingly recognized in clinical medicine to be important to delivery of good patient-centred care. However, there are a number of points I would like the authors to address.

Major comments

1) It is stated that items in the PDPCQ were rated “from 0 (not concerned) to 10 (most concerned)”, but it is unclear (e.g. in Table 2) how items were ranked. The meaning and distinction between the columns “Some concerns” and “Most concerns” in Table 2 is not explained. Why was fatigue, for example, which had a mean score of 4.40 in the “Some concerns” column, ranked higher than constipation which had a mean score of 5.16? (also I note that the mean/SD figures for Fatigue and Constipation look like exact mirror images of each other and I would ask the authors to verify that this is not an error?). In Table 4, I don’t understand how/why no motor symptoms achieved a ranking for HY1 patients – does this mean that all 6 patients with HY1 rated all 12 motor symptoms as 0 (“not concerned”)? This would seem highly unusual to me.

Response: We would like to apologise for the oversight of excluding this important information and would like to thank the reviewer for giving us the opportunity to revise the manuscript. Patients were asked to rate their concerns for each item on a severity scale from 0 (not concerned) to 10 (most concerned) based on their experience during the past month. Then, the severity of 0-6 was graded as ‘Some concern’ while 7-10 was considered as ‘Most concerning’. As this study focuses on the impact of disease stage and age at PD onset on patients’ primary concerns, we have revised the tables to include the results of ‘Most concerning’ as the main findings to avoid uncleared interpretation for our potential readers.

To clarify the issue on the grading of the severity of patients’ concerns, we have revised the manuscript, which reads as follows:

(Page 7)

Therefore, our study aimed to explore patient’s greatest concern about a range of factors, such as their overall feeling of happiness, the impact of adverse events, and issues regarding palliative care and assistive devices, in addition to motor symptoms and NMS.

(Page 9)

Patients were asked to rate their concerns for each item on a severity scale from 0 (not concerned) to 10 (most concerned) based on their experience during the past month. The severity was further classified as ‘Some concern’ for the rating between 0 and 6 and ‘Most concerning’ for the rating between 7 and 10. The distinction between ‘Some concern’ and ‘Most concerning’ was determined by the consensus of the Chulalongkorn Parkinson Patients’ Support Group, represented by two authors (RP and MC), who perceived that the severity for ‘Most concerning’ should reflect the 30% end of the severity spectrum.

Table 2 has also been revised to demonstrate the findings for most concerning symptoms in various domains together with overall severity.

With regards to table 4 where the reviewer does not understand how/why no motor symptoms achieved a ranking for HY1 patients, this is because we have only reported the most concerning symptoms in table 4 according to HY stages. As none of the motor symptoms were rated as most concerning by HY1 patients, they did not feature in this table. We have therefore revised the following statements to clarify the results of table 4 and provided further explanation in the discussion to clarify the results of concerns relating to motor symptoms rated by HY1 patients.

(Page 18)

When patients’ greatest concerns about motor symptoms and NMS were analysed according to their HY stage, it was found that patients at HY stage 1 generally did not report great concerns about motor symptoms whilst patients at more advanced HY stages described symptoms of greatest concern relating to problems with walking and/or balance, freezing of gait, and getting out of bed (Table 4). On the other hand, patients at HY stage 1 reported greatest concern about NMS such as constipation, lack of interest or enthusiasm, or urinary problems. Overall, constipation was rated as the most concerning NMS. While patients at HY stage 1 did not report great concerns about motor symptoms, they shared some concerns on problems with walking and/or balance in 66% of patients, followed by difficulty speaking and shaking both in half of patients.

(Page 30)

It is interesting to observe that none of patients at HY stage 1 reported their greatest concerns about motor symptoms, their greatest concerns related to constipation, lack of interest, and urinary problems. However, patients at HY stage 1 did share some concerns (but not greatest concerns) on a range of motor symptoms, including problems with walking and balance, difficulty speaking, and shaking but with lesser severity. It is possible that these HY stage 1 patients, who were relatively new to the diagnosis, were focusing on their most current troublesome NMS, rather than the less troublesome motor symptoms, which might have responded well to current dopaminergic medications. As far as we are aware, there is no previous information on patients’ concerns in different HY stages. The closest study that we could identify reported patient’s perspectives in early PD patients from the UK with up to 6 years of disease duration of which motor symptoms, including tremor, slowness, and stiffness, were rated as the most troublesome symptoms but bowel problems were also included within the top 10 most bothersome symptoms in this study [1]. Different results may reflect different study group populations. These findings should be further explored in a larger group of patients to determine a range of significant concerns that may be our targets for treatment in early stage patients.

2) Similarly, regarding the statement in the results: “Drug-induced dyskinesia was not rated by patients as a concerning symptom”, does this mean that no patient gave this item a rating of at least 1/10? This seems to be at odds with the authors’ statement that young-onset PD patients were concerned about drug-induced dyskinesia. This important (and perhaps controversial) point regarding dyskinesias not being an issue of patient was again mentioned in the Discussion and the authors should present the data in the manuscript text itself to substantiate this point.

Response: As clarified in item 1, we reported on the most concerning symptoms with regards to symptom fluctuations. As a result, drug-induced dyskinesia was not rated amongst the top three most concerning symptoms in both young-onset or typical onset PD patients as shown in table 5. However, young-onset PD patients (33.3%) did report significantly greater symptom concern on drug induced dyskinesia than typical onset PD patients (9%). Therefore, we have included the following statement to provide the results on drug-induced dyskinesias.

(Page 22)

Even though drug-induced dyskinesia was not rated amongst the top three most concerning symptoms by either groups of patients, young-onset PD patients reported drug-induced dyskinesia as a most concerning symptom significantly more than typical-onset PD patients (33.3% vs 9%, p < 0.001).

(Page 30-31)

In addition, drug-induced dyskinesia was not found to be a most concerning symptom in the patients surveyed in this study except for a group of young-onset PD patients who identified drug-induced dyskinesia as a most concerning symptom significantly more than typical-onset patients although they did not rate it within the top three most concerning symptoms related to fluctuation.

(Page 31)

When an impact of dyskinesia on activities of daily living (ADLs) was evaluated, the percentage of patients reporting severe impact on ADLs by dyskinesia was less than 5%. Moderate impact was less than 30% whereas the majority reported mild or even no impact from dyskinesia [36]. Nevertheless, dyskinesia is the visible sign that might lead to social embarrassment or stigmatisation and continue to be a matter of debate on its impact on different subgroups of PD patients. Whilst the prevalence of troublesome dyskinesia is falling in a number of recent studies, the presence of dyskinesia is still a matter of concern, particularly those with troublesome or disabling dyskinesia, or at-risk PD populations (e.g. young-onset patients) [37, 38].

3) I would probably tone down claims that the PDPCQ was “validated” (e.g. 1st sentence of the Discussion: “Our study using the validated PDPCQ…”), since it appears that only content validation/IOC was performed – and many other validation tests/metrics were not performed (e.g., can say “preliminary” validation was conducted). A brief inspection of the instrument reveals a number of areas that will need to be improved e.g., for future use: (i) “Shaking” without further clarification, to (presumably) denote “Tremor” (however, it is well known that patients not uncommonly say “shaking” to describe dyskinesias); (ii) I am not sure why “Social activities” – which will commonly be influenced by many issues including non-motor features such as anxiety – should be categorized as a “motor” concern; (iii) Although it is true that “Weight loss” is more common in advanced PD, studies have shown that this is often also an early feature of PD; (iv) I am doubtful that the dichotomous choice of “Need” vs “No need” really captures “concerns” about assistive devices, e.g., stigma associated with the use of walking aids; (v) In the “Adverse events” section, I have concerns about how patients are meant to interpret e.g., “General symptoms” or “Cardiovascular symptoms” (postural giddiness??). It is of course too late to alter the questionnaire for the purpose of publishing this paper, but some of these issues should at least be discussed as study limitations.

Response: We agree with the reviewer on the limitations of the current instrument. As such, we have replaced the term of “validated questionnaire” with “survey” and have addressed the limitations of the current survey as shown below.

(Page 35)

Limitations of the study relate to its single-centre design and cross-sectional assessment which limits the possibility to see how these concerns may have evolve as disease progresses. Moreover, the validation of this survey is still preliminary as demonstrated by content validation but still lacks a complete process of reliability and external validity assessment. It is also possible that certain items of the survey could be misinterpreted by patients. For example, “shaking” can be interpreted by patients as either tremor or dyskinesia. The exclusion of patients with dementia may potentially exclude conclusions or statements from patients with advanced disease.

4) The authors should not report that a result is “statistically significant” without specifying the actual values/effect size at the same time, e.g., in the Results: “…, both of which had statistically significant odd ratios”. The latter are arguably more important than statistically significance. Please rectify this elsewhere in the manuscript too.

Response: Supplementary data 3 was provided with results, including actual values and effect size. Moreover, we have revised the statistical analysis part, which is read as follows:

(Page 10)

An unpaired t-test was used to compare the differences for continuous variables where the data were fit to a normal distribution for the comparison of the above three subgroups where data was fitted to a normal distribution. In addition, an effect size for mean differences of the PDPC survey scores of PD patients with and without caregivers was calculated for Cohen’s d.

5) For Table 3, it is unclear how many/what factors were considered for entry into the model, prior to the 2 items (“Difficulty chewing/swallowing” and “Getting out of bed”) emerging as predictive factors.

Response: The following factors were included into the model, which is described as follows:

(Page 10-11)

To identify predictors of having a caregiver, binary logistic regression analysis was performed in which the presence of caregiver need was a dependent variable and twenty participant-related variables were selected to run into the logistic model as independent variables, including problems with walking and/or balance, getting out of bed, freezing of gait, constipation, daytime sleepiness, pain and/or aching, slow movement, muscle cramping, difficulty performing fine finger movements, any stiffness, marked decline in physical ability, cognitive difficulties (part of NMS), bedridden wheelchair bound, difficulty swallowing, cognitive difficulties (part of symptoms of the advance stage), age, gender, presence of postural instability, and presenting symptoms of bradykinesia. Goodness-of-fit statistics using the Hosmer–Lemeshow test helped to determine whether the model adequately described the data and indicated a poor fit if the significance value was <0.05. The logistic model was undertaken with Forward (Wald) stepwise technique in order to select the most predicable variables to determine caregiver need in PD patients. The predictors were reported as odds ratio (OR) with a p-value of <0.05 (2-tailed) considered statistically significant.

Minor comments

1) In the Results, the meaning of the statement “half of the patients…had support from caregivers”. Do the authors mean that half of the patients needed help from caregivers? In Table 1, I think the same thing is phrased as “Presence of caregiver” which could mean something else, e.g., that a caregiver was present during the administration of the questionnaire. The “presence of caregivers was significantly higher…” is again mentioned in the Results section, with unclear meaning.

Response: To avoid unclear meaning, we have provided the definition of the “presence of caregiver” in our study as follows:

(Page 9)

The presence of caregiver in this study refers to a stable main caregiver, which is defined as any person who, without being a professional or belonging to a social support network, usually lives with the patient and, in some way, is directly implicated in the patient’s care or is directly affected by the patient’s health problem [30].

2) In Table 1, bracket signs in the table are inverted, please correct.

Response: Thanks so much for spotting these errors. We are unsure why these inverted brackets occurred in the pdf version, but not the word document when submitted. We will check when submitting the revision to ensure that there are no typos or technical errors.

3) In Table 1, the meaning of “Presenting symptoms” is unclear. Do the authors mean symptoms endorsed by the patient to be present at the time when the questionnaire was done? Or symptoms occurring at the time of initial disease presentation?

Response: It is the presenting symptoms at the time of diagnosis and table 1 has been revised accordingly.

4) I am not sure that I agree with the statement: “Trying to fine-tune dopaminergic medications…to improve motor symptoms…is likely to worsen a patient’s constipation”. On what basis do the authors make this statement? I am not aware of good evidence indicating that levodopa worsens constipation, nor dopamine agonists except those with anticholinergic activity such as piribedil.

Response: We have removed this statement to avoid misunderstanding.

Reviewer #2: This is an important topic and overall the authors have done a laudable job. My main concern is with the “development and validation” of their scale which is not provided in sufficient detail and would probably be its own manuscript if done with reliable item selection and other psychometric methods. Other concerns are mainly to do with clarity. Comments by section.

Abstract

1) In methods it states this scale was developed and validated. It is not clear here whether this was done and previously published or if this was part of the current paper. If the goal of the current paper more details are needed.

Response: We have changed the term Parkinson’s Disease Patients’ Concerns Questionnaire to survey on Parkinson’s Disease Patients’ Concerns (PDPC Survey) and have provided additional details on the process of construction of this survey in the methods section.

(Page 3)

A 50-item survey on Parkinson’s Disease Patients’ Concerns (PDPC Survey) was developed by a multidisciplinary care team.

2) Unclear how a cross-sectional study could be “randomized”, nor how this relatively small study of a single new scale be called “comprehensive”.

Response: We have revised the sentence to read as follows:

(Page 3)

This study, in an Asian cohort, provides an assessment of a wide range of PD patients’ concerns, encompassing not only motor symptoms and NMS, but also treatment-related adverse events, care in the advance stage disease, and the need for assistive devices in an Asian patient cohort.

Intro

3) 2nd sentence in the first paragraph should have references.

Response: References have been included, thank you.

4) If a goal of this paper is to develop and validate a new scale this should be clearly stated. If this scale was previously validated, this should be referenced.

Response: The aim of this study was to explore patient’s concerns about a range of factors in addition to motor symptoms and NMS. The term ‘scale’ has been revised into a survey as previously mentioned.

Methods

5) What is ChulaPD?

Response: ChulaPD is the abbreviation for the name of our institute; Chulalongkorn Centre of Excellence for Parkinson’s Disease and Related Disorders. The details have been provided as follows:

(Page 7)

A multidisciplinary care team at Chulalongkorn Centre of Excellence for Parkinson’s Disease and Related Disorders (ChulaPD, www.chulapd.org)

(Page 9)

Between March and June 2019, the PDPC Survey-Thai version was administered by one of the healthcare team to PD patients attending outpatient clinics of the ChulaPD, which is a main tertiary referral centre for PD, affiliated with Chulalongkorn University Hospital and the Thai Red Cross society.

6) As I understand it, the questionnaire was developed by a movement team coming up with 50 questions to cover several areas of interest. I am not a scale development expert but this does not seem adequate – most scales go through several iterations of item development, including work with the population of interest to make sure items are representative, understandable and clinimetrically sound. It may be more fair to say you performed a cross-sectional survey and present those results than developed and validated a scale.

Response: We agree with the reviewer that this is a cross-sectional study with the survey to explore most concerns of Parkinson’s Disease patients. The manuscript has been revised throughout to reflect this change.

7) Do we know how patients interpreted the term “concerns” – e.g., current problems vs. future worries vs. both, or perhaps variable between people.

Response: We have undertaken a literature review and were unable to find the scope of concerns. In our personal view, concerns could be both current problems or future worries or even something in between. We have provided our personal view as follows:

(Page 5)

In a broad sense, concerns reflect what we believe or perceive and, in the setting of PD, could be current problems, future worries, both, or even something in between.

8) It is unclear what the domain “palliative care” means. It seems that this is used to described advanced disease.

Response: We have replaced the term “palliative care” with a more appropriate term as “care in the advanced stage”.

9) It is unclear what it means that the survey was “randomly” distributed. I assume this is simply a convenience sample and that there was no sampling strategy.

Response: The reviewer is correct and we have removed the term ‘random’ from the statement.

Results

10) Parentheses are backwards in Table 1

Response: This comment is similar to reviewer# 1. We are unsure why these inverted brackets occurred in the pdf version, but not the word document when submitted. We will check when submitting the revision to ensure that there are no typos or technical errors.

11) It is unclear how “given the most concern” was determined. Was this simply score = 10? The highest score? Using some cut-point? Whatever the method, it should be clearly described and justified.

Response: We would like to apologise for the oversight of excluding this important information and would like to thank the reviewer for giving us the opportunity to revise the manuscript. Patients were asked to rate their concerns for each item on a severity scale from 0 (not concerned) to 10 (most concerned) based on their experience during the past month. Then, the severity of 0-6 was graded as ‘Some concern’ while 7-10 was considered as ‘Most concerning’. As this study focuses on the impact of disease stage and age at PD onset on patients’ primary concerns, we have revised the tables to include the results of ‘Most concerning’ as the main findings to avoid uncleared interpretation for our potential readers.

To clarify the issue on the grading of the severity of patients’ concerns, we have revised the manuscript, which reads as follows:

(Page 7)

Therefore, our study aimed to explore patient’s greatest concerns about a range of factors, such as their overall feeling of happiness, the impact of adverse events, and issues regarding palliative care and assistive devices, in addition to motor symptoms and NMS.

(Page 9)

Patients were asked to rate their concerns for each item on a severity scale from 0 (not concerned) to 10 (most concerned) based on their experience during the past month. The severity was further classified as ‘Some concern’ for the rating between 0 and 6 and ‘Most concerning’ for the rating between 7 and 10. The distinction between ‘Some concern’ and ‘Most concerning’ was determined by the consensus of the Chulalongkorn Parkinson Patients’ Support Group, represented by two authors (RP and MC), who perceived that the severity for ‘Most concerning’ should reflect the 30% end of the severity spectrum.

12) The “caregiver support” section is confusing. How was “palliative care stage” defined? The statement on “factors predictive of need for caregiver support” is misleading. As I understand it, these are simply factors associated with having a caregiver.

Response: We have replaced the term ‘palliative care’ with ‘care in the advanced stage’ and have provided the definition of advanced PD as follows:

(Page 9)

Since there is no consensus on the definition of early and advanced stages of PD, we adopted the traditional classification of early and advanced stages according to the HY scale where bilateral segmental involvement with postural and gait impairment (HY stage > 3), which also marks a clinical milestone, classifies advanced stage whereas early stage refers to those with HY stage 1-2 [31].

With regards to caregiver support, we also agree with the reviewer that those factors were associated with having a caregiver. Therefore, the following sentences are included for further clarification.

(Page 9)

The presence of caregiver in this study refers to a stable main caregiver, which is defined as any person who, without being a professional or belonging to a social support network, usually lives with the patient and, in some way, is directly implicated in the patient’s care or is directly affected by the patient’s health problem [30].

(Page 10-11)

To identify predictors of having a caregiver, binary logistic regression analysis was performed in which the presence of caregiver need was a dependent variable and twenty participant-related variables were selected to run into the logistic model as independent variables, including problems with walking and/or balance, getting out of bed, freezing of gait, constipation, daytime sleepiness, pain and/or aching, slow movement, muscle cramping, difficulty performing fine finger movements, any stiffness, marked decline in physical ability, cognitive difficulties (part of NMS), bedridden wheelchair bound, difficulty swallowing, cognitive difficulties (part of symptoms of the advance stage), age, gender, presence of postural instability, and presenting symptoms of bradykinesia. Goodness-of-fit statistics using the Hosmer–Lemeshow test helped to determine whether the model adequately described the data and indicated a poor fit if the significance value was <0.05. The logistic model was undertaken with Forward (Wald) stepwise technique in order to select the most predicable variables to determine caregiver need in PD patients. The predictors were reported as odds ratio (OR) with a p-value of <0.05 (2-tailed) considered statistically significant.

(Page 17)

The predominant concerns in the advanced stage were factors found to be predictive of having a caregiver, namely chewing and swallowing, and getting out of bed, both of which had statistically significant odds ratios (Table 3 and Supplementary data 3).

13) I find it hard to believe that HY1 really had no concerns about motor symptoms. They ranked everything as 0? Perhaps this is an issue with the survey although I would believe that nonvoter concerns might outweigh motor concerns.

Response: We apologise for the misleading table in which we have corrected table 4 to indicate that only results of most concerning symptoms were included. None of the motor symptoms were rated as most concerning by HY1 patients. We have therefore revised the following statements to clarify the results of table 4 and provide the discussion to clarify the results of concerns on motor symptoms rated by HY1 patients.

(Page 18)

When patients’ greatest concerns about motor symptoms and NMS were analysed according to their HY stage, it was found that patients at HY stage 1 generally did not report great concerns about motor symptoms whilst patients at more advanced HY stages described symptoms of most concerns relating to problems with walking and/or balance, freezing of gait, and getting out of bed (Table 4). On the other hand, patients at HY stage 1 reported greatest concerns about NMS such as constipation, lack of interest or enthusiasm, or urinary problems. Overall, constipation was rated as the most concerning NMS. While patients at HY stage 1 did not report great concerns about motor symptoms, they shared some concerns on problems with walking and/or balance in 66% of patients, followed by difficulty speaking and shaking both in half of patients.

(Page 30)

It is interesting to observe that none of patients at HY stage 1 reported their greatest concerns about motor symptoms, their greatest concerns related to constipation, lack of interest, and urinary problems. However, patients at HY stage 1 did share some concerns (but not greatest concerns) on a range of motor symptoms, including problems with walking and balance, difficulty speaking, and shaking but with lesser severity. It is possible that these HY stage 1 patients, who were relatively new to the diagnosis, were focusing on their most current troublesome NMS, rather than the less troublesome motor symptoms, which might have responded to current dopaminergic medications. As far as we are aware, there is no previous information on patients’ concerns in different HY stages. The closest study that we could identify reported patient’s perspectives in early PD patients from the UK with up to 6 years of disease duration of which motor symptoms, including tremor, slowness, and stiffness, were rated as the most troublesome symptoms but bowel problems were also included within the top 10 most bothersome symptoms in this study [1]. Different results may reflect different study group populations. These findings should be further explored in a larger group of patients to determine a range of significant concerns that may be our targets for treatment in early stage patients.

14) Table 4 (and related text) is confusing. How was “rated 1st” determined? Most common (and if so is this simply a score above 1)? Highest mean score? Highest mean score amongst those reporting the symptoms? How is it possible that some categories have multiple items ranked 1st? Did they have exactly the same score?

Response: We have revised table 4. The ranking was performed based on the percentage of patients who rated that particular symptoms as most concerning. Therefore, it is possible that some symptoms have the same score.

15) For the subgroup analyses (e.g. by age of onset) do we know if the differences between groups were statistically significant? Some of the differences mentioned seem small.

Response: Effect size could not be determined in this subgroup analyses due to categorical data of these variables. However, statistical comparison was performed as shown in Supplementary data 4.

16) How is early and advanced stage PD defined? How is it that over 13% of early stage PD need wheelchairs?

Response: We provide the definition of early and advanced PD as shown below. As this study asked patients to rate their concerns on needs for assistive devices, which may be inclusive of future worries, it is possible that early PD patients rated their needs for wheelchairs based on their concerns for future symptoms. Additional statements were included for further clarification.

(Page 9)

Since there is no consensus on the definition of early and advanced stages of PD, we adopted the traditional classification of early and advanced stages according to the HY scale where bilateral segmental involvement with postural and gait impairment (HY stage > 3), which also marks a clinical milestone, classifies advanced stage whereas early stage refers to those with HY stage 1-2 [31].

(Page 32)

As patients rated this section based on their needs for assistive devices, the interpretation of their responses as ‘needed’ could have different meanings. For example, patients may indicate their needs for assistive devices based on either current symptoms or their worries for future symptoms. Likewise, patients may not express their needs for these devices as they may perceive these devices as a symbol of disability.

Discussion

17) This section starts by stating “the validated PDPCQ”. A reference is needed. I do not think this paper is adequate to claim this is a validated scale.

Response: The reviewer is correct and we have revised the sentence to read as follows:

(Page 28)

Our study using the PDPC survey found that patients’ concerns about their symptoms vary widely and depend on how they perceive their motor symptoms, NMS, fluctuations, and overall treatment experience, at different disease stages, which reflects in the results of previous studies (1, 2).

18) Second paragraph calls into question how patients are interpreting questions and whether most interpret them in the same way. If we do not know this basic question, or if the term in the survey is vague or could have multiple meanings it calls into question findings.

Response: The items of this survey was generated by the multidisciplinary team, which is also inclusive of patients and their caregivers. A positive content validation was also achieved when tested by another expert panel who were not involved with item generation. However, we also agree with the reviewer that it is possible that patients perceive their concerns in different ways as they may base their concerns for current symptoms or future symptoms or both. Nevertheless, our study aims to understand patients on their concerns, which can be subjective in some ways, but are also important for treating physicians to understand patient’s perspectives.

19) Another big concern is the exclusion of patients with MCI or dementia in a study that claims to be “comprehensive”. 75% of people with PD will develop dementia - excluding such persons limits conclusions and statements around people with advanced disease.

Response: As we aim this survey to explore patient’s concerns based on self-administered instrument, it is important for subjects to be cognitively impact in order to provide reliable responses. However, we also recognise this as part of the limitation in which the following statements are included.

(Page 35)

Limitations of the study relate to its single-centre design and cross-sectional assessment which limits the possibility to see how these concerns may have evolve as disease progresses. Moreover, the validation of this survey is still preliminary as demonstrated by content validation but still lacks a complete process of reliability and external validity assessment. It is also possible that certain items of the survey could be misinterpreted by patients. For example, “shaking” can be interpreted by patients as either tremor or dyskinesia. The exclusion of patients with dementia may potentially exclude conclusions or statements from patients with advanced disease.

I would like to confirm that all authors have read the manuscript; the paper has not been previously published, and is not under simultaneous consideration by another journal. There is also no ghost writing by anyone not named on the author list.

There is no conflict of interest on all authors and we will take full responsibility for the data, the analyses and interpretation, and the conduct of the research. We had full access to all of the data; and that we had the right to publish any and all data, separate and apart from the attitudes of the sponsor.

We would like to confirm that the manuscript has been reviewed by a native English speaker for style and grammatical accuracy. Thank you very much for consideration our manuscript for publication. Please let me know if there are any questions.

We are grateful to the editors and reviewers for the time and effort that they have put into helping us improve our manuscript.

Sincerely,

Roongroj Bhidayasiri

Corresponding author:

Roongroj Bhidayasiri, MD., FRCP., FRCPI.

Chulalongkorn Center of Excellence on Parkinson Disease and Related Disorders

Chulalongkorn University Hospital

1873 Rama 4 Road

Bangkok 10330

Thailand

Tel: +662-256-4000 ext. 70701

Fax: +662-256-4630

Email address: rbh@chulapd.org

Attachment

Submitted filename: ResponseReviewers-PONE-D-20-18129.docx

Click here for additional data file. (305KB, docx)

Decision Letter 1

Mathias Toft

30 Oct 2020

PONE-D-20-18129R1

Impact of disease stage and age at Parkinson’s onset on patients’ primary concerns: Insights for targeted management

PLOS ONE

Dear Dr. Bhidayasiri,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that the manuscript has substantially improved. There are only a few minor issues left, as pointed out by one of the reviewers. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Mathias Toft, MD, PhD

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

**********

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Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thank you, this is a much improved version of the manuscript.

___________________________________________________

Reviewer #2: The authors have done a laudable job of improving this paper. I have only a few remaining comments:

- Now that I understand "most concerning" I think the results (including abstract) might be more accurately labeled as "most commonly concerning" (meaning item where the most people rated it as highly concerning) rather than "most concerning", which I would take to mean as highest ratings of concern.

- In Methods, it may be prudent to rename first section "Survey development and partial validation" or "Survey development and steps of validation" and/or end section by saying that "other aspects of survey development and validation were not pursued" to make it clear to readers that this is not a fully validated or clinimetrically tested instrument.

- In tables I would eliminate the "Ranked 1st" "Ranked 2nd"... The order of the items is clear. I think the "Ranked 1st" adds some confusion as it gives the impression that patients actually rank ordered their responses, which did not happen as I understand it.

- The results section 'caregiver support' should be renamed. Perhaps "concerns in advanced disease' as it really does not assess caregiver support. Also, Table 3 should be similarly renamed or at minimum state items associated with presence of a caregiver rather than "predictors" which implies a temporal and causal association.

- I would change sentence on dementia in the Limitations section to something like: "As the majority of patients with PD will experience dementia, their exclusion in this study may limit the generalizability of results."

**********

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Reviewer #1: No

Reviewer #2: Yes: Benzi Kluger

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PLoS One. 2020 Dec 2;15(12):e0243051. doi: 10.1371/journal.pone.0243051.r004

Author response to Decision Letter 1

12 Nov 2020

12 November 2020

Mathias Toft, MD., PhD.

Academic Editor

PLoS One

Dear Prof. Toft,

Re: Manuscript # PONE-D-20-18129R1: Impact of disease stage and age at Parkinson’s onset on patients’ primary concerns: Insights for targeted management

Thank you very much for your letter of the 30th of October 2020. We found the editor’s and reviewer’s comments very helpful and respond to them as follows:

Reviewer #1: Thank you, this is a much improved version of the manuscript.

Response: We would like to thank the reviewer for his/her suggestions that have improved our manuscript.

Reviewer #2: The authors have done a laudable job of improving this paper. I have only a few remaining comments:

1) Now that I understand “most concerning” I think the results (including abstract) might be more accurately labeled as “most commonly concerning” (meaning item where the most people rated it as highly concerning rather than “most concerning”, which I would like mean as highest ratings of concern.

Response: Thanks so much for this suggestion. We have revised the manuscript to use the term ‘most commonly concerning’ instead of ‘most concerning’ in the manuscript. Moreover, we have clarified the term ‘most commonly concerning’ with the definition suggested by the reviewer. It reads as follows:

(Page 9)

Results were reported in a form of most commonly concerning symptoms, referring to what the most patients rated these symptoms as highly concerning.

2) In Methods, it may be prudent to rename the first section “Survey development and partial validation” or “Survey development and steps of validation” and/or end section by saying that “other aspects of survey development and validation were not pursued” to make it clear to readers that this is not a fully validated or clinimetrically tested instrument.

Response: We have renamed the section as “Survey development and steps of validation” and also ended the section by stating that other aspects of survey development and validation were not performed as shown on pages 7 and 8.

3) In tables, I would eliminate the “Ranked 1st” “Ranked 2nd” …. The order of the items are clear. I think the “Ranked 1st” adds some confusion as it gives the impression that patients actually rank ordered their responses, which did not happen as I understand it.

Response: Tables 2, 4, and 5 were revised as suggested by the reviewer.

4) The results section ‘caregiver support’ should be renamed. Perhaps “concerns in advanced disease’ as it really does not assess caregiver support. Also, Table 3 should be similarly renamed or at minimum state items associated with presence of a caregiver rather than “predictors” which implies a temporal and causal association.

Response: Revision of a section name and revision of table 3 were performed as suggested by the reviewer.

5) I would change sentence on dementia in the Limitations section to something like: “As the majority of patients with PD will experience dementia, their exclusion in this study may limit the generalizability of results.

Response: As suggested by the reviewer, we have revised the sentence to be as follows:

(Page 34)

As the majority of PD patients will experience dementia, the exclusion of this patient group from the study may limit the generalisability of results.

I would like to confirm that all authors have read the manuscript; the paper has not been previously published, and is not under simultaneous consideration by another journal. There is also no ghost writing by anyone not named on the author list.

There is no conflict of interest on all authors and we will take full responsibility for the data, the analyses and interpretation, and the conduct of the research. We had full access to all of the data; and that we had the right to publish any and all data, separate and apart from the attitudes of the sponsor.

We would like to confirm that the manuscript has been reviewed by a native English speaker for style and grammatical accuracy. Thank you very much for consideration our manuscript for publication. Please let me know if there are any questions.

We are grateful to the editors and reviewers for the time and effort that they have put into helping us improve our manuscript.

Sincerely,

Roongroj Bhidayasiri

Corresponding author:

Roongroj Bhidayasiri, MD., FRCP., FRCPI.

Chulalongkorn Center of Excellence on Parkinson Disease and Related Disorders

Chulalongkorn University Hospital

1873 Rama 4 Road

Bangkok 10330

Thailand

Tel: +662-256-4000 ext. 70701

Fax: +662-256-4630

Email address: rbh@chulapd.org

Attachment

Submitted filename: ResponseReviewers-PONE-D-20-18129R1.docx

Click here for additional data file. (256.9KB, docx)

Decision Letter 2

Mathias Toft

16 Nov 2020

Impact of disease stage and age at Parkinson’s onset on patients’ primary concerns: Insights for targeted management

PONE-D-20-18129R2

Dear Dr. Bhidayasiri,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

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Kind regards,

Mathias Toft, MD, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: (No Response)

**********

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If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: Yes: Benzi Kluger

Acceptance letter

Mathias Toft

19 Nov 2020

PONE-D-20-18129R2

Impact of disease stage and age at Parkinson’s onseton patients’ primary concerns: Insights for targeted management

Dear Dr. Bhidayasiri:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr Mathias Toft

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Table. The Parkinson’s Disease Patients’ Concerns Survey (PDPC Survey).

    (DOCX)

    Click here for additional data file. (29KB, docx)
    S2 Table. Comparison of the characteristics and PDPC Survey of patients with caregivers and those without.

    (DOCX)

    Click here for additional data file. (27.1KB, docx)
    S3 Table. Patients’ concerns on motor and non-motor symptoms: comparison between young-onset and typical-onset PD patients.

    (DOCX)

    Click here for additional data file. (34KB, docx)
    S1 Data. Development and validation of the Parkinson’s Disease Patients’ Concerns Survey (PDPC Survey).

    (DOCX)

    Click here for additional data file. (37.1KB, docx)
    Attachment

    Submitted filename: ResponseReviewers-PONE-D-20-18129.docx

    Click here for additional data file. (305KB, docx)
    Attachment

    Submitted filename: ResponseReviewers-PONE-D-20-18129R1.docx

    Click here for additional data file. (256.9KB, docx)

    Data Availability Statement

    All relevant data are within the manuscript and its Supporting Information files.

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