Correlates of variability in endurance shuttle walk test time in patients with chronic obstructive pulmonary disease

Anouk A F Stoffels; Bram van den Borst; Jeannette B Peters; Mariska P M Klaassen; Hanneke A C van Helvoort; Roy Meys; Peter Klijn; Chris Burtin; Frits M E Franssen; Alex J van ‘t Hul; Martijn A Spruit; Hieronymus W H van Hees; on behalf of the BASES consortium

doi:10.1371/journal.pone.0249786

. 2021 Apr 21;16(4):e0249786. doi: 10.1371/journal.pone.0249786

Correlates of variability in endurance shuttle walk test time in patients with chronic obstructive pulmonary disease

Anouk A F Stoffels ^1,^2,^3,^*, Bram van den Borst ¹, Jeannette B Peters ⁴, Mariska P M Klaassen ¹, Hanneke A C van Helvoort ¹, Roy Meys ^2,³, Peter Klijn ^5,⁶, Chris Burtin ⁷, Frits M E Franssen ^2,³, Alex J van ‘t Hul ¹, Martijn A Spruit ^2,³, Hieronymus W H van Hees ¹; on behalf of the BASES consortium^¶

Editor: Chris Harnish⁸

¹Department of Pulmonary Diseases, Dekkerswald Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands

²Department of Research and Development, CIRO, Horn, The Netherlands

³Department of Respiratory Medicine, Maastricht University Medical Center (MUMC+), NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht, The Netherlands

⁴Department of Medical Psychology, Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands

⁵Department of Pulmonary Rehabilitation, Merem Medical Rehabilitation, Hilversum, The Netherlands

⁶Department of Pulmonary Medicine, Amsterdam University Medical Center, Amsterdam, The Netherlands

⁷Reval Rehabilitation Research–Biomedical Research Institute, Faculty of Rehabilitation Sciences, Hasselt University, Diepenbeek, Belgium

⁸Mary Baldwin University Murphy Deming College of Health Sciences, UNITED STATES

Competing Interests: The authors have read the journal’s policy and have the following competing interests: F.M.E. Franssen is supported by grants and personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Chiesi, personal fees from GlaxoSmithKline, grants and personal fees from Novartis, personal fees from TEVA, outside the submitted work. B. van den Borst is supported by personal lecture fees from AstraZeneca and Boehringer Ingelheim bv. A.A.F. Stoffels, R. Meys, H.W.H. van Hees, P. Klijn, C. Burtin, M.A. Spruit, H.A.C. van Helvoort, J.B. Peters, M.P.M. Klaassen and A.J. van ‘t Hul declare that they do not have a conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

¶ Membership of the BASES consortium is listed in the Acknowledgments.

^✉

* E-mail: anouk.stoffels@radboudumc.nl

Roles

Anouk A F Stoffels: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Visualization, Writing – original draft, Writing – review & editing

Bram van den Borst: Methodology, Supervision, Writing – review & editing

Jeannette B Peters: Data curation, Writing – review & editing

Mariska P M Klaassen: Investigation, Writing – review & editing

Hanneke A C van Helvoort: Investigation, Writing – review & editing

Roy Meys: Writing – review & editing

Peter Klijn: Writing – review & editing

Chris Burtin: Writing – review & editing

Frits M E Franssen: Writing – review & editing

Alex J van ‘t Hul: Writing – review & editing

Martijn A Spruit: Funding acquisition, Writing – review & editing

Hieronymus W H van Hees: Conceptualization, Methodology, Supervision, Writing – original draft, Writing – review & editing

Chris Harnish: Editor

PMCID: PMC8059801 PMID: 33882094

Abstract

Background

The endurance shuttle walk test (ESWT) is used to evaluate exercise tolerance in patients with chronic obstructive pulmonary disease (COPD). The recommended pre-intervention tolerated duration (Tlim) is between 3–8 minutes for optimal interpretation of treatment effects. However, this window may be exceeded and factors determining ESWT Tlim are not completely understood. Therefore, we aimed to determine whether pulmonary function, physical and incremental shuttle walk test (ISWT) performance measures are associated with ESWT Tlim in COPD patients.

Methods

Assessment data from patients eligible for pulmonary rehabilitation was retrospectively analyzed. Inclusion criteria were: diagnosis of COPD and complete data availability regarding ESWT and ISWT. Patients performed an ESWT at 85% of ISWT speed and were divided into three groups (ESWT Tlim: <3 minutes, 3–8 minutes, >8 minutes). Subject characteristics, severity of complaints, pulmonary function, physical capacity and activity, exercise tolerance and quadriceps muscle strength were evaluated.

Results

245 COPD patients (FEV₁ 38 (29–52)% predicted) were included. Median ESWT Tlim was 6.0 (3.7–10.3) minutes, 41 (17%) patients walked <3 minutes and 80 (33%) patients walked >8 minutes. Body mass index, maximal oxygen consumption, Tlim on constant work rate cycle test, physical activity level, maximal ISWT speed, dyspnoea Borg score at rest and increase of leg fatigue Borg score during ISWT independently predicted Tlim in multivariate regression analysis (R² = 0.297, p<0.001).

Conclusion

This study reported a large variability in ESWT Tlim in COPD patients. Secondly, these results demonstrated that next to maximal ISWT speed, other ISWT performance measures as well as clinical measures of pulmonary function, physical capacity and physical activity were independent determinants of ESWT Tlim. Nevertheless, as these determinants only explained ~30% of the variability, future studies are needed to establish whether additional factors can be used to better adjust individual ESWT pace in order to reduce ESWT Tlim variability.

Introduction

The endurance shuttle walk test (ESWT) is commonly used to evaluate effects of interventions on exercise tolerance in patients with chronic obstructive pulmonary disease (COPD) [1, 2] in both research and clinical settings [3]. This accessible and low-cost field walking test is performed at an imposed constant pace and is therefore better controlled than other field walking tests, like the 6- and 12-minute walking tests [4–6]. Furthermore, the tolerated duration (Tlim) of the ESWT is considered to be highly responsive to interventions, especially in comparison to maximal walking tests [1, 7] and the change in ESWT Tlim has been associated with change in exercise capacity and quality of life [8, 9].

However, the potential effect size of interventions on Tlim of constant load tests is strongly determined by the load on which the test is performed [10]. Since Tlim has a negative hyperbolical relation with the relative load of the test, testing at higher relative loads will yield less potential improvement on Tlim [10–12]. Accordingly, ESWT load, i.e. pace, is set at a fixed percentage (usually 85%) of the maximum walking pace, pre-determined by an incremental shuttle walk test (ISWT) [6]. Despite this fixed pace, considerable variability in ESWT Tlim was recently observed in patients with COPD (ESWT Tlim = 353 seconds, 95% CI [299–407] [13]). Because effects sizes of interventions on ESWT Tlim depend on pre-intervention ESWT Tlim, a large variability in pre-intervention ESWT Tlim complicates statistical analysis of intervention efficacy and increases the number of participants required in clinical studies [12, 14]. Accordingly, a pre-intervention Tlim between 3 and 8 minutes has been recommended for constant load exercise tests, like the ESWT [15].

It is currently not completely understood why Tlim of some patients falls outside the recommended timeframe of 3–8 minutes. However, we do know that causes of exercise intolerance are multifactorial and heterogenous in patients with COPD [16]. Next to the severity of pulmonary dysfunction, extrapulmonary features, like muscle weakness and psychological status are known to determine tolerance to exercise [10, 16, 17]. Furthermore, the variability of endurance time on a constant work rate cycle exercise test (CWRT) with equal relative loads for all COPD patients was only partly explained by peak exercise capacity and maximal quadriceps strength [18], suggesting that variability of endurance time is determined by additional clinical variables. Whether these factors influence ESWT Tlim as well has not yet been determined. Lastly, procedural factors can also play a role in ESWT Tlim variability. For example, over- and underestimation of the maximal speed obtained from ISWT can lead to ESWT performance at an intensity not truly representing 85% of the peak capacity. Hence, a performance of the ISWT in accordance with the European Respiratory Society/American Thoracic Society Technical Standards is important [19], as well as maximal effort of the patient.

Collectively, considering that despite protocolized execution of ISWT and ESWT substantial heterogeneity is observed in ESWT Tlim in patients with COPD, hampering clinical evaluation of interventions, there is a need to better understand determinants of ESWT Tlim variation. Therefore, our primary aim was to determine whether pulmonary function, physical and ISWT performance variables are associated with ESWT Tlim in patients with COPD. A priori, we hypothesized that parameters of pulmonary function and physical performance are independent determinants of ESWT Tlim and can partly explain the high variability of ESWT Tlim in patients with COPD.

Materials and methods

Retrospective analyses were performed on an anonymized dataset from 306 patients that attended a comprehensive pulmonary rehabilitation (PR) program in Dekkerswald–Radboudumc (Nijmegen, The Netherlands) between September 2016 and December 2019. The data was collected during baseline assessment as part of standard care of the PR program. Inclusion criteria for the analyses were a primary diagnosis of COPD according to the Global Initiative for Chronic Obstructive Lung Disease criteria [20] and complete data availability regarding ISWT speed and ESWT speed and time. These criteria were met by 245 patient. A flowchart of in- and exclusion of patients is depicted in Fig 1.

Fig 1 — Definitions of abbreviations: COPD = chronic obstructive pulmonary disease, CPET = cardiopulmonary exercise test, CWRT = constant work rate test, HR = heartrate, ISWT = incremental shuttle walk test, ESWT = endurance shuttle walk test.

This study was in accordance to the principles of the Declaration of Helsinki. The local ethical board Arnhem/Nijmegen, The Netherlands, informed the authors that the Medical Research Involving Human Subject Act (WMO) did not apply to this retrospective study (2020–6621).

Measurements

Subject characteristics and severity of complaints as age, gender, weight, body mass index (BMI), Charlson Comorbidity Index [21], fat-free mass index, modified Medical Research Council (mMRC) [22], COPD Assessment Test [23], Hospital Anxiety and Depression Scale [24] and Checklist Individual Strength Fatigue [25] were systemically assessed.

Pulmonary function tests

Post-bronchodilator pulmonary function tests including spirometry (forced expiratory volume in one second, FEV₁; Tiffeneau index, FEV₁/vital capacity), static lung volumes (residual volume, RV; functional residual capacity, FRC; total lung capacity, TLC) and diffusion capacity for carbon monoxide (DL_CO) by single-breath method (MasterScreen PFT/Body; Jaeger, Würzburg, Germany) were executed according to the European Respiratory Society Recommendations [26] and related to predicted normal values [27, 28].

Physical performance tests

The ISWT required the patients to walk around two markers set nine meters apart (10 meters course) at a speed which increases every minute indicated by a pre-recorded audio signal. The patients were instructed to walk for as long as possible [29]. The ESWT was performed at 85% of the maximal ISWT speed and used the same course and auditory signal method. In contrast to the ISWT, the patients were required to walk at a constant speed throughout the test for as long as possible. The ESWT had a maximum test duration of 20 minutes for practical reasons [6]. Both tests were performed according to standardized protocols [6, 29] with on average one week in-between. The following ISWT and ESWT parameters were recorded: Tlim, walking distance, speed, resting and maximal values of transcutaneous peripheral oxygen saturation (SpO₂)_, heartrate (HR) and Borg scores (dyspnoea and leg fatigue). Furthermore, the ISWT distance in meters was calculated as percentage of predicted [30]. Patients with beta blockers (n = 30) or missing information regarding beta blockers (n = 31) were excluded from analyses on HR responses to exercise during both shuttle walk tests (Fig 1).

A symptom-limited ramp maximal cardiopulmonary exercise test (CPET) was performed on an electromagnetically braked cycle ergometer (Ergoselect, Ergoline, Bitz, Germany) according to the recommended guidelines [31] to determine the maximal workload (Wmax) and oxygen uptake (VO₂max). Furthermore, the maximal HR was recorded in order to determine the maximal HR during the ISWT relative to the maximal HR during the CPET (HRmax_ISWT/HRmax_CPET). The CWRT was performed at 65% of Wmax on the same cycle ergometer as the CPET. Patients cycled until symptom limitation or until pedalling rate decreased under 60 rotations per minute, with a maximum of 20 minutes. Only data of patients that performed CPET with maximal effort, as based on the European Respiratory Society and American Thoracic Society/ American College of Chest Physicians statements on CPET, were included in analysis of CPET and CWRT variables (n = 204) [31, 32] (Fig 1).

Isometric quadriceps strength (maximal voluntary contraction) was assessed with a computerized dynamometer (Biodex System 4 Pro, Biodex Medical Systems, Inc., New York, USA). Participants performed three maximal unilateral isometric knee extensions for five seconds at a knee angle of 60°, interspersed with 15 seconds of rest. The maximal voluntary contraction was defined as the highest peak torque (Nm) [33] and was both expressed as absolute value as well as related to predicted normal values [34].

Physical activity was measured using the Dynaport MoveMonitor (McRoberts BV, The Hague, The Netherlands) for a duration of seven (with a minimum of at least five) consecutive days and defined as steps per day and average physical activity level (PAL) [35, 36].

Statistical analysis

Statistical analyses were performed using SPSS statistical software program (IBM, New York, USA), version 25.0. Descriptive data were presented as mean ± SD, median (interquartile range 25–75%) or number of patients (percentage), as appropriate. Based on the ESWT Tlim, the subjects were divided into three groups (group 1: <3 minutes, group 2: 3–8 minutes, group 3: >8 minutes). These cut-off points were chosen to reflect the desirable ESWT duration of 3 to 8 minutes [15]. Accordingly, in the results section we focussed on differences in groups 1 and 3 compared to group 2.

Between-groups comparisons for continuous variables were tested by one-way analysis of variance (ANOVA) or Kruskal-Wallis test, as appropriate. Categorical variables were tested with a Chi-square test. When a statistically significant difference was obtained, a pairwise post-hoc test was performed and Bonferroni post-hoc testing was applied to correct for multiple comparisons. A p-value of <0.05 was considered significant.

Univariate and multivariate linear regression models were used to evaluate the association of pulmonary function, physical and ISWT performance variables with the ESWT Tlim. Univariate linear regression models were built using the ENTER method. Explanatory variables with a p-value <0.20 and not strongly correlated (r <0.8) with another variable of interest were used to build a multivariate linear regression model, using the backward method. Variables with a p-value <0.05 in the multivariate linear regression model were considered as independent predictors of ESWT Tlim.

Results

The included patients had a mean age of 61.4±7.8 years, a mean BMI of 25.8±5.7 kg/m², a median FEV₁ of 38 (29–52)% predicted and 47% were male (Table 1). The median ESWT Tlim was 6.0 (3.7–10.3) minutes. A total of 41 (17%) patients walked <3 minutes (group 1), 124 (50%) patients walked between 3–8 minutes (group 2) and 80 (33%) patients walked >8 minutes (group 3). Furthermore, 42 (17%) patients reached the maximum test duration of 20 minutes. The distribution of patients according to the ESWT Tlim is depicted per minute in Fig 2.

Table 1. Subject characteristics, severity of complaints and parameters of pulmonary function and physical performance of the whole group and the three subgroups based on tolerated duration during the ESWT.

	All patients with COPD (n = 245)	Group 1 (n = 41)	Group 2 (n = 124)	Group 3 (n = 80)
Variables		Tlim <3 min	Tlim = 3–8 min	Tlim >8 min	p-value
Gender (male, %)	114 (47)	17 (42)	61 (49)	36 (45)	0.653
Age (years)	61.4 ± 7.8	61.9 ± 7.1	62.4 ± 7.2	59.4 ± 8.6	0.021^†
BMI (kg/m²)	26 ± 6	26 ± 7	26 ± 5	25 ± 6	0.195
CCI ^a	1 (1–2)	1 (1–3)	1 (1–2)	1 (1–2)	0.853
FFMI ^b	16.9 ± 2.5	16.8 ± 3.1	17.2 ± 2.3	16.6 ± 2.5	0.296
Severity of complaints
mMRC score ^c	2 (1–3)	2 (2–3)	2 (1–3)	2 (1–3)	0.006^#^,^†
CAT score ^d	17.2 ± 7.0	17.3 ± 6.5	16.9 ± 7.4	17.7 ± 6.7	0.784
HADS anxiety score ^e	8.5 ± 4.2	8.7 ± 5.0	8.3 ± 4.0	8.6 ± 4.1	0.852
HADS depression score ^e	8.6 ± 3.8	8.6 ± 4.3	8.2 ± 3.7	9.1 ± 3.6	0.349
CIS fatigue score ^f	48 (43–53)	48 (42–52)	48 (44–53)	49 (44–54)	0.836
Pulmonary function parameters
FEV₁ (L) ^g	1.1 (0.8–1.5)	0.9 (0.7–1.2)	1.0 (0.8–1.5)	1.2 (0.9–1.8)	<0.001^*^,^#
FEV₁ (% predicted) ^g	38 (29–52)	31 (27–42)	37 (29–49)	44 (33–56)	0.001^#
Tiffeneau index (%) ^g	34.5 (28.0–45.5)	31.7 (26.7–38.6)	33.5 (26.9–43.7)	37.8 (30.8–50.2)	0.005^#
FRC (% predicted) ^h	163 ± 38	169 ± 37	165 ± 38	156 ± 39	0.158
RV (% predicted) ⁱ	191 ± 53	201 ± 52	191 ± 54	186 ± 53	0.394
TLC (% predicted) ⁱ	123 ± 19	125 ± 20	124 ± 19	122 ± 18	0.591
FRC/TLC (%) ^h	70 ± 9	72 ± 9	70 ± 9	67 ± 10	0.009^#
RV/TLC (%) ⁱ	56 ± 10	60 ± 9	56 ± 10	54 ± 10	0.026^#
DL_CO (mL/mmHg/min) ^j	3.6 ± 1.6	3.0 ± 1.4	3.6 ± 1.5	3.9 ± 1.8	0.011^#
DL_CO (% predicted) ^j	42 ± 16	36 ± 15	42 ± 15	45 ± 18	0.021^#
Physical performance parameters
Wmax (Watts) ^k	70 ± 34	53 ± 25	68 ± 34	82 ± 34	<0.001^#^,^†
VO₂Max (ml/min/kg) ^l	13.8 (11.8–16.8)	12.5 (10.7–13.7)	13.4 (11.8–16.1)	16.1 (13.6–18.3)	<0.001^#^,^†
VO₂Max (% predicted) ^l	58 (48–67)	52 (45–63)	57 (47–66)	61 (50–74)	0.008^#
CWRT time (s) ^m	300 (187–495)	224 (165–290)	294 (180–433)	327 (218–600)	0.028^#
MVC (Nm) ⁿ	117 ± 38	113 ± 30	120 ± 42	114 ± 37	0.414
MVC (% predicted) ⁿ	63 ± 15	64 ± 14	64 ± 16	62 ± 13	0.445
Physical activity (steps/day) ^o	3480 (2386–5168)	2651 (1517–3923)	3228 (2388–4752)	4732 (2934–6097)	<0.001^#^,^†
Physical activity (average PAL) ^p	1.34 (1.29–1.42)	1.30 (1.26–1.35)	1.34 (1.29–1.41)	1.38 (1.31–1.48)	<0.001^#^,^†

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Data is presented as mean ± SD, median (IQR 25–75%) or number of patients (percentage), as appropriate.

* indicates a significant difference after Bonferroni post-hoc correction between group 1 and group 2

^# indicates a significant difference after Bonferroni post-hoc correction between group 1 and group 3

^† indicates a significant difference after Bonferroni post-hoc correction between group 2 and group 3. Alphabetic characters in superscript indicate a sample size deviant from n = 245 (group 1: 41, group 2: 124, group 3: 80) with the following: a. n = 226 (37, 116, 73), b. n = 209 (37, 101, 71), c. n = 222 (39, 112, 71), d. n = 214 (37, 106, 71), e. n = 221 (39, 111, 71), f. n = 223 (39, 112, 72), g. n = 240 (41, 121, 78), h. n = 235 (39, 120, 76), i. n = 236 (39, 121, 76), j. n = 228 (39, 114, 75), k. n = 203 (33, 104, 66), l. n = 194 (33, 97, 64), m. n = 154 (21, 78, 55), n. n = 226 (40, 112, 74), o. n = 242 (40, 123, 79), p. n = 241 (40, 122, 79). Definitions of abbreviations: BMI = Body Mass Index, CAT = COPD Assessment Test, CCI = Charlson Comorbidity Index, CIS = Checklist Individual Strength, CWRT = constant work rate cycle test, DL_CO = single-breath carbon monoxide diffusion capacity, FEV₁ = forced expiratory volume in 1 second, FFMI = fat free mass index, FRC = functional residual capacity, HADS = Hospital Anxiety and Depression Scale, mMRC = modified Medical Research Council, MVC = maximal voluntary contraction, PAL = physical activity level, TLC = total lung capacity, Tlim = tolerated duration, RV = residual volume, VO₂max = maximal oxygen uptake, Wmax = maximal workload.

Subgroup characteristics

Gender, BMI, fat free mass index and Charlson Comorbidity Index were similar between groups. Patients in group 3 were younger (59.4±8.6) than patients in group 2 (62.4±7.2, p = 0.021). The severity of dyspnea sensation, as reflected by the mMRC score, was lower in patients from group 3 (median 2(1–3) and mean 1.8±1.2) than group 2 (median 2(1–3) and mean 2.2±1.2, p = 0.006). There were no differences in severity of complaints, COPD Assessment Test, Hospital Anxiety and Depression Scale and Checklist Individual Strength Fatigue scores, between the groups (Table 1).

Pulmonary function and physical performance parameters

Pulmonary function of patients in group 2 were similar to patients in group 1 and 3, except for a lower FEV₁ (L) in group 1 than group 2 (p<0.001). Measures of physical performance, like maximal exercise capacity, muscle strength and physical activity were comparable between patient in group 1 and 2. Patients in group 3 had a better physical capacity (Wmax and VO₂max) and were more physically active (steps/day and average PAL) in comparison to group 2 (all p-values <0.001) (Table 1).

ISWT performance parameters

The median ISWT distance of all patients was 280 (200–390) meters. Group 1, 2 and 3 walked 205 (173–328) meters, 285 (200–380) meters and 320 (213–438) meters, respectively. Patients in group 1 desaturated more during the ISWT than group 2 (all p-values <0.001). Furthermore, these patients had a higher rest and maximal dyspnoea Borg score in comparison to group 2 (p<0.001, p = 0.011, respectively). Although the HR before and at the end of the ISWT was comparable between the three groups, the maximal HR during ISWT in ratio to the maximal HR reached during CPET (HRmax_ISWT/HRmax_CPET) was lower in patients from group 3 than in patients from group 2 (p = 0.002). Other ISWT performance parameters were not significantly different for group 1 and 3 in comparison to group 2 (Table 2).

Table 2. ISWT performance parameters of the whole group and the three subgroups based on tolerated duration during the ESWT.

	All patients with COPD (n = 245)	Group 1 (n = 41)	Group 2 (n = 124)	Group 3 (n = 80)
Variables		Tlim <3 min	Tlim = 3–8 min	Tlim >8 min	p-value
Distance (m) ^a	280 (200–390)	205 (173–328)	285 (200–380)	320 (213–438)	0.004^#
Distance (% predicted) ^b	45 (30–58)	33 (25–49)	47 (29–58)	47 (34–64)	0.015^#
Speed (km/h)	4.8 (4.2–5.4)	4.2 (3.6–5.1)	4.8 (4.2–5.4)	4.8 (4.2–6.0)	0.029^#
SpO₂ rest (%)	96 (94–97)	95 (93–96)	96 (94–97)	96 (94–98)	0.146
SpO₂ at max (%)	89 (85–94)	85 (82–91)	90 (85–94)	90 (87–94)	0.001^*^.^#
SpO₂ delta (max-rest, %)	-7 (-11- -2)	-9 (-13- -6)	-6 (-11- -2)	-5 (-9- -1)	0.002^*^.^#
HR rest (bpm) ^c	84 ± 12	86 ± 12	84 ± 13	83 ± 10	0.632
HR at max (bpm) ^c	113 ± 19	114 ± 16	114 ± 21	110 ± 17	0.507
HRmax_ISWT/HRmax_CPET ^d	92 ± 14	97 ± 10	94 ± 17	87 ± 11	0.002^#^,^†
HR delta (max-rest, bpm) ^c	29 ± 15	27 ± 11	30 ± 17	27 ± 15	0.379
Borg score dyspnoea rest	2 (1–3)	2 (1–3)	2 (1–3)	1 (0–2)	0.058
Borg score dyspnoea max	5 (4–7)	7 (5–7)	5 (4–7)	5 (3–7)	<0.001^*^.^#
Borg score dyspnoea delta	3 (2–5)	5 (3–6)	3 (2–5)	3 (2–5)	0.011^*^.^#
Borg score fatigue rest	2 (1–3)	3 (1–5)	2 (1–3)	2 (1–4)	0.221
Borg score leg fatigue max	5 (3–7)	5 (3–7)	5 (3–7)	4 (3–6)	0.238
Borg score leg fatigue delta	2 (1–4)	3 (1–5)	2 (1–4)	2 (0–3)	0.065

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Data is presented as mean ± SD or median (IQR 25–75%), as appropriate.

* indicates a significant difference after Bonferroni post-hoc correction between group 1 and group 2

^# indicates a significant difference after Bonferroni post-hoc correction between group 1 and group 3

ESWT performance parameters

Patients with an ESWT Tlim >8 minutes had a higher maximal oxygen saturation and higher resting and maximal dyspnoea Borg score during the ESWT than patients from group 2 (all p-values <0.001). Besides speed and time, other ESWT performance parameters of patients from group 1 and 3 were comparable to group 2 (S1 Table).

Predictors of ESWT time

Univariate linear regression models that were used to explain ESWT Tlim variability are documented in S2 and S3 Tables. Age, BMI, mMRC and several variables of pulmonary function (FEV₁, Tiffeneau index, FRC, FRC/TLC, RV/TLC and DL_CO), physical performance (Wmax, VO₂max, CWRT time, steps/day and average PAL) and ISWT performance (distance, speed, SpO₂, HRmax_ISWT/HRmax_CPET and Borg scores for dyspnoea and leg fatigue) were significant explanatory variables of ESWT Tlim in univariate analyses.

In a multivariate linear regression model, BMI, VO₂max, CWRT time, average PAL, ISWT speed, dyspnoea Borg score at rest and increase of leg fatigue Borg score during ISWT were independent predictors of ESWT Tlim (S4 Table). This model explained ~30% of the variability in ESWT Tlim (R² = 0.297, p<0.001).

Discussion

The current study confirmed that patients with COPD display a large variability in ESWT Tlim, even though ESWT was performed at a fixed percentage of pre-determined maximal walking speed. To our knowledge, this is the first study that determined possible predictors of ESWT Tlim in patients with COPD. We found that BMI, VO₂max, CWRT time, average PAL, ISWT speed, dyspnoea Borg score at rest and increase of leg fatigue Borg score during ISWT are independent predictors of ESWT Tlim. However, collectively these determinants can only explain ~30% of ESWT Tlim variability.

ESWT Tlim highly variable

A large interindividual variability in ESWT Tlim was illustrated by the notion that half of the patients with COPD performed the ESWT outside the desired duration of 3–8 minutes. Furthermore, a required termination of the test was needed in 17% of the patients as they reached the maximum test duration of 20 minutes, but probably could have walked even longer. This large interindividual variability is in accordance with a recent study of Maltais et al., who investigated the responsiveness of the ESWT to bronchodilation [13]. In their analysis the authors were urged to exclude patients that had a baseline ESWT Tlim of more than 15 minutes to allow measurable room for improvement on a post-intervention ESWT. So, high interindividual variability in ESWT Tlim requires a larger number of participants in clinical studies to detect an effect of interventions. The interpretation of intervention efficacy is even more complicated as the potential effect size (i.e. post–pre intervention) of ESWT Tlim depends on the pre-intervention ESWT Tlim due to the hyperbolic nature of the load-duration relationship [12]. Therefore, in a population with a high interindividual variability in ESWT Tlim, individual effects of interventions are difficult to compare [12, 14, 15]. The best solution to reduce this variability is to determine the load-duration relationship in every individual. However, this is clinically impractical because it requires the completion of several ESWT tests at various intensities. Another possibility is to perform a second ESWT at an adjusted pace in patients with an ESWT Tlim <3 or >8 minutes. However, the size of the adjustment in pace has not been determined yet and a second ESWT is not always possible due to practical reasons like time constraints. Therefore, it is important to search for other possibilities to reduce the variability in ESWT Tlim. One option would be to better predict the ESWT Tlim prior to its performance in order to individually adjust the ESWT pace with clinical available measures. Therefore, this study further investigated correlates of ESWT Tlim variability.

Pulmonary function and physical performance parameters

Patients performing the ESWT longer than 8 minutes had a higher physical capacity and activity in comparison to group 2. In addition, exercise tolerance obtained by CWRT was also positively related to the ESWT Tlim. On the other hand, patients that could not sustain the ESWT for at least 3 minutes, were characterized by a lower FEV₁ (L) than patients in group 2 and several pulmonary function measures were negatively associated with ESWT Tlim. Pulmonary dysfunction is a well-known contributor to exercise intolerance in patients with COPD [10, 11]. In short, ventilatory capacity is limited by airflow obstruction and hyperinflation, which may even exacerbate during exercise. On the other hand, ventilatory demand in patients with COPD may be increased as a result of abnormal pulmonary gas exchange, increased work of the respiratory muscles and early lactate production in the peripheral muscles [16, 37–40]. This leads to increased sensations of dyspnoea during exercise and explains why the severity of pulmonary dysfunction is related to the ability to sustain a certain exercise load [37, 38]. However, it should be stressed that the load of the ESWT is normalized for maximal exercise capacity, as ESWT pace is individually set at 85% of maximal ISWT pace. Despite this normalization, pulmonary function, physical capacity and physical activity are still related to the time patients can sustain this individually assessed pace. This suggests that the load-duration relationship is affected by these measures. The load-duration relation is described by two parameters; the critical load and the curvature constant [10–12]. Neder et al. previously reported that both parameters are reduced in patients with COPD in comparison to healthy controls [11]. The results of the current study suggest that even within the COPD population, critical load and the curvature constant might be influenced by pulmonary function, physical capacity and physical activity.

Thus, the current findings suggest that, in addition to maximal ISWT pace, measures of pulmonary function, physical capacity and physical activity, if clinically available, might be helpful to more adequately set ESWT pace. It appears that patients with more severe airway obstruction should be set at paces slower than 85% of maximal pace and patients with higher physical capacity and activity levels at paces faster than 85% of maximal pace. However, exact cut-off values and sizes of adjustment should be explored in future studies.

ISWT performance parameters

Because ESWT pace is based on maximal ISWT speed, it is essential that the ISWT is performed with maximal effort and using a standardized operating procedure. Therefore, we investigated performance measures obtained during ISWT. In contrast to healthy individuals, the exercise capacity of most patients with COPD is not limited by cardiac output [37]. So maximum HR during ISWT cannot be used to establish maximal effort in patient with COPD. Accordingly, we examined ISWT HR in ratio to the maximum HR obtained during CPET, i.e. HRmax_ISWT/HRmax_CPET. We found that this ratio was significantly lower in patients that displayed an ESWT Tlim >8 minutes (group 3). Furthermore, the ratio was negatively associated with ESWT Tlim. This indicates that some patients with an ESWT time >8 minutes might have performed sub-maximally on their ISWT. A longer ESWT Tlim was also associated with a reduced increase of perceived leg fatigue during ISWT. Although this is a subjective measure, it is in line with a sub-maximal effort during the ISWT. A more objective indication of maximal effort can be provided by additional physiological measures like minute ventilation, oxygen consumption and/or blood lactate values [31], but these would make the ISWT less accessible and more expensive. Our data suggest that if maximal attained HR during CPET is available it can be used together with simple non-invasive measurement of HR during ISWT to provide an estimation of ISWT effort.

Additionally, patients with a shorter ESWT Tlim desaturated more during the ISWT than patients with a longer ESWT Tlim, which was also reported during the ESWT. This might suggest that patients who desaturate more during the ISWT should perform the ESWT at a lower relative load than 85%.

Predicting ESWT

Because our data showed that several clinically obtained measures significantly correlated with ESWT Tlim, we further investigated if a model could be built to predict ESWT Tlim. Based on a multivariate linear regression model, BMI, VO₂max, CWRT time, physical activity, ISWT speed, dyspnoea Borg score at rest and delta leg fatigue Borg score during ISWT were identified as independent predictors of ESWT Tlim. Although each of these parameters significantly contributes to ESWT Tlim variability, the total explained variance is only ~30%. Therefore, it is important to evaluate additional factors that might be associated with ESWT Tlim. For example, dynamic hyperinflation and reduced leg muscle endurance are known to frequently occur in patients with COPD and affect exercise tolerance independent of the severity of pulmonary dysfunction [2, 39, 41–43]. Further research is necessary to assess if these or other factors could improve the accuracy of predicting ESWT Tlim. Eventually, a proper prediction model with clinical available measures might help clinicians to identify patients that are expected to reach an ESWT Tlim outside the desired timeframe of 3–8 minutes [44] and to decide if ESWT pace should be set a different level than 85% of maximal ISWT pace.

Study limitations

In our design ESWT pace was based on patients’ maximal pace obtained from one ISWT. Because Dyer et al. reported a learning effect in a second ISWT [45], two ISWT tests are recommended when the ISWT is used to measure change over time or interventions [19]. However, when ISWT is only used to set ESWT pace, one test has been postulated to be sufficient [46]. Although we expect that performing two ISWT’s prior to ESWT might reduce the interindividual variability, it does not necessarily eliminate the need of a second ESWT in all patients. Furthermore, two ISWT’s would increase the amount of tests in all patients, while our data show that with one ISWT half of the patients perform their ESWT within the desired duration of 3–8 minutes.

Conclusion

This study confirmed a large interindividual variability in ESWT Tlim in patients with COPD, as only half of the patients reached an ESWT Tlim within the desired duration of 3–8 minutes. Our data showed that next to maximal ISWT speed, other ISWT performance measures as well as clinically available measures of pulmonary function, physical capacity and physical activity were independent determinants of ESWT Tlim. Nevertheless, these determinants could only explain ~30% of its variability. Therefore, future studies are needed to establish whether these and additional factors can be used to better adjust individual ESWT pace in order to reduce ESWT Tlim variability.

Supporting information

S1 Table. ESWT parameters of the whole group and the three subgroups based on tolerated duration during the ESWT.

(PDF)

Click here for additional data file.^{(56.5KB, pdf)}

S2 Table. Univariate linear regression models for the subject characteristics, severity of complaints, pulmonary function and physical performance with the tolerated duration on the ESWT.

(PDF)

Click here for additional data file.^{(31.1KB, pdf)}

S3 Table. Univariate linear regression models for the ISWT parameters with the tolerated duration on the ESWT.

(PDF)

Click here for additional data file.^{(37.4KB, pdf)}

S4 Table. Multivariate linear regression analysis to predict tolerated duration on the ESWT.

(PDF)

Click here for additional data file.^{(28.5KB, pdf)}

Acknowledgments

We would like to thank A.R.T. Donders (Radboudumc) for his input in the statistical analyses and interpretation and W. Derave (Ghent University) for his input and collaboration within the BASES consortium, in the context of which the current manuscript was written. The BASES consortium consists of M.A. Spruit (CIRO, lead author, e-mail: martijnspruit@ciro-horn.nl), A.A.F. Stoffels (Radboudumc), R. Meys (CIRO), P. Klijn (Merem), H.W.H. van Hees (Radboudumc), C. Burtin (Hasselt University), F.M.E. Franssen (CIRO), B. van den Borst (Radboudumc), J. De Brandt (Hasselt University), M.J.H. Sillen (CIRO), E.F.M. Wouters (CIRO), E. bij de Vaate (Merem), F.N. Schleich (CHU Sart-Tilman Liege), M. Hayot (University of Montpellier–Montpellier CHU), P. Pomiès (University of Montpellier–Montpellier CHU), W. Derave (Ghent University) and I. Everaert (Ghent University).

Data Availability

The data underlying this study has been uploaded to the EASY DANS database and can be accessed at the following DOI: https://doi.org/10.17026/dans-xd6-2fw9.

Funding Statement

The BASES consortium is financially supported by Lung Foundation, the Netherlands (#5.1.18.232). Dr. F.M.E. Franssen received support in the form of grants and personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Chiesi, personal fees from GlaxoSmithKline, grants and personal fees from Novartis, personal fees from TEVA, outside the submitted work. Dr. B. van den Borst received support in the form of personal lecture fees from AstraZeneca and Boehringer Ingelheim bv. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.

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PLoS One. doi: 10.1371/journal.pone.0249786.r001

Decision Letter 0

Chris Harnish

12 Feb 2021

PONE-D-20-32526

Correlates of variability in endurance shuttle walk test time in patients with chronic obstructive pulmonary disease

PLOS ONE

Dear Dr. Stoffels,

Thank you for submitting your manuscript to PLOS ONE and for your patience on this review. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. To facilitate your revisions, I have outline some key areas to address, in addition to our reviewers. These include:

Following your purpose statement in the intro, add clearly identified hypotheses.
Please reword the conclusion statements for the abstract and paper to the past tense.
Be sure to proof read for consistent use of formatting.
I agree with the reviewer. A flow chart of some type would aid for the inclusion/exclusion section.
Likewise, please include effect sizes.
Suggestion: Line 231, change high variability (vague) to ESWT Tlim highly variable
As noted above, much of the conclusion is written in present tense.

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Abstract

Line 28: Suggest changing to not completely understood.

Line 32: If there is room, please include inclusion/exclusion criterion

Line 35: Please add statistical analyses used.

Line 43: suggest moving to past tense: Secondly, these results demonstrated …

Introduction

Overall the introduction is well defined and written.

Line 67: Like within the abstract, suggest changing to not completely understood.

Methods

Line 114: nine meters, instead of nine meter. (same with 10 meters).

Line 124: percentage of predicted…please be more specific of the predicted metric.

Line 127: Paragraphs starting here are indented while all others beforehand are not. Please revise.

Line 124-126: Suggest having a separate paragraph prior to test that describe inclusion and exclusion criterion. Further a flow chart may aid the reader in understanding how the sample was obtained.

Statistical analyses: Suggest including an effect size index analysis for significant difference findings as this will give further context of the magnitude of these potential differences.

Results

Well described

Discussion

Overall well done .

**********

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PLoS One. 2021 Apr 21;16(4):e0249786. doi: 10.1371/journal.pone.0249786.r002

Author response to Decision Letter 0

19 Mar 2021

Response to reviewers

We would like to thank the editor and the reviewer for their constructive comments and giving us the opportunity to revise our manuscript. We provided a point-by point reply below and adapted the manuscript accordingly.

*The reported page and line numbers correspond to the manuscript with track changes (view: all markup).

Comments editor

C1. Following your purpose statement in the intro, add clearly identified hypotheses.

R1. We have added our hypothesis after the aim in the introduction: “A priori, we hypothesized that parameters of pulmonary function and physical performance are independent determinants of ESWT Tlim and can partly explain the high variability of ESWT Tlim in patients with COPD”, see page 6, lines 102-105.

C2. Please reword the conclusion statements for the abstract and paper to the past tense.

R2. The conclusion statement in the abstract and paper has been changed to the past tense, see page 4, lines 54-60 (abstract) and pages 20-21, lines 401-408 (paper).

C3. Be sure to proof read for consistent use of formatting.

R3. We have proof read the article and made some changes to obtain a consistent format of the manuscript. Changes are marked in the tracked changes version of the revised manuscript.

C4. I agree with the reviewer. A flow chart of some type would aid for the inclusion/exclusion section.

R4. We agree with the reviewer and made a flow chart that shows how the number of patients used for the analyses was reached, see figure 1.

C5. Likewise, please include effect sizes.

R5. Thank you for your suggestion. We assume that the reviewer suggests to include a column in tabel1, 2 and S2 with standardized effect sizes on differences of the parameters described. We have discussed this topic with our statistician (dr. A.R.T. Donders). In our opinion, the interpretation of the magnitude of differences will not be improved by including such effect size numbers, because 1) effect sizes of 2 or 3 comparisons per parameter are difficult to reflect in one number and 2) both non-parametric and parametric testing was applied, which affects the interpretation of effect sizes. So, we think that the raw data as presented in table 1,2 and S2 is the most appropriate way to show the magnitude of the differences across the three groups. Nevertheless, as we reviewed table 1, we noted that the difference in mMRC score may not be clear to the readers. In the revised manuscript we therefore expressed the mean mMRC score in the text as well ‘Patients in group 3 were younger (59.4 ± 8.6 years) than patients in group 2 (62.4 ± 7.2 years, p=0.021). The severity of dyspnea sensation, as reflected by the mMRC score, was lower in patients from group 3 (median 2(1-3) and mean 1.8±1.2) than in patients from group 2 (median 2(1-3) and mean 2.2±1.2, p=0.006).’., see page 11, lines 214-216.

C6. Suggestion: Line 231, change high variability (vague) to ESWT Tlim highly variable

R6. Thank you for this suggestion, it has been changed to ‘ESWT Tlim highly variable’ in the manuscript on page 16, line 297.

C7. As noted above, much of the conclusion is written in present tense.

R7. The conclusion has been rewritten in the past tense, see pages 20-21, lines 401-408.

‘This study confirmed a large interindividual variability in ESWT Tlim in patients with COPD, as only half of the patients reached an ESWT Tlim within the desired duration of 3-8 minutes. Our data showed that next to maximal ISWT speed, other ISWT performance measures as well as clinically available measures of pulmonary function, physical capacity and physical activity were independent determinants of ESWT Tlim. Nevertheless, these determinants could only explain ~30% of its variability. Therefore, future studies are needed to establish whether these and additional factors can be used to better adjust individual ESWT pace in order to reduce ESWT Tlim variability.’

C8. Please ensure that your manuscript meets PLOS ONE’s style requirements, including those for file naming. The PLOS ONE style templates can be found at: https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

R8. The manuscript has been checked and adapted to the PLOS ONE requirements.

C9. In the methods section please provide a reference to the main study from which the secondary analysis was performed form.

R9. The data is obtained as part of standard care during baseline assessment of a pulmonary rehabilitation program in our center. There is no main study from which this is a secondary analysis. However, as we understand the confusion, the term ‘standard care’ has been added to the methods section, ‘The data was collected during baseline assessment as part of standard care of the PR program.’ see page 7, lines 112-113.

C10. We note that the grant information you provided in the ‘Funding information’ and ‘Financial Disclosure’ sections do not match. When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for the study in the ‘Funding Information’ section.

R10. Thank you for noticing. The financial disclosure should be changed to ‘The BASES consortium is financially supported by the Lung Foundation, the Netherlands (#5.1.18.232).’ as mentioned in the cover letter.

The mentioned grants of F. Franssen and B. van den Borst have no influence and are unrelated to the submitted article. Furthermore, this information has already been mentioned in the ‘conflicts of interests’ section in the manuscript. We apologize for the confusion and our mistake. As we cannot change the financial disclosure section ourselves, we would appreciate if you can change this for us. If you have further questions regarding the funding, please contact us.

Initially, we did not provide a name for recipient of the grant of the Lung foundation as this has been provided to the BASES consortium. We have changed this to Martijn Spruit as he is the lead author of the BASES consortium.

C11. Thank you for stating the following in the Competing Interests section:

"Dr. F.M.E. Franssen is supported by grants and personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Chiesi, personal fees from GlaxoSmithKline, grants and personal fees from Novartis, personal fees from TEVA, outside the submitted work. Dr. B. van den Borst is supported by personal lecture fees from AstraZeneca and Boehringer Ingelheim bv. A.A.F. Stoffels, R. Meys, H.W.H. van Hees, P. Klijn, C. Burtin, M.A. Spruit, H.A.C. van Helvoort, J.B. Peters, M.P.M. Klaassen and A.J. van ‘t Hul declare that they do not have a conflict of interest."

Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf.

R11. We have added the statement to the ‘conflicts of interest’ section, see page 23, line 439.

C12. One of the noted authors is a group or consortium [BASES consortium]. In addition to naming the author group, please list the individual authors and affiliations within this group in the acknowledgements section of your manuscript. Please also indicate clearly a lead author for this group along with a contact email address.

R12. We have listed the individual authors of the BASES consortium to the acknowledgements section, including the affiliations, see page 22, lines 415-421.

‘The BASES consortium consists of M.A. Spruit (CIRO, lead author, e-mail: martijnspruit@ciro-horn.nl), A.A.F. Stoffels (Radboudumc), R. Meys (CIRO), P. Klijn (Merem), H.W.H. van Hees (Radboudumc), C. Burtin (Hasselt University), F.M.E. Franssen (CIRO), B. van den Borst (Radboudumc), J. De Brandt (Hasselt University), M.J.H. Sillen (CIRO), E.F.M. Wouters (CIRO), E. bij de Vaate (Merem), F.N. Schleich (CHU Sart-Tilman Liege), M. Hayot (University of Montpellier – Montpellier CHU), P. Pomiès (University of Montpellier – Montpellier CHU), W. Derave (Ghent University) and I. Everaert (Ghent University).’

C13. Please include captions for you Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information Guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.

R13. We have added a Supporting Information Caption to the manuscript, see page 23, lines 441-445.

‘S1 Table. ESWT parameters for the whole group and subgroups.

S2 Table. Univariate linear regression models for the clinical parameters and ESWT Tlim.

S3 Table. Univariate linear regression models for the ISWT parameters and ESWT Tlim

S4 Table. Multivariate linear regression analysis to predict ESWT Tlim.’

Reviewer 1

C1. Abstract: line 28: Suggest changing to not completely understood.

R1. We agree with this suggestion and it has been changed to ‘.. factors determining ESWT Tlim are not completely understood.’ in the manuscript on page 3, line 35.

C2. Abstract: line 32: If there is room, please include inclusion/exclusion criterion

R2. The inclusion criteria have been added to the abstract: ‘Inclusion criteria were: diagnosis of COPD and complete data availability regarding ESWT and ISWT.’ see page 3, lines 39-40.

C3. Abstract: line 35: Please add statistical analyses used.

R3. Thank you for this suggestion. We understand the additional value of describing the statistical analyses in the abstract. However, the maximal number of words does not allow us to describe the statistical analyses clearly and complete. Therefore, we have chosen to leave the statistical analysis out of the abstract.

C4. Abstract: line 43: suggest moving to past tense: Secondly, these results demonstrated..

R4. Thank you for the suggestion, the conclusion has been changed to the past tense, see page 4, lines 54-60.

‘Conclusion: This study reported a large variability in ESWT Tlim in COPD patients. Secondly, these results demonstrated that next to maximal ISWT speed, other ISWT performance measures as well as clinical measures of pulmonary function, physical capacity and physical activity were independent determinants of ESWT Tlim. Nevertheless, as these determinants only explained ~30% of the variability, future studies are needed to establish whether additional factors can be used to better adjust individual ESWT pace in order to reduce ESWT Tlim variability.’

C5. Introduction: Overall the introduction is well defined and written.

Line 67: Like within the abstract, suggest changing to not completely understood.

R5. Thank you for the suggestion, this was adjusted in the manuscript on page 5, line 84.

C6. Methods: line 114: nine meters, instead of nine meter. (same with 10 meters).

R6. Thank you for the suggestion, it has been changed in the manuscript to ‘The ISWT required the patients to walk around two markers set nine meters apart (10 meters course) …’ on page 8, lines 146-147.

C7. Methods: line 124: percentage of predicted…please be more specific of the predicted metric.

R7. We have added ‘in meters’ after ISWT distance to clarify the used metric ‘the ISWT distance in meters was calculated as percentage of predicted’, see page 9, lines 155-156.

C8. Methods: line 127: Paragraphs starting here are indented while all others beforehand are not. Please revise.

R8. We have indented all paragraphs.

C9. Methods: line 124-126: Suggest having a separate paragraph prior to test that describe inclusion and exclusion criterion. Further a flow chart may aid the reader in understanding how the sample was obtained.

R9. We agree that this will help the reader to understand how the sample was obtained, so we added a flowchart with in- and exclusion criteria to the manuscript, see figure 1.

C10. Methods: statistical analyses: Suggest including an effect size index analysis for significant difference findings as this will give further context of the magnitude of these potential differences.

R10. Thank you for your suggestion. If we understand correctly, you suggest to include a

column in tabel1, 2 and S2 with standardized effect sizes on differences of the parameters

described in those tables. We have discussed this topic with our statistician (dr. A.R.T.

Donders). We think that the interpretation of such effect size is hampered, because 1)

effect sizes of 2 or 3 comparisons per parameter are difficult to reflect in one number and

2) both non-parametric and parametric testing was applied. So, in our opinion the raw

data as presented in table 1,2 and S2 is the most appropriate way to show the magnitude

of the differences across the three groups. Nevertheless, as we reviewed table 1, we noted that the difference in mMRC score may not be clear to the readers. In the revised manuscript we therefore expressed the mean mMRC score in the text as well ‘Patients in group 3 were younger (59.4 ± 8.6 years) than patients in group 2 (62.4 ± 7.2 years, p=0.021). The severity of dyspnea sensation, as reflected by the mMRC score, was lower in patients from group 3 (median 2(1-3) and mean 1.8±1.2) than in patients from group 2 (median 2(1-3) and mean 2.2±1.2, p=0.006).’., see page 11, lines 214-216.

C11. Results: well described.

C11. Thank you!

C12. Discussion: overall well done.

C12. Thank you very much for your constructive comments!

Attachment

Submitted filename: Response to reviewers.docx

Click here for additional data file.^{(30.5KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0249786.r003

Decision Letter 1

Chris Harnish

25 Mar 2021

Correlates of variability in endurance shuttle walk test time in patients with chronic obstructive pulmonary disease

PONE-D-20-32526R1

Dear Dr. Stoffels,

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.

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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 #1: All comments have been addressed

**********

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

Reviewer #1: Yes

**********

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

Reviewer #1: Yes

**********

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

Reviewer #1: Yes

**********

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

Reviewer #1: Yes

**********

6. Review Comments to the Author

Reviewer #1: The addressed the reviewer comments. I have no other editorial comments. I commend the authors on their work.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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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 #1: Yes: Garrett Scott Bullock

PLoS One. doi: 10.1371/journal.pone.0249786.r004

Acceptance letter

Chris Harnish

12 Apr 2021

PONE-D-20-32526R1

Correlates of variability in endurance shuttle walk test time in patients with chronic obstructive pulmonary disease

Dear Dr. Stoffels:

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.

If we can help with anything else, please email us at plosone@plos.org.

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

Kind regards,

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on behalf of

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Associated Data

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

Supplementary Materials

S1 Table. ESWT parameters of the whole group and the three subgroups based on tolerated duration during the ESWT.

(PDF)

Click here for additional data file.^{(56.5KB, pdf)}

S2 Table. Univariate linear regression models for the subject characteristics, severity of complaints, pulmonary function and physical performance with the tolerated duration on the ESWT.

(PDF)

Click here for additional data file.^{(31.1KB, pdf)}

S3 Table. Univariate linear regression models for the ISWT parameters with the tolerated duration on the ESWT.

(PDF)

Click here for additional data file.^{(37.4KB, pdf)}

S4 Table. Multivariate linear regression analysis to predict tolerated duration on the ESWT.

(PDF)

Click here for additional data file.^{(28.5KB, pdf)}

Attachment

Submitted filename: Response to reviewers.docx

Click here for additional data file.^{(30.5KB, docx)}

Data Availability Statement

The data underlying this study has been uploaded to the EASY DANS database and can be accessed at the following DOI: https://doi.org/10.17026/dans-xd6-2fw9.

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PERMALINK

Correlates of variability in endurance shuttle walk test time in patients with chronic obstructive pulmonary disease

Anouk A F Stoffels

Bram van den Borst

Jeannette B Peters

Mariska P M Klaassen

Hanneke A C van Helvoort

Roy Meys

Peter Klijn

Chris Burtin

Frits M E Franssen

Alex J van ‘t Hul

Martijn A Spruit

Hieronymus W H van Hees

Roles

Abstract

Background

Methods

Results

Conclusion

Introduction

Materials and methods

Fig 1. Flowchart of in- and exclusion of patients for analysis.

Measurements

Pulmonary function tests

Physical performance tests

Statistical analysis

Results

Table 1. Subject characteristics, severity of complaints and parameters of pulmonary function and physical performance of the whole group and the three subgroups based on tolerated duration during the ESWT.

Fig 2. The distribution of patients according to the ESWT Tlim per minute.

Subgroup characteristics

Pulmonary function and physical performance parameters

ISWT performance parameters

Table 2. ISWT performance parameters of the whole group and the three subgroups based on tolerated duration during the ESWT.

ESWT performance parameters

Predictors of ESWT time

Discussion

ESWT Tlim highly variable

Pulmonary function and physical performance parameters

ISWT performance parameters

Predicting ESWT

Study limitations

Conclusion

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Chris Harnish

Roles

Author response to Decision Letter 0

Decision Letter 1

Chris Harnish

Roles

Acceptance letter

Chris Harnish

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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