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. 2021 Oct 21;16(10):e0258897. doi: 10.1371/journal.pone.0258897

Validation of the Korean version of the composite autonomic symptom scale 31 in patients with Parkinson’s disease

Jong Hyeon Ahn 1,2,#, Jin Myoung Seok 3,#, Jongkyu Park 3, Heejeong Jeong 4, Younsoo Kim 5, Joomee Song 1,2, Inyoung Choi 1,2, Jin Whan Cho 1,2, Ju-Hong Min 1,2, Byoung Joon Kim 1,2,*, Jinyoung Youn 1,2,*
Editor: Antonina Luca6
PMCID: PMC8530281  PMID: 34673815

Abstract

Purpose

The composite autonomic symptom scale-31 (COMPASS-31) is a self-rated questionnaire that evaluates diverse autonomic symptoms. In the present study, we developed the Korean version of the COMPASS-31 (K-COMPASS-31) with appropriate translation, and verified its reliability and internal and external validity in patients with Parkinson’s disease (PD).

Methods

The original COMPASS-31 was translated independently into Korean by two bilingual neurologists. Test-retest reliability was evaluated at a 2-week interval. We investigated the correlations between the K-COMPASS-31, the scale for outcomes in PD-autonomic (SCOPA-AUT), and the results of an autonomic function test (AFT), respectively.

Results

A total of 90 patients with PD (47 females; mean age, 63.4 ± 10.8 years) were enrolled. The K-COMPASS-31 showed excellent test-retest reliability (intra-class correlation coefficient = 0.874, p < 0.001) and internal validity (Cronbach’s α-coefficient = 0.878). The COMPASS-31 was positively correlated with SCOPA-AUT (r = 0.609, p < 0.001) and the results of the AFT.

Conclusions

In conclusion, the K-COMPASS-31 showed excellent reliability and validity for the assessment of autonomic symptoms in PD patients. The K-COMPASS-31 is an easy-to-repeat and widely used tool for investigating autonomic dysfunction in various neurologic disorders and enables comparison of autonomic dysfunction among neurologic disorders. We recommend the K-COMPASS-31 as a valid instrument for use in clinical practice for patients with PD.

Introduction

Autonomic dysfunction is one of the central features of non-motor symptoms in Parkinson’s disease (PD) [1]. Objective evaluation of autonomic function in PD is an essential part of differential diagnosis [2]; however, autonomic function tests require extensive time and expensive equipment only available at tertiary centres. Thus, some studies have used patient-reported questionnaires as a surrogate for the assessment of autonomic dysfunction in PD patients [3]. The scale for outcomes in Parkinson’s disease-autonomic (SCOPA-AUT), which was developed to evaluate autonomic symptoms, is widely used in patients with PD [4]. To better understand autonomic dysfunction in PD in comparison with other neurological disorders that involve the autonomic system, other reliable questionnaires that include parameters that can be compared with the results of autonomic function testing (AFT) are needed.

The composite autonomic symptom scale-31 (COMPASS-31) questionnaire, a self-rated questionnaire that evaluates diverse autonomic symptoms [5], has been reported as a useful tool for the evaluation of autonomic dysfunction in many neurological diseases including multiple sclerosis, small fibre neuropathy, and parkinsonism [6–8]. Therefore, in the present study, we developed a Korean version of the COMPASS-31 with appropriate translation, and verified its reliability and internal and external validity in patients with PD by evaluating agreement between the COMPASS-31 and AFT results.

Materials and methods

Subjects and clinical assessments

This study was approved by the local institutional review board of Samsung Medical Centre, Soonchunhyang University Hospital Cheonan, Gyeongsang National University Changwon Hospital, and Samsung Changwon Hospital, and all enrolled subjects provided written informed consent. We prospectively enrolled patients with PD from January 2019 to October 2020 from movement disorder clinics at four tertiary medical centres including Samsung Medical Centre, Soonchunhyang University Hospital Cheonan, Gyeongsang National University Changwon Hospital, and Samsung Changwon Hospital. Patients were enrolled if they were diagnosed with PD based on the UK Brain Bank Criteria for PD [9]. Patients were excluded if they had structural brain lesions, other known neurodegenerative diseases, cognitive impairment (mini-mental status examination score of < 26 or fulfilment of DSM-IV criteria for dementia) [10], psychiatric disorders requiring medication, malignancy, or musculo-skeletal problems mimicking parkinsonism. In addition, we also excluded patients with medical conditions including cardiac failure or arrhythmia, end-stage renal disease, diabetes mellitus, and other autonomic neuropathies that could affect AFT results.

Demographic and clinical data were collected for all enrolled patients. Parkinsonian motor symptoms were evaluated with the Unified Parkinson’s Disease Rating Scales (UPDRS) part III, and modified Hoehn and Yahr (H&Y) stages during the medication ‘ON’ state [11,12]. The UPDRS part III was grouped into tremor (items 20 and 21), rigidity (item 22), bradykinesia (items 23, 24, 25, 26, and 31), and axial motor symptoms (items 27, 28, 29, and 30) [13]. Patients were classified into three subtypes according to dominant parkinsonian symptoms: tremor-dominant (TD), akinetic-rigid (AR) and the mixed subtypes [14]. Levodopa equivalent daily dose (LEDD) was calculated based on a previous study [15]. Global cognition was checked with the Korean version of the mini-mental state examination (K-MMSE) [16] and parkinsonian non-motor symptoms were evaluated with the Korean version of the non-motor symptoms scale for PD (K-NMSS) [17]. In addition, quality of life was assessed using PD questionnaire-39 (PDQ-39) [18].

COMPASS-31 questionnaire and translation

The COMPASS-31 questionnaire consists of 31 items in 6 domains: orthostatic intolerance (4 items), vasomotor (3 items), secretomotor (4 items), gastrointestinal (12 items), bladder (3 items), and pupillomotor (5 items). The total sum score for all domains adjusted with each weighting factor is from 0 to 100; a higher COMPASS-31 score indicates more severe autonomic symptoms [5]. The original COMPASS-31 English version was translated into Korean independently by two bilingual neurologists, who subsequently worked together to create a single Korean version. A panel of authors reviewed discrepancies between the Korean translation version and the original English version to confirm the accuracy of the Korean version of the COMPASS-31 (K-COMPASS-31). Finally, we tested the K-COMPASS-31 in 5 patients with PD, and interviews with them were conducted for validation.

Validation procedure

The K-COMPASS-31 was completed twice at 2-week intervals; the second K-COMPASS-31 score was used only for test-retest reliability evaluation. In addition to the K-COMPASS-31, the SCOPA-AUT and AFT battery were also applied in all patients as comparators for validation.

SCOPA-AUT is a brief, widely used questionnaire for patients with PD, which has 25 items that assess six areas; the item scores range from 0 (‘never’) to 3 (‘often’) with a maximum score of 69. The Korean version of the SCOPA-AUT was validated recently [19]. Our AFT battery included heart rate response to deep breathing (HRDB), the Valsalva manoeuvre, sympathetic skin response (SSR), and blood pressure and heart rate response to the head-up tilt test (HUT). Enrolled patients underwent the AFT battery in a standardized manner as previously reported [19–21].

Statistical analyses

Appropriate summary statistics were used to describe categorical and continuous variables. Continuous data were presented as mean with standard deviation (SD) or median with interquartile range (IQR); categorical variables were presented as absolute and relative frequencies. Sample size for the reliability test was calculated using the analysis methods suggested by Walter et al. with an acceptable reliability of 0.75, an expected reliability of 0.9, a significant level of 0.5 and a power of 80% [22]. Cronbach’s α-coefficient was used for internal consistency analysis of the K-COMPASS-31 total and for each domain, and test-retest reliability was assessed using the intra-class correlation coefficient (ICC). Validity was assessed using correlation analysis between the K-COMPASS-31 and SCOPA-AUT; Pearson partial correlation was adjusted for potential confounders that included age, sex, disease duration, education year, PD subtype, UPDRS III, and LEDD. The association of the K-COMPASS-31 with other variables including age, disease duration, UPDRS, H&Y, LEDD, NMSS, and PDQ-39 summary index (PDQ-39 SI) was also investigated. A p-value < 0.05 was considered significant. Statistical analyses were performed using SPSS for Windows version 25 (SPSS Inc. Version 25.0 Chicago, IL).

Results

Subjects and clinical characteristics

A total of 90 patients with PD (47 females, 52.2%; mean age, 63.4 ± 10.8 years) were finally enrolled. The mean disease duration was 4.2 ± 4.2 years, H&Y was 1.8 ± 0.8, and UPDRS part III score was 19.6 ± 11.3; LEDD was 417.7 ± 346.9 and only one patient was drug-naïve. Twenty-four (26.7%) patients exhibited the TD subtype, 58 patients (64.4%) the AR, and 8 patients (8.9%) the mixed subtype. Autonomic symptoms and AFT results were evaluated in all enrolled patients, and mean SCOPA-AUT score was 16.4 ± 11.2. The results of the AFT battery including HRDB, the Valsalva manoeuvre, blood pressure, and heart rate response to the HUT, sympathetic skin response and orthostatic hypotension (OH) are presented in Table 1.

Table 1. Demographic data and results of autonomic function tests for enrolled patients with Parkinson’s disease.

Enrolled patients with PD (n = 90)
Female, n (%) 47 (52.2)
Age, years (SD) 63.4 (10.8)
Disease duration, years (SD) 4.2 (4.2)
UPDRS part III (SD) 19.6 (11.3)
Motor subtype, TD/mixed/AR, n (%) 24/8/58 (26.7/8.9/64.4)
H & Y stage (SD) 1.8 (0.8)
LEDD, mg (SD) 417.7 (346.9)
MMSE (SD) 27.3 (2.1)
Autonomic function profile
SCOPA-AUT (SD) 16.4 (11.2)
E:I ratio (IQR) 1.11 (1.07–1.18)
Valsalva ratio (IQR) 1.35 (1.18–1.53)
Pressure recovery time, sec (IQR) 1.7 (1.0–4.7)
Abnormality in SSR, n (%) 13 (14.4)
Orthostatic hypotension, n (%) 23 (25.6)
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PD, Parkinson’s disease; SD, Standard deviation; IQR, Interquartile range; UPDRS, Unified Parkinson’s disease rating scale; TD, Tremor dominant subtype; AR, Akinetic-rigid subtype; H & Y, Modified Hoehn and Yahr; LEDD, Levodopa equivalent daily dose; MMSE, Mini-mental status exam; SCOPA-AUT, Scale for outcomes in Parkinson’s disease-autonomic; E:I, Expiratory: Inspiratory.

Intra-individual reliability of the K-COMPASS-31

The total K-COMPASS-31 score for enrolled patients with PD was 22.0 ± 17.4 and ranged from 0 to 75.8; the K-COMPASS-31 scores for each of the six domains of autonomic symptoms are presented in Table 2. Thirty-three patients in our study underwent K-COMPASS-31 test-retest, which showed excellent test-retest reliability with an intra-class correlation coefficient was 0.874 (95% CI, 0.744–0.938; p < 0.001). Cronbach’s α-coefficient for the K-COMPASS-31 was 0.878, and the six domains of the K-COMPASS-31 also showed good internal validity (Table 2).

Table 2. Total and domain scores of the K-COMPASS-31.

Total (n = 90) Cronbach’s α
K-COMPASS-31 domains Mean (SD) Median (range)
Total score 22.0 (17.4) 17.4 (0–75.8) 0.878
Orthostatic intolerance 9.7 (11.3) 4.0 (0–36.0) 0.879
Vasomotor 0.3 (0.9) 0 (0–4.2) 0.906
Secretomotor 4.5 (3.6) 4.3 (0–15.0) 0.605
Gastrointestinal 5.0 (3.4) 4.9 (0–13.4) 0.679
Bladder 1.8 (2.1) 1.1 (0–10.0) 0.702
Pupillomotor 0.7 (1.0) 0 (0–5.0) 0.849
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K-COMPASS-31, Korean version of the composite autonomic symptom score-31; SD, standard deviation.

Correlation with other objective and subjective measurements

Total and subdomain scores for the K-COMPASS-31 were compared with clinical features, AFT results, and the SCOPA-AUT for validation. There were significant correlations between K-COMPASS-31 score and the AFT results. E:I ratio and Valsalva ratio were negatively correlated (r = -0.240, p = 0.023; r = -0.247, p = 0.019) indicating cardiovagal dysfunction [23], and pressure recovery time (PRT), which represented adrenergic function, was positively correlated with K-COMPASS-31 score (r = 0.345, p < 0.001) (Fig 1). However, after adjusting for confounders including age, sex, disease duration, education year, PD subtype, UPDRS III, and LEDD, the K-COMPASS-31 score was correlated with E:I ratio and PRT (Table 3).

Fig 1. Correlation between the K-COMPASS-31 and SCOPA-AUT, and parameters of the autonomic function test.

Fig 1

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The K-COMPASS-31 correlated negatively with E:I ratio (r = -261, p = 0.017) (A), but not with Valsalva ratio (r = - 0.187, p = 0.091) (B), and correlated positively with pressure recovery time (r = 0.243, p = 0.027) (C). The K-COMPASS-31 score was higher in PD patients with abnormal sympathetic skin response (SSR) (19.1 ± 15.4 vs. 39.0 ± 19.3, p < 0.001) (D) and with orthostatic hypotension (33.4 ± 21.4 vs. 18.1 ± 13.9, p < 0.001) (E). Correlation matrix revealed a positive correlation between the K-COMPASS-31 and SCOPA-AUT and their subdomain scores. Pearson’s correlation coefficient values are shown (F). Correlations with nonsignificant p-values are denoted with an "X" (p ≥ 0.05).

Table 3. Correlation among K-COMPASS-31 scores, clinical features, and the results of autonomic function tests.

K-COMPASS-31 domains Agea Disease durationb SCOPA-AUTc AFT UPDRS part III H&Yc MMSEc LEDDe NMSSc PDQ-39-SIc
E:I ratioc Valsalva ratioc PRTc Totald Axiald Tremord Rigidityd Bradykinesiad
Total score -0.045 0.328g 0.609g -0.261g -0.187 0.243g 0.194 0.223e -0.038 0.215g 0.150 0.076 -0.197 0.117 0.370g 0.368g
Orthostatic intolerance 0.046 0.227g 0.472g -0.163 -0.136 0.220g 0.135 0.099g 0.004 0.160 0.124 0.037 -0.187 0.132 0.306g 0.300g
Vasomotor 0.058 0.237g 0.240g -0.145 -0.237g 0.248g 0.040 -0.061 0.088 0.049 0.051 -0.126 -0.048 0.080 0.108 0.113
Secretomotor -0.057 0.291g 0.456g -0.194 -0.203 0.140 0.409g 0.446g -0.013 0.378g 0.332g 0.173 -0.077 -0.040 0.319g 0.300g
Gastrointestinal -0.226g 0.192 0.559g -0.344g -0.181 0.217g 0.060 0.180g -0.084 0.060 0.007 -0.007 -0.169 0.089 0.174 0.208
Bladder -0.056 0.408g 0.474g -0.255g -0.041 0.137 -0.051 0.119 -0.193 0.064 -0.120 0.173 -0.132 0.033 0.313g 0.330g
Pupillomotor -0236g 0.286g 0.121 -0.016 -0.0065 -0.201 0.086 0.206 -0.043 0.032 0.046 0.055 -0.007 0.148 0.288g 0.234
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K-COMPASS-31, Korean version of the composite autonomic symptom score-31; SCOPA-AUT, Scale for outcomes in Parkinson’s disease-autonomic; E:I, Expiratory:inspiratory; PRT, pressure recovery time; UPDRS, Unified Parkinson’s disease rating scale; H&Y, Modified Hoehn and Yahr; MMSE, mini-mental state examination; LEDD, levodopa equivalent daily dose; NMSS, non-motor symptoms scale for Parkinson’s disease; PDQ-39 SI, Parkinson’s disease questionnaire-39 summary index.

aPearson partial correlation test adjusted for sex, disease duration, education years, Parkinson’s disease subtype, UPDRS III, and LEDD.

bPearson partial correlation test adjusted for age, sex, education years, Parkinson’s disease subtype, UPDRS III, and LEDD.

cPearson partial correlation test adjusted for age, sex, disease duration, education years, Parkinson’s disease subtype, UPDRS III, and LEDD.

dPearson partial correlation test adjusted for age, sex, disease duration, education years, Parkinson’s disease subtype, and LEDD.

ePearson partial correlation test adjusted for age, sex, disease duration, education years, Parkinson’s disease subtype, and UPDRS III.

gp value < 0.05.

The K-COMPASS-31 total scores were positively correlated with the SCOPA-AUT scores (r = 0.626, p < 0.001). Subdomain scores of the K-COMPASS-31 were also correlated with the SCOPA-AUT total score. The pupillomotor domain of the K-COMPASS-31 was not correlated with the total SCOPA-AUT but was correlated with the pupillomotor subscore of the SCOPA-AUT (Fig 1).

Correlation with other clinical features of Parkinson’s disease

K-COMPASS-31 total scores were correlated with disease duration (r = 0.328, p < 0.002). Among the UPDRS part III subscores, K-COMPASS-31 total score and subdomain scores were associated with the subscore of axial symptoms. There were positive correlations between K-COMPASS-31 total score and patient clinical features including LEDD, NMSS, and the PDQ-39 summary index (PDQ-39 SI) (Table 3).

Discussion

This study is the first to validate a Korean language version of the COMPASS-31. The COMPASS-31 is an abbreviated questionnaire based on a well-established autonomic symptom profile [5]. This questionnaire has been translated into many languages and validated for various neurological diseases [6,8,24–27]. Here, we validated the Korean version of the COMPASS-31; the results of our study showed good reliability and internal validity for the K-COMPASS-31. Our study validated the COMPASS-31 translated into Korean, and includes the first validation study of the COMPASS-31 in patients with PD.

In PD patients, the SCOPA-AUT is a widely used questionnaire for the assessment of dysautonomia. The strength of the SCOPA-AUT is that it is a well-organized questionnaire specific to PD, and the SCOPA-AUT has been suggested to represent autonomic involvement in PD even better than the objective AFT [28]. At the same time, the limitation is that SCOPA-AUT is too focused on PD, and there was no significant correlation between SCOPA-AUT and AFT in a previous study [28]. Therefore, even though SCOPA-AUT is a sensitive measurement tool for autonomic dysfunction in PD, it is not especially useful for evaluating and comparing dysautonomia between PD and other diseases. However, the K-COMPASS-31 was significantly correlated with both the SCOPA-AUT and objective parameters of AFT in our study. Thus, the results of our study suggest that the K-COMPASS-31 could be a potential surrogate for evaluating autonomic function in patients with PD as well as other patients with various disorders that present with autonomic dysfunction.

Considering that the prevalence of autonomic dysfunction in PD patients has continuously increased over time, repetitive evaluation of autonomic symptoms may be needed, and the COMPASS-31 is more advantageous than the objective AFT for this in several aspects. First of all, the COMPASS-31 takes less time and is less costly. Additionally, autonomic dysfunction in PD patients involves various body systems that include gastrointestinal, urinary, sexual, cardiovascular, pupillary motor, and thermoregulatory function. Conventional AFT does not cover all types of autonomic dysfunction in PD patients, such as gastrointestinal, urinary, and pupillary dysfunction [29], which require specialized tests and equipment. Self-reported questionnaires like the COMPASS-31 include questions on various autonomic symptoms and can thus detect a variety of autonomic symptoms in PD patients. Therefore, validation of the K-COMPASS-31 can help to distinguish PD from multiple system atrophy and contribute to timely diagnosis and management of autonomic dysfunction to improve prognosis and quality of life for PD patients.

Autonomic dysfunction is a common and disabling symptom in PD patients. It increases the risk of falls, exacerbates motor dysfunction, and decreases quality of life [30]. Among types of autonomic dysfunction, OH affects nearly half of PD patients, representing a major non-motor symptom burden of PD [3,31]. In this study, 23 patients (25.6%) showed OH during HUT. The patients with OH had a higher total K-COMPASS-31 score and orthostatic intolerance subscore than those without OH (33.4 ± 21.4 vs. 18.1 ± 13.9, p < 0.001; 16.5±13.1 vs. 7.3 ± 9.6, p = 0.001). The total score and orthostatic intolerance subscore of the K-COMPASS-31 correlated moderately with PRT (r = 0.243; r = 0.220), which reflects adrenergic dysfunction and is defined as the time interval from the time of lowest blood pressure in phase 3 to when the blood pressure reaches baseline during the Valsalva manoeuvre [23,32]. Considering this difference in K-COMPASS-31 scores according to the presence of OH and the correlation between PRT and the K-COMPASS-31 scores, the K-COMPASS-31 score, especially its orthostatic intolerance subscore, might be helpful for evaluating characteristics of OH in patients with PD. For the evaluation of cardiovagal dysfunction, K-COMPASS-31 showed a negative correlation with E:I ratio, but was not correlated with Valsalva ratio after adjusting for confounders. A previous validation study of the COMPASS-31 showed similar results, in that COMPASS-31 correlated well with overall AFT score but not with AFT scores for cardiovagal function [26]. E:I ratio might be more suitable for evaluating cardiovagal dysfunction in patients with PD because of difficulties in performing the Valsalva manoeuvre [33].

In terms of motor symptoms, the K-COMPASS-31 was not correlated with UPDRS III total score but was correlated with the axial symptoms subscore. K-COMPASS-31 score was also associated with LEDD. We evaluated UPDRS III scores based on the medication “ON” state and the “ON” UPDRS III score was limited with respect to reflecting the severity of PD patient motor symptoms [34]. In contrast, LEDD, which is a surrogate marker of disease progression, was correlated with K-COMPASS-31 total and subscores [15]. In addition, K-COMPASS-31 score was correlated with disease duration, NMSS, and PDQ-39 SI in PD patients, and these results coincided with a previous study that suggested an association between longer disease duration and severe autonomic dysfunction [1].

The limitation of the present study is that most of the enrolled patients were taking PD medication, and evaluation was done during the medication ‘ON’ state. Dopaminergic medications can affect the presence or severity of autonomic symptoms and the results of objective testing, which might be a confounder in our study. However, because most patients with PD are treated daily with dopaminergic medications, evaluation of autonomic function in medicated patients might be a suitable comparison for real clinical practice.

In conclusion, the K-COMPASS-31 showed excellent reliability and validity for the assessment of autonomic symptoms in PD patients. The COMPASS-31 is easy to repeat and is widely used to investigate autonomic dysfunction in various neurologic disorders; therefore, its use in PD would allow comparison of autonomic dysfunction among different neurologic disorders. We believe that this questionnaire is valid to use in clinical practice for patients with PD and it is expected to be validated in various neurologic disorders.

Supporting information

S1 Data

(XLSX)

Click here for additional data file. (29KB, xlsx)

Acknowledgments

Declarations

Disclosure. J. Youn received speakers’ honoraria from SK Chemicals, Boston Scientific, and research support from Medtronic and Boston Scientific.

Ethics approval/Consent to participate. This study was approved by the local institutional review board of each involved hospital, and all enrolled subjects provided written informed consent (SMC 2019-02-121).

Data Availability

All relevant data are within the paper and its Supporting information files.

Funding Statement

The author(s) received no specific funding for this work.

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Decision Letter 0

Antonina Luca

8 Jun 2021

PONE-D-21-13501

Validation of the Korean version of the composite autonomic symptom scale 31 in patients with Parkinson’s disease

PLOS ONE

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Reviewer #1: Validation of the Korean version of the composite autonomic symptom scale 31 in patients with Parkinson’s disease

In the present study the Authors developed a Korean version of COMPASS-31 and verified its reliability and validity in patients with PD. The study design is appropriate, the sample size is adequate, the paper is well-written although a review by an experienced English speaker is recommended. Nevertheless, I have some major points of criticism:

1)Materials and methods:

-Subjects and clinical assessment:

•the Authors assessed possible correlation between K-COMPASS-31 score and Axial, Tremor, Rigidity and Bradykinesia UPDRS III subscores. In this section a formal definition of these UPDRS III subscores is needed.

•Clinical PD phenotypes should be described in study population using a standardized approach and taken into account in data interpretation (Stebbins GT et al. How to identify tremor dominant and postural instability/gait difficulty groups with the movement disorder society unified Parkinson's disease rating scale: comparison with the unified Parkinson's disease rating scale. Mov Disord. 2013 May;28(5):668-70). Otherwise, the lack of PD phenotypes characterization must be considered in interpreting the results and therefore adequately discussed.

-Statistical analysis:

•an internal consistency analysis has been appropriately performed by using Cronbach’s α-coefficient. However, it is not clear if a factorial analysis has been performed in order to assess the internal validity of K-COMPASS-31 domains’ scores. In fact, even if it is not described in “Statistical analysis” section, in “Results” (Line 220) the Authors state that all of the K-COMPASS-31 domains showed good internal validity. Therefore, this point must be clarified and Cronbach’s α-coefficients for each domain adequately reported.

•Considering the large number of PD patients enrolled in the study, a Pearson’s correlation analysis could be performed.

•The external validity of K-COMPASS-31 has been properly assessed by a correlation analysis with AFT and SCOPA-AUT. In particular, a correlation analysis between K-COMPASS-31 total score and subscores and SCOPA-AUT total score has been performed. I believe that could be useful to explore potential correlation between corresponding subscores of both scales, while it is not useful to assess a correlation between K-COMPASS-31 subscores and SCOPA-AUT total score.

•Correlation analysis has been appropriately adjusted by potential confounders. In line 187 the Authors state that potential confounders included: age, disease duration, education years and UPDRS III. Nevertheless, according to results (Table 3), disease duration does not seem to be considered in adjusted correlation analysis. In particular, I believe that disease duration (which was significantly correlated with all of the K-COMPASS-31 score domains) should be considered as a potential confounder in correlation analysis between K-COMPASS-31 and all of the variables assessed. Similarly, LEDD should be considered in correlations with clinical severity-related scores. Finally, also sex should be considered as a priori potential confounder.

2)Results and Discussion: a statistically significant age-adjusted positive correlation between K-COMPASS-31 (total score and orthostatic intolerance, secretomotor and gastrointestinal subscores) and PRT has been found. Considering that PRT indicates an adrenergic failure, the Authors suggest that K-COMPASS-31 may be useful in evaluating the characteristics of orthostatic hypotension in PD. This point should be better discussed considering that the AFT battery used did not encompass the Active Standing test which conceptually differs from HUT. Moreover, HUT test results must be shown and properly discussed.

3)Tables:

-Table 3: superscript letters do not match table description. Moreover, a more definite separation between UPDRS-III and AFT description is needed.

Reviewer #2: The manuscript is technically sound piece of scientific research with data that supports the conclusions. the manuscript presented in an intelligible fashion. Also statistical analysis was appropriate. But there are restrictions about data availability.

For Authors: would you explain the cut off point of the Korean version of the composite autonomic symptom scale 31 to differentiate PD patients with and without autonomic disturbance, and the sensitivity and specificity of it.

**********

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Reviewer #2: No

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PLoS One. 2021 Oct 21;16(10):e0258897. doi: 10.1371/journal.pone.0258897.r002

Author response to Decision Letter 0

15 Sep 2021

PONE-D-21-13501

Title: Validation of the Korean version of the composite autonomic symptom scale 31 in patients with Parkinson’s disease

Dear Antonina Luca, MD, PhD Academic Editor at PLoS One,

We would like to express our sincere gratitude for your thorough consideration and scrutiny of our manuscript. Through the accurate and keen comments made by the reviewers, we realized the critical points at issue in our analyses and manuscript. After we received the reviewers’ criticisms, we exerted our best effort to achieve the scientific and literary levels required by PLoS One.

This response and the revised manuscript are the result of our hard work to respond to the comments. Additionally, we revised our manuscript as a short communication, thus there are a few more changes other than the response to reviewers’ comments. We hope our revised manuscript will be considered positively and be accepted by PLoS One.

------------------------------------------------------------------------------------------------------------------------------- 

Reviewer #1:

In the present study the Authors developed a Korean version of COMPASS-31 and verified its reliability and validity in patients with PD. The study design is appropriate, the sample size is adequate, the paper is well-written although a review by an experienced English speaker is recommended. Nevertheless, I have some major points of criticism:

Response: Thank you for giving us the opportunity to strengthen our manuscript with your valuable comments and queries. Our manuscript has been revised by professional English editing service (eWorldEditing, https://www.eworldediting.com/).

1)Materials and methods:

-Subjects and clinical assessment:

•the Authors assessed possible correlation between K-COMPASS-31 score and Axial, Tremor, Rigidity and Bradykinesia UPDRS III subscores. In this section a formal definition of these UPDRS III subscores is needed.

Response: Thank you for the comment. We have added the definition of the UPDRS subscores and the reference at the methods section. (Page 8, Line 150-153).

Page 8, Line 150-153

The UPDRS part III was grouped into tremor (items 20 and 21), rigidity (item 22), bradykinesia (items 23, 24, 25, 26, and 31), and axial motor symptoms (items 27, 28, 29, and 30) [13].

•Clinical PD phenotypes should be described in study population using a standardized approach and taken into account in data interpretation (Stebbins GT et al. How to identify tremor dominant and postural instability/gait difficulty groups with the movement disorder society unified Parkinson's disease rating scale: comparison with the unified Parkinson's disease rating scale. Mov Disord. 2013 May;28(5):668-70). Otherwise, the lack of PD phenotypes characterization must be considered in interpreting the results and therefore adequately discussed.

Response: Thanks for the valuable comment. As you pointed out, the motor subtypes of PD could be associated with the autonomic involvements. Two classifications for motor subtypes were widely used; one is tremor dominant (TD) vs. postural instability/gait difficulty (PIGD), and the other is TD vs. akinetic-rigid (AR) subtype [1]. In general, the non-TD (PIGD or AR) subtypes seem to show more advanced neurodegeneration and less favorable outcomes than the TD subtype. In this study, we evaluated parkinsonism with Unified Parkinson’s disease rating scale (UPDRS), not the movement disorder society (MDS) UPDRS, and used UPDRS III without UPDRS II. Therefore, we have divided the subjects into TD, AR, and mixed subtypes (table 1), and we hope that this is acceptable.

When we compared the clinical and demographic data among the subtypes, there were no significant differences except that AR subtype showed the higher LEDD (the first table attached on the response to reviewers file). In terms of the K-COMPASS-31, AR subtype had higher secretomotor domain score than TD, but there were no differences in other domains (the second table attached on the response to reviews file). We thought the differences from motor subtypes could be biased because we examined the enrolled subjects on ‘ON’ state. Considering the previous study [1] that 72.2% of participants were evaluated in the off state, the subtype in our study could be changed with medication. Additionally, we tried to validate Korean version of COMPASS-31 in PD patients in this study, thus we added the subtypes of enrolled subjects in table 1, but we did not show the comparison among the subtypes in our manuscript. For the correlation analysis, we definitely agree with your opinion that motor subtype is important factor, thus we added motor subtypes as the confounder factor for the correlation analysis. However, if you still think it is better to show the data among subtypes in table 1, we are happy to add the additional data.

Methods (Page 8, line 152-153)

Patients were classified into three subtypes according to dominant parkinsonian symptoms: tremor-dominant (TD), akinetic-rigid (AR) and the mixed subtypes [14].

Reference

[1] Kang GA, Bronstein JM, Masterman DL, Redelings M, Crum JA, Ritz B. Clinical characteristics in early Parkinson's disease in a central California population-based study. Mov Disord. 2005 Sep;20(9):1133-42.

Statistical analysis:

•an internal consistency analysis has been appropriately performed by using Cronbach’s α-coefficient. However, it is not clear if a factorial analysis has been performed in order to assess the internal validity of K-COMPASS-31 domains’ scores. In fact, even if it is not described in “Statistical analysis” section, in “Results” (Line 220) the Authors state that all of the K-COMPASS-31 domains showed good internal validity. Therefore, this point must be clarified and Cronbach’s α-coefficients for each domain adequately reported.

Response: The reviewer’s point was well-taken. We have added Cronbach’s α-coefficient in each domains and Cronbach’s α-coefficient of the K-COMPASS 31 subdomains showed similar with the original study. We have evaluated the validity of the K-COMPASS-31 using Pearson’s partial correlation analysis with SCOPA-AUT, and the K-COMPASS-31 showed well correlated with the SCOPA-AUT. The results have been presented in Table 3 and Figure 1 (F) of the manuscript (Page 10, line 191-198 and Page 13, line 248-252).

Methods (Page 10, line 191-198)

Cronbach’s α-coefficient was used for internal consistency analysis of the K-COMPASS-31 total and for each domain, and test-retest reliability was assessed using the intra-class correlation coefficient (ICC). Validity was assessed using correlation analysis between the K-COMPASS-31 and SCOPA-AUT; Pearson partial correlation was adjusted for potential confounders that included age, sex, disease duration, education year, PD subtype UPDRS III, and LEDD. The association of the K-COMPASS-31 with other variables including age, disease duration, UPDRS, H&Y, LEDD, NMSS, and PDQ-39 summary index (PDQ-39 SI) was also investigated.

Results (Page 13, line 248-252)

K-COMPASS-31 total scores were positively correlated with SCOPA-AUT scores (r = 0.626, p < 0.001). Subdomain scores of the K-COMPASS-31 were also correlated with SCOPA-AUT total score. The pupillomotor domain of the K-COMPASS-31 was not correlated with total SCOPA-AUT, but was correlated with the pupillomotor subscore of SCOPA-AUT (Fig 1).

•Considering the large number of PD patients enrolled in the study, a Pearson’s correlation analysis could be performed.

Response: Thank you for the comment. We have performed the Pearson’s correlation analysis rather than Spearman correlation analysis and replace the methods and results as you recommended (page, line ,table 3 and Figure 1)

Methods (page, line)

Validity was assessed by the correlation analysis between the K-COMPASS-31 and SCOPA-AUT, using Pearson partial correlation adjusting for potential confounders that included age, sex, disease duration, education year, PD subtype UPDRS III, and LEDD. The association of the K-COMPASS-31 and other variables including age, disease duration, UPDRS, H&Y, LEDD, NMSS, and PDQ-39 summary index (PDQ-39 SI) were investigated, as well.

•The external validity of K-COMPASS-31 has been properly assessed by a correlation analysis with AFT and SCOPA-AUT. In particular, a correlation analysis between K-COMPASS-31 total score and subscores and SCOPA-AUT total score has been performed. I believe that could be useful to explore potential correlation between corresponding subscores of both scales, while it is not useful to assess a correlation between K-COMPASS-31 subscores and SCOPA-AUT total score.

Response: Thanks for the insightful comment. As you suggested, we have performed correlation analysis between K-COMPASS-31 (total and subscores) and SCOPA-AUT (total and subscores) as you can find out in the figure 1 (F) (correlation matrix). The K-COMPASS-31 scores showed correlation with the SCOPA-AUT total and subscore. Vasomotor domain of the K-COMPASS-31 and pupillomotor score did not show significant correlation with other symptoms, but they were well correlated with the associated SCOPA-AUT subscores (Vasomotor of COMPASS and cardiovascular, pupillomotor of COMPASS-31 and SCOPA-AUT). We had also added brief discussion about the correlations (Page Line).

Discussion (Page Line)

However, the K-COMPASS-31, and its subscores were significantly correlated with both the SCOPA-AUT and the objective parameters of AFT in our study.

•Correlation analysis has been appropriately adjusted by potential confounders. In line 187 the Authors state that potential confounders included: age, disease duration, education years and UPDRS III. Nevertheless, according to results (Table 3), disease duration does not seem to be considered in adjusted correlation analysis. In particular, I believe that disease duration (which was significantly correlated with all of the K-COMPASS-31 score domains) should be considered as a potential confounder in correlation analysis between K-COMPASS-31 and all of the variables assessed. Similarly, LEDD should be considered in correlations with clinical severity-related scores. Finally, also sex should be considered as a priori potential confounder.

Response: Your point was well-taken. As you suggested, we have performed the Pearson partial correlation with potential confounders using, age, sex, disease duration, LEDD, UDPRS III, and educational years.

There was no difference between re-analysis and original analysis, except the correlation between the Valsalva ratio and the K-COMPASS-31 total score. The results suggest that E:I ratio might be more suitable for evaluation of cardiovagal dysfunction in patients with Parkinson’s disease because of difficulties in the performance of Valsalva maneuver. We have revised the methods, results and discussion section according to the re-analysis ((page10, line 193-198, page 13, line 240-252, and page 17, line 331-337, Table 3, Figure 1).

Methods (page10, line 193-198)

Validity was assessed using correlation analysis between the K-COMPASS-31 and SCOPA-AUT; Pearson partial correlation was adjusted for potential confounders that included age, sex, disease duration, education year, PD subtype UPDRS III, and LEDD. The association of the K-COMPASS-31 with other variables including age, disease duration, UPDRS, H&Y, LEDD, NMSS, and PDQ-39 summary index (PDQ-39 SI) was also investigated.

Results (page 13, line 240-252)

There were significant correlations between K-COMPASS-31 score and the AFT results. E:I ratio and Valsalva ratio were negatively correlated (r = -0.240, p = 0.023; r = -0.247, p = 0.019) indicating cardiovagal dysfunction [23], and pressure recovery time (PRT), which represented adrenergic function, was positively correlated with K-COMPASS-31 score (r = 0.345, p < 0.001) (Fig 1). However, after adjusting for confounders including age, sex, disease duration, education year, PD subtype UPDRS III, and LEDD, K-COMPASS-31 score was correlated with E:I ratio and PRT (Table 3).

K-COMPASS-31 total scores were positively correlated with SCOPA-AUT scores (r = 0.626, p < 0.001). Subdomain scores of the K-COMPASS-31 were also correlated with SCOPA-AUT total score. The pupillomotor domain of the K-COMPASS-31 was not correlated with total SCOPA-AUT, but was correlated with the pupillomotor subscore of SCOPA-AUT (Fig 1).

Discussion (Page 17, line 331-337)

For the evaluation of cardiovagal dysfunction, K-COMPASS-31 showed a negative correlation with E:I ratio, but was not correlated with Valsalva ratio after adjusting for confounders. A previous validation study of the COMPASS-31 showed similar results, in that COMPASS-31 correlated well with overall AFT score but not with AFT scores for cardiovagal function [26]. E:I ratio might be more suitable for evaluating cardiovagal dysfunction in patients with Parkinson’s disease because of difficulties in performing the Valsalva manoeuvre [33].

2)Results and Discussion: a statistically significant age-adjusted positive correlation between K-COMPASS-31 (total score and orthostatic intolerance, secretomotor and gastrointestinal subscores) and PRT has been found. Considering that PRT indicates an adrenergic failure, the Authors suggest that K-COMPASS-31 may be useful in evaluating the characteristics of orthostatic hypotension in PD. This point should be better discussed considering that the AFT battery used did not encompass the Active Standing test which conceptually differs from HUT. Moreover, HUT test results must be shown and properly discussed.

Response: Thank you for this comment. The active standing test (AST) was not included in our AFT battery. Considering the testing methods of AST and HUT, AST is more physiologically feasible test mimics daily activities. However, older adults with parkinsonism cannot change their position easily, HUT might be more convenient and suitable method to detect orthostatic hypotension (OH) [1] both tests are widely accepted and used as diagnostic tools for evaluation of orthostatic intolerance [2]. In our study, 23 patients (25.6%) showed OH during HUT, which is assigned according to the previous consensus statement on the definition of OH [3]. The scores of K-COMPASS-31 was higher in patients with OH than those without OH (33.4±21.4 vs. 18.1 ±13.9, p < 0.001); orthostatic intolerance subscore was also higher in patients with OH (16.5±13.1 vs. 7.3±9.6, p = 0.001). Therefore, K-COMPASS-31 score might be helpful to evaluate OH in patients with PD. We have revised Table 1 and Figure 1 and discussion section.

References

1. Aydin AE, Soysal P, Isik AT. Which is preferable for orthostatic hypotension diagnosis in older adults: active standing test or head-up tilt table test? Clin Interv Aging 2017;12:207-212.

2. Brignole M, Moya A, de Lange FJ, et al. 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J 2018;39:1883-1948.

3. Freeman R, Wieling W, Axelrod FB, et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clin Auton Res 2011;21:69-72.

Discussion (Page 16, line 321-331)

In this study, 23 patients (25.6%) showed OH during HUT. The patients with OH had a higher total K-COMPASS-31 score and orthostatic intolerance subscore than those without OH (33.4 ± 21.4 vs. 18.1 ± 13.9, p < 0.001; 16.5±13.1 vs. 7.3 ± 9.6, p = 0.001). The total score and orthostatic subscore of the K-COMPASS-31 correlated moderately with PRT (r = 0.243; r = 0.220), which reflects adrenergic dysfunction and is defined as the time interval from the time of lowest blood pressure in phase 3 to when the blood pressure reaches baseline during the Valsalva manoeuvre [23, 32]. Considering this difference in K-COMPASS-31 scores according to the presence of OH and the correlation between PRT and the K-COMPASS-31 scores, the K-COMPASS-31 score, especially its orthostatic intolerance subscore, might be helpful for evaluating characteristics of OH in patients with PD.

3)Tables:

-Table 3: superscript letters do not match table description. Moreover, a more definite separation between UPDRS-III and AFT description is needed.

Response: Thank you for the comment. We have modified the table 3 to make easier to understand, as you recommended.

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Reviewer #2:

The manuscript is technically sound piece of scientific research with data that supports the conclusions. the manuscript presented in an intelligible fashion. Also statistical analysis was appropriate. But there are restrictions about data availability.

Response: Thank you for the comment. We can provide all the anonymized data under the approval of IRB if there’s reasonable request for raw data. We have added the data availability statement at the manuscript (page 5, line 84)

Data availability statement (Page 5, line 84)

The full data are not publicly available because of participant privacy and consent. Anonymized data will be shared by upon reasonable requests from any qualified investigators for 3 years after the date of publication.

For Authors: would you explain the cutoff point of the Korean version of the composite autonomic symptom scale 31 to differentiate PD patients with and without autonomic disturbance, and the sensitivity and specificity of it.

Response: Thank you for the valuable comment. It is great idea to set cut-off value for the presence of autonomic dysfunction. However, autonomic involvements in PD can present with diverse symptoms and it is difficult to dichotomize PD patients based on the present of autonomic dysfunction. In PD, most of them have some degree of dysautonomic symptoms, and there were no definition or gold standard to define the dysautonomia in PD. In the present study, only 4 of 90 (4.4%) patients showed ‘0’ score in the K-COMPASS-31, cutoff value of the K-COMPASS-31 not that useful for the PD. However, the COMPASS-31 would be useful for the differential diagnosis of PD from MSA-P, as we investigated before [1], and we hope further investigations will be conducted using the K-COMAPSS-31 for comparing the autonomic dysfunction in various disorders.

Reference

1. Kim Y, Seok JM, Park J, Kim KH, Min JH, Cho JW, Park S, Kim HJ, Kim BJ, Youn J. The composite autonomic symptom scale 31 is a useful screening tool for patients with Parkinsonism. PLoS One. 2017 Jul 6;12(7):e0180744.

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Decision Letter 1

Antonina Luca

8 Oct 2021

Validation of the Korean version of the composite autonomic symptom scale 31 in patients with Parkinson’s disease

PONE-D-21-13501R1

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Acceptance letter

Antonina Luca

13 Oct 2021

PONE-D-21-13501R1

Validation of the Korean version of the composite autonomic symptom scale 31 in patients with Parkinson’s disease

Dear Dr. Youn:

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