Skip to main content
PLOS ONE logoLink to PLOS ONE
. 2022 Apr 21;17(4):e0267427. doi: 10.1371/journal.pone.0267427

The physical activity health paradox and risk factors for cardiovascular disease: A cross-sectional compositional data analysis in the Copenhagen City Heart Study

Melker S Johansson 1,2,*, Andreas Holtermann 1,2, Jacob L Marott 3, Eva Prescott 3,4, Peter Schnohr 3, Mette Korshøj 1,5, Karen Søgaard 2,6
Editor: Gianluigi Savarese7
PMCID: PMC9022831  PMID: 35446893

Abstract

Background

Studies indicate that physical activity during leisure and work have opposite associations with cardiovascular disease (CVD) risk factors, referred to as the physical activity health paradox. We investigated how sedentary behaviour and physical activity types during leisure and work are associated with systolic blood pressure (SBP), waist circumference (WC), and low-density lipoprotein cholesterol (LDL-C) in an adult general population sample using compositional data analysis.

Methods

Participants wore accelerometers for 7 days (right thigh and iliac crest; 24 h/day) and had their SBP, WC, and LDL-C measured. Accelerometer data was analysed using the software Acti4 to derive daily time spent in sedentary behaviour and physical activity types. The measure of association was quantified by reallocating time between sedentary behaviour and 1) walking, and 2) high-intensity physical activity (HIPA; sum of climbing stairs, running, cycling, and rowing), during both domains.

Results

In total, 652 participants were included in the analyses (median wear time: 6 days, 23.8 h/day). During leisure, the results indicated that less sedentary behaviour and more walking or more HIPA was associated with lower SBP, while during work, the findings indicated an association with higher SBP. During both domains, the findings indicated that less sedentary behaviour and more HIPA was associated with a smaller WC and lower LDL-C. However, the findings indicated less sedentary behaviour and more walking to be associated with a larger WC and higher LDL-C, regardless of domain.

Conclusions

During leisure, less sedentary behaviour and more walking or HIPA seems to be associated with a lower SBP, but, during work, it seems to be associated with a higher SBP. No consistent differences between domains were observed for WC and LDL-C. These findings highlight the importance of considering the physical activity health paradox, at least for some risk factors for CVD.

Introduction

The favourable effects of leisure time physical activity on the risk of cardiovascular disease (CVD) and mortality are well established [17]. In contrast, occupational physical activity may increase the risk of both CVD-specific and all-cause mortality, at least among men [810], and evidence on the association between occupational physical activity and risk factors for CVD, risk of ischemic heart disease (IHD), and major cardiovascular events is inconclusive [914]. The contrasting health effects from physical activity during leisure and work have been referred to as the physical activity health paradox [15].

Current physical activity recommendations are mainly based on evidence from leisure time physical activity [16,17]. However, a large proportion of the general population accumulates most of their daily physical activity at work, in particular groups with lower socioeconomic status [18]. Therefore, it is important to investigate the opposing health effects from occupational physical activity. The physical activity health paradox may be explained by differences in characteristics (e.g., duration, intensity, and time for restitution) and physiological responses (e.g., average 24-hour heart rate and blood pressure) of physical activity during leisure and work [19]. It has also been suggested to be explained by methodological limitations [20]. Firstly, the detrimental health effects of occupational physical activity may be confounded by socioeconomic status [20], because a low socioeconomic status is associated with high occupational physical activity [18] and poor health [21,22]. Secondly, the findings may be attributed to the use of self-reported measurements of physical activity, which compared to device-based measurements, have a higher risk of misclassification that can lead to inaccurate exposure measurements [23]. Thirdly, most previous studies have investigated associations between physical activity and risk factors for CVD [1,3,8,24] without taking the co-dependency between durations of different types of physical activity into account. This has both conceptual and statistical limitations that can be addressed by compositional data analysis (CoDA) [2528].

Our study objectives were to investigate how sedentary behaviour, walking, and high intensity physical activity (HIPA) during leisure and work are associated with risk factors for CVD (i.e., SBP, WC, and LDL-C) in a general population sample using CoDA.

Methods

Data source and study design

For this cross-sectional study, we used data from the fifth examination of the Copenhagen City Heart Study (CCHS), collected from October 2011 to February 2015. In total, 9215 individuals who were ≥20 years old and lived in two parts of Copenhagen, Denmark, were invited of which 4543 participated (49.3%) (Fig 1). These were randomly chosen from the Copenhagen Population Register using a national registration number. Briefly, invitations were sent three weeks prior to a planned health examination. The invitations included a questionnaire and a pre-paid postcard where the individuals could confirm, change the appointment, or decline to participate. The source population, recruitment and invitation procedure, data collection, and data processing in the CCHS are described in detail elsewhere [29,30]. We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement to report this study.

Fig 1. Formation of the final study population of eligible participants in the fifth examination of the Copenhagen City Heart Study.

Fig 1

N/n indicates number of participants. The sum across reasons for exclusion of non-eligible study participants exceeds 1367 since some participants fulfilled more than one exclusion criterion.

The Danish Data Protection Agency approved the analysis of the study data (approval no.: 2001-54-0280; 2007-58-0015, 2012-58-0004, HEH-2015-045, I-suite 03741). The National Committee on Health Research Ethics approved the data collection (approval no.: VEK: H-KF 01-144/01 31104). Participation was voluntary and in agreement with the Declaration of Helsinki. Written consent to participate in the fifth examination of the CCHS was obtained from the participants.

Data collection

Questionnaire

Data across a wide range of domains were collected with a self-administered questionnaire. See S1 Table for an overview of the questions relevant for this study.

Physical examination

The study participants underwent a physical examination at a public hospital in the Capital Region of Denmark. Medical specialists, medical students and medical laboratory technicians who were trained in the examination procedures undertook the examination.

For the current study, the relevant tests were measurements of blood pressure, WC, and LDL-C. We also used height and weight for descriptive purposes. Three blood pressure measurements were taken on participants’ non-dominant arm using an automatic blood pressure monitor (OMRON M3, OMRON Healthcare, Hoofddorp, Netherlands) after five minutes of rest in a seated position. This test procedure has been used in previous examinations of the CCHS and is in line with the 2020 International Society of Hypertension Global Hypertension Practice Guidelines [31]. The participants’ WC was measured at the estimated midpoint between the lower margin of the last palpable rib and the top of the iliac crest. Using standardised procedures, venipunctures were taken, and LDL-C was determined directly (Sanofi Genzyme, Cambridge, Massachusetts, USA). Height was measured without shoes on a fixed scale to the nearest 0.1 centimetre. Weight was measured with clothes but without shoes, on a consultation scale (Seca, Hamburg, Germany) to the nearest 0.1 kilogram.

Accelerometer-based measurement of physical activity

As part of a sub-study, all participants were asked to wear accelerometers 24-hours per day for seven consecutive days to measure their physical activity. Totally, 2335 participants gave consent and had one tri-axial accelerometer attached on the anterior aspect of the right thigh midway between the greater trochanter and patella oriented along the axis of the thigh, and a second accelerometer on the lateral aspect of the right iliac crest (ActiGraph GT3X+; sampling frequency: 30 Hz; ActiGraph, Pensacola, Florida, USA). To secure a fixed position during the measurement period, we attached the accelerometers to the skin using double-sided medical tape (Hair-Set for hairpieces; 3M, Maplewood, Minnesota, USA) and covered them with adhesive film (OpSite Flexifix; Smith & Nephew, London, UK).

The study staff asked the study participants to fill out a diary with their working hours, leisure time, time in bed, and periods of non-wear time, and to make a daily reference measurement by standing still for 15 seconds and note the time in the diary. In addition, the participants were asked to only remove the accelerometers if they visited a sauna or in case of adverse skin reactions, discomfort, pain, or affected sleep. Finally, the participants were asked to return the accelerometers at the test centre or by mail using a pre-paid envelope after the measurement period. The accelerometers were initialised, and raw data was downloaded with the manufacturer’s software (ActiLife version 5) by the study staff.

Processing of raw accelerometer data

Detection of body postures and physical activity types

We used the MATLAB-software Acti4 (National Research Centre for the Working Environment, Copenhagen, Denmark) to detect and derive the daily time spent lying, sitting, standing, moving (i.e., small movements without regular walking while in a standing posture), walking, climbing stairs (i.e., up and down), running, cycling and rowing. The detection of body postures and physical activity types is based on an algorithm that uses inclinations and accelerations from the accelerometers [32]. The sensitivity and specificity of this activity-classification has been reported to be >90% during standardised and semi-standardised conditions for all body postures and physical activity types except climbing stairs which has a lower sensitivity (i.e., sensitivity: 75.4%; specificity: 99.7%) [32,33]. We used the daily reference measurements to define the individual angle between the vertical axis of the accelerometer and the axis of the thigh, which was used in the activity-detection algorithm.

Leisure and work, time in bed, quality control, and non-wear time. We defined each participant’s leisure time and working hours based on diary information. This made it possible to derive time spent in the physical activity types during leisure and work, respectively.

Time in bed was defined by a combination of accelerometer and diary data (i.e., self-reported bedtime/get up time). More specifically, we adjusted any inconsistencies between the diary data and detected lying/non-lying activity types of more than 15 minutes, by setting the time to the nearest five minutes of the observed lying/non-lying activity.

As a quality control, we visually inspected the activity classification over time for each individual, to identify and investigate any abnormalities in the data (e.g., extreme levels of rowing or lack of sitting).

We manually added non-wear time based on diary information and visual inspection of the activity-classification over time. Additionally, Acti4 detects non-wear time automatically based on criteria that has been described in detail elsewhere [32].

Eligibility criteria

We included participants who had registered work time during the measurement period and ≥5 days of measurements with ≥16 h of accelerometer recordings per day. There were no requirements on number of workdays, number of hours of work per day, or day of the week (i.e., weekday or weekend day). Any days marked as ‘sick days’ in the diary were excluded. Participants who reported use of antihypertensive, diuretics or cholesterol lowering drugs, or had missing values in any of the outcome variables were excluded.

Definition of variables

Physical activity composition

The daily physical activity composition consisted of time spent sedentary (i.e., sum of lying and sitting), standing, moving, walking, and in HIPA (i.e., sum of climbing stairs, running, cycling, and rowing) during leisure and work, plus time in bed. Since not all participants climbed stairs, ran, cycled, or rowed during the measurement period, some participants had zero minutes in these activity types. Because physical activity types (i.e., compositional parts) that consist of zeros cannot be included in CoDA, we merged climbing stairs, running, cycling and rowing into the combined activity class HIPA.

Outcomes

As outcome variables, we used SBP (mm Hg), WC (cm), and LDL-C (mmol/L). We used the average of the three blood pressure measurements.

Covariates and variables for descriptive analyses

Sex, age, number of years of education, smoking status, average number of units of alcohol per week, and self-reported use of prescribed medication for cardiovascular disease, antidepressants or sedatives, asthma or bronchitis, or diabetes were included as covariates in our analyses.

For descriptive purposes, we categorised body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) into underweight (<18.5 kg/m2), normal weight (18.5-<25.0 kg/m2), overweight (25.0-<30.0 kg/m2), and obese (≥30 kg/m2) [34]. Furthermore, we categorised blood pressure into normal (systolic: <140 mm Hg and diastolic: <90 mm Hg; i.e., includes high normal), grade 1 hypertension (systolic: 140-≤159 mm Hg or diastolic: 90-≤99 mm Hg), grade 2 hypertension (systolic: 160-≤179 mm Hg or diastolic: 100-≤109 mm Hg), and grade 3 hypertension (systolic: ≥180 mm Hg or diastolic: ≥110 mm Hg) [35]. Finally, WC was categorised into >88 cm for women and >94 cm for men [36]. Further details about how these variables were derived can be found in S2 Table.

Statistical analyses

Descriptive statistics

We used frequencies with percentages or medians with the first and third quartile (Q1-Q3) to describe the characteristics of the study population. Medians were used due to skewed distributions of some of the continuous variables.

Investigation of selection bias

We compared the characteristics of the study participants who did not fulfil the inclusion criteria with those who fulfilled using Mann-Whitney U test, Pearson’s Chi-squared test (p-values <0.05 were considered to indicate differences between groups) and by assessing 95% confidence intervals (CI) of proportions and medians. The CIs were calculated with the Wilson’s score method [37] and the normal approximation method for proportions and medians, respectively.

Data transformation

The sample space of compositional data (i.e., the simplex) has a geometry that is incompatible with standard statistical methods. To make these methods applicable, we transformed the physical activity composition with the isometric log-ratio (ilr) transformation [25,38]. This resulted in a set of ilr-coordinates that represent the physical activity composition in a sample space (i.e., the real coordinate space) that allows the use of standard statistical methods [26]. Specifically, we constructed pivot ilr-coordinates, in which the first coordinate (ilr1) represents the first part of the composition relative to the geometric mean of the remaining parts [38].

Modelling process and reallocation of time

We investigated how the physical activity composition (expressed as ilr-coordinates) were associated with each outcome using linear regression models (i.e., crude and adjusted analyses). The modelling process was conducted through three steps:

  1. Firstly, we fitted multiple linear regression models with the ilr-coordinates representing the physical activity composition and potential confounders as covariates (i.e., only in the adjusted analyses) and SBP, WC, and LDL-C as outcome. Observations with missing values in the covariates were not included in the adjusted models (n = 69). The model assumptions were checked by plotting standardised residuals against a) continuous covariates (i.e., assumption of linearity) and b) fitted values (i.e., assumption of homogeneous variance), and by quantile-quantile (Q-Q) plots of the residuals (i.e., assumption of normally distributed residuals).

  2. Secondly, because the model estimates of the ilr-coordinates are not directly interpretable (due to the ilr-transformation), we theoretically reallocated time between sedentary behaviour and 1) walking, and 2) HIPA to quantify the measure of association in an understandable way [26]. Specifically, for work and leisure, respectively, we reallocated the geometric mean composition (i.e., reference composition) according to time reallocation 1 and 2. That is, the reallocations were made pairwise (a.k.a. one-to-one reallocations) during work and during leisure, respectively; all remaining physical activity types were kept constant. For example, if 10 minutes were reallocated from sedentary behaviour to walking in a theoretical composition consisting of 315 minutes sedentary behaviour, 100 minutes standing, 60 minutes walking and 5 minutes HIPA during work, it would result in 305 minutes sedentary behaviour and 70 minutes walking during work, with the duration of the remaining physical activity types, in both domains, kept constant.

    Because the geometric mean of walking and HIPA was lower during work than leisure, we could not reallocate the same absolute duration of time during work and leisure. For time reallocation 1, we therefore reallocated 10 to 30 minutes between sedentary behaviour and walking during work, and 10 to 50 min during leisure time, in 10-minute portions. For time reallocation 2, we reallocated 1 to 2 minutes between sedentary behaviour and HIPA during work, and 1 to 10 minutes during leisure, in 1- and 2-minute portions.

  3. Thirdly, we used the fitted values from the linear regression models to estimate each outcome given the reference- and reallocated compositions. Then, we calculated the difference in outcome by subtracting the estimated outcome of the reference-composition from the estimated outcome of each reallocated composition [26,27].

Sensitivity analyses

To investigate the influence of excluding individuals taking antihypertensives, diuretics, or cholesterol lowering drugs, we conducted sensitivity analyses including 1) all study participants regardless of medication use, and 2) limited to those with the medications use.

We used RStudio (version 1.3.1093) [39] running R (version 4.0.3) [40] for all analyses, and, specifically, the packages compositions [41] and robCompositions [42] for the analyses involving CoDA.

Results

Cohort characteristics

We have illustrated the cohort formation in Fig 1 and presented characteristics of the study population in Table 1. The median number of valid days was 6 and the study participants wore the accelerometers for a median time of 23.8 h/day. Furthermore, the median number of workdays was 4 and 94% had >1 workday. The median worktime was 7.6 h/day. There were 58% women, and the median age was 48.6 years. The median SBP, WC, and LDL-C was 128 mm Hg, 83 cm, and 3.0 mmol/L, respectively.

Table 1. Characteristics of 652 adults participating in the fifth examination of the Copenhagen City Heart Study.

N = 652
Characteristics n (%) / Median (Q1, Q3)
Accelerometer wear time 652 (100.0)
    Median h/day 23.8 (23.1, 24.0)
Number of valid days of measurement 652 (100.0)
    Median number of days 6.0 (6.0, 7.0)
Working hours 652 (100.0)
    Median h/day 7.6 (6.7, 8.3)
Number of workdays 652 (100.0)
    Median number of days 4.0 (3.0, 4.0)
Sex distribution 652 (100.0)
    Women 378 (58.0)
    Men 274 (42.0)
Age 652 (100.0)
    Median years 48.6 (36.1, 57.1)
Number of years of education 652 (100.0)
    Median years 13.0 (12.0, 14.0)
Level of education 651 (99.9)
    No further education beyond primary school 47 (7.2)
    Short education (up to 3 years) 44 (6.8)
    Vocational or comparable education (1–3 years) 105 (16.1)
    Higher education (≥3 years) 176 (27.0)
    University education 279 (42.9)
Household income 644 (98.8)
    Low (<200 000 DKK) 69 (10.7)
    Middle (200 000–600 000 DKK) 238 (37.0)
    High (≥600 000 DKK) 337 (52.3)
Smoking status 639 (98.0)
    Non-smoker 295 (46.2)
    Previous smoker 253 (39.6)
    Current smoker 91 (14.2)
Average weekly number of units of alcohol per week 594 (91.1)
    Median units/week 6.0 (3.0, 11.0)
Use of prescribed medication 652 (100.0)
    Yes 49 (7.5)
Self-reported general health 648
    Excellent or Very good 328 (50.6)
    Good 256 (39.5)
    Less good or Poor 64 (9.9)
Systolic blood pressure 652 (100.0)
    Median (mmHg) 127.8 (117.5, 138.0)
Diastolic blood pressure 652 (100.0)
    Median (mmHg) 77.0 (70.5, 83.5)
Blood pressure classification 652 (100.0)
    Normal 486 (74.5)
    Grade 1 hypertension 147 (22.6)
    Grade 2 or 3 hypertension 19 (2.9)
Waist circumference 652 (100.0)
    Median (cm) 83.0 (76.0, 92.0)
Waist circumference classification 652 (100.0)
    Women >80 cm 413 (63.3)
    Men >94 cm 239 (36.7)
BMI 652 (100.0)
    Underweight 7 (1.1)
    Normal 393 (60.3)
    Overweight 203 (31.1)
    Obese 56 (8.6)
Low density lipoprotein cholesterol 652 (100.0)
    Median (mmol/L) 3.0 (2.5, 3.7)

N/n, number of observations.

y, years.

Q1-Q3, first and third quartile.

DKK, Danish kroner.

mm Hg, millimetre of mercury.

Blood pressure classification is based on the 2013 European Society of Hypertension/European Society of Cardiology guidelines for the management of arterial hypertension (the normal category includes high normal).

BMI, body mass index.

BMI was classified according to the WHO classification (Underweight, <18.5 kg/m2; Normal weight, 18.5-<25.0 kg/m2; Overweight, 25.0-<30.0 kg/m2; Obese, ≥30 kg/m2.

mmol/L, millimol per litre (molar concentration).

The geometric mean of each part of the physical activity composition is presented in Table 2, stratified by leisure and work.

Table 2. Geometric mean of 24-h physical activity composition among 652 participants in the fifth examination of the Copenhagen City Heart Study stratified by domain.

Physical activity type Domain
Leisure
Minutes (%) of a 24-h day
Work
Minutes (%) of 24-h day
Sedentary behaviour 372.71 (25.88) 234.24 (16.27)
Standing 126.97 (8.82) 74.62 (5.18)
Moving 49.10 (3.41) 22.46 (1.56)
Walking 56.80 (3.94) 32.51 (2.26)
HIPA 10.88 (0.76) 2.46 (0.17)
Time in bed 457.26 (31.75) -

HIPA, high-intensity physical activity (sum of climbing stairs, running, cycling and rowing).

Investigation of selection bias

The study participants who did not fulfil the inclusion criteria were older, had a lower level of education, and a lower household income, a higher median SBP and WC, a lower LDL-C, and a higher proportion were previous or current smokers, reported use of prescribed medicine, rated their general health as less good or poor, and were classified as overweight and obese, and with hypertension compared to those who fulfilled the inclusion criteria (S4 Table).

Model validation

The model validation did not reveal any substantial violations of the model assumptions (S1 File). However, specifically for the SBP-model, the variation of the standardised residuals slightly increased across the fitted values. For all three models, the residuals were not perfectly normally distributed, but the deviations were considered too small to substantially affect the model fit.

Time reallocations

All estimates presented here are from the adjusted analyses. Results from the crude analyses can be found in S2 File. We emphasise that all time reallocations were made with the mean composition as the starting point.

Systolic blood pressure

During leisure, the results indicated that less sedentary behaviour and more walking compared to the reference composition was associated with a lower SBP, while the results indicated an association with a higher SBP during work (Fig 2A and Table 3). Importantly, the size of the estimated differences in SBP differed markedly between the domains. For example, the absolute difference in SBP given 30 minutes less walking and 30 minutes more sedentary behaviour during work was 11 times larger than that during leisure (work: -6.7 [95% CI: -16.2, 2–9] mm Hg vs. leisure: 0.6 [-2.7, 3.8] mm Hg). The same pattern of opposite associations was evident for less sedentary behaviour and more HIPA during leisure and work. Although the CIs included zero, the majority of the values indicated a lower and higher SBP during leisure and work, respectively (e.g., 10 min, leisure: -0.7, 95% CI: -1.5, 0.2; Fig 2B and Table 4).

Fig 2.

Fig 2

Adjusted estimated differences in systolic blood pressure (mm Hg, y-axis) given the reallocation of time between sedentary behaviour and A) walking, and B) HIPA among 652 adults. A negative value on the x-axis reflects the pairwise reallocation of time from sedentary behaviour to walking or HIPA, while a positive value reflects the reallocation of time from walking or HIPA to sedentary behaviour. The origin represents the reference composition (i.e., 372.7 and 234.2 min sedentary behaviour, 127.0 and 74.6 min standing, 49.1 and 22.5 min moving, 56.8 and 32.5 min walking, and 10.9 and 2.5 min HIPA, during leisure and work, respectively, and 457.3 min in bed). The difference in outcome was calculated by subtracting the estimated outcome of the reference composition from the estimated outcome for each reallocated composition. SBP is systolic blood pressure. HIPA is high-intensity physical activity (i.e., sum of climbing stairs, running, cycling, and rowing). Vertical lines correspond to the 95% confidence intervals.

Table 3. Estimated adjusted differences in systolic blood pressure, waist circumference, and low-density lipoprotein cholesterol given time reallocations between sedentary behaviour and walking during leisure and work among 652 adults in the fifth examination of the Copenhagen City Heart Study.
Time reallocations Leisure
Estimated difference in outcome (95% CI)
Work
Estimated difference in outcome (95% CI)
Systolic blood pressure (mm Hg)
    -50 min (sedentary behaviour → walking) -1.16 (-4.01, 1.69) -
    -40 -0.91 (-3.30, 1.48) -
    -30 -0.67 (-2.56, 1.22) 1.67 (-0.83, 4.16)
    -20 -0.44 (-1.78, 0.90) 1.23 (-0.60, 3.05)
    -10 -0.22 (-0.93, 0.50) 0.69 (-0.33, 1.70)
    0 (reference composition) 0 (0, 0) 0 (0, 0)
    10 0.21 (-0.64, 1.06) -0.95 (-2.33, 0.43)
    20 0.41 (-1.48, 2.30) -2.47 (-6.04, 1.10)
    30 0.60 (-2.66, 3.85) -6.66 (-16.19, 2.88)
    40 0.77 (-4.47, 6.02) -
    50 min (walking → sedentary behaviour) 0.92 (-8.17, 10.00) -
Waist circumference (cm)
    -50 min (sedentary behaviour → walking) 0.56 (-1.29, 2.40) -
    -40 0.50 (-1.05, 2.05) -
    -30 0.42 (-0.80, 1.65) 1.25 (-0.37, 2.86)
    -20 0.32 (-0.55, 1.18) 0.92 (-0.26, 2.10)
    -10 0.18 (-0.28, 0.64) 0.52 (-0.14, 1.18)
    0 (reference composition) 0 (0, 0) 0 (0, 0)
    10 -0.24 (-0.79, 0.31) -0.72 (-1.62, 0.17)
    20 -0.56 (-1.78, 0.66) -1.89 (-4.20, 0.42)
    30 -1.03 (-3.13, 1.08) -5.13 (-11.29, 1.03)
    40 -1.75 (-5.14, 1.64) -
    50 min (walking → sedentary behaviour) -3.26 (-9.13, 2.62) -
Low-density lipoprotein cholesterol (mmol/L)
    -50 min (sedentary behaviour → walking) 0.16 (-0.01, 0.33) -
    -40 0.14 (-0.003, 0.28) -
    -30 0.11 (-0.001, 0.22) 0.09 (-0.05, 0.24)
    -20 0.08 (0.001, 0.160) 0.07 (-0.04, 0.18)
    -10 0.04 (0.001, 0.090) 0.04 (-0.02, 0.10)
    0 (reference composition) 0 (0, 0) 0 (0, 0)
    10 -0.05 (-0.10, -0.003) -0.05 (-0.13, 0.03)
    20 -0.12 (-0.23, -0.01) -0.13 (-0.35, 0.08)
    30 -0.21 (-0.41, -0.02) -0.35 (-0.92, 0.21)
    40 -0.35 (-0.66, -0.04) -
    50 min (walking → sedentary behaviour) -0.62 (-1.16, -0.08) -

Analyses adjusted for age, sex, level of education, number of alcohol units/week, smoking status, and use of prescribed medication.

69 observations were not included in the adjusted models due to missing values in some covariates.

CI, confidence interval.

mm Hg, mm of mercury.

mmol/L, mmol per litre.

Reference composition corresponds to: 372.7 and 234.2 min sedentary behaviour, 127.0 and 74.6 min standing, 49.1 and 22.5 min moving, 56.8 and 32.5 min walking, and 10.9 and 2.5 min HIPA, during leisure and work, respectively, and 457.3 min in bed (i.e., geometric mean).

HIPA, high-intensity physical activity which consists of climbing stairs (up/down), running, cycling, and rowing.

Table 4. Estimated adjusted differences in systolic blood pressure, waist circumference, and low-density lipoprotein cholesterol given time reallocations between sedentary behaviour and high intensity physical activity during leisure and work among 652 adults in the fifth examination of the Copenhagen City Heart Study.
Time reallocations Leisure
Estimated difference in outcome (95% CI)
Work
Estimated difference in outcome (95% CI)
Systolic blood pressure (mm Hg)
    -10 min (sedentary behaviour → HIPA) -0.69 (-1.54, 0.17) -
    -8 -0.57 (-1.29, 0.15) -
    -6 -0.44 (-1.02, 0.13) -
    -4 -0.31 (-0.72, 0.10) -
    -2 -0.16 (-0.38, 0.06) 0.22 (-0.44, 0.88)
    -1 -0.08 (-0.20, 0.03) 0.13 (-0.25, 0.50)
    0 (reference composition) 0 (0, 0) 0 (0, 0)
    1 0.09 (-0.04, 0.22) -0.19 (-0.77, 0.38)
    2 0.19 (-0.08, 0.45) -0.62 (-2.47, 1.23)
    4 0.41 (-0.18, 1.01) -
    6 0.70 (-0.34, 1.74) -
    8 1.11 (-0.61, 2.84) -
    10 min (HIPA → sedentary behaviour) 2.00 (-1.28, 5.26) -
Waist circumference (cm)
    -10 min (sedentary behaviour → HIPA) -1.35 (-1.90, -0.80) -
    -8 -1.14 (-1.60, -0.67) -
    -6 -0.90 (-1.27, -0.53) -
    -4 -0.64 (-0.90, -0.38) -
    -2 -0.34 (-0.49, -0.20) -0.18 (-0.61, 0.25)
    -1 -0.18 (-0.25, -0.11) -0.10 (-0.35, 0.14)
    0 (reference composition) 0 (0, 0) 0 (0, 0)
    1 0.20 (0.11, 0.28) 0.16 (-0.22, 0.53)
    2 0.41 (0.24, 0.58) 0.50 (-0.70, 1.69)
    4 0.92 (0.53, 1.30) -
    6 1.60 (0.92, 2.27) -
    8 2.63 (1.51, 3.74) -
    10 min (HIPA → sedentary behaviour) 4.92 (2.80, 7.03) -
Low-density lipoprotein cholesterol (mmol/L)
    -10 min (sedentary behaviour → HIPA) -0.07 (-0.12, -0.02) -
    -8 -0.06 (-0.11, -0.02) -
    -6 -0.05 (-0.08, -0.02) -
    -4 -0.04 (-0.06, -0.01) -
    -2 -0.02 (-0.03, -0.01) -0.01 (-0.05, 0.03)
    -1 -0.01 (-0.020, -0.003) -0.01 (-0.03, 0.02)
    0 (reference composition) 0 (0, 0) 0 (0, 0)
    1 0.01 (0.003, 0.018) 0.01 (-0.02, 0.04)
    2 0.02 (0.01, 0.04) 0.03 (-0.08, 0.14)
    4 0.05 (0.02, 0.09) -
    6 0.09 (0.03, 0.15) -
    8 0.14 (0.04, 0.25) -
    10 min (HIPA → sedentary behaviour) 0.27 (0.07, 0.46) -

Model adjusted for age, sex, level of education, number of alcohol units/week, smoking status, and use of prescribed medication.

69 observations were not included in the adjusted models due to missing values in some covariates.

CI, confidence interval.

mm Hg, mm of mercury.

mmol/L, mmol per litre.

Reference composition corresponds to: 372.7 and 234.2 min sedentary behaviour, 127.0 and 74.6 min standing, 49.1 and 22.5 min moving, 56.8 and 32.5 min walking, and 10.9 and 2.5 min HIPA, during leisure and work, respectively, and 457.3 min in bed (i.e., geometric mean).

HIPA, high-intensity physical activity which consists of climbing stairs (up/down), running, cycling, and rowing.

Waist circumference

During both leisure and work, the results indicated less sedentary behaviour and more walking to be associated with a larger WC; however, the CIs included zero (Fig 3A and Table 3). In contrast, during leisure and work, less sedentary behaviour and more HIPA was associated with a smaller WC, although the estimates during work were small. Also, for work, the CIs included zero, but most values suggested a smaller WC (Fig 3B and Table 4). The estimated difference in WC given the time reallocations was not symmetric. For example, during work, the reallocation of 30 min walking to sedentary behaviour was associated with a 5 cm smaller WC (95% CI: -11.29, 1.03) compared to an estimated 1 cm larger WC given the opposite time reallocation. Additionally, the smaller WC (i.e., -5 cm) is about five times larger than the estimated difference observed for the corresponding time reallocation during leisure (i.e., -1 cm).

Fig 3.

Fig 3

Adjusted estimated differences in waist circumference (cm, y-axis) given the reallocation of time between sedentary behaviour and A) walking, and B) HIPA among 652 adults. A negative value on the x-axis reflects the pairwise reallocation of time from sedentary behaviour to walking or HIPA, while a positive value reflects the reallocation of time from walking or HIPA to sedentary behaviour. The origin represents the reference composition (i.e., 372.7 and 234.2 min sedentary behaviour, 127.0 and 74.6 min standing, 49.1 and 22.5 min moving, 56.8 and 32.5 min walking, and 10.9 and 2.5 min HIPA, during leisure and work, respectively, and 457.3 min in bed). The difference in outcome was calculated by subtracting the estimated outcome of the reference composition from the estimated outcome for each reallocated composition. WC is waist circumference. HIPA is high-intensity physical activity (i.e., sum of climbing stairs, running, cycling, and rowing). Vertical lines correspond to the 95% confidence intervals.

Low-density lipoprotein cholesterol

During both leisure and work, the results indicated that less sedentary behaviour and more walking was associated with a higher LDL-C (e.g., 20 min: 0.08, 95% CI: 0.00, 0.16 mmol/L) (Fig 4A and Table 3). During leisure, less sedentary behaviour and more HIPA was associated with a lower LDL-C (e.g., 10 min: -0.07, 95% CI: -0.12, -0.02 mmol/L). During work, the estimates followed the same pattern but were smaller and the CIs included zero (Fig 4B and Table 4).

Fig 4.

Fig 4

Adjusted estimated differences in low-density lipoprotein cholesterol (mmol/L, y-axis) given the reallocation of time between sedentary behaviour and A) walking, and B) HIPA among 652 adults. A negative value on the x-axis reflects the pairwise reallocation of time from sedentary behaviour to walking or HIPA, while a positive value reflects the reallocation of time from walking or HIPA to sedentary behaviour. The origin represents the reference composition (i.e., 372.7 and 234.2 min sedentary behaviour, 127.0 and 74.6 min standing, 49.1 and 22.5 min moving, 56.8 and 32.5 min walking, and 10.9 and 2.5 min HIPA, during leisure and work, respectively, and 457.3 min in bed). The difference in outcome was calculated by subtracting the estimated outcome of the reference composition from the estimated outcome for each reallocated composition. LDL-C is low-density lipoprotein cholesterol. HIPA is high-intensity physical activity (i.e., sum of climbing stairs, running, cycling, and rowing). Vertical lines correspond to the 95% confidence intervals.

Sensitivity analyses

Similar results were observed across the three outcomes when study participants taking antihypertensives, diuretics, or cholesterol lowering drugs were included in the analyses (Table A-C in S3 File). When the analyses were limited to those taking these drugs (n = 146), the estimated differences in SBP for time reallocations between sedentary behaviour and walking followed the same pattern but were larger than in the main analyses. However, the estimated differences in SBP given time reallocations between sedentary behaviour and HIPA followed an opposite pattern compared to the main analysis (Table D in S3 File). Opposite patterns were also found for WC and LDL-C. Specifically, for WC in the sedentary behaviour and walk-reallocations during leisure and the sedentary behaviour and HIPA-reallocations during work, and for LDL-C in the sedentary behaviour and walk-reallocations during both domains and in the sedentary behaviour and HIPA-reallocations during work (Table E and F in S3 File).

Discussion

Summary of findings

During leisure, the findings indicated less sedentary behaviour and more walking or more HIPA to be associated with a lower SBP, while during work, the findings indicated an association with a higher SBP. During both domains, the findings indicated that less sedentary behaviour and more HIPA was associated with a smaller WC and a lower LDL-C. Furthermore, the findings indicated less sedentary behaviour and more walking to be associated with a larger WC and a higher LDL-C, regardless of domain.

Interpretation of findings

Systolic blood pressure

During leisure, the results indicated less sedentary behaviour and more walking or more HIPA compared to the reference composition to be associated with a lower SBP. In contrast, during work, the results indicated an association with a higher SBP (Fig 2, Tables 3 and 4). Although not statistically significant, these findings support that these physical activity types can have either beneficial or detrimental associations with a CVD risk factor depending on domain [8,15]. Importantly, the results from the time reallocations should be seen relative to the reference composition (Table 2).

These findings may be explained by differences in characteristics between physical activity during leisure and work [19]. Regular physical activity of moderate or higher intensity that takes place during relatively short time periods may, given sufficient time for restitution, facilitate beneficial central and peripheral adaptations of the cardiovascular system (e.g., lower heart rate, blood pressure, and inflammatory biomarkers), which decrease the risk of CVD. However, contextual factors and work conditions (e.g., productive demands, degree of control, heavy lifting, and awkward or static body postures) [15,19] make occupational physical activity different from physical activity during leisure with regards to the intensity, duration, and variation of the physical activity, as well as restitution [15,19]. Combinations of high occupational physical activity and insufficient restitution have been suggested to increase average daily heart rate, blood pressure, and levels of inflammatory biomarkers [13,15,19], which all increase the risk of CVD [19]. These mechanisms could explain our findings of a contrasting association between physical activity types during leisure and work, and SBP (Fig 2, Tables 3 and 4). As previously mentioned, measurement error (i.e., use of self-reported physical activity data) has also been suggested to explain the physical activity health paradox. Our findings do not support this since they are based on device-based measurements of physical activity.

There is considerable evidence that leisure time physical activity has favourable effects on SBP [6,4345], while sedentary behaviour during leisure seems to be weakly associated with SBP [46]. However, to our knowledge, fewer studies have investigated how occupational physical activity are associated with SBP, and their findings are inconclusive [13,4753]. For example, among studies investigating both leisure time and occupational physical activity, two studies found an association between higher leisure time physical activity and a lower SBP [13,48], which is in agreement with the findings in this study (i.e., the reallocation of time from sedentary behaviour to walking or to HIPA during leisure). In addition, one study found higher leisure time physical activity to be associated with a higher SBP [51], while two other studies did not find any association [13,50]. The results in the current study disagree with these studies. On the other hand, our findings related to the reallocation of time from sedentary behaviour to walking or HIPA during work (i.e., indications of an association with a higher SBP) agree with three of these studies [13,52,53], but disagree with six other studies [13,4751]; of which four did not find any association [13,4951]. Only two of these previous studies used accelerometer data [13,48], and only one used CoDA [48]; the remaining studies used self-reported data and a ‘traditional’ analytical approach (i.e., did not take the co-dependency between physical activity types or intensities into account). Furthermore, all studies used general population samples, except three studies that used working populations [13,48,52]. Therefore, based on studies that have investigated how physical activity during both leisure and work are associated with SBP, the association between occupational physical activity and SBP is inconclusive.

Our results indicated a 1.7 (95% CI: -0.8, 4.2) mm Hg higher SBP given 30 minutes less sedentary behaviour and 30 minutes more walking during work, and an 0.7 (95% CI: -2.6, 1.2) mm Hg lower SBP given the same time reallocation during leisure. Furthermore, 30 minutes less walking and 30 minutes more sedentary behaviour during work suggested a 6.7 (95% CI: -16.2, 2.9) mm Hg lower SBP. This difference is 11 times larger than that of the opposite reallocation during leisure (i.e., 30 min less sedentary behaviour and 30 min more walking: -0.7, 95% CI: -2.6, 1.2 mm Hg), and could be expected to reduce the risk of CVD-specific mortality by over 20% based on the known linear relationship between SBP and CVD [54,55]. Since even small changes in the population mean SBP can have substantial impact on CVD risk (i.e., affecting the prevalence of hypertension) [5456], these findings could, potentially, have important implications in population-based prevention of CVD [44].

Waist circumference

During both domains, our results indicated less sedentary behaviour and more walking compared to the reference composition to be associated with a larger WC (Fig 3, Table 3). This finding may, potentially, be attributed to differences in occupation, socioeconomic status, and health, since low socioeconomic status is known to be associated with poor health [21], including overweight and dyslipidaemia [22]. That is, individuals with lower socioeconomic status who, in general, have poorer health are more likely to have occupations that involve little sedentary behaviour and high physical activity [18], such as long durations of walking. Further, we emphasise that the association between physical activity and overweight is bidirectional, and that other factors not considered in our analyses (e.g., diet) are influencing a person’s WC. Importantly, these findings highlight that our estimates represent measures of associations, and not causal effects [57]. Furthermore, we found less sedentary behaviour and more HIPA during leisure to be associated with a smaller WC (e.g., 10 min less sedentary and 10 min more HIPA: -1.35, 95% CI: -1.90, -0.80 cm; Fig 3, Table 4). The estimates during work followed the same pattern but were small and the CIs included zero. This is in line with existing evidence from observational and intervention studies [5861]. The current findings also support that domain-specific characteristics of physical activity do not affect risk factors for which diet is most important [6264].

In previous studies based on total or leisure time physical activity, less sedentary behaviour and more physical activity, in particular HIPA, is reported to be associated with lower WC [58]. The results for WC in the present study are in agreement with this (i.e., given the reallocation of time from sedentary behaviour to HIPA in both domains). However, to our knowledge, few studies have investigated how both leisure time and occupational physical activity are associated with WC [47,5153,6567]. Only two of these studies used accelerometer-data [66,67], and one used iso-temporal substitution modelling [67]; the remaining studies used self-reported data and ‘traditional’ analyses. None of these studies found contrasting associations between leisure and work, although some only found associations during one of the two domains [47,51,66]. In the current study, the reallocation of time from sedentary behaviour to walking during both domains seemed to be associated with a larger WC, which is incongruent with one previous study that did not find an association between less sedentary behaviour and more walking [67]. On the other hand, the results in our study indicated an association between less sedentary time and more HIPA and a smaller WC, which is in line with two previous studies [51,67]. Finally, in five studies that focussed on sedentary behaviour, the direction of the reported associations is varied, but the findings do not suggest that physical activity during leisure and work have contrasting associations with WC [47,52,53,65,66].

From a population-based prevention-perspective, even small shifts in the population mean of WC, such as the 1.4 cm smaller WC given 10 minutes less sedentary behaviour and 10 more minutes of HIPA during leisure, can have implications for public health, since it may decrease the prevalence of individuals at increased risk for CVD due to a high WC.

Low-density lipoprotein cholesterol

For LDL-C, during both domains the results indicated that less sedentary behaviour and more walking was associated with a higher LDL-C (Fig 4, Table 3). Similar to WC, and as previously discussed, one potential explanation to these findings may be confounding by socioeconomic status and occupation, which are linked to poor health [18,21,22]. Furthermore, during leisure and work, the results indicated that less sedentary behaviour and more HIPA was associated with a lower LDL-C (e.g., 10 minutes during leisure: -0.07, 95% CI: -0.12, -0.02 mmol/L; Fig 4, Table 4). This is in line with clinical guidelines, where leisure time physical activity is regarded to have a smaller effect on LDL-C (i.e., <5%) compared to, for example, high-density lipoprotein cholesterol (HDL-C) (i.e., >10%) [63]. These findings also support that differences in the characteristics of physical activity during leisure and work do not affect LDL-C differently. This is likely because LDL-C is mainly influenced by total energy expenditure, and not by type of physical activity, posture, or pattern of accumulation over time [62,63,68].

The results for LDL-C in the current study indicated different associations between the two reallocations but did not differ between domains (Fig 4, Tables 3 and 4). During both leisure and work, the reallocation of time from sedentary behaviour to walking suggested an association with a higher LDL-C. This is in agreement with one study only investigating occupational physical activity [49], but in disagreement with other studies that have investigated how sedentary behaviour or physical activity during both leisure and work is associated with LDL-C [51,52,65]. Furthermore, during both domains, less sedentary behaviour and more HIPA seemed to be associated with a lower LDL-C. This disagrees with findings from three studies [51,52,65], where similar associations were reported for sedentary behaviour during leisure but not for work (except for the study by Honda et al. [52] where indications of opposite associations during leisure and work are reported). All mentioned studies used self-reported data and ‘traditional’ analyses. Hence, given the results of our study and previous literature, the association between physical activity during leisure and work, and LDL-C is unclear.

On a population-level, a 1 mmol/L lower non-HDL-C (i.e., total cholesterol minus HDL-C) has been reported to lower IHD-mortality by 30% [69]. This translates to 0.3% lower IHD-mortality for every 0.01 mmol/L lower LDL-C. Therefore, even small improvements in LDL-C on a population-level like those observed in the current study, could, in combination with improvements in other modifiable risk factors (e.g., poor diet, high SBP, obesity, smoking, high alcohol consumption, and others), likely contribute to the prevention of incident IHD [70,71]. However, the potentially detrimental association between less sedentary behaviour and more HIPA during work and SBP should be kept in mind.

Sensitivity analyses

The results of the sensitivity analysis where those taking antihypertensives, diuretics, or cholesterol lowering drugs were included did not differ substantially from the main analysis (Table A-C in S3 File). However, the second sensitivity analysis indicated that the association between sedentary behaviour, walking, and HIPA during work and leisure, and SBP, WC, and LDL-C among those reporting the use of antihypertensives, diuretics, or cholesterol lowering drugs differed from those not taking these medications (Table D-F in S3 File). For example, the estimated differences in SBP for the sedentary behaviour and walk-reallocations were markedly larger during both domains. On the other hand, a pattern opposite to the one found in the main analysis was observed for the sedentary behaviour and HIPA-reallocations. We emphasise that there were differences in the geometric mean (i.e., the starting points for the time reallocations) of the physical activity types between those taking and not taking antihypertensives, diuretics, or cholesterol lowering drugs. Specifically, those taking antihypertensives, diuretics, or cholesterol lowering drugs were on average more sedentary and less active during leisure but less sedentary and more active during work compared to those not taking these medications. This should be kept in mind when interpreting these results. Also, the lower number of individuals (n = 146) results in less precision of the estimates.

Methodological considerations

Firstly, we emphasise that our estimates are based on cross-sectional data and should be interpreted as measures of association and not causal effects [57]. We also acknowledge the risk for reversed causality, in particular for WC because the relationship between physical activity and adiposity measurements appears to be bi-directional [72]. We also emphasise that the findings should be interpreted from a primary prevention perspective, since study participants reporting the use of antihypertensives, diuretics, and cholesterol lowering medicine were excluded because the use of these medications could modify the investigated relationships.

We know from a previous study, that those who accepted to wear accelerometers in the fifth examination of the CCHS and those who fulfilled our accelerometer data inclusion criteria are different than their counterparts on several characteristics [30]. In addition, those who fulfilled the inclusion criteria of this study differed from those not fulfilling the criteria. As in all epidemiological studies including working populations, a healthy worker effect may be present in the current study [73]. We acknowledge the apparent selection bias, but emphasise that representativeness is not an aim in itself [74,75] when estimating measures of association or investigating physiological mechanisms (i.e., where normal biological variation without the influence of ‘external’ factors, such as medication, is important) [74,75]. Furthermore, the results of the sensitivity analyses indicated that the exclusion of individuals taking antihypertensives, diuretics, or cholesterol lowering drugs did not influence the overall results. However, they indicated that the association between physical activity and sedentary behaviour during leisure and work, and risk factors for CVD may be different among individuals with pre-existing CVD.

Given the reported high sensitivity and specificity [32,33], we consider the validity and precision of Acti4’s physical activity classification to be high. However, some details are important to emphasise when interpreting the results. Firstly, the measurements do not capture the load in specific tasks such as heavy lifting, pushing, pulling, or awkward body positions (does not include measurements of the weight of materials, people, or tools handled), which are known to impose high physical demands, and therefore, could be important [13,14]. Secondly, common to all accelerometer-based measurements of physical activity, the measurements do not include the relative intensity of the physical activity. Thirdly, we do not know whether the measurement period accurately reflects the study participants’ typical physical activity level. Finally, we do not have data on job title, and on past or cumulative job exposure. These limitations imply a risk for misclassification of the exposure which, potentially, could lead to an underestimation of the health effects.

With regards to our outcomes, the risk that some SBP measurements were affected by white coat hypertension or masked hypertension should be acknowledged. This limitation could be overcome in future studies by the use of ambulatory blood pressure, which also seems to be a stronger predictor of CVD [76]. Furthermore, the magnitude of measurement error in WC has been reported to be highly varying [77], which should be acknowledged. We used WC rather than BMI or waist-hip ratio since it has been suggested to be a stronger predictor for CVD [36]. Finally, our LDL-C measurements were based on non-fasting blood samples. Importantly, since habitual meals do not affect LDL-C to a significant degree [71,78], we do not believe this to have affected the precision of the LDL-C measurements. We chose LDL-C as a clinically relevant biomarker of dyslipidaemia due to its strong association with CVD risk and central role in the management of CVD (e.g., risk assessment and treatment target). Furthermore, the literature regarding the association between physical activity and LDL-C is inconclusive, and therefore, we believe our study can supplement existing knowledge.

It should be emphasised that the geometric mean time spent in the physical activity types was used as the reference composition in our time reallocations. Although in line with previous studies [26,27], one limitation with this approach is that the estimated outcome may be less accurate for study participants with a more extreme composition compared to the estimates of those whose composition lies closer to the reference. This is reflected in the wider confidence intervals seen for the time reallocations furthest away from the reference composition. Additionally, since the time spent in HIPA in general, and, in particular, during work was quite low in our study population, we could only investigate small time reallocations between sedentary behaviour and HIPA.

In general, the estimates were small, and the CIs were wide, in particular for the work-specific time reallocations. This is likely a consequence of the size of our study population, and the relatively small number of participants with a long duration of HIPA during work, which results in a large variation. A larger study population would likely result in less variation and thereby improved precision of the estimates, which could increase the confidence when interpreting the results.

Perspectives

In general, all physical activity is considered to be health beneficial compared to sedentary behaviour. This is, for example, reflected in current physical activity recommendations [16,79], and the results of the current study support the importance of an active leisure for good health. However, as previous studies and our results indicate [8,12,80], public health messages such as ‘sit less and move more’, may not be well suited for population groups that are highly physically active during work. On the one hand, more leisure time physical activity may lead to increased fitness and workability (i.e., both physical and mental capacity), which could decrease the relative workload and thereby the risk of CVD and other non-communicable diseases. On the other hand, more leisure time physical activity may lead to cardiovascular overload and a vicious cycle of decreasing fitness over time; a scenario in which rest and restitution should be recommended. Currently, for several health outcomes it is still unclear how individuals with high occupational physical activity should best compensate during leisure. One potential alternative is workplace-based initiatives, such as aerobic exercise during work hours. Although such interventions may have unintended negative health effects such as increased SBP [81], they can improve cardiorespiratory fitness, workability, and health [8183]. It is, therefore, highly important to take the potentially contrasting health effects of leisure time- and occupational physical activity into account in physical activity recommendations for adults.

This study exemplifies how a 24-hour approach that integrates different domains can improve our knowledge about how physical activity and health outcomes are associated, and the results highlight the importance of considering physical activity during both leisure and work. The results also reflect the fact that durations of physical activity types are co-dependent, and that the association between a physical activity type and health outcome depends on how the day is composed and on what activity type an increase in one activity displaces. However, there is a need for studies with larger study samples and prospective data that further investigate the health effects of walking and other physical activity types during both leisure and work. Combining device-based measurements with data on previous job titles, job exposure matrices, routinely collected administrative data (e.g., periods of sick leave periods, retirement), or questionnaire data to improve the exposure assessment and minimise misclassification could be a fruitful avenue for future studies. There is also a need to better understand how existing knowledge can be implemented to increase physical activity levels in the population, and what to recommend to population groups with high occupational physical activity levels with regards to their leisure time physical activity.

Conclusions

Less sedentary behaviour and more walking or HIPA seems to be associated with a lower SBP during leisure, but, during work, it seems to be associated with a higher SBP. In contrast, no consistent differences between domains were observed for WC and LDL-C. These findings highlight the importance of considering the physical activity health paradox, at least for some risk factors for CVD. The adverse health effects associated with occupational physical activity should inform physical activity recommendations.

Supporting information

S1 Table. Overview of questions and responses.

(PDF)

S2 Table. Overview of derived variables.

(PDF)

S3 Table. Variation matrix of parts in physical activity composition.

(PDF)

S4 Table. Comparison of characteristics of non-eligible and eligible participants.

(PDF)

S1 File. Linear regression models.

(PDF)

S2 File. Time reallocations.

(PDF)

S3 File. Sensitivity analyses.

(PDF)

Acknowledgments

PS established and designed the CCHS. PS and AH developed the initial idea and designed and funded the accelerometer measurements in the fifth round of the CCHS. MSJ, KS, AH and MK contributed to the conception and design of the present study. MSJ led the work with the processing of the raw accelerometer data, performed the analyses, the initial data interpretation, and formulated and developed the manuscript. AH, JLM, EP, PS, MK, and KS contributed with critical revising during the development of the manuscript. All authors have discussed the results and have given approval to the publishing of the final version of the manuscript. We acknowledge the research personnel of the CCHS for their work with the data collection, research personnel at the National Research Centre for the Working Environment for their contribution in the processing and analyses of the accelerometer data, and all individuals in the fifth examination of the CCHS for their participation.

Data Availability

The data generated and analysed for this study contains potentially identifiable or sensitive information and can therefore not be shared publicly (General Data Protection Regulation, European Union). However, anybody can apply for the use of data by contacting the secretariat director of the Copenhagen City Heart Study. For contact information, please see https://www.frederiksberghospital.dk/afdelinger-og-klinikker/oesterbroundersoegelsen/kontakt/Sider/default.aspx. The authors of the present study had no special privileges in accessing the data that other interested researchers would not have.

Funding Statement

The Danish Heart Foundation, the Beckett Foundation, the Danish Lung Association, the IMK – Almene Fond, and Helene and Viggo Bruun’s Foundation funded the fifth examination of the CCHS. The funders were not involved in the design and management of the study, in the collection, analysis or the interpretation of data, in the preparation of the manuscript, or in the decision to submit the manuscript for publication. MSJ received funding from the Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark (Faculty Scholarship), and the National Research Centre for the Working Environment, Copenhagen, Denmark (internal funding). The remaining authors received no specific funding for this work.

References

  • 1.Hamer M, Chida Y. Walking and primary prevention: a meta-analysis of prospective cohort studies. British journal of sports medicine. 2008;42(4):238–43. Epub 2007/12/01. doi: 10.1136/bjsm.2007.039974 . [DOI] [PubMed] [Google Scholar]
  • 2.Kelly P, Kahlmeier S, Gotschi T, Orsini N, Richards J, Roberts N, et al. Systematic review and meta-analysis of reduction in all-cause mortality from walking and cycling and shape of dose response relationship. The international journal of behavioral nutrition and physical activity. 2014;11:132. Epub 2014/10/26. doi: 10.1186/s12966-014-0132-x ; PubMed Central PMCID: PMC4262114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Nordengen S, Andersen LB, Solbraa AK, Riiser A. Cycling is associated with a lower incidence of cardiovascular diseases and death: Part 1—systematic review of cohort studies with meta-analysis. British journal of sports medicine. 2019;53(14):870–8. Epub 2019/06/04. doi: 10.1136/bjsports-2018-099099 . [DOI] [PubMed] [Google Scholar]
  • 4.Nordengen S, Andersen LB, Solbraa AK, Riiser A. Cycling and cardiovascular disease risk factors including body composition, blood lipids and cardiorespiratory fitness analysed as continuous variables: Part 2-systematic review with meta-analysis. British journal of sports medicine. 2019;53(14):879–85. Epub 2019/06/04. doi: 10.1136/bjsports-2018-099778 . [DOI] [PubMed] [Google Scholar]
  • 5.Pedisic Z, Shrestha N, Kovalchik S, Stamatakis E, Liangruenrom N, Grgic J, et al. Is running associated with a lower risk of all-cause, cardiovascular and cancer mortality, and is the more the better? A systematic review and meta-analysis. British journal of sports medicine. 2019. Epub 2019/11/07. doi: 10.1136/bjsports-2018-100493 . [DOI] [PubMed] [Google Scholar]
  • 6.Oja P, Kelly P, Murtagh EM, Murphy MH, Foster C, Titze S. Effects of frequency, intensity, duration and volume of walking interventions on CVD risk factors: a systematic review and meta-regression analysis of randomised controlled trials among inactive healthy adults. British journal of sports medicine. 2018;52(12):769–75. Epub 2018/06/03. doi: 10.1136/bjsports-2017-098558 . [DOI] [PubMed] [Google Scholar]
  • 7.Kraus WE, Powell KE, Haskell WL, Janz KF, Campbell WW, Jakicic JM, et al. Physical Activity, All-Cause and Cardiovascular Mortality, and Cardiovascular Disease. Medicine and science in sports and exercise. 2019;51(6):1270–81. Epub 2019/05/17. doi: 10.1249/MSS.0000000000001939 ; PubMed Central PMCID: PMC6527136. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Coenen P, Huysmans MA, Holtermann A, Krause N, van Mechelen W, Straker LM, et al. Do highly physically active workers die early? A systematic review with meta-analysis of data from 193 696 participants. British journal of sports medicine. 2018;52(20):1320–6. Epub 2018/05/16. doi: 10.1136/bjsports-2017-098540 . [DOI] [PubMed] [Google Scholar]
  • 9.Holtermann A, Schnohr P, Nordestgaard BG, Marott JL. The physical activity paradox in cardiovascular disease and all-cause mortality: the contemporary Copenhagen General Population Study with 104 046 adults. European Heart Journal. 2021;42(15):1499–511. doi: 10.1093/eurheartj/ehab087 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Cillekens B, Huysmans MA, Holtermann A, van Mechelen W, Straker L, Krause N, et al. Physical activity at work may not be health enhancing. A systematic review with meta-analysis on the association between occupational physical activity and cardiovascular disease mortality covering 23 studies with 655 892 participants. Scand J Work Environ Health. 2021. Epub 20211017. doi: 10.5271/sjweh.3993 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Allesøe K, Holtermann A, Aadahl M, Thomsen JF, Hundrup YA, Søgaard K. High occupational physical activity and risk of ischaemic heart disease in women: the interplay with physical activity during leisure time. European journal of preventive cardiology. 2015;22(12):1601–8. Epub 20141013. doi: 10.1177/2047487314554866 . [DOI] [PubMed] [Google Scholar]
  • 12.Hall C, Heck JE, Sandler DP, Ritz B, Chen H, Krause N. Occupational and leisure-time physical activity differentially predict 6-year incidence of stroke and transient ischemic attack in women. Scand J Work Environ Health. 2019;45(3):267–79. Epub 2018/11/19. doi: 10.5271/sjweh.3787 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Clays E, De Bacquer D, Van Herck K, De Backer G, Kittel F, Holtermann A. Occupational and leisure time physical activity in contrasting relation to ambulatory blood pressure. BMC public health. 2012;12:1002–. doi: 10.1186/1471-2458-12-1002 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Korshøj M, Hannerz H, Marott JL, Schnohr P, Prescott E, Clays E, et al. Does occupational lifting affect the risk of hypertension? Cross-sectional and prospective associations in the Copenhagen City Heart Study. Scandinavian journal of work, environment & health. 2019:3850. doi: 10.5271/sjweh.3850 . [DOI] [PubMed] [Google Scholar]
  • 15.Holtermann A, Hansen JV, Burr H, Søgaard K, Sjøgaard G. The health paradox of occupational and leisure-time physical activity. British journal of sports medicine. 2012;46(4):291–5. Epub 20110401. doi: 10.1136/bjsm.2010.079582 . [DOI] [PubMed] [Google Scholar]
  • 16.Piercy KL, Troiano RP, Ballard RM, Carlson SA, Fulton JE, Galuska DA, et al. The Physical Activity Guidelines for Americans. Jama. 2018;320(19):2020–8. Epub 2018/11/13. doi: 10.1001/jama.2018.14854 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.World Health Organization. WHO guidelines on physical activity and sedentary behaviour. Geneva: World Health Organization, 2020. [PubMed] [Google Scholar]
  • 18.Beenackers MA, Kamphuis CBM, Giskes K, Brug J, Kunst AE, Burdorf A, et al. Socioeconomic inequalities in occupational, leisure-time, and transport related physical activity among European adults: a systematic review. The international journal of behavioral nutrition and physical activity. 2012;9:116. doi: 10.1186/1479-5868-9-116 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Holtermann A, Krause N, van der Beek AJ, Straker L. The physical activity paradox: six reasons why occupational physical activity (OPA) does not confer the cardiovascular health benefits that leisure time physical activity does. British journal of sports medicine. 2018;52(3):149–50. Epub 2017/08/12. doi: 10.1136/bjsports-2017-097965 Epub 2017 Aug 10. . [DOI] [PubMed] [Google Scholar]
  • 20.Shephard RJ. Is there a ’recent occupational paradox’ where highly active physically active workers die early? Or are there failures in some study methods? British journal of sports medicine. 2019;53:1557–9. doi: 10.1136/bjsports-2018-100344 . [DOI] [PubMed] [Google Scholar]
  • 21.Mackenbach JP, Stirbu I, Roskam A-JR, Schaap MM, Menvielle G, Leinsalu M, et al. Socioeconomic inequalities in health in 22 European countries. N Engl J Med. 2008;358(23):2468–81. doi: 10.1056/NEJMsa0707519 . [DOI] [PubMed] [Google Scholar]
  • 22.Tang KL, Rashid R, Godley J, Ghali WA. Association between subjective social status and cardiovascular disease and cardiovascular risk factors: a systematic review and meta-analysis. BMJ open. 2016;6(3):e010137. Epub 2016/03/20. doi: 10.1136/bmjopen-2015-010137 ; PubMed Central PMCID: PMC4800117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Dowd KP, Szeklicki R, Minetto MA, Murphy MH, Polito A, Ghigo E, et al. A systematic literature review of reviews on techniques for physical activity measurement in adults: a DEDIPAC study. The international journal of behavioral nutrition and physical activity. 2018;15(1):15. Epub 2018/02/10. doi: 10.1186/s12966-017-0636-2 ; PubMed Central PMCID: PMC5806271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Katzmarzyk PT, Powell KE, Jakicic JM, Troiano RP, Piercy K, Tennant B. Sedentary Behavior and Health: Update from the 2018 Physical Activity Guidelines Advisory Committee. Medicine and science in sports and exercise. 2019;51(6):1227–41. Epub 2019/05/17. doi: 10.1249/MSS.0000000000001935 ; PubMed Central PMCID: PMC6527341. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Pawlowsky-Glahn V, Egozcue JJ, Tolosana-Delgado R. Statistics in Practice: Modeling and Analysis of Compositional Data. New York, UNITED KINGDOM: John Wiley & Sons, Incorporated; 2015. [Google Scholar]
  • 26.Dumuid D, Pedisic Z, Stanford TE, Martin-Fernandez JA, Hron K, Maher CA, et al. The compositional isotemporal substitution model: A method for estimating changes in a health outcome for reallocation of time between sleep, physical activity and sedentary behaviour. Statistical methods in medical research. 2019;28(3):846–57. Epub 2017/11/22. doi: 10.1177/0962280217737805 . [DOI] [PubMed] [Google Scholar]
  • 27.Dumuid D, Stanford TE, Martin-Fernandez JA, Pedisic Z, Maher CA, Lewis LK, et al. Compositional data analysis for physical activity, sedentary time and sleep research. Statistical methods in medical research. 2018;27(12):3726–38. Epub 2017/05/31. doi: 10.1177/0962280217710835 . [DOI] [PubMed] [Google Scholar]
  • 28.Lloyd CD, Pawlowsky-Glahn V, Egozcue JJ. Compositional Data Analysis in Population Studies. Annals of the Association of American Geographers. 2012;102(6):1251–66. [Google Scholar]
  • 29.The Copenhagen city heart study. European Heart Journal Supplements. 2001;3(suppl_H):H1–H83. doi: 10.1016/S1520-765X(01)90110-5 [DOI] [Google Scholar]
  • 30.Johansson MS, Korshøj M, Schnohr P, Marott JL, Prescott EIB, Søgaard K, et al. Time spent cycling, walking, running, standing and sedentary: a cross-sectional analysis of accelerometer-data from 1670 adults in the Copenhagen City Heart Study. BMC public health. 2019;19(1):1370. doi: 10.1186/s12889-019-7679-z [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Unger T, Borghi C, Charchar F, Khan NA, Poulter NR, Prabhakaran D, et al. 2020 International Society of Hypertension Global Hypertension Practice Guidelines. Hypertension. 2020;75(6):1334–57. Epub 20200506. doi: 10.1161/HYPERTENSIONAHA.120.15026 . [DOI] [PubMed] [Google Scholar]
  • 32.Skotte J, Korshoj M, Kristiansen J, Hanisch C, Holtermann A. Detection of physical activity types using triaxial accelerometers. Journal of physical activity & health. 2014;11(1):76–84. Epub 2012/12/20. doi: 10.1123/jpah.2011-0347 . [DOI] [PubMed] [Google Scholar]
  • 33.Stemland I, Ingebrigtsen J, Christiansen CS, Jensen BR, Hanisch C, Skotte J, et al. Validity of the Acti4 method for detection of physical activity types in free-living settings: comparison with video analysis. Ergonomics. 2015;58(6):953–65. Epub 2015/01/16. doi: 10.1080/00140139.2014.998724 . [DOI] [PubMed] [Google Scholar]
  • 34.World Health Organization. Body mass index—BMI: World Health Organization Regional Office for Europe; [cited 2018 October 10]. Available from: http://www.euro.who.int/en/health-topics/disease-prevention/nutrition/a-healthy-lifestyle/body-mass-index-bmi. [Google Scholar]
  • 35.Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M, et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Journal of hypertension. 2013;31(7):1281–357. Epub 2013/07/03. doi: 10.1097/01.hjh.0000431740.32696.cc . [DOI] [PubMed] [Google Scholar]
  • 36.World Health Organization. Waist circumference and waist–hip ratio: report of a WHO expert consultation, Geneva, 8–11 December 2008. Geneva: 2011.
  • 37.Newcombe RG. Two-sided confidence intervals for the single proportion: comparison of seven methods. Statistics in medicine. 1998;17(8):857–72. Epub 1998/05/22. doi: . [DOI] [PubMed] [Google Scholar]
  • 38.Hron K, Filzmoser P, de Caritat P, Fišerová E, Gardlo A. Weighted Pivot Coordinates for Compositional Data and Their Application to Geochemical Mapping. Mathematical Geosciences. 2017;49(6):797–814. doi: 10.1007/s11004-017-9684-z PubMed PMID: pub.1084749868. [DOI] [Google Scholar]
  • 39.RStudio Team. RStudio: Integrated Development for R. Boston, MA: RStudio, Inc.; 2016. [Google Scholar]
  • 40.R Core Team. R: A language and environment for statistical computing. 3.5.1 ed. Vienna, Austria: R Foundation for Statistical Computing; 2018. [Google Scholar]
  • 41.van den Boogaart KG, Tolosana-Delgado R, Bren M. compositions: Compositional Data Analysis. R package version 1.40–2 ed2018.
  • 42.Templ M, Hron K, Filzmoser P. robCompositions: An R-package for Robust Statistical Analysis of Compositional Data. In: Pawlowsky‐Glahn V, Buccianti A, editors. Compositional Data Analysis. Wiley Online Books; 2011. p. 341–55. [Google Scholar]
  • 43.Naci H, Salcher-Konrad M, Dias S, Blum MR, Sahoo SA, Nunan D, et al. How does exercise treatment compare with antihypertensive medications? A network meta-analysis of 391 randomised controlled trials assessing exercise and medication effects on systolic blood pressure. British journal of sports medicine. 2019;53(14):859–69. Epub 2018/12/20. doi: 10.1136/bjsports-2018-099921 . [DOI] [PubMed] [Google Scholar]
  • 44.Olsen MH, Angell SY, Asma S, Boutouyrie P, Burger D, Chirinos JA, et al. A call to action and a lifecourse strategy to address the global burden of raised blood pressure on current and future generations: the Lancet Commission on hypertension. Lancet (London, England). 2016;388(10060):2665–712. Epub 2016/09/23. doi: 10.1016/S0140-6736(16)31134-5 . [DOI] [PubMed] [Google Scholar]
  • 45.Hanson S, Jones A. Is there evidence that walking groups have health benefits? A systematic review and meta-analysis. British journal of sports medicine. 2015;49(11):710–5. Epub 2015/01/21. doi: 10.1136/bjsports-2014-094157 ; PubMed Central PMCID: PMC4453623. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Lee PH, Wong FKY. The association between time spent in sedentary behaviors and blood pressure: a systematic review and meta-analysis. Sports medicine (Auckland, NZ). 2015;45(6):867–80. doi: 10.1007/s40279-015-0322-y . [DOI] [PubMed] [Google Scholar]
  • 47.Saidj M, Jørgensen T, Jacobsen RK, Linneberg A, Oppert J-M, Aadahl M. Work and leisure time sitting and inactivity: Effects on cardiorespiratory and metabolic health. European journal of preventive cardiology. 2016;23(12):1321–9. Epub 2015/12/03. doi: 10.1177/2047487315619559 . [DOI] [PubMed] [Google Scholar]
  • 48.Gupta N, Korshoj M, Dumuid D, Coenen P, Allesoe K, Holtermann A. Daily domain-specific time-use composition of physical behaviors and blood pressure. The international journal of behavioral nutrition and physical activity. 2019;16(1):4. Epub 2019/01/12. doi: 10.1186/s12966-018-0766-1 ; PubMed Central PMCID: PMC6327498. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Poggio R, Melendi S, Gutierrez L, Elorriaga N, Irazola V. Occupational Physical Activity and Cardiovascular Risk Factors Profile in the Adult Population of the Southern Cone of Latin America: Results From the CESCAS I Study. Journal of occupational and environmental medicine. 2018;60(9):e470–e5. doi: 10.1097/JOM.0000000000001398 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Masala G, Bendinelli B, Occhini D, Bruno RM, Caini S, Saieva C, et al. Physical activity and blood pressure in 10,000 Mediterranean adults: The EPIC-Florence cohort. Nutr Metab Cardiovasc Dis. 2017;27(8):670–8. Epub 2017/06/15. doi: 10.1016/j.numecd.2017.06.003 . [DOI] [PubMed] [Google Scholar]
  • 51.Vaara JP, Kyröläinen H, Fogelholm M, Santtila M, Häkkinen A, Häkkinen K, et al. Associations of leisure time, commuting, and occupational physical activity with physical fitness and cardiovascular risk factors in young men. Journal of physical activity & health. 2014;11(8):1482–91. Epub 2013/12/31. doi: 10.1123/jpah.2012-0504 . [DOI] [PubMed] [Google Scholar]
  • 52.Honda T, Chen S, Kishimoto H, Narazaki K, Kumagai S. Identifying associations between sedentary time and cardio-metabolic risk factors in working adults using objective and subjective measures: a cross-sectional analysis. BMC public health. 2014;14:1307–. doi: 10.1186/1471-2458-14-1307 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Dempsey PC, Hadgraft NT, Winkler EAH, Clark BK, Buman MP, Gardiner PA, et al. Associations of context-specific sitting time with markers of cardiometabolic risk in Australian adults. The international journal of behavioral nutrition and physical activity. 2018;15(1):114–. doi: 10.1186/s12966-018-0748-3 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Lewington S, Clarke R, Qizilbash N, Peto R, Collins R, Prospective Studies C. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet (London, England). 2002;360(9349):1903–13. Epub 2002/12/21. doi: 10.1016/s0140-6736(02)11911-8 . [DOI] [PubMed] [Google Scholar]
  • 55.Ettehad D, Emdin CA, Kiran A, Anderson SG, Callender T, Emberson J, et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet (London, England). 2016;387(10022):957–67. Epub 2016/01/03. doi: 10.1016/S0140-6736(15)01225-8 . [DOI] [PubMed] [Google Scholar]
  • 56.NCD Risk Factor Collaboration (NCD-RisC). Contributions of mean and shape of blood pressure distribution to worldwide trends and variations in raised blood pressure: a pooled analysis of 1018 population-based measurement studies with 88.6 million participants. Int J Epidemiol. 2018;47(3):872–83i. Epub 2018/03/27. doi: 10.1093/ije/dyy016 ; PubMed Central PMCID: PMC6005056. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Hernán MA. The C-Word: Scientific Euphemisms Do Not Improve Causal Inference From Observational Data. American journal of public health. 2018;108(5):616–9. Epub 2018/03/22. doi: 10.2105/AJPH.2018.304337 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Grgic J, Dumuid D, Bengoechea EG, Shrestha N, Bauman A, Olds T, et al. Health outcomes associated with reallocations of time between sleep, sedentary behaviour, and physical activity: a systematic scoping review of isotemporal substitution studies. The international journal of behavioral nutrition and physical activity. 2018;15(1):69. Epub 2018/07/14. doi: 10.1186/s12966-018-0691-3 ; PubMed Central PMCID: PMC6043964. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Maillard F, Pereira B, Boisseau N. Effect of High-Intensity Interval Training on Total, Abdominal and Visceral Fat Mass: A Meta-Analysis. Sports medicine (Auckland, NZ). 2018;48(2):269–88. doi: 10.1007/s40279-017-0807-y . [DOI] [PubMed] [Google Scholar]
  • 60.Keating SE, Johnson NA, Mielke GI, Coombes JS. A systematic review and meta-analysis of interval training versus moderate-intensity continuous training on body adiposity. Obes Rev. 2017;18(8):943–64. Epub 2017/05/17. doi: 10.1111/obr.12536 . [DOI] [PubMed] [Google Scholar]
  • 61.Wewege M, van den Berg R, Ward RE, Keech A. The effects of high-intensity interval training vs. moderate-intensity continuous training on body composition in overweight and obese adults: a systematic review and meta-analysis. Obes Rev. 2017;18(6):635–46. Epub 2017/04/11. doi: 10.1111/obr.12532 . [DOI] [PubMed] [Google Scholar]
  • 62.McArdle WD, Katch FI, Katch VL. Exercise physiology: nutrition, energy, and human performance. 8 ed. Philadelphia: Wolters Kluwer Health, Lippincott Williams & Wilkins; 2015. [Google Scholar]
  • 63.Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. European heart journal. 2019:ehz455. doi: 10.1093/eurheartj/ehz455 . [DOI] [PubMed] [Google Scholar]
  • 64.Authors/Task Force M, Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts) Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Atherosclerosis. 2016;252:207–74. doi: 10.1016/j.atherosclerosis.2016.05.037 . [DOI] [PubMed] [Google Scholar]
  • 65.Saidj M, Jørgensen T, Jacobsen RK, Linneberg A, Aadahl M. Separate and joint associations of occupational and leisure-time sitting with cardio-metabolic risk factors in working adults: a cross-sectional study. PloS one. 2013;8(8):e70213–e. doi: 10.1371/journal.pone.0070213 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Gupta N, Hallman DM, Mathiassen SE, Aadahl M, Jørgensen MB, Holtermann A. Are temporal patterns of sitting associated with obesity among blue-collar workers? A cross sectional study using accelerometers. BMC public health. 2016;16:148–. doi: 10.1186/s12889-016-2803-9 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Gupta N, Heiden M, Aadahl M, Korshøj M, Jørgensen MB, Holtermann A. What Is the Effect on Obesity Indicators from Replacing Prolonged Sedentary Time with Brief Sedentary Bouts, Standing and Different Types of Physical Activity during Working Days? A Cross-Sectional Accelerometer-Based Study among Blue-Collar Workers. PloS one. 2016;11(5):e0154935–e. doi: 10.1371/journal.pone.0154935 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.Authors/Task Force Members:, Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts) Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Atherosclerosis. 2016;252:207–74. doi: 10.1016/j.atherosclerosis.2016.05.037 . [DOI] [PubMed] [Google Scholar]
  • 69.Lewington S, Whitlock G, Clarke R, Sherliker P, Emberson J, Halsey J, et al. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet (London, England). 2007;370(9602):1829–39. Epub 2007/12/07. doi: 10.1016/s0140-6736(07)61778-4 . [DOI] [PubMed] [Google Scholar]
  • 70.Rose G. Sick individuals and sick populations. International journal of epidemiology. 2001;30(3):427–32; discussion 33–4. Epub 2001/06/21. doi: 10.1093/ije/30.3.427 . [DOI] [PubMed] [Google Scholar]
  • 71.Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. 2019;73(24):e285–e350. doi: 10.1016/j.jacc.2018.11.003% J Journal of the American College of Cardiology. [DOI] [PubMed] [Google Scholar]
  • 72.Barone Gibbs B, Aaby D, Siddique J, Reis JP, Sternfeld B, Whitaker K, et al. Bidirectional 10-year associations of accelerometer-measured sedentary behavior and activity categories with weight among middle-aged adults. International journal of obesity (2005). 2020;44:559–67. Epub 2019/08/30. doi: 10.1038/s41366-019-0443-8 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.McMichael AJ. Standardized Mortality Ratios and the "Healthy Worker Effect": Scratching Beneath the Surface. Journal of Occupational and Environmental Medicine. 1976;18(3):165–8. 00005122-197603000-00009. doi: 10.1097/00043764-197603000-00009 [DOI] [PubMed] [Google Scholar]
  • 74.Rothman KJ. Six persistent research misconceptions. J Gen Intern Med. 2014;29(7):1060–4. Epub 2014/01/23. doi: 10.1007/s11606-013-2755-z . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Rothman KJ, Gallacher JEJ, Hatch EE. Why representativeness should be avoided. International journal of epidemiology. 2013;42(4):1012–4. doi: 10.1093/ije/dys223 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 76.Hansen TW, Kikuya M, Thijs L, Björklund-Bodegård K, Kuznetsova T, Ohkubo T, et al. Prognostic superiority of daytime ambulatory over conventional blood pressure in four populations: a meta-analysis of 7,030 individuals. Journal of hypertension. 2007;25(8):1554–64. doi: 10.1097/HJH.0b013e3281c49da5 . [DOI] [PubMed] [Google Scholar]
  • 77.Verweij LM, Terwee CB, Proper KI, Hulshof CT, van Mechelen W. Measurement error of waist circumference: gaps in knowledge. Public health nutrition. 2013;16(2):281–8. Epub 2012/05/26. doi: 10.1017/S1368980012002741 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.Nordestgaard BG, Langsted A, Mora S, Kolovou G, Baum H, Bruckert E, et al. Fasting is not routinely required for determination of a lipid profile: clinical and laboratory implications including flagging at desirable concentration cut-points—a joint consensus statement from the European Atherosclerosis Society and European Federation of Clinical Chemistry and Laboratory Medicine. European Heart Journal. 2016;37(25):1944–58. doi: 10.1093/eurheartj/ehw152 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79.World Health Organization. Global recommendations on physical activity for health. Geneva: World Health Organization, 2010. [PubMed] [Google Scholar]
  • 80.Smith P, Ma H, Glazier RH, Gilbert-Ouimet M, Mustard C. The Relationship Between Occupational Standing and Sitting and Incident Heart Disease Over a 12-Year Period in Ontario, Canada. Am J Epidemiol. 2018;187(1):27–33. doi: 10.1093/aje/kwx298 ; PubMed Central PMCID: PMC5860480. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81.Korshøj M, Lidegaard M, Skotte JH, Krustrup P, Krause N, Søgaard K, et al. Does aerobic exercise improve or impair cardiorespiratory fitness and health among cleaners? A cluster randomized controlled trial. Scandinavian journal of work, environment & health. 2015;41(2):140–52. Epub 2014/12/30. doi: 10.5271/sjweh.3475 . [DOI] [PubMed] [Google Scholar]
  • 82.Lidegaard M, Søgaard K, Krustrup P, Holtermann A, Korshøj M. Effects of 12 months aerobic exercise intervention on work ability, need for recovery, productivity and rating of exertion among cleaners: a worksite RCT. Int Arch Occup Environ Health. 2018;91(2):225–35. Epub 2017/11/04. doi: 10.1007/s00420-017-1274-3 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83.Gram B, Holtermann A, Søgaard K, Sjøgaard G. Effect of individualized worksite exercise training on aerobic capacity and muscle strength among construction workers—a randomized controlled intervention study. Scandinavian journal of work, environment & health. 2012;38(5):467–75. Epub 2011/11/04. doi: 10.5271/sjweh.3260 . [DOI] [PubMed] [Google Scholar]

Decision Letter 0

Pedro Tauler

12 Feb 2021

PONE-D-21-00560

The physical activity health paradox and risk factors for cardiovascular disease: a cross-sectional compositional data analysis in the Copenhagen City Heart Study

PLOS ONE

Dear Dr. Melker Staffan Johansson,

Thank you for submitting your manuscript to PLOS ONE. 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.

Mainly discussion and interpretation of results and conclussions need clarifications and crrections. Some aspects of methodology should be also clarified and/or completed.

Please submit your revised manuscript by Mar 21 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Pedro Tauler, Ph.D.

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1) 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

2)  We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

3) We note that you have included the phrase “data not shown” in your manuscript. Unfortunately, this does not meet our data sharing requirements. PLOS does not permit references to inaccessible data. We require that authors provide all relevant data within the paper, Supporting Information files, or in an acceptable, public repository. Please add a citation to support this phrase or upload the data that corresponds with these findings to a stable repository (such as Figshare or Dryad) and provide and URLs, DOIs, or accession numbers that may be used to access these data. Or, if the data are not a core part of the research being presented in your study, we ask that you remove the phrase that refers to these data.

4) Please include captions for your 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.

5)  Thank you for submitting the above manuscript to PLOS ONE. During our internal evaluation of the manuscript, we found significant text overlap between your submission and the following previously published works, some of which you are an author.

- https://www.researchsquare.com/article/rs-10805/v3

- https://kclpure.kcl.ac.uk/ws/files/115120458/accepted_plos_version.pdf

We would like to make you aware that copying extracts from previous publications, especially outside the methods section, word-for-word is unacceptable. In addition, the reproduction of text from published reports has implications for the copyright that may apply to the publications.

Please revise the manuscript to rephrase the duplicated text, cite your sources, and provide details as to how the current manuscript advances on previous work. Please note that further consideration is dependent on the submission of a manuscript that addresses these concerns about the overlap in text with published work.

We will carefully review your manuscript upon resubmission, so please ensure that your revision is thorough.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

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

Reviewer #1: 1. The study presents the results of original research. THIS IS ORIGINAL RESEARCH

2. Results reported have not been published elsewhere. RESULTS ARE NOT PUBLISHED BEFORE

3. Experiments, statistics, and other analyses are performed to a high technical standard and are described in sufficient detail. ALL THESE ARE WELL EXPLAINED

4. Conclusions are presented in an appropriate fashion and are supported by the data. ARE STILL INSUFICIENTS, CAN BE IMPROVED

5. The article is presented in an intelligible fashion and is written in standard English. WELL DONE

6. The research meets all applicable standards for the ethics of experimentation and research integrity. YES

7. The article adheres to appropriate reporting guidelines and community standards for data availability. YES

FOR MORE DETAILS, PLEASE SEE THE ATTACHED DOCUMENT

Reviewer #2: See attached file

**********

6. 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.

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

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

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Attachment

Submitted filename: PONE, REVIEWER COMMENTS.docx

Attachment

Submitted filename: 210131 Review PONE-D-21-00560.docx

PLoS One. 2022 Apr 21;17(4):e0267427. doi: 10.1371/journal.pone.0267427.r002

Author response to Decision Letter 0


16 Jan 2022

Response to reviewers’ comments

PONE-D-21-00560

The physical activity health paradox and risk factors for cardiovascular disease: a cross-sectional compositional data analysis in the Copenhagen City Heart Study

Dear Dr. Pedro Tauler,

Thanks for letting us revise our manuscript. We would like to acknowledge the reviewers for taking their time to assess our manuscript and providing valuable feedback. A point-by-point response can be found below. Changes made in the manuscript have been highlighted using the track-changes function in Word.

Reviewer 1

To be accepted for publication in PLOS ONE, research articles must satisfy the following criteria:

1. The study presents the results of original research. THIS IS ORIGINAL RESEARCH

2. Results reported have not been published elsewhere. RESULTS ARE NOT PUBLISHED BEFORE

3. Experiments, statistics, and other analyses are performed to a high technical standard and are described in sufficient detail. ALL THESE ARE WELL EXPLAINED

4. Conclusions are presented in an appropriate fashion and are supported by the data. ARE STILL INSUFICIENTS, CAN BE IMPROVED

5. The article is presented in an intelligible fashion and is written in standard English. WELL DONE

6. The research meets all applicable standards for the ethics of experimentation and research integrity. YES

7. The article adheres to appropriate reporting guidelines and community standards for data availability. YES

Background

1. The purpose of the study needs to be fixed (talk about objectives, believe there is one)

Supplementary information received after contacting the editor: “Regarding the comment from the reviewer, the aim of the study should be clearly stated taking into account previous background reported and the lack of studies in the field. No reason has been provided to include in the aim that "The measure of association was quantified by reallocating time between 1) sedentary behaviour and walking, and 2) sedentary behaviour and HIPA, during leisure and work.", which, in turn, seems information more adequate about the study desing. Furthermore, it is not clear from the aim whether, for example, sitting time and walking time would be considered together in the analysis as dependent variables, or each one would be considered in different analysis.“

Response: We acknowledge that the use of time reallocations relates more to the methods section and have deleted it from the objectives. It is described in the statistical analysis-section on p. 12-13.

In the present study, the durations of the specific physical behaviours are the independent variables (i.e., the explanatory variables) and the three risk factors for CVD: systolic blood pressure, waist circumference, and low-density lipoprotein cholesterol are the dependent variables (i.e., the outcomes). Each of these outcomes are considered in the present study population in three separate analyses.

Action: We have omitted the following sentence: “The measure of association was quantified by reallocating time between 1) sedentary behaviour and walking, and 2) sedentary behaviour and HIPA, during leisure and work.” from the introduction.

Since we clearly distinguish the physical behaviour composition (i.e., the exposure or explanatory variables) from the outcomes in the statistical analysis section (e.g., p. 12, line: 265-267 and 269-271), no action has been taken in relation to the question about the dependent variables of the study.

Results

2. First paragraph> some data within the text are repeated in Table1, and again for table 2

Response: We acknowledge that some data in Table 1 and Table 2 have been repeated in the first and second paragraph, respectively, of the results section.

Action: The text in the first paragraph has been shortened to: “We have illustrated the cohort formation in Figure 1 and presented characteristics of the study population in Table 1. The median number of valid days was 6 and the study participants wore the accelerometers for a median time of 23.8 h/day. Furthermore, the median number of workdays was 4 and 94% had >1 workday. The median worktime was 7.6 h/day. There were 58% women, and the median age was 48.6 years. The median SBP, WC, and LDL-C was 128 mm Hg, 83 cm, and 3.0 mmol/L, respectively.” (p. 14, line: 311-316).

Similarly, the second paragraph has been shortened to “The geometric mean of each part of the physical activity composition is presented in Table 2, stratified by leisure and work.” (p. 16, line: 319-320).

3. Line 336> how was the judgement of the models/residuals? That may be important to explain a little bit more

Response: We examined the distribution of the residuals using quantile-quantile (Q-Q) plots of standardized residuals from the regression models. Any deviations from the projected solid line indicates non-normal distributions (in particular shapes similar to a hammock). In an ideal world, the residuals follow the line; however, small deviations are not uncommon in real-world data but may not compose a problem. We acknowledge that this is a subjective process and have therefore included the Q-Q plots in Figure A-C in the Supporting information File S1 (as part of the original submission). However, “judged” may be poor wording and we have therefore paraphrased the sentence.

Action: It now reads: “For all three models, the residuals were not perfectly normally distributed, but the deviations were considered too small to substantially affect the model fit.” (p. 17, line: 333-335).

4. In my opinion, tables 3 and 4 are huge, and that makes a little bit harder to understand what is there.

Response: We acknowledge that Table 3-4 are large as they both contain all results from the time reallocations across the three outcomes. However, in order to facilitate comparisons across outcomes and domains, we prefer to keep this condensed presentation.

Action: None.

Discussion

5. Major concern> Results indicated that less SB and more walking to be associated with a larger WC. This is a major finding contradicting what is known. The explanation of this finding needs to be addressed deeper making a better case. What is already explained is confusing. Occupations that involve less SB and long walking (more PA) may impact WC in a positive way independently of socioeconomic status. I would like to see more on this to be more convincing. Low income is associated with poor health, but I am not sure that low-income people who work in environments that include high PA would have larger WC. In my opinion it is important to identify other variables or circumstances that may have some associations with the previous finding to explain, convince, and make a better case.

6. LDL-C> same as above. These 2 results need to be deeper explained

7. Compensation and nutrition may have something here in both variables

Response comment 5-7:

Firstly, this study is based on cross-sectional data and does, therefore, not show causal effects but associations. Secondly, the time reallocations are conducted to quantify the investigated associations since the beta-coefficients of the ilr-coordinates cannot be interpreted directly in the same way as a linear regression model fitted with non-compositional variables (due to the ilr-transformation). In essence, the time reallocations show the predicted difference in the mean outcome (i.e., at a population level) given theoretical changes in the mean physical behaviour composition. Therefore, this does not reflect changes in the outcomes on an individual level but reflects that, in this cohort, individuals who sit less and walk more during work compared to those with an average physical behaviour composition have a larger WC and higher LDL-C.

Re “Occupations that involve less SB and long walking (more PA) may impact WC in a positive way independently of socioeconomic status.”: We believe there has been a misunderstanding. This is not what we mean. Occupations that involve low levels of sedentary behaviour and longer duration of walking are most often held by individuals with lower socioeconomic status, which is associated with poorer health such as obesity and dyslipidaemia. That is, our results could be confounded by socioeconomic status, despite the fact that we have tried to adjust for this by including level of education in the regression models.

Action comment 5-7: We have paraphrased the discussion related to WC to soften the description of the potential explanation to the findings. It now reads: “During both domains, our results indicated less sedentary behaviour and more walking compared to the reference composition to be associated with a larger WC (Figure 3, Table 3). This finding may, potentially, be attributed to differences in occupation, socioeconomic status, and health, since low socioeconomic status is known to be associated with poor health (22), including overweight and dyslipidaemia (23). That is, individuals with lower socioeconomic status who, in general, have poorer health are more likely to have occupations that involve little sedentary behaviour and high physical activity (18), such as long durations of walking. Further, we emphasise that the association between physical activity and overweight is bidirectional, and that other factors not considered in our analyses (e.g., diet) are influencing a person’s WC. Importantly, these findings highlight that our estimates represent measures of associations, and not causal effects (58).” (p. 26, line: 501-511).

Similarly, we have elaborated the discussion related to LDL-C. It now reads: “For LDL-C, during both domains the results indicated that less sedentary behaviour and more walking was associated with a higher LDL-C (Figure 4, Table 3). Similar to WC, and as previously discussed, one potential explanation to these findings may be confounding by socioeconomic status and occupation, which are linked to poor health (18, 22, 23).” (p. 28, line: 544-547).

Methodological considerations

8. LDL was chosen due to the relationship with CVD, however, HDL could be more important due to the protective effect, and also because PA seems to have incremental effects on HDL levels but less effects on LDL. In this case, it may be important to explain why HDL was not used as variable.

Response: As we mention in the discussion, we chose LDL-C because it is most clinically relevant as a risk factor for CVD and plays a more central role in the management of CVD (e.g., risk calculation) than HDL. In addition, only few studies have investigated LDL and the association to device-based measurements of physical behaviours.

We agree that several other relevant biomarkers could have been chosen but have limited our focus to the current three risk factors, to restrict the number of analyses.

Action: We have clarified the choice of LDL. It now reads: “We chose LDL-C as a clinically relevant biomarker of dyslipidaemia due to its strong association with CVD risk and central role in the management of CVD (e.g., risk assessment and treatment target). Furthermore, the literature regarding the association between physical behaviours and LDL-C is inconclusive, and therefore, we believe our study can supplement existing knowledge.” (p. 32, line: 647-651).

Perspectives

9. From line 572 to line 584, if compensation for PA is included, it would help to understand people’s behavior and some results from the study.

Response: We acknowledge that physical behaviours in the two domains could to some extent compensate for each other. This is now incorporated in the paragraph.

Action: It now reads: However, as previous studies and our results indicate (8, 12, 80), public health messages such as ‘sit less and move more’, may not be well suited for population groups that are highly physically active during work. On the one hand, more leisure time physical activity may lead to increased fitness and workability (i.e., both physical and mental capacity), which could decrease the relative workload and thereby the risk of CVD and other non-communicable diseases. On the other hand, more leisure time physical activity may lead to cardiovascular overload and a vicious cycle of decreasing fitness over time; a scenario in which rest and restitution should be recommended. Currently, for several health outcomes it is still unclear how individuals with high occupational physical activity should best compensate during leisure. One potential alternative is workplace-based initiatives, such as aerobic exercise during work hours. Although such interventions may have unintended negative health effects such as increased SBP (81), they can improve cardiorespiratory fitness, workability, and health (81-83). It is, therefore, highly important to take the potentially contrasting health effects of leisure time- and occupational physical activity into account in physical activity recommendations for adults. (p. 36, line: 673-687).

Conclusions

10. I would like to see the take home message here and not the already known results from the study. What is the impact of the study, what it apports to the knowledge, why is important to consider SB, walking, and HIPA during leisure and work.

Response: We have paraphrased the conclusion towards a clearer take home message.

Action: The conclusion now reads: “Less sedentary behaviour and more walking or HIPA seems to be associated with a lower SBP during leisure, but, during work, it seems to be associated with a higher SBP. In contrast, no consistent differences between domains were observed for WC and LDL-C. These findings highlight the importance of considering the physical activity health paradox, at least for some risk factors for CVD. The adverse health effects associated with occupational physical activity should inform physical activity recommendations.” (p. 34, line: 706-711).

Correspondingly, we have paraphrased the conclusion in the abstract. It now reads: “During leisure, less sedentary behaviour and more walking or HIPA seems to be associated with a lower SBP, but, during work, it seems to be associated with a higher SBP. No consistent differences between domains were observed for WC and LDL-C. These findings highlight the importance of considering the physical activity health paradox, at least for some risk factors for CVD.” (p. 2-3, line: 45-49).

Reviewer 2

RE: MS PONE-D-21-00560 The physical activity health paradox and risk factors for cardiovascular disease: a cross-sectional compositional data analysis in the Copenhagen City Heart Study

Review, January 28, 2021

General Comments:

1) This study of differential associations between domain-specific leisure time and occupational physical activity with three common cardiovascular disease risk factors addresses an important occupational and public health issue: identification of potentially modifiable underlying mechanisms of the emerging physical activity health paradox using innovative physical activity exposure assessment (wearable sensors employing accelerometry), appropriate differentiation of work and leisure, and innovative analytic approaches estimating effects using compositional data analysis. This is a seminal contribution to the evolving literature regarding the PA health paradox and deserves publication in a high-quality journal.

2) Additional major strengths of this manuscript include an obvious command over the most relevant literature in this field and appropriate citations throughout. Only few modifications are recommended (see details below). The paper is very well written, concise, and in virtually flawless English language. Provision of additional details in supplemental files are also noted as a positive feature.

3) The major acknowledged limitations include the cross-sectional design and potential sample selection bias. There are several other limitations that deserve to be discussed: conservative biases leading to underestimation of health effects due to exposure misclassification, healthy worker effects, and exclusion of eligible participants with pre-existing health conditions (such as IHD or hypertension) that are known to modify the health effects of both leisure and occupational physical activity.

4) Since data on pre-existing conditions appear to be available (these data have been used to exclude up to 2/3 of study participants) respective subgroup analyses appear to be possible within the available data set. This reviewer strongly recommends to provide additional sensitivity analyses using a larger sample that does not exclude these eligible participants and to also supplement stratified analyses in respective subsamples based on common pre-existing conditions such as IHD and hypertension that have been shown to be effect modifiers in earlier research.

5) Use consistent terminology: The title refers correctly to the technical term “physical activity health paradox,” however abstract and text often instead use “physical behavior.” I would recommend to stay consistent with the title throughout the manuscript and also with the decades-old research literature and consistently use the term “physical activity.”

In cardiovascular research the term “behaviour” is considered to point to activities over which the individual has control and thus is responsible for and able to “change behavior.” While this label has been applied in CVD research to smoking, drinking, and also leisure time physical activity, it has the tendency to distract from the social determinants of even the most private individual behaviors, it but it definitely not a good choice to characterize occupational physical activity where the activity is determined by the physical environment, explicit employer direction (e.g. the mandate to stand when serving customers in a bank even if the job could be performed sitting), or inherent in the job task itself and thus to a large extent out of the control of the individual worker. These may be subtle distinctions, however, given the long history of occupational medicine where inherently unsafe working conditions were ascribed to random acts of nature (“accidents”) or individual personal worker traits or behaviors (“accident-prone worker”, “unsafe behavior”) in order to abdicate employer responsibility and liability, shifting the more neutral term (with regard to agency/control) of “activity” to “behavior” may be perceived as implicitly “blaming the victim” – a historical legacy burden in occupational medicine and even public health that had many disastrous consequences for legions of workers, their families, and their communities in the past centuries and even today.

Response to general comments 1-5: We appreciate the kind words and thank reviewer 2 for the thorough review, which we believe have helped us improve the manuscript. Since there is an overlap between the general comments and the detailed comments, we have focused on providing specific responses and actions to the 38 detailed comments below.

Briefly, regarding 3), we agree that there are several additional limitations that can be discussed. Conservative bias has been addressed in relation to detailed comment 29 (discussion of potential exposure misclassification). Healthy worker effect has been addressed; see action below. The exclusion of participants with pre-existing health conditions have been addressed in relation to detailed comment 6 and 7.

Regarding 4), we used self-reported use of medication as a proxy for pre-existing health conditions. The suggested sensitivity analyses have been conducted and added to the Supplementary files.

Regarding 5), the “physical activity health paradox” refers to different health effects from leisure time physical activity and occupational physical activity. The use of terminology has been addressed in relation to detailed comment 1.

Action to general comments 1-5: We have added a sentence acknowledging the potential of a healthy worker effect. It reads: “As in all epidemiological studies including working populations, a healthy worker effect may be present in the current study (73).” (p. 30, line: 615-615).

Specific actions in response to general comment 3, 4, and 5 are described in the detailed comments below.

Detailed Comments:

Abstract:

1) Line 32: Use consistent terminology: The title refers correctly to the technical term “physical activity health paradox,” however abstract and text often instead use “physical behavior.” I would recommend to stay consistent with the title throughout the manuscript and also with the decades-old research literature and consistently use the term physical activity.

Aside: Additional comment addressing the broader research context: It is important to note that in cardiovascular research the term “behaviour” is used to indicate activities over which the individual has control and thus is in general considered responsible for and assumed to have the ability to “change behavior.” In medical and epidemiological cardiovascular disease research this label has been applied consistently to smoking, drinking, and also leisure time physical activity, under the heading “health behaviors”. While this labeling has the unfortunate tendency to distract from the social determinants (that have been identified for even the most private individual behaviors such as suicide, see Durkheim’s 19th century seminal study of the same title), this is a widely accepted convention. However, to characterize OPA as a “behavior” is a problematic choice because the physical activity at work is mostly not a choice but instead determined by the physical and organizational work environment, explicit employer direction (e.g. the mandate to stand when serving customers if the job could be performed sitting), or inherent in the job task itself. Thus the intensity of OPA, its duration, and the work/rest/cycle is effectively out of the control of the individual worker, especially those who are performing high levels of OPA or repetitive tasks. Accordingly, the occupational health literature has been referred to PA at work as “occupational physical activity”, “physical workload”, “physical job demands” as more appropriate terms for most paid labor than terms that have connotations of individual choice or even a moral undertone like in “good or bad behavior.”

These are subtle distinctions, however, OPA happens in social context where performing heavy work is associated with low status, low pay, excessive health and mortality risks. Behavioralism, “the advocacy or adherence to a behavioral approach to social phenomena” as defined in the dictionary combined with a tragic history of little attention by academia, and a long and shameful history of occupational medicine where unsafe working conditions, safety hazards inherent in a specific job design or work task have been attributed to random acts of nature (“accidents” instead of “work injury”) or individual personal worker traits (“accident-prone worker”), or behaviors (“unsafe behavior”, “worker negligence,” “human factor,”) or even a kind of mental illness (“accident neurosis” “Unfallneurose,” “pension neurosis,” “Rentenneurose”) if the victim of a work-injury demands compensation - these “behaviors” (?!) of medical professionals, academicians, scientists, and legal experts ignore the root causes of work-related injuries and illnesses and collude with regulators’ and/or employers’ attempts to deny their responsibilities for providing a safe work environment and their legal liability to compensate their injured workers for lost income, health, limbs, or life. Shifting the more neutral (with regard to agency/control) term of “activity” to “behavior” (with a connotation of worker choice and good/bad or health/unhealthy behavior) may thus be a subtle form of shifting the burden of work-related injury, illness, and disability or death and the legal mandate for primary prevention at the workplace onto the individual worker and thus implicitly “blaming the victim” – a historical legacy burden in occupational medicine and even public health that had many tragic consequences for legions of workers, their families, and their communities in the past centuries and even today.

Response: We agree that physical activity and stationary behaviours during work are for many individuals not a matter of choice but determined by work demands and organisation. We used the term physical behaviours as an umbrella term encompassing physical activity (i.e., any bodily movement produced by skeletal muscles that results in energy expenditure) and stationary behaviours (e.g., sedentary behaviour and standing; that is, behaviours that do not involve any movement). However, we acknowledge the possibility for misunderstandings and have therefore followed the advice and changed the terminology used.

Action: We have changed “physical behaviours” to “physical activity” or “physical activity and sedentary behaviour” throughout the entire manuscript (highlighted with tracked changes).

Background:

2) Line 71-74: The way references are inserted in this summary of the literature is confusing. The 2018 meta-analyses by Coenen et al. is cited as if it represents and individual study and for providing evidence for “beneficial health effects” and “no association with all-cause mortality” while this is a recent review that did not investigate health effects but only all-cause mortality (which is a different outcome) and actually concluded in the abstract: “Conclusions The results of this review indicate detrimental health consequences associated with high level occupational physical activity in men, even when adjusting for relevant factors (such as leisure time physical activity). These findings suggest that research and physical activity guidelines may differentiate between occupational and leisure time physical activity.” I would recommend to rewrite this summary, clearly differentiating between CVD risk factors, and CVD/IHD incidence, and cardiovascular and all-cause mortality, between reviews and individual studies, and between older reviews and newer reviews, because you are referring to “currently inconclusive” results.

Results regarding traditional CVD risk factors may be more inconclusive, results regarding all-cause mortality are more conclusive, at least for men. There is also a development in the literature: reviews of more recent studies and of higher methodological quality conclude that OPA effects on different outcomes are detrimental (Li 2013, Coenen 2018).

Response: We acknowledge that the use of references in the summary of the literature could be confusing. We have followed the reviewers suggestions and rewritten it as a short and clear introduction based on recent reviews and recently published individual studies.

Action: The summary now reads: “Leisure time physical activity has well-established health benefits (1). For example, walking, cycling, and running, are considered to have favourable effects on risk factors for cardiovascular disease (CVD) and to lower the risk of mortality (2-7). However, emerging evidence indicate that occupational physical activity is associated with an increased risk of all-cause mortality, at least among men (8-10). Further, results from individual studies and literature reviews on the risk of ischemic heart disease (IHD) and major cardiovascular events from occupational physical activity are mixed (9-12). Similarly, the evidence regarding occupational physical activity and risk factors for CVD is currently inconclusive (10, 13, 14).” (p. 3, line: 55-63).

3) Line 81-82: This paragraph is clearly written, however, the last sentence starts with “therefore” but is not clearly stated why we should investigate “how,” by which mechanism, OPA affects health outcomes. (To understand it better and/or to identify additional points of interventions along the causal chain leading form OPA to health outcomes? Or to confirm biological pathways and plausibility? Or any other good reason you want to emphasize?)

Response: The “how” should have been an “if”.

Action: We have paraphrased the paragraph. It now reads: “… Therefore, it is important to investigate if occupational physical activity is associated with health outcomes in addition to other domains.” (p. 4, line: 70-71).

4) line 90: “importantly” twice?

Response: We have paraphrased to improve readability.

Action: The sentence now reads: “These differences in physical activity may be important for the effects on some risk factors (e.g., SBP), while not influencing risk factors that depend more on total energy expenditure (20), such as waist circumference (WC) or low-density lipoprotein cholesterol (LDL-C).” (p. 4, line: 79-81).

Methods:

5) line 179-190: I think this is a clear and important strength of this study: using two accelerometers and advanced algorithms that can differentiate between these different activities (with the possible exception of climbing stairs). What are the respective values of sensitivity and specificity for biking?

Response: The sensitivity and specificity for cycling have been found to be 99.9 and 100.0 during standardised conditions (1).

Action: None.

6) line 209-214: Eligibility criteria: Exclusion of individuals using anti-hypertensives, diuretics, or cholesterol-lowering drugs is problematic for several reasons: (1) it excludes a large percent of the study population and thereby further limiting representativeness of an already highly selected sample. (2) Any exclusion based on these medications need to be justified for each outcome separately. Does it make sense to exclude anti-cholesterol meds when examining SBP outcome, or anti-cholesterol drugs when examining WC? In the former case, one may have not have excluded people with hypertension (if this was intended) but rather those who were not diagnosed or did not seek or get or adhere to treatment… etc. these choices are likely to introduce different selection biases that need to be addressed, if not here, at least in the discussion section (3) Most importantly, this will systematically exclude persons with some common pre-existing cardiovascular health conditions (treated hypertension and some other treated CVD) which have been shown to strongly interact with OPA in previous epidemiological research (see for example large differences in HRs in Table 4 in the Hall 2019 study you cite, and 4 other studies cited the method section of this paper justifying this approach). Did you collect data on persons with those conditions? The results section and Figure 1 seem to imply this. In fact, these exclusions lead to a loss of nearly 70% participants (1367 out of 2009 participants) due to a combination of these exclusion criteria and one unrelated factor (minimum wear time of sensors). Given these large numbers, it is important to breakdown the n for each exclusion criterion and add this in Figure 1 and/or text.

Response:

1) The exclusion criteria excluded 643 (32%) of the 2019 study participants with accelerometer data: 545 used antihypertensives (incl. diuretics), 297 used cholesterol lowering drugs, and 199 used both drugs. Importantly, not excluding those using antihypertensives or cholesterol lowering drugs would result in 152 study participants more (i.e., 804 in total). Furthermore, these exclusion criteria were chosen as an attempt to better isolate the potential association between the physical behaviour composition and the three risk factors among untreated, apparently healthy individuals. For transparency regarding selection bias, the differences in characteristics between included and excluded individuals are described in the results section (p. 16-17, line: 324-329) and presented in Table S4 in the Supplementary files.

2) Re “Does it make sense to exclude anti-cholesterol meds when examining SBP outcome, or anti-cholesterol drugs when examining WC?”: The main reason for applying the same inclusion criteria for all three outcomes (i.e., using one study population) was to avoid having three slightly different study populations, which potentially could have confused the reader. We would like to emphasise that there is a substantial overlap since 67% of those using cholesterol lowering drugs also used antihypertensives.

3) We have data about self-reported conditions and self-reported use of medications on the excluded observations. The latter is used as a proxy for pre-existing cardiovascular disease. Also, we agree that it is important to show the number of individuals fulfilling each exclusion criteria.

Action: We have performed sensitivity analyses to investigate the influence of excluding individuals taking antihypertensives, diuretics, or cholesterol lowering drugs on the results. The results of these are briefly described in the results section (p. 22-23, line: 416-428) and presented in Table A-F in Supplementary file S3. See action to detailed comment 7 for further details.

Finally, we have added the number of individuals excluded for each specific exclusion criteria in Figure 1.

7) ibid: On the other hand, given the large sample of persons with these conditions, possibly the majority of the original study population, I would strongly suggest to examine the potential of selection bias by performing respective sensitivity analyses stratifying by these conditions and also examine how overall results would change if you included these people in the main analysis with all participants who participated and who were otherwise eligible. This is not only important for assessing quantitatively the potential risk of selection bias but even more important because 21st century working populations in developed countries typically include a large percentage of workers with such conditions or medications and we need to understand if those workers experience different PA health effects in order to develop safe PA recommendations that not only differentiate between OPA and LTPA but also between healthy workers and the increasing number of workers with those conditions and in order to tailor any recommendations and interventions accordingly.

Response: We see the reviewer’s point and have conducted the suggested sensitivity analyses. Specifically, we have conducted sensitivity analyses among a) study participants regardless of medication use (i.e., no exclusion of individuals taking antihypertensives, diuretics, or cholesterol lowering drugs), as well as b) among participants taking antihypertensives or cholesterol lowering drugs. Due to the low number of individuals and the large overlap (67%), we have not separated the analyses by the two types of drugs. The results are presented in Table A-F in Supplementary file S3.

Actions: In the methods section, we have added the following description of the sensitivity analyses: “To investigate the influence of excluding individuals taking antihypertensives, diuretics, or cholesterol lowering drugs, we conducted sensitivity analyses including all study participants regardless of medication use, and among those with the medications use, respectively.” (p. 14, line: 302-304).

In the results section, we have added the following: “Similar results were observed across the three outcomes when study participants taking antihypertensives, diuretics, or cholesterol lowering drugs were included in the analyses (Table A-C in File S3). When the analyses were limited to those taking these drugs (n=146), the estimated differences in SBP for time reallocations between sedentary behaviour and walking followed the same pattern but were larger than in the main analysis. However, the estimated differences in SBP given time reallocations between sedentary behaviour and HIPA followed an opposite pattern compared to the main analysis (Table D in File S3). Opposite patterns were also found for WC and LDL-C. Specifically, for WC in the sedentary-behaviour and walk-reallocations during leisure and the sedentary behaviour and HIPA-reallocations during work, and for LDL-C, in the sedentary-behaviour and walk-reallocations during both domains and in the sedentary behaviour and HIPA-reallocations during work (Table E and F in File S3).” (p. 22-23, line: 417-428).

In the discussion, we have added the following: “The results of the sensitivity analysis where those taking antihypertensives, diuretics, or cholesterol lowering drugs were included did not differ substantially from the main analysis (Table A-C in File S3). However, the second sensitivity analysis indicated that the association between sedentary behaviour, walking, and HIPA during work and leisure, and SBP, WC, and LDL-C among those reporting the use of antihypertensives, diuretics, or cholesterol lowering drugs differed from those not taking these medications (Table D-F in File S3). For example, the estimated differences in SBP for the sedentary behaviour and walk-reallocations were markedly larger during both domains. On the other hand, a pattern opposite to the one found in the main analysis was observed for the sedentary behaviour and HIPA-reallocations. We emphasise that there were differences in the geometric mean (i.e., the starting points for the time reallocations) of the physical activity types between those taking and not taking antihypertensives, diuretics, or cholesterol lowering drugs. Specifically, those taking antihypertensives, diuretics, or cholesterol lowering drugs were on average more sedentary and less active during leisure but less sedentary and more active during work compared those not taking these medications. This should be kept in mind when interpreting these results. Also, the lower number of individuals (n=146) results in less precision of the estimates.” (p. 29-30, line: 583-599).

In relation to the discussion of selection bias, we have added the following: “Furthermore, the results of the sensitivity analyses indicated that the exclusion of individuals taking antihypertensives, diuretics, or cholesterol lowering drugs did not influence the overall results. However, they indicated that the association between physical activity and sedentary behaviour during leisure and work, and risk factors for CVD may be different among individuals with pre-existing CVD.” (p. 31, line: 619-623).

8) Line 216-223: The descriptors for different PA composites used in the text do not correspond to the answer categories shown in Supplemental Table A1 for OPA and LTPA questions (e.g. I cannot find the item “climbing stairs” in that table). Since this is part of your key exposure variables, please provide a detailed account of all related questionnaire items and the specific re-coding or combinations you used.

Response: We emphasise that the analyses in this study are all based on device-based measurements of physical behaviours during leisure and work. The data presented in Table S1 defines questions and responses of the self-reported variables (i.e., collected with questionnaire, such as self-reported LTPA and OPA). However, these data were not used in the current analysis and should therefore not be included in the table. This information has survived from a previous iteration of the manuscript and should have been deleted. We apologise for the confusion.

Action: The information about the questions and responses regarding LTPA and OPA in Table S1 has been deleted.

9) line 226: Since BP is your key outcome measure, you should provide more detail about its measurement, specifically, if your protocols adhered to any of the standard guidelines for blood pressure measurements.

Response: As the study is the fifth examination of a large general population study, the protocol for the clinical tests followed procedures from earlier examinations to make valid comparisons possible. The test procedure follows, in general, the recommendations outlined in the 2020 International Society of Hypertension Global Hypertension Practice Guidelines (2).

Action: We have added some information to the description of the blood pressure measurements. It now reads: “Three blood pressure measurements were taken on participants’ non-dominant arm using an automatic blood pressure monitor (OMRON M3, OMRON Healthcare, Hoofddorp, Netherlands) after five minutes rest in a seated position. This test procedure has been used in previous examinations of the CCHS and is in line with the 2020 International Society of Hypertension Global Hypertension Practice Guidelines (32).” (p. 7, line: 145-150).

10) line 275: Not sure what you mean by “results for the daily physical behavior composition as a whole” – please show and explain data in your response to this review and/or as supporting information in the appendix

Response: We acknowledge that the sentence was confusing and have decided to omit it since it is not essential for the interpretation of the results of this study.

Action: The sentenced referred to has been omitted to avoid confusion.

11) line 283-286: “One-to-one-reallocations” separately within work and within leisure seems to be very appropriate and actual crucial for your study aims and appropriate for future interventions since both domains are highly separated in terms of degree of self-determination and require different intervention strategies. This step has helped me to re-evaluate the promise of composition analysis in this field, in early formulations I saw, this was not emphasized or I missed it. Have your PA-intensity and domain-specific approaches used by others or have most other researchers reallocated PA across intensity levels and across domains? It may be worth highlighting your approach if it is innovative as such here (providing the rationale) and in the discussion (comparing with others and pointing to consequences), as this seem to me a major contribution of your paper.

Response: We agree that separate time reallocations within work and leisure, respectively, are appropriate. To our knowledge, this is what most previous studies using compositional data analysis have done. Some previous studies have, however, conducted time reallocations involving more than two physical behaviours (i.e., “many-to-one reallocations”).

Action: None.

12) I am pleased to see that this study defines “sedentary behavior” at work as sitting and does not include light standing/walking work because the common practice of many researchers combining sitting and “light standing” work into a common category “sedentary” is problematic because there is strong evidence that standing alone (with some walking but an mostly upright work posture) is a potentially strong risk factor for progression of atherosclerosis and CVD and mortality compared to sitting (even after adjustment for SES and other potential confounders (see Canadian study by Peter Smith, 2018 on AMI, and several Finnish studies by Krause et al. and Hall 2019 whom you cite). Combining sitting with standing causes a strong conservative misclassification bias by inflating the baseline risk in any reference group that contains standing work in addition to sitting work. Question: Could you assess the magnitude of this potential misclassification bias by a (not recommended) sensitivity analysis that uses “sitting or standing at work” (without lifting) as the reference group? That would be a nice extra contribution to the field and could be put into the appendix for a reference for other researchers. Your study, with objective measurements would be uniquely able to compare reference groups based on sitting alone or sitting and standing combined.

Response: We agree with the reviewer that standing may be a risk factor for CVD and that it should not be merged with sedentary behaviour. However, we feel that this question may deserve a more thorough investigation which lies beyond the scope of the present paper.

Action: None.

Results:

13) line 307 ff and Table 1: The text and tables describe the distribution of study characteristics as medians and the first and third quartile. Is there any specific reason for this choice? Regardless, while these descriptors are not wrong and could still be provided in the appendix, this table should show the means the full range of all continuous variables to allow the reader to better compare this study population and its exposures and other covariates with other study populations in the literature that typically show means and full ranges.

Response: The specific reason for using medians and first and third quartiles (stated in the methods section, p. 11, line: 246-247), was skewed distributions of some of the continuous variables. We consider medians to be more appropriate measurements of the central tendency in these cases and have kept Table 1 as is. We do, however, acknowledge that mean with standard deviation are commonly used in summary statistics of study populations sometimes even in spite of non-normal distributions.

Action: None.

14) line 345-49 Results for SBP: The description of results focuses on the patterns of point estimates of change in terms of the direction of change, which are the most important results. However, the rest of the description ignores the second most important data: effect sizes and instead implicitly focuses on statistical significance testing (using CIs as a substitute for p-values) while ignoring additional substantive quantitative information contained in both point estimates and CIs.

For example, reallocation from reference to more sedentary behavior shows only small increases in BP between +0.21 and +0.60 mmHg for LTPA but rather substantial decreases from -0.95 to -6.66 mmHG for OPA. For a 30 min reallocation of walking to sedentary behavior, the absolute effect size (absolute change in BP) for OPA is 11 times larger than for LTPA: -6.66 compared to +0.6 mmHg and reaches an effect size that is substantial and could be expected to decrease the risk of CVD by over 20% based on the known linear relationship between SBP and CVD.

Although it is correct that all CIs include zero, there are notable differences in CIs across domains: CIs for LTPA point estimates are more balanced around the zero value while CIs for OPA point estimates are heavily tipped towards negative values (decreases) in BP. For the 30 min reallocation of walking to sedentary behavior mentioned above, the CIs for LTPA covers values between -2.66 to +3.85 and for OPA -16.19 to +2.88. These CIs are wide and thus indicate relative imprecise estimates that include zero, therefore the data are compatible with effects in either direction, especially for LTPA: the range of values within the CI interval for LTPA are nearly equally compatible with similar decreases or increases in SBP. In contrast, the majority of values within the CI for OPA are negative and negative values much larger than positive values, the data are therefore much more compatible with large decreases in SBP than (much smaller) increases in SBP. Taking these more detailed observations together, the overall results are clearly much more compatible with a detrimental effect of walking at work than not and also point in this direction much more than the results point into the direction of the smaller potential beneficial effect of LTPA. Despite a lack of statistical significance, these results are much more compatible with your hypothesis of the presence of the PA health paradox than with similar effects across domains. While your description of the results is not wrong, it implicitly relies too much on the single data point of statistical significance. Your description and especially your overall interpretation of the data should consider the entirety of information contained in CIs, not just the equivalence of one specific data point at the edge of the 95% CI interval that is equivalent to a p-value of 0.05. Instead of answering the narrow question, do 95% of all values lie above this one arbitrary point along the continuum of results within the CI, one needs to consider if the majority of points within the CI points to an increase or decrease in SBP. Several decades of scholarly work, textbooks of modern epidemiology (e.g. by Rothman, Greenland et al), and official statements of the American Statistical Association (2015) all encourage to base conclusions on effect estimation and making full use of the data included in CIs instead of relying primarily on statistical significance testing or its equivalent in the interpretation of CIs.

In this spirit, I would suggest to represent all effect estimates in the tables with the same font and not to bold those data and CIs that do not include zero. The emphasis should be on results that are substantitive, e.g. point to a relevant change in the health risks that are known to be associated with your cardiovascular risk factor under study. For example, it is known that above about 115 mmHG, the relationship between SBP and CVD outcomes is monotone positive and virtually linear and that the risk of acute myocardial infarction (AMI) in a population increases by about 10% for each 2-3 mm Hg average increase in any population. Since AMI is a rather common disease, a 10% increase means thousands of people in DK and millions of people worldwide. Therefore, even a “small” 1 or 2 mmHG change in SPB that may be deemed irrelevant by clinicians for an individual patient is considered important in occupational and public health concerned with prevention of CVD in whole populations. From that perspective, researchers have considered even relative relative small changes of 1 mmHG or less as substantive and of public health significance. From that perspective, it is much more important to ask the question if 95% CI’s include values of that magnitude or more than the question if it includes zero values.

Response: We fully agree in the reviewer’s approach to interpretation of CIs and effect sizes and acknowledge that we have not communicated this clearly.

Action: We have changed the paragraph in the results section and, in accordance with the reviewer’s recommendations, emphasized the effect sizes. It now reads: “During leisure, the results indicated that less sedentary behaviour and more walking compared to the reference composition was associated with a lower SBP, while the results indicated an association with a higher SBP during work (Figure 2A and Table 3). Importantly, the size of the estimated differences in SBP differed markedly between the domains. For example, the absolute difference in SBP given 30 minutes less walking and 30 minutes more sedentary behaviour during work was 11 times larger than that during leisure (work: -6.7 [95% CI: -16.2, 2-9] mm Hg vs. leisure: 0.6 [-2.7, 3.8] mm Hg). The same pattern of opposite associations was evident for less sedentary behaviour and more HIPA during leisure and work. Although the CIs included zero, the majority of the values indicated a lower and higher SBP during leisure and work, respectively (e.g., 10 min, leisure: -0.7, 95% CI: -1.5, 0.2; Figure 2B and Table 4).” (p. 17-18, line: 341-351).

Additionally, we have modified the last paragraph in the discussion of the SBP results. It now reads: “Our results indicated a 1.7 (95% CI: -0.8, 4.2) mm Hg higher SBP given 30 minutes less sedentary behaviour and 30 minutes more walking during work, and an 0.7 (95% CI: -2.6, 1.2) mm Hg lower SBP given the same time reallocation during leisure. Furthermore, 30 minutes less walking and 30 minutes more sedentary behaviour during work suggested a 6.7 (95% CI: -16.2, 2.9) mm Hg lower SBP. This difference is 11 times larger than that of the opposite reallocation during leisure (i.e., 30 min less sedentary behaviour and 30 min more walking: -0.7, 95% CI: -2.6, 1.2 mm Hg), and could be expected to reduce the risk of CVD-specific mortality by over 20% based on the known linear relationship between SBP and CVD (55, 56). Since even small changes in the population mean SBP can have important implications for CVD risk (i.e., affecting the prevalence of hypertension) (55-57), these findings could, potentially, have important implications in population-based prevention of CVD (45).” (p. 25-26, line: 488-499).

In the tables, bold is no longer used to highlight estimates where the CI does not include 0.

15) line 350-54 Results for WC: This description mentions results of “less sedentary behavior and more walking,” but not of “more sedentary behaviour and less walking” although the latter reallocation leads to substantially larger BP changes for both LTP and OPA. Similarly to SPB above, reallocation of 30 min of occupational walking to sedentary work led to a very substantial -5cm reduction of WC, five times as much than the reduction observed when the same amount of walking during leisure is reallocated to sedentary behavior.

Response: The results of “more sedentary behaviour and less walking” is shown as the positive part of the x-axis in Figure 3. However, for clarity, we prefer to consistently describe the same direction of the time reallocations in the text. The asymmetry of the results mentioned by the reviewer is clearly seen in the figures, but we agree that this should be explicitly conveyed to the reader.

Action: We have paraphrased the description of the results for WC. It now reads: “During both leisure and work, the results indicated less sedentary behaviour and more walking to be associated with a larger WC; however, the CIs included zero (Figure 3A and Table 3). In contrast, during leisure and work, less sedentary behaviour and more HIPA was associated with a smaller WC, although the estimates during work were small. Also, for work, the CIs included zero, but most values suggested a smaller WC (Figure 3B and Table 4). The estimated difference in WC given the time reallocations was not symmetric. For example, during work, the reallocation of 30 min walking to sedentary behaviour was associated with a 5 cm smaller WC (95% CI: -11.29, 1.03) compared to an estimated 1 cm larger WC given the opposite time reallocation. Additionally, the smaller WC (i.e., -5 cm) is about five times larger than the estimated difference observed for the corresponding time reallocation during leisure (i.e., -1 cm).” (p. 20-21, line: 369-379).

16) line 354-55 WC: the sentence “We found no association during work” is not backed up by the data. I would suggest to replace by a similar wording you used for HIPA and LDL in the next paragraph: “During work, the estimates followed the same pattern, but were even smaller …”

Response: We agree that the previous formulation was not backed up by data.

Action: We have omitted “We found no association during work (Figure 3B and Table 4).” and added: “In contrast, during leisure and work, less sedentary behaviour and more HIPA was associated with a smaller WC, although the estimates during work were small. Also, for work, the CIs included zero, but most values suggested a smaller WC (Figure 3B and Table 4).” (p. 20, line: 371-374).

17) line 357-362 Results for LDL, Table 4, row -1 min, column Work: CI does not include point estimate (data entry error?)

Response: Thank you for spotting this data entry error.

Action: The numbers have been corrected to “ -0.01 (-0.03, 0.02)” (p. 19-20, Table 4, LDL-C, row -1 min, column work).

Discussion:

18) line 377-383 SBP: You state correctly “Although not statistically significant, these findings support…” the PA paradox. Since SBP is one of the most important global CVD risk factor, you may want to provide the reader with a more detailed interpretation of results that help the reader to understand why you do not dismiss results that are not statistically significant. See comment #14 above.

Response: We agree and have discussed the implications of the results in more depth in one of the subsequent paragraphs (i.e., p. 25-26, line: 488-499).

Action: Please see responses to comment 14.

19) line 391: replace “makes” by “make” (plural)

Response: Thanks for pointing out this error.

Action: We have changed “makes” to “make” (p. 24, line: 453).

20) line 390-396: suggest to add the reference 18 to reference 14 each time mentioned here and add also consider to reference a couple of review papers that summarize the effect of BP and HR on CVD (some are cited in reference 18) if you have enough room for references. You may also mention the very simple explanation that cumulative exposure to higher BP and HR during work hours can be expected to increase CVD risk based on these positive associations between SPB and HR – it is a predictable outcome based on the well-established hemodynamic theory of arteriosclerosis (review paper by S Glagov 1988 “Hemodynamics and atherosclerosis” and/or M.J. Thubricar, Vascular mechanics and pathology, Springer, New York, 2007)

Response: We agree that the use of reference 18 is relevant.

Action: Reference 18 (now reference 19) has been added in relation to the use of reference 14 (i.e., p. 24, line: 453, 455, and 458).

21) line 401: insert “objective” before “device-based”

Response: We have chosen to consistently use “device-based measurements” instead of objective measurements since it has been questioned if the interpreted results from device-based measurements truly are “objective”.

Action: None.

22) line 426-33: In this paragraph you mention replacing sedentary activities with more walking at work may increase SBP by 1.7 mmHg and how this represents a substantially increased CVD risk on a population level. This makes totally sense and is in line with my earlier comments asking for stating this clearly. However, I think it is crucial to also point out the even higher prevention potential for replacing walking time at work by sedentary time by stating something like that (see comment #14 above) “While reallocation from reference to more sedentary LTPA behavior shows only small increases in BP between +0.21 and +0.60 mmHg, reduction of walking at work by 30 min and allocating this time to sitting at work results in rather substantial average decreases -6.66 mmHG. For a 30 min reallocation of walking to sedentary behavior, the absolute effect size (absolute change in BP) for OPA is infect 11 times larger than for LTPA: -6.66 compared to +0.6 mmHg and reaches an effect size that is substantial and could be expected to decrease the risk of CVD by over 20% based on the known linear relationship between SBP and CVD.” I think it is important to state this observation explicitly because the average reader who is has been reached by public health messages advocating a decrease of sitting at work will not pick this counter-intuitive statement that it may be actually much more advantageous to replace walking by sitting at work.

Response: The reviewer raises a good point, and we acknowledge that this message has not been clear and explicit in our wording.

Action: See action to detailed comment 14.

23) line 450-52: suggest to replace “total energy expenditure” by “diet” here because (a) energy expenditure itself is an independent CVD risk factor and (b) an integral part of relative aerobic workload the OPA measure that takes the important mismatch between physical work demands in terms of energy burned and workers cardiorespiratory fitness i.e. the capacity to burn that energy (V02max) into account. (c) There is little evidence that total energy expenditure is most important for WC or obesity, it seems that the source of energy (sugar vs protein or fat) and endocrine effects of sugar and thus the high sugar content of soda-drinks and processed food may instead be the determining factors for central obesity (see comprehensive in-depth review in book by Gary Taubes for the specific literature: “Good calories, bad calories: fats, carbs, and the controversial science of diet and health”).

Response: We acknowledge the reviewer’s point.

Action: We have paraphrased so the sentence now reads: “The current findings also support that domain-specific characteristics of physical activity do not affect risk factors for which diet is most important (20, 63, 64).”

24) line 499-500: This statement (“i.e. only borderline during work”) is vague because it does not explain what “borderline” it refers to although I would assume that it is based on comparisons of statistical significance between PA domains instead of any minimum relevant effect size or effect estimation. The statement is problematic because the actually measured effects are different than this statement suggests: 50% higher for LTPA compared to OPA when adding 2 min of HIPA (0.02 vs 0.01 mmol/l), identical when adding or substracting 1 minute HIPA (0.01 mmol/l) and 50% higher for OPA (0.03 vs 0.2 mmol/l) when reducing HIPA by 2 min as shown in Table 4.

Pointing out that only the LTPA findings are statistically significant does not summarize these results well. It looks more like consistent but small substantial effects overall regardless of direction and statistically significance testing. However, this assessment would be premature without consideration of how important any small LDL changes in the observed range maybe at the population level. You provide this info in your next paragraph: 30% for 1 mmol; this translates into 0.3% -0.9% lower IHD mortality, this seems to be still substantial on a population level although is much smaller than the examples given for SBP above. Your conclusion that the relationship between PA domains and LDL-C is unclear holds. However, this needs to be balanced against the potentially larger detrimental effects these reallocations may have with regard to SBP.

Response: We acknowledge that “borderline” is vague, can be misunderstood, and that the summary of the results could be improved in accordance with the reviewer’s interpretation. Furthermore, the relative differences between the domains (e.g., a 50% higher estimated difference in LDL-C for time reallocations during leisure compared to work) are indeed correct. However, for the time reallocations during work, the estimates are close to zero with relatively symmetrical CIs. It can therefore be problematic to make any strong interpretations of these results’ potential implications. We have therefore tried to balance the interpretation.

Action: The sentence now reads: “Furthermore, during both domains, less sedentary behaviour and more HIPA seemed to be associated with a lower LDL-C.” (p. 28, line: 564-565).

In addition, we have changed the following paragraph to reflect the potentially detrimental effects of the time reallocations on SBP that are larger than those on LDL-C. It now reads: “On a population-level, a 1 mmol/L lower non-HDL-C (i.e., total cholesterol minus HDL-C) has been reported to lower IHD-mortality by 30% (69). This translates to 0.3% lower IHD-mortality for every 0.01 mmol/L lower LDL-C. Therefore, even small improvements in LDL-C on a population-level like those observed in the current study, could, in combination with improvements in other modifiable risk factors (e.g., poor diet, high SBP, obesity, smoking, high alcohol consumption, and others), likely contribute to the prevention of incident IHD (70, 71). However, the potentially detrimental association between less sedentary behaviour and more HIPA during work and SBP should be kept in mind.” (p. 29, line: 573-581).

25) line 500 cited reference 47 by Honda 2014: It may be interesting to note that Honda reported (under fully adjusted model 3 in their Table 3) that 60 min of sedentary LTPA increases LDL by 0.77 mmol/L, while sedentary OPA, in contrast, decreases LDL by the -0.73 mmol/l. Similar paradoxical effects were shown for SBP (and less convincingly for WC) although the authors choose to totally ignore these findings because they were not statistically significant. However, a closer examination of confidence intervals (-1.78 to 0.31 for LDL) shows that their data are much more compatible with the PA paradox than not. I attach this table with my highlights here for your quick reference.

Response: We acknowledge that the contrasting findings in the study by Honda et al. were not clear from our previous wording.

Action: To better reflect the contrasting findings reported by Honda et al., this section now reads: “This disagrees with findings from three studies (52, 53, 65), where similar associations were reported for sedentary behaviour during leisure but not for work (except for the study by Honda et al. (49) where indications of opposite associations during leisure and work are reported).” (p. 28, line: 565-568).

26) Line 510: “being overweight” is entered as a CVD risk factor. May be replacing it by “obesity” would be appropriate: If I recall it correctly, a closer look at the evidence suggests a bi-modal risk relationship between BMI with elevated risks for underweight and normal weight persons, lowest risk for overweight, and increasing risk for obese and above.

Aside: Interestingly, in several Finnish cohort studies, BMI was not at all (HR=1.0) related to CVD and mortality outcomes in models that include occupational physical activity (and virtually all other known CVD risk factors). Hi BMI is also partly a function of high muscle mass which is related to the capacity to perform heavy labor and thus may be an intricate correlate of high OPA but with no independent effect on CVD once OPA is controlled for. Consequently, the literature on overweight and CVD is probably still inconclusive.’

Response: We acknowledge the reviewer’s point.

Action: We have replaced “being overweight” with “obesity” (p. 29, line: 578).

27) Line 519-20: From a primary prevention perspective it is paramount not to exclude 2/3 of the general population that has these potentially modifying factors – we want to know how this works out in real populations not a selected minority group of mostly healthy individuals who are already at the lowest risk for CVD, they are the least in need of additional research! It seems that you have data on persons with theses potentially confounding or effect modifying factors (based on the many exclusions you reported based on these factors). Could you rerun your analyses with everybody included and compare this with your current results as a sensitivity analysis? And thereafter investigate this further with stratified analyses by how much these factors may change relationships (in a supplement or in a separate paper)? See also comments and specific suggestions in comments #6 and #7 above.

Response: We have conducted sensitivity analyses based on a) all study participants, regardless of use of antihypertensives or cholesterol lowering drugs, and b) only study participants using antihypertensives, diuretics, or cholesterol lowering drugs. Please note that the exclusion criteria related to the use of specific medications did not exclude two thirds of the eligible study participants. As seen in Supporting information file S3, these sensitivity analyses included 804 and 146 study participants, respectively (compared to n=652 in the main analyses).

Action: Please see action in response to detailed comment 7.

28) Line 527-529: While I agree that representativeness is not as important as validity (because what sense would it make to generalize findings of questionable validity?). I also agree that normal physiology needs to be studied in normal or healthy persons (but not necessarily young, or college-educated, or athletic etc. because what is normal will change during the life cycle – think of menopause and other normal changes). “Normal” is a quite difficult selection criterion as is “external”, after there are not really any people on earth that are not influenced by a myriad of “external” factors, medication is just one of the ones we actually can and should measure and thus take into account.

Instead of controlling for these factors by either excluding participants or by adjustment in multivariate models, these factors and their influence on the exposure-disease relationships need to be actively investigated. Two basic steps have been suggested above: investigate the potential impact quantitatively by comparing changes in effect estimates (not statistical significance!) caused by adding this modifying factor to multivariate models and investigate multiplicative and additive interactions or (better) by comparing effect estimates from analyses stratified on categories of this potentially modifying factor. (More sophisticated mediation analysis may be needed to disentangle the different effects those factors may have but they are best reserved for prospective data with repeat measures).

Exclusion of people with potentially effect modifying characteristics is not helping to clarify their potential impact and is actually detrimental for primary prevention efforts that need to address high risk populations that are often characterized by these very factors that led to the exclusion of otherwise eligible study participants. This is the main weakness of this paper but it could be addressed by adding the suggested sensitivity analyses.

The selection of analytic samples from general study populations for epidemiological investigation into the associations between ubiquitous PA exposures and highly prevalent CVD risk factors with a goal to solve occupational and public health problems associated with these risks, need to be different than samples selected for the study of physiological experiments, or sports performance, or clinical interventions designed for patients only. While I think that your study is a wonderful contribution, it would be best to strive for resolving these issues instead of excluding two thirds of eligible participants from further investigation (and thus basic knowledge needed to design interventions for them). I hope it is clear that I am not asking for restricting research to representative samples, I agree wholeheartedly with Rothman whom you cite on this topic, but he and I myself actually argue for non-representative analytic sampling strategies, including stratified analyses, that allow to make inferences of potentially modifying factors such as pre-existing CVD that have already been shown to exert strong modifying effects on CVD risk in other studies and are common in our societies and our aging workforce too. Again, sampling for such a study may include oversampling certain subgroups to make comparisons between subgroups more comparable (study design B in Rothman 2012 you cited). Thanks for citing his papers, it was a pleasure to reread them!

Response: We agree with the reviewer. The suggested stratified analysis has been conducted as a sensitivity analysis.

Action: Please see actions to detailed comment 7.

29) line 537: limitations of exposure assessment by accelerator data: You may want to mention three additional important limitations here: 1) inability to consider the weight of materials, people, or tools handled (need for additional ergonomic assassments), 2) questionable implicit assumption that observed exposure during a short time window accurately reflects typical exposure (need to assess that separately by diary or survey or experts), 3) inability to assess past and cumulative overall exposure that may be most relevant for adverse chronic health effects such as CVD (need for repeat measurements over long study periods that is typically not feasible; need for assessing past exposure through detailed job histories based on self-report, administrative records, and expert assessments, e.g. a job exposure matrix, JEM). Occupational exposure assessment that solely relies on accelerometer-based snap-shots of current exposure is not necessarily more valid than self-reports or JEMs, and may in fact lead to massive exposure misclassification, especially if job tenure is short which is the case in many low SES jobs.

Response: We acknowledge that these are additional limitations that could be added to the manuscript. Also, we find that this strengthens the argument of not using objective device-based measurements as a term for a general exposure assessment.

Action: We have changed the wording of the paragraph discussing limitations of the exposure assessment (p. 31). It now reads: “Firstly, the measurements do not capture the load in specific tasks such as heavy lifting, pushing, pulling, or awkward body positions (does not include measurements of the weight of materials, people, or tools handled), which are known to impose high physical demands, and therefore, could be important (13, 14). Secondly, common to all accelerometer-based measurements of physical behaviours, the measurements do not include the relative intensity of the physical activity. Thirdly, we do not know whether the measurement period accurately reflects the study participants’ typical physical activity level. Finally, we do not have data on job title, and on past or cumulative job exposure. These limitations imply a risk for misclassification of the exposure which, potentially, could lead to an underestimation of the health effects.” (p. 31, line: 627-636).

30) line 548-51 LDL-C: Comment: LDL-C appears to be indeed a strong and, as prospective cohort studies of OPA and CVD have shown, also a rather independent CVD risk factor that is therefore not a prime candidate for being a major mediator or confounder of the OPA -CVD relationship. However, this needs to be determined in prospective studies that also take the effects of widely-prescribed lipid-lowering drugs and pre-existing CVD into consideration.

Response: We thank the reviewer for this comment and agree that our results should trigger prospective studies investigating this, which would be of value to improve our understanding of these relationships.

Action: None.

31) line 566-67: See comment # on “borderline” Although not the subject of any academic paper I am aware of, it is well-known among occupational health researchers, ergonomists, and manual workers themselves, that physically demanding work is only endurable if workers avoid as much as possible HIPAs that make them sweat or breathless during work (i.e. avoid the intensity that may produce training benefits in terms of cardiorespiratory fitness as it does during LTPA or athletic training) because working conditions typically do not allow for self-paced work with adequate recovery time and it is impossible for most workers to change out of sweat-drained wet clothes into dry clothes causing during work shifts. Therefore, larger sample sizes are not likely to change the noted limitation of few minutes of HIPA, it is an inherent characteristic of most real-world heavy labor.

Getting more accurate data instead will be dependent on implementing another form of composition analysis: improvement of all sources of exposure misclassification of OPA as outlined in comment #29 above: combining sensor-based methods with detailed job histories, JEMs, and other available data (e.g., administrative cumulative data on work hours, workdays, and leave time such as vacation, sick days, family leave, continuing education or retraining, unemployment, disability, retirement etc.) to construct more accurate exposure measures, and exposure measures that actually capture the relevant cumulative OPA exposures. Such improved imprecision of exposure assessment may help to reduce the conservative misclassification bias that plagues the literature and may be responsible for imprecision, underestimation of related chronic health consequences, and an overall inconclusive evidence base. Further, avoiding of categorization of continuous outcome measures artificially introduced by researchers during survey development or during data analysis, and replacing quantile categorization by categories that are demarcated by actual threshold effects in risk, is a much more promising and more feasible and cost-efficient approach for yielding more precise and also more valid health effect estimates.

Response: We agree that “larger sample sizes are not likely to change the noted limitation of few minutes of HIPA”. However, the limitation we try to emphasise is the imprecision of the estimates. Given a larger sample size, the variation in our data set would likely be smaller, which would lead to more narrow CIs and hence more precise estimates. However, we also agree that combining device-based measurements with other types of exposure measurements could be an important approach to further this research area.

Action: We have paraphrased to avoid the word “borderline” (in line with response to comment #24). The paragraph now reads: “In general, the estimates were small, and the CIs were wide, in particular for the work-specific time reallocations. This is likely a consequence of the size of our study population, and the relatively small number of participants with a long duration of HIPA during work, which results in a large variation. A larger study population would likely result in less variation and thereby improved precision of the estimates, which could increase the confidence when interpreting the results.” (p. 32, line: 663-668).

32) line 569-72: I would also reference Peter Smith’s Canadian landmark cohort study on AMI here (“The relationship between occupational standing and sitting and incident heart disease over a 12-year period in Ontario, Canada,” Am J Epidem, 2018;187:27-33), which is also good example how JEM’s can be utilized for objective OPA assessment in very large samples that are typically beyond feasibility regarding accelerometer- or direct ergonomic observation.

Response: We agree that the suggested reference could be added, since it supports the statement.

Action: We have added the reference to the sentence “However, as previous studies and our results indicate (8, 12, 80), public health messages such as ‘sit less and move more’, may not be well suited for population groups that are highly physically active during work.” (p. 33, line: 673-675).

33) line 577: Can you be specific about the health outcomes and provide respective references here?

Response: We have paraphrased to soften the statement.

Action: It now reads: “Currently, for several health outcomes it is still unclear how individuals with high occupational physical activity should best compensate during leisure.” (p. 33, line: 680-682).

34) line 584: I would suggest to cite here some of the existing evidence regarding null effects of LTPA (e.g., Krause N, Brand RJ, Arah OA, Kauhanen J, Occupational physical activity and 20-year incidence of acute myocardial infarction: results from the Kuopio Ischemic Heart Disease Risk Factor Study, Scand J Work Environ Health, 2015;41(2):124-139) and regarding even detrimental effects of LTPA (e.g., Eaton CB, Medalie JH, Flocke SA, Zyzanski SJ, Yaari S, Goldbourt U,Self-reported physical activity predicts long-term coronary heart disease and all-cause mortalities. Twenty- one-year follow-up of the Israeli Ischemic Heart Disease Study. Arch Fam Med 1995;4(4):323–329; more references can be found in PA guidelines talking about risks of LTPA), as well as specific literature regarding “overtraining effects in sports”?

Response: The paragraph has been paraphrased in relation to other comments, which made the suggested references redundant.

Action: None.

35) line 587: Reference 73(Korshøj et al. 2015) does not support the introduction of aerobic exercise during work. This RCT showed average increases of systolic blood pressure by 3.6 mm Hg (95% CI 1.1-6.0) relative the control group. It is important to cite this study but as a warning regarding unintended consequences of such a program instead as confirmation for this approach.

Response: This is true, and this reference deserves more attention. However, in a larger perspective considering all monitored effects, the most important is that a positive change was seen for a number of clinically recognized risk factors. That is, although the mean SBP increased following the intervention, we consider the benefits of the exercise intervention to outweigh the potential harms.

Action: The potential of unintended consequences has been emphasised. The section now reads: “One potential alternative is workplace-based initiatives, such as aerobic exercise during work hours. Although such interventions may have unintended negative health effects such as increased SBP (81), they can improve cardiorespiratory fitness, workability, and health (81-83).” (p. 33, line: 682-685).

36) line 587-99: The point is not to consider OPA in PA, that is already being done implicitly by counting any PA towards recommended PA goals. The pressing issue for a revision of PA guidelines is instead to acknowledge the PA health paradox and the need for more targeted and safe PA recommendations that take potential differential effects of OPA and LTPA and baseline CVD health status into account.

Response: We acknowledge the reviewer’s point and have paraphrased.

Action: The sentence now reads: “It is, therefore, highly important to take the potentially contrasting health effects of leisure time- and occupational physical activity into account in physical activity recommendations for adults.” (p. 33, line: 685-687).

37) line 596: see comment #31 above re “larger sample size”. Maybe avoidance of unnecessary misclassification is worth mentioning here?

Response: We agree that a short sentence about how the exposure assessment may be improved (with less misclassification) in future studies could fit nicely here.

Action: In continuation to detailed comment 29 and 31, we have added “Combining device-based measurements with data on previous job titles, job exposure matrices, routinely collected administrative data (e.g., periods of sick leave periods, retirement), or questionnaire data to improve the exposure assessment and minimise misclassification could be a fruitful avenue for future studies.” (p. 34, line: 697-701).

38) line 602-609: This overall conclusion summarizes the main findings well and is backed up by the data. Given the discussion of WC and LDL_C results above, it may be appropriate to replace “No difference between domains ..” by “No consistent differences ….”

Response: We see the reviewer’s point and have paraphrased in line with the suggestion.

Action: It now reads: “In contrast, no consistent differences between domains were observed for WC and LDL-C.” (p. 34, line: 707-708).

References

1. Skotte J, Korshoj M, Kristiansen J, Hanisch C, Holtermann A. Detection of physical activity types using triaxial accelerometers. Journal of physical activity & health. 2014;11(1):76-84.

2. Unger T, Borghi C, Charchar F, Khan NA, Poulter NR, Prabhakaran D, et al. 2020 International Society of Hypertension Global Hypertension Practice Guidelines. Hypertension. 2020;75(6):1334-57.

Attachment

Submitted filename: Response to reviewers_Johansson et al_Revision 1_120122.docx

Decision Letter 1

Gianluigi Savarese

7 Feb 2022

PONE-D-21-00560R1The physical activity health paradox and risk factors for cardiovascular disease: a cross-sectional compositional data analysis in the Copenhagen City Heart StudyPLOS ONE

Dear Dr. Johansson,

Thank you for submitting your manuscript to PLOS ONE. 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.

Please submit your revised manuscript by Mar 24 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Gianluigi Savarese

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

Minor comments:

The Background is definitely too long and reads as a review. The Authors are invited to shorten this section. Most of what explained here belongs to the discussion.

There were some missing data. How were they handled?

[Note: HTML markup is below. Please do not edit.]

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?

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

Reviewer #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?

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

Reviewer #1: Yes

**********

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

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

Reviewer #1: Yes

**********

6. Review Comments to the Author

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

Reviewer #1: I am willing to accept the manuscript. I will just recommend the authors to go through the paper and review carefully grammar and spelling to make sure there are no mistypes or something.

Otherwise, congratulations on this good paper.

**********

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.

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

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

Reviewer #1: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2022 Apr 21;17(4):e0267427. doi: 10.1371/journal.pone.0267427.r004

Author response to Decision Letter 1


10 Mar 2022

Response to reviewers’ comments

PONE-D-21-00560

The physical activity health paradox and risk factors for cardiovascular disease: a cross-sectional compositional data analysis in the Copenhagen City Heart Study

Dear Dr. Gianluigi Savarese,

We would like to acknowledge you and the reviewer for taking your time to assess our manuscript and providing valuable feedback. Re the Journal requirements, we have checked the reference list to make sure it is complete and correct. A point-by-point response can be found below. Changes made in the manuscript have been highlighted using the track-changes function in Word.

With kind regards on behalf of all authors,

Melker S. Johansson

Additional Editor Comments:

Minor comments:

1. The Background is definitely too long and reads as a review. The Authors are invited to shorten this section. Most of what explained here belongs to the discussion.

Response: We acknowledge that the introduction was too long.

Action: The introduction has been shortened substantially from 636 words to 352 (p. 3-4, line: 55-84.

2. There were some missing data. How were they handled?

Response: We interpret the editor’s comment to relate to the missing values of some of the covariates included in the adjusted regression models. We acknowledge that the sentence given in the legends of Table 3 and Table 4 was not clear and have therefore paraphrased.

Action: The sentence in the legend of Table 3 and Table 4 now reads: “69 observations were not included in the adjusted models due to missing values in some covariates.” (p. 18 and 19). In addition, we have added the following sentence in the Methods section: “Observations with missing values in the covariates were not included in the adjusted models (n=69).” (p.11, line: 247-248).

Reviewers' comments:

Reviewer 1

I am willing to accept the manuscript. I will just recommend the authors to go through the paper and review carefully grammar and spelling to make sure there are no mistypes or something. Otherwise, congratulations on this good paper.

Response: We thank the reviewer for the comments, which have helped us improve the manuscript. Finally, we have reviewed the manuscript for grammatical and spelling errors and typos.

Attachment

Submitted filename: Response to reviewers_Johansson et al_Revision 2_070322.docx

Decision Letter 2

Gianluigi Savarese

11 Apr 2022

The physical activity health paradox and risk factors for cardiovascular disease: a cross-sectional compositional data analysis in the Copenhagen City Heart Study

PONE-D-21-00560R2

Dear Dr. Johansson,

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

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

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

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. 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.

Kind regards,

Gianluigi Savarese

Academic Editor

PLOS ONE

Acceptance letter

Gianluigi Savarese

14 Apr 2022

PONE-D-21-00560R2

The physical activity health paradox and risk factors for cardiovascular disease: a cross-sectional compositional data analysis in the Copenhagen City Heart Study

Dear Dr. Johansson:

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,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Gianluigi Savarese

Academic Editor

PLOS ONE

Associated Data

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

    Supplementary Materials

    S1 Table. Overview of questions and responses.

    (PDF)

    S2 Table. Overview of derived variables.

    (PDF)

    S3 Table. Variation matrix of parts in physical activity composition.

    (PDF)

    S4 Table. Comparison of characteristics of non-eligible and eligible participants.

    (PDF)

    S1 File. Linear regression models.

    (PDF)

    S2 File. Time reallocations.

    (PDF)

    S3 File. Sensitivity analyses.

    (PDF)

    Attachment

    Submitted filename: PONE, REVIEWER COMMENTS.docx

    Attachment

    Submitted filename: 210131 Review PONE-D-21-00560.docx

    Attachment

    Submitted filename: Response to reviewers_Johansson et al_Revision 1_120122.docx

    Attachment

    Submitted filename: Response to reviewers_Johansson et al_Revision 2_070322.docx

    Data Availability Statement

    The data generated and analysed for this study contains potentially identifiable or sensitive information and can therefore not be shared publicly (General Data Protection Regulation, European Union). However, anybody can apply for the use of data by contacting the secretariat director of the Copenhagen City Heart Study. For contact information, please see https://www.frederiksberghospital.dk/afdelinger-og-klinikker/oesterbroundersoegelsen/kontakt/Sider/default.aspx. The authors of the present study had no special privileges in accessing the data that other interested researchers would not have.


    Articles from PLoS ONE are provided here courtesy of PLOS

    RESOURCES