Cycling and sports, but not walking, are associated with 10-year cardiovascular disease incidence: the MORGEN Study.
ABSTRACT Physical activity is inversely related to cardiovascular diseases. However, the type of activities that contribute most to these beneficial effects remain unclear. For this reason, we investigated self-reported leisure time physical activities in relation to fatal/nonfatal cardiovascular disease incidence.
The Dutch Monitoring Project on Risk Factors for Chronic Diseases Study, carried out between 1993 and 1997, is a prospective cohort study of over 23000 men and women aged 20–65 years from the general Dutch population.
From 1994 till 1997 physical activity was assessed with a questionnaire in 7451 men and 8991 women who were followed for an average of 9.8 years. Cox proportional hazards models were used adjusting for age, sex, other physical activities, smoking, alcohol consumption, and educational level.
Almost the entire study population (97%) was engaged in walking, about 75% in regular cycling, and about half the population in sports or gardening. Cycling [hazard ratio (HR): 0.82, 95% confidence interval (CI): 0.71–0.95] and sports (HR: 0.74, 95% CI: 0.64–0.87) were both inversely related to cardiovascular disease incidence, whereas walking and gardening were not. For sports (P < 0.001), but not for cycling (P = 0.06), we found a dose - response relationship with respect to cardiovascular disease incidence. Engaging in both cycling and sports resulted in an even greater risk reduction (HR: 0.64, 95% CI: 0.52–0.77).
In this relatively active population, types of activities of at least moderate intensity, such as cycling and sports were associated with lower CVD incidence, whereas activities of lower intensity, such as walking and gardening, were not.
- SourceAvailable from: PubMed Central[Show abstract] [Hide abstract]
ABSTRACT: Physical activity (PA) confers some protection against development of heart failure (HF) but little is known of the role of intensity and duration of exercise. In a prospective cohort study of men and women free of previous MI, stroke or HF with one or more examinations in 1976-2003, we studied the association between updated self-assessed leisure-time PA, speed and duration of walking and subsequent hospitalization or death from HF. Light and moderate/high level of leisure-time PA and brisk walking were associated with reduced risk of HF in both genders whereas no consistent association with duration of walking was seen. In 18,209 subjects age 20-80 with 1580 cases of HF, using the lowest activity level as reference, the confounder-adjusted hazard ratios (HR) for light and moderate/high leisure-time physical activity were 0.75 (0.66-0.86) and 0.80 (0.69-0.93), respectively. In 9,937 subjects with information on walking available and 542 cases of HF, moderate and high walking speed were associated with adjusted HRs of 0.53 (0.43-0.66) and 0.30 (0.21-0.44), respectively, and daily walking of ½-1 hrs, 1-2 and >2 hrs with HR of 0.80 (0.61-1.06), 0.82 (0.62-1.06), and 0.96 (0.73-1.27), respectively. Results were similar for both genders and remained robust after exclusion of HF related to coronary heart disease and after a series of sensitivity analyses. Speed rather than duration of walking was associated with reduced risk of HF. Walking is the most wide-spread PA and public health measures to curb the increase in HF may benefit from this information.PLoS ONE 03/2014; 9(3):e89909. · 3.53 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The contribution of sufficient sleep duration to lower CVD risk in addition to sufficient physical activity, a healthy diet, (moderate) alcohol consumption, and non-smoking has not been investigated yet. The MORGEN study is a prospective cohort study including 8128 men and 9759 women aged 20-65 years, free of CVD at baseline. Sufficient physical activity (≥3.5 h/week cycling or sports), a healthy diet (Mediterranean Diet Score ≥5), (moderate) alcohol consumption (≥1 beverage/month), non-smoking, and sufficient sleep duration (≥7 hours) were assessed by self-administered questionnaires between 1994 and 1997. Cardiovascular morbidity and mortality were ascertained through linkage with national registers. Hazard ratios and preventable proportions were calculated adjusted for age, sex, and educational level. During 10-14 years of follow up, 607 composite CVD events (fatal CVD, nonfatal myocardial infarction and stroke) occurred, of which 129 were fatal. Those with the four traditional healthy lifestyle factors had a 57% lower risk of composite CVD (HR 0.43, 95% CI 0.31-0.59) and a 67% lower risk of fatal CVD (HR 0.33, 95% CI 0.16-0.68) compared with those with none or one healthy lifestyle factor. Sleeping sufficiently in addition to the four traditional lifestyle factors resulted in a 65% lower risk of composite CVD (HR 0.35, 95% CI 0.23-0.52), and an 83% lower risk of fatal CVD (HR 0.17, 95% CI 0.07-0.43). Sufficient sleep and adherence to all four traditional healthy lifestyle factors was associated with lower CVD risk. When sufficient sleep duration was added to the traditional lifestyle factors, the risk of CVD was further reduced.European journal of preventive cardiology. 07/2013;
- [Show abstract] [Hide abstract]
ABSTRACT: To investigate the prevalence of active transport (AT, defined as walking or bicycling for transport) and to explore the association between AT and health outcomes, we conducted a population-based cross-sectional study in Jiangsu, China, where walking and bicycling are still the main modes of transport. In this study, 8400 community residents aged 18 or above were interviewed following a multistage random sampling method (100% response rate). Face-to-face questionnaire survey data, anthropometric measurements, and biochemical data from blood tests were collected. Results show that 49.6% of the subjects, as part of daily transport, actively traveled on average 5.3 days per week, 53.5 minutes per day, and 300.3 minutes per week. There was an inverse correlation between AT and some health outcomes: AT respondents had a higher prevalence of cholesterol disorder; AT respondents who actively travelled every day had a higher risk of diabetes, whilst AT respondents with shorter daily or weekly duration had a lower risk of obesity, central obesity, and cholesterol disorder. Moreover, AT influences more health aspects among urban residents than among rural residents. Findings of this study do not support the notion that AT is beneficial to population health. Further research is needed in determining the negative side effects of AT.Journal of Environmental and Public Health 01/2013; 2013:624194.
European Journal of Cardiovascular Prevention
The online version of this article can be found at:
2011 18: 41European Journal of Cardiovascular Prevention & Rehabilitation
Marieke P Hoevenaar-Blom, GC Wanda Wendel-Vos, Annemieke MW Spijkerman, Daan Kromhout and WMM
Cycling and sports, but not walking, are associated with 10-year cardiovascular disease incidence: the
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Original scientific paper
Cycling and sports, but not walking, are
associated with 10-year cardiovascular
disease incidence: the MORGEN Study
Marieke P Hoevenaar-Blom1,2, GCW Wendel-Vos1,
Annemieke MW Spijkerman1, Daan Kromhout2and
Background: Physical activity is inversely related to cardiovascular diseases. However, the type of activities that con-
tribute most to these beneficial effects remain unclear. For this reason, we investigated self-reported leisure time physical
activities in relation to fatal/nonfatal cardiovascular disease incidence.
Design: The Dutch Monitoring Project on Risk Factors for Chronic Diseases Study, carried out between 1993 and 1997,
is a prospective cohort study of over 23000 men and women aged 20–65 years from the general Dutch population.
Methods: From 1994 till 1997 physical activity was assessed with a questionnaire in 7451 men and 8991 women who
were followed for an average of 9.8 years. Cox proportional hazards models were used adjusting for age, sex, other
physical activities, smoking, alcohol consumption, and educational level.
Results: Almost the entire study population (97%) was engaged in walking, about 75% in regular cycling, and about half
the population in sports or gardening. Cycling [hazard ratio (HR): 0.82, 95% confidence interval (CI): 0.71–0.95] and
sports (HR: 0.74, 95% CI: 0.64–0.87) were both inversely related to cardiovascular disease incidence, whereas walking
and gardening were not. For sports (P<0.001), but not for cycling (P¼0.06), we found a dose-response relationship
with respect to cardiovascular disease incidence. Engaging in both cycling and sports resulted in an even greater risk
reduction (HR: 0.64, 95% CI: 0.52–0.77).
Conclusion: In this relativelyactivepopulation, types of activities of at least moderate intensity, such as cycling and sports
were associated with lower CVD incidence, whereas activities of lower intensity, such as walking and gardening, were not.
Cardiovascular disease, cycling, gardening, primary prevention, sports, walking
Received 22 December 2009; accepted 29 April 2010
Over the past few decades, many epidemiological stud-
ies have shown a clear inverse association between
physical activity and cardiovascular diseases (CVD).1
In a recent meta-analysis, including almost 900,000
participants, physical activity was associated with a
35% lower risk of fatal CVD when comparing active
mainly on occupational physical activity and total
physical activity. Over the years, however, interest
has shifted towards daily leisure time physical activi-
ties, such as walking and cycling, because of a wider
range of activities that are also easier to modify than
occupational physical activities. Therefore leisure time
physical activities make a suitable target for public
between leisure time physical activity and CVD.2,3
1Centre for Prevention and Health Services Research, National Institute
for Public Health and the Environment, Bilthoven, The Netherlands.
2Division of Human Nutrition, Wageningen University, Wageningen,
Marieke P Hoevenaar-Blom, Centre for Prevention and Health Services
Research (PZO), NationalInstitute for
Environment, PO Box 1, 3720 BA Bilthoven, The Netherlands
Public Health andthe
European Journal of Cardiovascular
Prevention & Rehabilitation
! The European Society of
Reprints and permissions:
However, it remains unclear what specific type of activ-
ities contribute most to these beneficial effects, as few
studies have addressed the impact of different types of
activities on CVD.4–6For this reason, we aimed at inves-
tigating specific types of leisure time physical activity
(walking, gardening, cycling, and sports) in relation to
CVD incidence in a population-based sample of the
uated dose—response relationships and the impact of
combinations of different types of activities.
The Dutch Monitoring Project on Risk Factors for
Chronic Diseases (MORGEN) Study was carried out
in The Netherlands between 1993 and 1997 in 10 448
men and 12,652 women. Random sex—age stratified
samples were drawn from municipal population regis-
ters in three towns in The Netherlands (Doetinchem,
Maastricht, and Amsterdam). The average response
rate in the MORGEN Study was 45%.7
From 1994 till 1997 physical activity was assessed with
an identical questionnairefor 8142men and 9778women.
Exclusion criteria for the present analyses were no
informed consent for follow-up of vital status (n¼1017),
pregnancy at baseline (n¼106), prevalent myocardial
activity (n¼13). After these exclusions, 7451 men and
8991 women remained for the present analyses.
Questionnaires. Physical activity was assessed with a
validated8physical activity questionnaire designed for
the ‘European Prospective Investigation into Cancer
and nutrition’ (EPIC) including questions on occupa-
tional and leisure time physical activity. The question
on cycling included cycling towards and from work and
in leisure time as an example and the question on walk-
ing additionally included shopping as an example. For
the MORGEN Study, the questionnaire was extended
with two open-ended questions on type, frequency, and
duration of sports, and one open-ended question on
other strenuous activities.
showed that the EPIC questionnaire was suitable for
ranking participants according to their physical activ-
ity level.8The 11-month reproducibility (Spearman cor-
relation coefficients) of the questionnaire for men
yielded 0.57 for walking, 0.47 for cycling, and 0.71
for gardening, and for women, 0.57, 0.72, and 0.67,
respectively.8Spearman correlation coefficients relative
to a 3-day activity diary, repeated four times, were, for
men: 0.32 for walking, 0.46 for cycling, and 0.43 for
gardening and odd jobs, and for women 0.33, 0.48,
and 0.47, respectively.8
moderate intensity physical activity,9which in The
Netherlands has been defined as at least 4.0 metabolic
equivalents (METs).10Although walking (3.5 METs)
does not classify as ‘moderate intensity’ in The
Netherlands, this activity has repeatedly been shown to
be associated with reduced risk of CVD.11–13Moreover,
walking is an important leisure time activity in The
Netherlands, both in terms of frequency and duration.
Therefore, we investigated walking (Ainsworth code:
3.5 METs), gardening (Ainsworth code:
08245,144.0 METs), cycling (Ainsworth code: 02010,14
7.0 METs), and sports (?4.0 METs) as specific types of
leisure time physical activity possibly related to CVD.
Time spent on occupational physical activities (con-
tinuous) of at least moderate intensity was included as
confounder. Gardening, cycling, and sports were classi-
least some walking, participants who reported less than
3.5h/week (30min per day) were used as the reference
category for walking. To study dose-response relation-
ships, we divided cycling and sports into three categories
(0,>0–3.5, and ?3.5h/week).
Educational level was classified as low (lower voca-
tional training or primary school), medium (secondary
school and intermediate vocational training), or high
(higher vocational training or university). Smoking
was categorized as yes or no, and alcohol consumption
as none, moderate (male: ?2 glasses/female: ?1 glass
per day), or high (male:>2 glasses/female: >1 glass per
day). Self-reported CVD risk factor medication was
defined as using cholesterol lowering medication or
Physical examination. Weight and height were mea-
sured to the nearest 0.1kg and 0.5cm without shoes.
Body mass index (BMI) was calculated as weight in
kilograms (minus one kilogram for light clothing)
divided by height in meters squared. BMI was classified
as normal (<25kg/m), overweight (25–30kg/m2), or
obese (?30kg/m2). Nonfasting plasma total cholesterol
and HDL cholesterol were determined in the Lipid
Reference Laboratory of the University Hospital
Dijkzigt in Rotterdam using standardized enzymatic
methods.15Systolic blood pressure was recorded twice
with a random zero sphygmomano meter at the appear-
ance of sounds (first-phase Korotkoff) in sitting posi-
The average of the two blood pressure
measurements was included in the present analyses.
Ascertainment of fatal and nonfatal events.
Information on mortality and morbidity follow-up
42European Journal of Cardiovascular Prevention & Rehabilitation 18(1)
was availableup to1 January 2006. Vital statuswas iden-
tified using the municipal population register with a loss-
to-follow-up below 0.1%. Cause of death was obtained
vided by the national hospital discharge register. On the
be uniquely linked to a single person.16In a validation
study with an approximate 33% overlap of participants
from our study, a high sensitivity (84%) and a positive
predictive value (97%) were observed for coronary heart
disease hospital admissions.17
Fatal (primary or secondary cause of death) and
nonfatal CVD were defined according to ICD-9,18
codes 410–414, 415.1, 427.5, 428, 430–438, 440–444,
798.1, 798.2 and 798.9 and corresponding ICD-1019
codes for the fatal cases after 1996.
Cox proportional hazards models were used to estimate
hazard ratios (HRs) and 95% confidence intervals
(CIs). Participants were either followed up to the first
nonfatal cardiovascular event, death, emigration, or
were censored at 1 January 2006.
Three consecutive models were used. The first model
was adjusted for age and sex. The second model was
additionally adjusted for hours per week spent on phys-
ical activities (both occupational and leisure time) other
than the one under study, lifestyle factors (smoking and
alcohol consumption), and educational level. As bio-
logical risk factors such as BMI, total and HDL cho-
lesterol, and systolic blood pressure are possible
intermediates in the association between physical activ-
ity and CVD, we additionally adjusted for these factors
in a third model. As no difference occurred in the
hazard ratios, we will report only the hazard ratios of
the second model. There was no interaction with age
(younger or older than 50 years), or sex, and the pro-
portional hazard assumption was satisfied. To study
dose-response relationships, we performed tests for
linear trend using the median values of the respective
category as continuous parameters. Analyses were per-
formed using SAS 9.1 software (SAS Institute, Inc.,
Cary, North Carolina, USA).
Baseline characteristics of the study population are
shown in Table 1. Participants were, on average,
41.9?11.2 years old at baseline, and 45% were male.
Walking and cycling contributed the most to the time
spent on leisure time physical activities. Almost the
entire study population was engaged in walking (97%),
about 75% in regular cycling and about half of the
population in gardening or sports. Intensities of sports
ranged from 4.0 to 12.0.
Table 2 shows the 10 most frequently reported sports
for men and women. During 9.8 years of follow-up, 362
Table 1. Baseline characteristics of participants in the
MORGEN Study, 1994–1997a,b
42.4 (11.1)41.6 (11.4)
Leisure time physical activity (%)
Walking (3.5 MET)96.496.5
Gardening (4.0 MET)
Cycling (7.0 MET)
Sports (?4.0 MET)
Lifestyle factors (%)
Biological risk factors
Total cholesterol (mmol/l)
HDL cholesterol (mmol/l)
Systolic blood pressure (mmHg)
Self-reported CVD risk
factor medication (%)e
Cardiovascular cases (n)
Fatal CVD66 28
BMI, body mass index; HDL, high-density lipoprotein; CVD, cardiovascu-
aWith consent for follow-up and free from baseline CVD, pregnancy and
without missing data on physical activity, n¼16 442;bData presented as
mean (sd);clow (lower vocational training or primary school), medium
(secondary school and intermediate vocational training), high (higher
vocational training or university);
?1 glass per day), high (male: >2 glasses/female: >1 glass per day);
eCholesterol-lowering and/or antihypertensive medication.
dModerate (male: ?2 glasses/female:
Hoevenaar-Blom et al. 43
fatal and nonfatal CVD events occurred in women,
compared with 561 in men.
Walking or gardening was not associated with CVD
incidence. Inverse associations with CVD incidence
were observed for cycling (HR: 0.82, 95% CI:
0.71–0.95) and sports (HR: 0.74, 95% CI: 0.64–0.87)
(Table 3). Cycling for up to 3.5h/week was protective
(HR: 0.82, 0.69–0.97) compared with not cycling, but
cycling for 3.5h/week or more did not give additional
protection (P for trend¼0.06) (Figure 1). The dose-
response relationship was
sports than for cycling. Engaging in sports for up to
3.5h/week resulted in a 23% lower risk for CVD inci-
dence (HR: 0.77, 0.65–0.91) and in a 34% (HR: 0.66,
0.50–0.88) lower risk when more than 3.5h/week were
spent on sports, compared with not engaging in sports
(P for trend<0.001).
Engaging in both cycling and sports increased the
protective effect of these separate types of activities
on CVD incidence (Figure 2). The HR for engaging
in cycling, but not in sports, was 0.83 (0.70–0.97), for
sports, but no cycling, 0.73 (0.53–0.99), and for both
cycling and sports 0.64 (0.52–0.77).
In this relatively active population, cycling and sports
were both inversely associated with CVD incidence, but
walking and gardening were not. For sports, but not
for cycling, a dose—response relationship was observed
with CVD incidence. Furthermore, the results of our
study suggest that engaging in both cycling and sports
was strongly related to CVD incidence.
Our results showed that specific leisure time physi-
cal activities of higher intensity, such as cycling and
sports, were inversely associated with CVD incidence
in contrast to activities of lower intensity, such as
Table 2. Ten most frequent reported sports for men and women in the MORGEN Study
No. of men
Soccer, casual, general
Swimming183106 Swimming, leisurely, not lap
Jogging 120207 4015
Health club exercise, general
Badminton15030 4.5 Badminton, social singles
and doubles, general
Skiing, downhill, moderate
Swimming183106 Swimming, leisurely, not lap
Aerobic dancing, general
Fitness for strength20306 Calisthenics, home exercise,
light or moderate effort
Health club exercise, general
Skiing, downhill, moderate
Walking, 3.5mph, uphill
MET, metabolic equivalent; MORGEN, The Dutch Monitoring Project on Risk Factors for Chronic Diseases Study.aThis information was derived from
Ainsworth et al.14
44European Journal of Cardiovascular Prevention & Rehabilitation 18(1)
walking and gardening. Moderate-to-vigorous inten-
sity physical activity has been hypothesized to reduce
blood pressure, improve the blood lipid profile, endo-
thelial function, lower systemic inflammation, and
to have an antithrombotic effect and will thereby
lower the damage due to atherosclerosis of the car-
diac, cerebral,and peripheralblood vessels.20,21
Table 3. Hazard ratios (95% CI) of CVD incidence for walking, gardening, cycling and sports in participants aged 20–65 years at
baseline in the MORGEN Study, 1994–1997a
No. at risk No. of CVD casesPerson yearsModel 1b
7735397 739601.00– 1.00–
8707 526837120.90 (0.79–1.03) 0.94 (0.83–1.08)
3862 290365471.00– 1.00–
12580633 121125 0.74 (0.65–0.86) 0.82 (0.71–0.95)
CVD, cardiovascular disease; MET, metabolic equivalent; MORGEN, The Dutch Monitoring Project on Risk Factors for Chronic Diseases Study.
aParticipants were followed up to January 1st2006;bAdjusted for age (continuous) and sex;cAdditionally adjusted for other physical activities (both
occupational and leisure) than the one under study, current smoking (yes, no), alcohol consumption (never/former, moderate, or high) and educational
level (low, medium, or high);dSports ?4.0 METs.
P for trend <0.01
P for trend=0.06
P for trend<0.001P for trend<0.001
> 0 to 3.5 h/week
≥ 3.5 h/week
Figure 1. Dose–response relationship between sports, cyclic
and CVD incidence. Model 1 was adjusted for age (continuous)
and sex; model 2 was additionally adjusted for other physical
current smoking (yes, no), alcohol consumption (never/former,
moderate or high), and educational level (low, medium, or high).
No cycling, no sports
No cycling, sports
Cycling, no sports
Figure 2. Hazard ratios of cardiovascular disease incidence for
refernce category. Model 1 was adjusted for age (continuous) and
sex; model 2 was additionally adjusted for other physical activities
(both occupational and leisure) than the one under study, current
smoking (yes, no), alcohol consumption (never/former, moderate
or high) and educational level (low, medium, or high).
Hoevenaar-Blom et al. 45
As adjustments for blood pressure, HDL, and total
cholesterol in our investigation had no influence on
the associations of the activities with CVD incidence,
these factors cannot explain our results. We were not
able to assess the effects of systemic inflammation,
endothelial function, and the antithrombotic effect
on our results.
Several large prospective investigations and a recent
meta-analysis found inverse associations between walk-
ing and CVD,11–13but we did not find an association.
A possible explanation could be that in our investiga-
tion the validity of walking is lower than for the other
activities, which might have attenuated an existing
association. However, activities of lower intensity gen-
erally have lower reproducibility and validity than
activities of higher intensity.13Therefore, the lower
validity of walking cannot fully explain the lack of asso-
ciation in this study where others have found an asso-
ciation. The most likely explanation for not finding an
association is that almost everybody walked. Only 3%
of our population did not walk at all, and 21% walked
less than 3.5h/week or 30min/day. The mean walking
duration among those who reported any walking in this
study was 13.6?12.2h/week and the median 9.0 (inter-
quartile range: 4.0–20.0h/week). One of the reasons for
this high frequency and duration of walking could be
that walking was assessed in a broad sense, for exam-
ple, not only taking a walk but also walking for trans-
portation, shopping, and walking at work.4,5In a
population with a walking pattern comparable with
the current population, no association with CVD was
observed,6which suggests that walking lowers risk in
relatively inactive populations only.
Consistent with our finding, Andersen et al.22found
a 38% lower risk of all cause mortality for cycling on
average 3h/week compared with not cycling. We found
only two studies investigating the independent associa-
tion between cycling and CVD.5,6These investigations
did not find any associations, which might be because
of the limited number of participants cycling a substan-
tial amount of time. The protective association we
found for sports in relation to CVD is consistent with
This study had some limitations. First, physical
activity was recorded only at baseline. Second, as in
most other prospective studies, our results were based
on self-reported physical activity. Although our ques-
tionnaire was shown to be reproducible and valid,8
recall and social desirability bias may have occurred.
Especially for a low-intensity activity as walking recall
bias is possible. Both limitations could have resulted in
bias towards the null hypothesis. A major strength of
this study is the large study population of relatively
young (20–65 years) and active men and women from
The Netherlands. The Netherlands is a country with a
relatively high level of physical activity compared with
other countries.26–28Moreover, we were able to study
cycling in detail, as cycling is a frequently used means
of transportation in The Netherlands. Another strength
is the extensive physical activity questionnaire which
made it possible to address several individual leisure
time physical activities simultaneously. Only few stud-
ies have reported multiple separate types of activities in
relation to CVD. Furthermore, the comprehensive data
collection made it possible to adjust for several
We conclude that in this relatively active population,
types of activities of at least moderate intensity, such as
cycling and sports were associated with lower CVD
incidence, whereas activities of lower intensity, such
as walking and gardening, were not. Engaging in both
cycling and sports gave the greatest risk reduction, and
may therefore be a good way to prevent CVD.
The Monitoring Project on Risk Factors for Chronic Diseases
(MORGEN study) was financially supported by the Ministry
of Health, Welfare and Sport of The Netherlands and the
National Institute of Public Health and the Environment.
The authors would like to thank the epidemiologists and
field workersof theMunicipal
Amsterdam, Doetinchem, and Maastricht for their important
contribution to the data collection for this study. The project
steering committee consisted of Dr H.B. Bueno de Mesquita,
Professor H.A. Smit, Dr W.M.M. Verschuren and Professor
J.C. Seidell (Project Director). Data management was pro-
vided by A. Blokstra. No funding received, no information
from this paper has been published before, no conflicts of
interest to be declared.
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