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08: Collaborative research in the interface−The sixth survey of the Tromsø Study (Tromsø 6) in 2007

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© 2013 the Nordic Societies of Public HealthDOI: 10.1177/1403494812469851

Scandinavian Journal of Public Health, 2013; 41: 65–80

Background

Population-based studies are acknowledged as an excellent source of data for epidemiological research on risk factors and causes of common and serious diseases. Starting with the famous Framingham study in 1948, cardiovascular surveys have now been conducted worldwide. In Norway, large regional car-diovascular health surveys began in the early 1970s.

The Tromsø Study

The Tromsø Study is a population-based, pro-spective study of various health issues, symptoms,

and chronic diseases, and a resource for the sur-veillance of disease risk factors [1]. The study is run and owned by the University of Tromsø. It was initiated in 1974 as a combined population health survey and a research study of cardiovascu-lar diseases, and it has gradually expanded to include several chronic diseases. Six surveys have been carried out 6–7 years apart, referred to as Tromsø 1–6 (Table I). All surveys include ques-tionnaire data, sampling of biological specimens, and clinical measurements.

The sixth survey of the Tromsø Study (Tromsø 6) in 2007–08: Collaborative research in the interface between clinical medicine and epidemiology: Study objectives, design, data collection procedures, and attendance in a multipurpose population-based health survey

ANNE ELISE EGGEN1, ELLISIV B. MATHIESEN1,2, TOM WILSGAARD1, BJARNE K. JACOBSEN1 & INGER NJØLSTAD1

1University of Tromsø, Tromsø, Norway, and 2University Hospital of North Norway, Tromsø, Norway

AbstractAims: To provide a synopsis of the sixth survey of the Tromsø Study, Tromsø 6, objectives and new target areas, study design, follow-up studies, data collection, attendance, and participant characteristics. Methods: The Tromsø Study, initiated in 1974, is an epidemiological, prospective study of health conditions and chronic diseases, and a resource for the surveillance of disease risk factors. The purpose of Tromsø 6 (2007–08) was to collect novel and repeated measurements of exposure data and to assess levels of disease risk factors. Tromsø 6 included a main study that comprised two screening visits and several follow-up studies. Main study data collection: First visit (n=12,984): questionnaires, interviews, measurements of height, weight, hip and waist circumference, heart rate, blood pressure, forearm bone density, grip strength, pain sensitivity measurements, and blood and hair samples and nose and throat swab cultures. Second visit (n=7307): sampling of biological specimens (blood, urine, nose and throat swab cultures) and clinical examinations (12-lead electrocardiography, cognitive tests, visual acuity test, retinal photography, carotid ultrasound, spirometry, dual-energy X-ray absorptiometry, and echocardiography. Results: A total of 12,984 participants aged 30–87 years were examined. The attendance rate was 66%, lower than in previous Tromsø Study surveys. The attendance was lowest in the youngest and oldest, those invited for the first time, and lower in men than women. Conclusions: The completion of the survey with this comprehensive data collection went satisfactorily. The decreasing attendance rate calls for new recruitment strategies and optimisation of the study organisation to facilitate attendance.

Key Words: Attendance, biological specimen, cohort studies, data collection, epidemiological methods, health survey management, prospective study, questionnaires, risk factors, study design

Correspondence: Anne Elise Eggen, Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, N-9037, Norway. E-mail: [email protected]

(Accepted 8 November 2012)

469851SJP41110.1177/1403494812469851A E Eggen et al.The sixth survey of the Tromsø Study (Tromsø 6) in 2007–082013

STUDY DESIGN ARTICLE



66 A. E. Eggen et al.

The first surveys had the typical design for tradi-tional large-scale, cardiovascular epidemiological health surveys: questionnaire data and a study site visit with biological measurements limited to blood pressure, heart rate, height, weight, and serum lipid assessments. The design and the scope of the study have gradually changed over the years. From the fourth survey onwards, there has been a closer col-laboration between epidemiological and clinical research. Large subgroups including several thou-sand subjects were invited to a second screening visit with more extensive examinations. This collaborative perspective was brought one step further in Tromsø 6. The study forms the basis for several clinical fol-low-up studies of various designs (Table II). The infrastructure of Tromsø 6 can be visualised as an “umbrella” covering about 50 projects at the inter-face of epidemiology and clinical medicine. We aimed to organise a joint collection of data to be used by several research groups.

Study objectives and new target areas

The purpose of the sixth survey was to collect new and repeated exposure data from previous and new participants in the Tromsø Study and to assess the levels of disease risk factors in the popu-lation for healthcare planning and preventive health projects.

New research topics in Tromsø 6 were assessment of pain sensitivity, retinal imaging, environmental pol-lutant exposure, and Staphylococcus aureus carrier state. Chronic pain is a major health problem in Western societies [2], and pain sensitivity may be of importance for the development of chronic pain [3]. Previous stud-ies of pain sensitivity have mainly been limited to small, non-representative samples, and Tromsø 6 represents a population-based effort to determine the role of pain sensitivity in chronic pain problems.

Diabetic retinopathy and age-related macular degeneration are the most important causes of impaired vision in developed countries. Retinal imag-ing was mainly designed to investigate the prevalence of, and risk factors for, diabetic retinopathy, age-related macular degeneration, and retinal microvas-cular calibers in the population, and to form the basis for further follow-up studies.

There is a great concern regarding persistent organic pollutants and toxic metals in the Arctic region as some compounds and trace elements are transported to the northern regions by wind and ocean currents and tend to accumulate and biomag-nify through the food chain [4]. Other and newer pol-lutants are present in modern textiles, cosmetics, and building materials. Environmental pollutants may be related to various hazardous health effects, and popu-lation-based studies are needed to establish more knowledge in this field. To our knowledge, no con-taminant studies have been performed in large, gen-eral and more urban populations in the High North.

The burden of disease from S. aureus is high and especially worrying due to widespread resistance to antibiotics. There is limited knowledge concerning the rate of infection in the general population. Tromsø 6 was designed to study infection rate of S. aureus, the characteristics of the host and S. aureus bacteria that lead to colonisation, and determination of methicillin-resistant S. aureus colonisation rates.

Some of the on-going research topics in the Tromsø Study were continued in Tromsø 6:

Cardiovascular diseases: Studies of established and novel cardiovascular risk factors and how they change over time: in particular, studies of coronary heart dis-ease, stroke subtypes, cardiac arrhythmias, and venous thromboembolism [5].

Atherosclerosis: Studies of the development and progression of ultrasound-assessed carotid atheroscle-rosis (plaque, stenosis, and intima–media thickness),

Table I. The examination year, age, and sex, number of attending subjects (n), and attendance (%) in the six surveys from 1974 to 2008: the Tromsø Study.

Survey Examination years

Age (years) n Sex Attendance (%)

Tromsø 1 1974 20–49 6595 Men 74.4a

Tromsø 2 1979–80 20–54b 16,621 Men/women 77.5a

Tromsø 3 1986–87 12–67c 21,826 Men/women 75.2a

Tromsø 4 1994–95 25–97 27,158 Men/women 72.3a

Tromsø 5 2001–02 30–89 8130 Men/women 78.5a

Tromsø 6 2007–08 30–87 12,984 Men/women 65.7d

aThe source of the invitation file to Tromsø 1–5 was the population registry of Norway, 6 months before the surveys began. The rate of participation is not adjusted for subjects who had died or emigrated out of the municipality.b20–49 in women.cAll men aged 20–61 and women aged 20–56 were invited to participate, plus a sample of teenagers (12–19) and older women.dThe Tromsø 6 invitation file was updated monthly for deaths and emigration from Tromsø during the study period.



The sixth survey of the Tromsø Study (Tromsø 6) in 2007–08 67

predictors of atherosclerosis (cardiovascular risk factors, novel biomarkers, gene variants), and the rela-tionship between atherosclerosis and cardiovascular diseases, cognitive impairment, microvascular changes, and mortality [6].

Diabetes: Studies of the prevalence of known and unknown diabetes and predictors of the disease by

measuring non-fasting glucose, glycated haemoglo-bin (HbA1c), the Finnish Diabetes risk score ques-tions [7], and relevant diabetes gene markers (polymorphisms) and by using variables (e.g., HbA1c, glucose, lipids, height, weight, waist and hip circumference, and blood pressure) from previous surveys [8].

Table II. Planned follow-up studies: the Tromsø Study: Tromsø 6.

Sub-studies Tromsø 6 Type of study

High dosage vitamin D in the treatment of osteoporosis in postmenopausal women

RCT

Prevention of type 2 diabetes with high dosage vitamin D among subjects with reduced glucose tolerance

RCT

Vitamin D and its influence on cardiovascular disease Case–control Cross-sectionalDiagnosis of type 2 diabetes based on HbA1c measurements Follow-up examination Case finding Cross-sectionalVitamin D and its influence on intraocular pressure Follow-up examination Case–controlPopulation-based study of renal function and chronic kidney disease: role of glomerular filtration rates as a risk factor for kidney disease and cardiovascular disease

Follow-up examination

Longitudinal cohortPrevalence and factors predicting elevated creatine kinase in a population


Case–controlPre-eclampsia as a predictor of cardiovascular disease later in life


Case–controlThe importance of insulin and leptin resistance on the development of metabolic syndrome and cardiovascular disease


Case–controlChronic post-operative pain: prevalence, risk factors and pain mechanisms. Tromsø Pain Study


Studies of predictors for dementia development: Tromsø Dementia Study


Case–controlThe Activity Study: the association between objectively measured physical fitness and self-reported physical activity, and associations with metabolic profile and chronic disease


ValidationType D personality, affective symptoms, and indicators of cardiovascular diseases

Questionnaire

Case–controlScreening for coeliac disease ScreeningChronotype, circadian rhythm control and health risks in sub-Arctic inhabitants

Questionnaire

Case–controlSleep disturbances in an Arctic population Follow-up questionnaire Case–controlUse of complementary and alternative/traditional medicine and perceived effects of the treatment: prevalence and development in use

Questionnaire

Longitudinal cohortDecisions about why and how to quit smoking Qualitative interview

study




Cognitive function: The prevalence of dementia and cognitive decline as assessed by mini-mental state examination and other instruments, studies of the risk factors for cognitive decline in a general pop-ulation, and associations between baseline measure-ments of atherosclerosis and types of plaques and future cognitive function. Furthermore, to study the associations between cognitive function and cardio-vascular risk factors measured seven to 20 years pre-viously [9].

Lung function: Studies of chronic obstructive pul-monary disease prevalence, changes and predictors of changes in lung function over time, as well as the rela-tionship between lung function, the use of medicines, recent respiratory infections, serum levels of C-reactive protein (CRP), and oxygen saturation [10].

Bone density: To study bone density, osteoporosis, and fractures in terms of prevalence, risk factors, and secular trends [11].

Cancer: Risk factors for the incidence of site-specific cancers and studies of metabolic profiles and physical activity in relation to breast cancer risk and prognosis [12].

Use of medicines: Studies of how medicine use is associated with, and has effects on, risk factors and disease [13].

The aim of this paper is to provide a synopsis of Tromsø 6, with a description of the study objectives, new target areas, study design, follow-up studies, data collection, attendance, and characteristics of the participants.

Methods

Population

The Tromsø Study cohort consists of people living in the municipality of Tromsø, Norway, situated at 69° N. Among the current 70,000 inhabitants, about 60,000 people live in the city like town-centre, while the rest is scattered throughout the whole munici-pality (2558 square kilometres). Tromsø is a centre of education, research, administration and fishing related activities. The population is growing and is dominated by Caucasians of mainly Norwegian ori-gin, but also includes a Sami minority. Tromsø may be considered as representative of a Northern European, white, urban population.

Invitation

In the Tromsø 4 survey (1994–5), all Tromsø inhab-itants aged 55–74 years, and a 5–10% random sam-ple of those 25–54 and 75–85 years of age, were invited. A large sub group (n=7965) attended a sec-ond visit that included ultrasound examination of the

carotid arteries, echocardiography, and bone scan. Those participants still residing in Tromsø by September 2007 were invited to Tromsø 6, along with whole birth cohorts and random samples of other birth cohorts, as specified below. In principle, inviting total birth cohorts would be preferable. Due to economic constraints, a careful consideration of age groups and sample size within the age groups was made on a scientific basis and according to the Tromsø 6 research project protocols. All subgroups to be invited were predefined before study start. In addition, participants had to attend the first visit in order to be invited to the second visit.

First visit. All residents aged 40–42 and 60–87 (n=12,578), a 10% random sample of individuals aged 30–39 (n=1056), a 40% random sample of individuals aged 43–59 (n= 5787), and subjects who had attended the second visit of Tromsø 4, if not already included in the three groups above (n=341), were invited (Figure 1). All citizens in Norway have a unique national identity number which are included in a population registry at Statistics Norway. Prior to study start an invitation file was created (September 2007) using the population registry as source. The file was periodically updated throughout the study period with respect to mortality and emigration from Tromsø.

Second visit. The population eligible for the second visit included those who fulfilled one of the following criteria (Figure 1): (1) all subjects who were eligible for the first visit aged 50–62 and 75–84 years (n=7657); (2) 20% random sample of men and women who were eligible for the first visit and were aged 63–74 (n=942); and (3) subjects, if not already included in the two groups above, who had attended the second visit of Tromsø 4 (n=2885).

Attendance

Tromsø 6 was carried out from 1 October 2007 to 19 December 2008. All examinations took place between 09:00 and 18:00 hours. A personal invitation, an information folder, and a four-page questionnaire were posted to the participants about 2 weeks before the suggested appointments [14]. Although an appointment date was given, the participants were free to attend the survey whenever suitable within the opening hours of the survey. Non-respondents were given one reminder. The participants were expected to read the information folder at home and sign the informed consent form when they attended the study site. Those eligible for the second visit were given an appointment date and time.




The organisation of the data collection is illustrated in Figure 2. The first and second visits took place at the same study site. The participants attended the sec-ond visit about 4 weeks after the first visit (90% of the participants between 9 and 83 days apart).

First visit

Table III shows participation (%) in the first visit according to age and sex. A total of 19,762 subjects (30–87 years) were invited and 12,984 subjects were examined (65.7%). About 80% of the participants in

First visit

Born 1920-1947 aged 60-87

Born 1948-1964aged 43-59 40% sample

Born 1965-1967aged 40-42

12,984 subjects attended 1st visit, of those 7958 subjects were invited to the second visit Second visit

Born 1923-1932 aged 75-84

Born 1920-1922 aged 85-87a

Born 1945-1947aged 60-62



7307 (91.8%) attended of those invited to the second visit.

aRestricted to those who participated in the second visit Tromsø 4.


19,762 subjects invited, 11,484 subjects of those were eligible for the second visit

Born 1958-1969aged 38-49a

Figure 1. Flow chart of the eligible subjects at the first and second visit. The Tromsø Study: Tromsø 6Whole birth cohorts (white boxes) and samples (grey boxes).

Station 1Reception Informed consent Height/weight Hand out Questionnaire 2

Approx 5 min n=12,984

Station 3Pain sensitivity

Approx 15 min n=10,566

Station 4Biobank sampling: Blood, hair, nose&throat swabs Measurements:hip/waist, blood pressure, pulse InterviewQuestionnaire 1 check Approx 25 min n=see text and table VI and VII

First visit

Second visit

Station 1Reception Blood/urine Visual acuity 12-lead ECG n=see text and table VII Approx.10 min n=7307

Station 2Cognitive tests

Approx. 20 min

n=5795

Station 3Ultrasound of the right carotid artery

Approx.15 min

n=7084

Station 4Eye exams Retinal photo OTC Interview

Approx.5 min

n=6541

Station 2SXA Forearm bone density Grip strength

Approx 10 min n=3632

Station 5Lung function Spirometry O2-saturation Interview

Approx.5 min

n=6438

Station 6DXA Bone density hip, vertebra, body composition Approx.20 min

n=3854

Station 7Echo- cardiography

Approx.25 min

n=2285

Total: Approx. one hour

Total: Approx. two hours

sample sample

Figure 2. Flow chart for examination sites at the first and second visit; measurements, clinical examinations, interview. The Tromsø Study: Tromsø 6




Tromsø 6 had also attended Tromsø 4. The partici-pation rate was higher among women (68.4%) than men (62.9%), a consistent finding in all age groups under 70 years. In both men and women, the level of participation was highest among subjects aged 60–69 years: 73.5% and 80.0%, respectively. The lowest participation rates were observed among the oldest participants and youngest men.

The participation rate was higher among those who had taken part in previous surveys (73%) than among those who were invited for the first time (42%) (Table IV). The rates of participation among first-ever attendees were similar in all age groups, except for the oldest group.

Second visit

A total of 7307 attended the second visit (i.e. 91.8% of those who received an invitation during the first visit; Table V). The study site (first and second visit) closed on the same date. A few eligible to the second

visit who attended first visit later than 19 November 2009, did not receive an invitation to the second due to limited capacity. Attendance rate among those 11,484 predefined as being eligible for the second visit was 64%.

Participant characteristics

Table VI shows the participant characteristics accord-ing to sex and 10-year age groups. The educational level in our study was somewhat higher as compared to the general Norwegian population and to the Tromsø population [15]. More than 90% defined themselves as being of Norwegian origin. The large majority of the remaining 10% defined themselves as being of Sami or Finnish origin. The proportion of participants with college or university degrees strongly decreased with increasing age in both men and women. Body mass index, waist circumference, sys-tolic blood pressure, the proportion on blood pres-sure-lowering and lipid-lowering drugs, and the prevalence of self-reported diabetes increased with age in both men and women. The prevalence of smoking was higher among the middle-aged women compared to the young and old.

Data collection

The first questionnaire (Q1) was filled in at home and brought to the study site, where it was checked by a research technician for inconsistencies and incomplete data. The participants were then handed a second questionnaire (Q2) together with a pre-stamped and addressed envelope. Q2 could be filled in at home or at the site. The majority of the partici-pants filled in the questionnaire before they left the study site. All examinations, measurements, and laboratory work followed standardised procedures performed by trained health personnel. Missing data were mainly attributed to sick leave of the

Table III. Attendance according to age and sex. The Tromsø Study: first visit Tromsø 6.

Age (years) Invited (n) Attended (n) Participation (%)

Men Women Men Women Men Women

30–34 242 257 90 130 37.2 50.635–39 302 284 122 167 40.4 58.840–44 2036 2047 1075 1292 52.8 63.145–49 952 922 588 621 61.8 67.450–54 855 905 534 666 62.5 73.655–59 847 800 613 623 72.4 77.960–64 1634 1581 1165 1281 71.3 81.065–69 1068 1054 830 827 77.7 78.570–74 691 745 516 549 74.7 73.775–79 506 711 325 439 64.2 61.780–84 372 604 162 261 43.5 43.285–87 120 227 34 74 28.3 32.6Total 9625 10,137 6054 6930 62.9 68.4

Table IV. Attendance (%) among first-time invitees compared to those who had previously attended. The Tromsø Study: first visit Tromsø 6.

Age (years) Invited (n) Attendance (%)

First-time invitees Previously attended First-time invitees Previously attended

Men Women Men Women Men Women Men Women

30–39 455 428 89 113 35.2 49.8 58.4 74.340–49 1303 1033 1685 1936 38.9 49.9 68.6 72.250–59 307 253 1395 1452 35.2 47.4 74.5 80.560–69 259 188 2443 2447 34.0 47.3 78.1 82.570–79 54 111 1143 1345 24.1 47.8 72.4 69.580–87 41 67 451 764 22.0 17.9 41.5 42.3Total 2419 2080 7206 8057 36.6 48.2 71.7 73.6




personnel, technical problems, and time constraints among the participants.

Questionnaires and interviews

Q1 (four pages) is available for 12,970 subjects (99.9%) and covered topics such as various health issues, symptoms and diseases, use of medicines and healthcare services, disability, employment and soci-oeconomic status, lifestyle, and reproduction (women only). Q2 (28 pages) is available for 12,440 subjects (95.8%) and covered more detailed infor-mation on topics already covered in Q1 as well as other topics such as health-related quality of life (EQ-5D), social network and life contentment. An English translation of the questionnaires is available at the Tromsø Study homepage [14].

All participants were interviewed about the Finnish Diabetes risk score questions [7], while women were asked about their menopausal status and current and former hormone therapy for the treatment of menopausal problems and birth control.

Measurements

Height (cm) and weight (kg) (n=12,964) were meas-ured to the first decimal in participants who wore light clothing and no footwear on an automatic elec-tronic scale, the Jenix DS 102 stadiometer (Dong Sahn Jenix, Seoul, Korea). Hip (n=12,521) and waist (n=12,513) circumference were measured without outerwear by using a measuring tape. Hip circumfer-ence was measured around the widest part of the thigh while waist circumference was measured across the belly button.

Heart rate (n=12,822) and systolic and diastolic blood pressure (n=12,908) were measured using an automated device, the Dinamap Pro care 300 Monitor (GE Healthcare, Norway). The cuff was

chosen after the circumference of the upper arm was measured. Three readings on the upper right arm were taken in a sitting position, separated by a 1-min interval and after a 2-min rest. The average of the last two measurements was used in most analyses.

Biological specimens

Blood samples. The participants were not required to fast, but they were only allowed to drink water and black coffee during their visits. Blood samples were collected both during the first (n=12,882) and second visit (n=7232), 50 and 20 ml, respectively. Time since last meal was recorded. Venipuncture was performed with subjects in a sitting position. A light tourniquet was used and released before sampling. The blood analyses performed are shown in Table VII. After 30 minutes at room temperature, the coagulated samples were centrifuged at 2000 g for 10 minutes, and the sera were transferred within 1 hour to plastic tubes, and kept between 1°C and 10°C. The blood samples were sent twice daily to the Department of Labora-tory Medicine, University Hospital North Norway, Tromsø, which is an accredited laboratory (ISO-standard 17025).

Serum total cholesterol and triglycerides were ana-lysed within 10 hours by an enzymic colorimetric method and high-density lipoprotein cholesterol was analysed by a homogeneous enzymic colorimetric method. CRP was analysed by a highly sensitive CRP method (particle-enhanced immunoturbidimetric assay). The three analyses were performed on a Modal PPE auto-analyser with reagents from Roche Diagnostics Norway AS. Determinations of HbA1c were performed the next day on blood samples col-lected in EDTA anticoagulation vessels, determined by high-performance liquid chromatography (HPLC) using an automated analyser (Variant II, Bio-Rad Laboratories, Hercules, CA, USA). Serum insulin was measured in defrosted non-fasting samples from

Table V. Number of eligible subjects and subjects invited to attend the second visit (invited when they attended the first visit) and atten-dance among the invitees according to age and sex: the Tromsø Study: second visit Tromsø 6.

Age (years) Men Women

Eligible (n) Invited (n) Attended (n) Attendance (%) Eligible (n) Invited (n) Attended (n) Attendance (%)

38–39 10 6 4 66.7 22 17 17 100.040–49 88 67 62 92.5 190 148 143 96.650–59 1702 1057 985 93.2 1705 1221 1147 93.960–69 1743 1300 1226 94.3 2317 1907 1790 93.970–79 1090 786 708 90.1 1350 928 828 89.280–87 471 191 156 81.7 796 330 241 73.0Total 5104 3407 3141 92.2 6380 4551 4166 91.5

Eligible subjects included subjects who did not receive an invitation to the second visit (n=238) due to a fully booked appointment list (attended later first visit later than 19.11.2008).




Table VII. Blood analyses performed: the Tromsø Study: first and/or second visit Tromsø 6.

Measurements and analyses n

Total cholesterol 12,830HDL-cholesterol 12,827Triglycerides 12,830hsCRPa 12,829Non-fasting glucosea 12,830HbA1c 12,771Haemoglobin 12,759White blood cells 12,755Thrombocytes 12,698Calcium 12,830Creatinine 12,830Cystatin C 12,829Creatine kinase 12,828Vitamin D 12,817Gamma-glutamyltransferaseb 5426ASATb 5426ALATb 5426Fibrinogen 12,774Phosphate 12,829TSHc 7212Uric acidc 7211Insulinc 7210Proinsulinc 7205

aBoth first and second visit: second visit n=7211.bThe first 5426 participants.cSecond visit only.ALAT, alanine aminotransferase; ASAT, aspartate aminotransfer-ase; hsCRP, high-sensitivity C-reactive protein; HDL, high-density lipoprotein; TSH, thyroid-stimulating hormone.

Tab

le V

I.

Des

crip

tive

cha

ract

eris

tics

of

the

part

icip

ants

by

age

and

sex

(n=

12,9

84).

The

Tro

msø

Stu

dy: T

rom

sø 6

.

Var

iabl

eM

enW

omen

30

–39

year

s (n

=21

2)40

–49

year

s (n

=16

63)

50–5

9 ye

ars

(n=

1147

)60

–69

year

s (n

=19

95)

70–8

7 ye

ars

(n=

1037

)30

–39

year

s (n

=29

7)40

–49

year

s (n

=19

13)

50–5

9 ye

ars

(n=

1289

)60

–69

year

s (n

=21

08)

70–8

7 ye

ars

(n=

1323

)

Bod

y m

ass

inde

x (k

g/m

2 )27

.6±

4.0

27.1

±3.

827

.5±

3.8

27.6

±3.

726

.6±

3.6

25.5

±4.

726

.1±

4.8

26.1

±4.

427

.2±

4.7

27.1

±4.

6W

aist

cir

cum

fere

nce

(cm

)97

.4±

10.4

97.5

±10

.599

.3±

10.6

100.

9±10

.210

0.5±

10.7

87.6

±12

.489

.1±

12.3

89.8

±11

.892

.6±

11.9

92.7

±12

.0S

ysto

lic b

lood

pre

ssur

e (m

mH

g)12

7.7±

12.9

128.

3±15

.413

5.0±

19.0

142.

1±20

.214

8.2±

22.5

112.

6±12

.811

7.5±

16.2

128.

0±20

.014

1.3±

22.3

154.

3±25

.4D

iast

olic

blo

od p

ress

ure

(mm

Hg)

76.4

±9.

179

.5±

9.9

82.5

±10

.082

.2±

10.1

79.2

±10

.469

.8±

8.8

72.6

±9.

775

.1±

9.8

76.0

±10

.076

.2±

11.1

Tot

al c

hole

ster

ol (

mm

ol/l)

5.2±

1.0

5.6±

1.0

5.7±

1.0

5.5±

1.1

5.3±

1.1

4.8±

0.9

5.2±

1.0

5.9±

1.0

6.0±

1.1

6.0±

1.1

HD

L c

hole

ster

ol (

mm

ol/l)

1.2±

0.3

1.3±

0.3

1.3±

0.4

1.4±

0.4

1.4±

0.4

1.5±

0.4

1.5±

0.4

1.7±

0.4

1.7±

0.5

1.7±

0.5

Tri

glyc

erid

es (

mm

ol/l)

1.9±

1.1

1.9±

1.2

1.7±

1.0

1.6±

0.9

1.4±

0.8

1.2±

0.8

1.3±

1.2

1.4±

0.8

1.5±

0.8

1.5±

0.7

Cur

rent

use

of

bloo

d pr

essu

re-

low

erin

g dr

ugs

3.8

(8)

6.3

(104

)18

.3 (

208)

31.0

(60

5)41

.3 (

412)

3.1

(9)

5.2

(99)

15.1

(19

3)30

.9 (

645)

47.6

(60

9)

Cur

rent

use

of

lipid

-low

erin

g dr

ugs

0.9

(2)

3.9

(65)

12.3

(14

0)24

.1 (

472)

33.2

(32

8)0.

0 (0

)1.

5 (2

8)9.

1 (1

16)

17.9

(37

2)27

.5 (

344)

Sel

f-re

port

ed d

iabe

tes

1.0

(2)

2.4

(39)

4.9

(55)

7.7

(151

)8.

1 (8

1)2.

4 (7

)2.

1 (4

0)3.

5 (4

4)5.

3 (1

09)

8.3

(106

)C

urre

nt s

mok

ers

20.1

(42

)21

.9 (

363)

21.7

(24

7)17

.8 (

351)

15.2

(15

3)19

.9 (

58)

25.7

(48

6)26

.3 (

336)

19.7

(40

7)13

.2 (

168)

Col

lege

/uni

vers

ity

educ

atio

n60

.0 (

127)

46.5

(77

1)42

.6 (

484)

37.6

(74

1)23

.9 (

239)

64.5

(18

9)55

.1 (

1047

)41

.3 (

528)

26.8

(55

8)12

.2 (

154)

Val

ues

are

mea

n±st

anda

rd d

evia

tion

or

% (

n). N

umbe

rs v

ary

betw

een

12,7

05 a

nd 1

2,96

4 du

e to

mis

sing

val

ues.

HD

L, h

igh-

dens

ity

lipop

rote

in.

second-visit attendees by an ELISA method (DRG Instruments, Marburg, Germany). The insulin assay showed no cross-reactivity with proinsulin, and the intra- and inter-assay variabilities were 1.79 and 2.88%, respectively. Intact proinsulin was measured in serum samples by a commercial ELISA kit (DRG Instruments, Marburg, Germany), using anti-proinsulin monoclonal antibodies, with no cross-reactivity with insulin, C-peptide, or 32-33 split proinsulin. Frozen blood samples (–70°C) have been stored for later analyses and DNA extraction (plasma, serum, and buffy coat).

Urine samples. Urine samples of morning spot urine from three consecutive days were collected from 7218 subjects who attended the second visit. The urine samples were sent to the metabolic research laboratory twice daily and were analysed within 20 hours. The presence of protein, glucose, blood, nitrite, and leucocytes was assessed by a dipstick in each of the three samples. Renal albumin excretion was assessed as albumin/creatinine ratio, calculated by dividing the mean of three urine albumin concen-trations (in mg) by mean creatinine concentrations




(in mmol). Urine creatinine was measured using col-orimetric methods (Jaffes reaction), and an autoanal-yser (ABX PENTRA, Horiba ABX, Montpellier, France). The urine albumin concentration was mea-sured by an immunoturbidimetric method on an autoanalyser. Urine orosomucoid was measured by a highly sensitive EU-labelled fluorometric immunoas-say (DELFIA) in the Department of Quality and Research, Regional Hospital of Randers, University of Aarhus, Denmark. Tween 20 was added to the urine samples, which were stored at –20°C; they were thawed at 37°C before analysis, which was based on a self-developed application in the AutoDELFIA system.

Hair samples. A collection of hair strands (n=8617) were cut with a pair of scissors from an area close to the scalp in the neck region or at the back of the head. The hair sample was attached to a piece of cardboard by a stapler and placed into a plastic bag. The participants were asked whether they had put permanent or colour products in their hair.

Nose and throat swabs. For the detection of S. aureus colonisation, both anterior nares and palatine tonsils were sampled with NaCl-moistened sterile rayon-tipped swabs that were placed in Amies charcoal transport medium (Copan, Brescia, Italy). All speci-mens were transported to the Department of Micro-biology and Infection Control, University Hospital of North Norway, on the day of collection and cultured within 3 days. From October 2007 to July 2008, nasal and throat swab cultures were collected from all attendees aged 30–49 years and from random samples of older attendees. Among the 4026 partici-pants who underwent this first set of swab cultures, 2986 participants underwent a repeated set as a part of the second visit. The participants were interviewed about the use of antibiotics and exposure to sun and/or solarium, current symptoms of respiratory tract infection, work in the healthcare services, recent hos-pital stays, and undergone tonsillectomy.

Clinical examinations

First visit. For pain sensitivity testing, cold pressor test was performed in 10,566 participants (81.4%), they also underwent testing of either the heat-pain threshold (n=4094) or the pressure-pain threshold (n=4807).

For the cold pressor test, the participants sub-merged their dominant hand and wrist in cold water as long as they were able to, up to maximum 106 s. A circulating water bath (Julabo PF40-HE, JULABO Labortechnik GmbH, Germany) at 3°C,

connected to an external plexi-glass container, was used in the test. Time to withdrawal of the hand from the cold water was recorded. Pain intensity was recorded 4 seconds after start of the test and every 9 seconds thereafter on an 11-point numeric rating scale (NRS), with 0 = “no pain” and 10 = “the most intense pain imaginable” as the anchors. Before, during and after the cold pressor test the participants were continuously monitored with a non-invasive beat-to-beat blood pressure monitor (Finometer, Finapres Medical System, Amsterdam, Netherlands).

For the pressure-pain threshold test, a hand-held pressure algometer (Somedic, Sweden) was applied to the cuticle of the ring finger of the participant’s non-dominant hand. Pressure was increased by 30 kPa/second until the participant reported feeling pain corresponding to 5 on a 0–10 numerical rating scale or until the safety limit of 800 kPa was reached.

For the heat-pain threshold test, heat stimuli were applied to the volar surface of the forearm using a 3×3 cm ATS somatosensory stimulator (MEDOC, Israel). Stimulation started from a baseline tempera-ture of 32.0°C and increased by 1°C/second until the subjects reported that the sensation had changed from warmth to pain (threshold) or the safety limit of 50°C was reached. The thermode temperature then returned to baseline at a rate of 8°C/second. The heat- and pressure-pain threshold test was repeated three times.

Bone mineral density was measured on the distal and ultradistal forearm (radius and ulna from the 8-mm point and 24 mm proximally) in about 3600 participants who had been examined by the same procedure in Tromsø 4 and/or Tromsø 5, using a sin-gle energy X-ray absorptiometry device (DTX-100, Osteometer MediTech, Hawthorne, CA, USA).

Grip strength was measured on the non-dominant hand in the same participants (n=3632) and regis-tered using a Martin-type squeeze dynamometer (12-0295, Vigorimeter) as kPa, generated by the manual compression of an air-filled rubber bulb con-nected to a manometer.

Second visit

12-lead ECG. A standard 12-lead electrocardio-gram was taken in 6200 participants (84.9%) by a Cardiovit AT-104 PC electrocardiograph with a PC interface (Schiller, Baar, Switzerland).

Pulmonary function test (spirometry). Pulmonary function test was performed in 6438 participants (88.2%) with the use of a Sensor Medics Vmax Encore 20 (VIASYS), following the European Res-piratory Society/American Thoracic Society standard-




ised criteria. A reversibility test was not performed. The FEV1% predicted and FVC% predicted were calculated based on the equation of Langhammer et al. [16]. Oxygen saturation was also measured using the NONIN Pulsoximeter, model Onyx II (n= 6477). A questionnaire concerning recent symptoms of respiratory tract infections such as the common cold, bronchitis, or other airway infections and ques-tions about drug use due to infections or asthma was completed by participants when they attended the spirometry test site.

Cognitive function. Cognitive function was assessed by four standardised tests, and 5795 par-ticipants (79.3%) were tested with at least one test and 3929 participants (53.8%) with all tests. The twelve-word memory test is a modification of the Californian verbal learning test and gives a measure of verbal episodic memory. The digit-symbol cod-ing test, a subtest of the Wechsler Adult Intelligence test, examined psychomotor speed, attention, and mental flexibility. The finger tapping test is mainly a test for psychomotor tempo. The mini-mental state examination (version MMSE-2:SV) is a 30-point questionnaire for testing various functions, including arithmetic, memory, and orientation.

Eye examinations. Visual acuity was measured in 6826 participants (93.5%) using a Nidek AR 660A autorefractor. Retinal photographs were taken in 6541 participants. The photos were taken in mydria-sis 10–30 minutes after the application of tropika-mid. The procedure included six images of both eyes using a Visucam PRONM digital fundus camera (Carl Zeiss Meditec, Germany). Optical coherence tomography was performed using a Cirrus HD OCT (Carl Zeiss Meditec). The participants were inter-viewed about eye diseases and the use of vision aids. About 200 participants refused to have eye photo-graphs taken.

Ultrasound examination of the carotid artery. Ultra-sound examination of the carotid artery was per-formed in 7084 participants (97%) and comprised measuring the intima–media thickness in the near and far walls of the distal common carotid artery and in the far wall of the carotid bifurcation, plaque measurements (number, thickness, area, and echo-genicity) taken in the near and far walls of the dis-tal common carotid, bifurcation, and the proximal internal carotid artery. Two GE Health Care Vivid 7 duplex scanners with M12L transducers (5.6–14 MHz linear transducer) were used. The examina-tions were performed by trained sonographers.

Bone mineral densitometry. Bone mineral densi-tometry was measured by dual-energy X-ray absorp-tiometry in participants who also underwent bone mineral densitometry in Tromsø 4 and/or 5. A total

of 4251 participants were invited for a bone scan, and 3854 participants were examined. Valid dual hip scans were performed in 3727 participants, and bone mineral densitometry of the vertebra was meas-ured in 2887 participants. Whole-body scans were performed in about 1000 participants. All scans were performed using Lunar Prodigy DXA densitometry (GE Medical systems, Madison, WI, USA).

Transthoracic echocardiography. Transthoracic echocardiography was performed in participants who had undergone echocardiography in Tromsø 4 and/or Tromsø 5. Doppler tracings and adequate M-mode recordings for measuring aortic, mitral and lung vein flows for calculations of left ventricular dimensions and function and tissue Doppler recordings at the AV plane level were performed. Of 2361 invited partici-pants, 2285 were examined with an Acuson Seqouia C 512 echocardiography system. It had a second harmonic 3.5-MHz probe with an incorporated 2.5-MHz Doppler probe (Siemens, Germany), and frame rate of 70 frames/second (acoustic clip) following the American Society of Echocardiography Guidelines with additions for Doppler measurements of aortic, mitral and lung vein flows, and tissue velocities.

Inter- and intra-observer studies

Reproducibility was evaluated for echocardiography, ultrasound examination of the carotid artery, and bone mineral density measurements (dual-energy X-ray absorptiometry). Seventy-two participants who attended the second visit were recruited during a 2-week period. They were re-examined twice the following week by the same technician who exam-ined them during the first examination, and by another technician who was working at the same examination site.

For pain sensitivity measurements, a convenience sample of 272 subjects was examined a second time, 1–2 months after the initial examination. In this sec-ond examination, the cold pressor test and heat-pain threshold test were repeated using the same proce-dure and equipment as in the main study. The tests were repeated a second time after a 15-min break.

The nasal and throat swab culture methods were evaluated, on the basis of the results from the 108 participants who were invited when they attended the second visit. In order to address the inter-observer agreement, an extra set of cultures was taken by a second technician about 60 minutes later. In order to test whether or not the time interval between cultures affected the carrier state, the participants came for a third visit 7 days later for repeated nasal and throat swab cultures. The agreement between the gold standard, the 1-week interval, and the flexible




interval method for assessment of the S. aureus nasal and throat carrier status was examined.

Technical staff

Research technicians were hired to carry out the data collection, including registered nurses and other health professionals such as medical secretaries, practical nurses, pharmacy technicians, bioengineers, physiotherapists, sonographers, and echocardiogra-phy technicians. They went through a 3–4-week training period prior to the start of the study.

Adverse events

Adverse events during the examinations were rarely reported and mainly consisted of minor symptoms, such as transient discomfort or dizziness. The most serious episodes were fainting (n=16). Of the 81 transient adverse events reported following the cold pressor test, eight were due to fainting. Although only a few adverse events were reported, these events underline the importance of a trained staff, necessary equipment, and strict emergency routines.

Feedback to participants and referrals for pathological findings

Before attendance the participants were informed of their right to opt out of receiving information on their own screening results, and, regardless of their deci-sion, that the Tromsø Study for ethical reasons reserved the right to inform all participants of serious pathological findings. One participant rejected to be informed of own screening results. All others received an information letter some 14 days after attendance, containing screening values of blood pressure, height, weight, and serum high-density lipoprotein and total cholesterol. Those with values exceeding predefined cut-off limits for blood pressure (9.0 %) and total cholesterol (2.0%) were recommended to contact their own primary physician for a check-up.

A total of 20 participants were referred directly to the university hospital outpatient clinic because blood pressure, serum glucose, or haemoglobin val-ues indicated need for emergent action.

When test results indicated a non-emergent clini-cal disease (e.g. deviant glucose, blood cells counts, liver enzymes), predefined cut-off criteria were used to identify those who were to receive individual infor-mation letter and a referral to primary or specialist health care. Ninety-one participants were diagnosed with type 2 diabetes at the hospital outpatient clinic, having been referred because of high serum glucose and/or HbA1c. There was no routine information to

participants of tests performed for research reasons only and of unknown clinical importance.

Pathological findings during ultrasound examina-tions, echocardiography, bone scan, spirometry, and fundus photography were followed up at the relevant hospital outpatient clinic. Criteria and time frames for referral were defined in advance by the research-ers in charge of the examination, who in most cases also were hospital employed clinical specialists. The clinical examinations alone led to almost 800 refer-rals. Structural heart disease, osteoporosis, and carotid stenosis were the most common reasons for referral.

Table VIII shows the outcome of the feedback sys-tem for deviant test results, predefined cut-off values, and type of response given just after or during the first visit, and Table IX shows the pathological find-ings during the second visit to Tromsø 6. All tables are now included in the main manuscript.

Follow-up studies

Recruitment to the several follow-up studies was based on participation in the main study of Tromsø 6 (Table II). They had different objectives and designs, from case–control studies to randomised controlled clinical intervention trials, as well as observational studies and qualitative in-depth interviews in selected groups. Accordingly, some studies implied interventions, new clinical exami-nations and/or measurements, while others were limited to new questionnaires sent by mail. The participants’ eligibility for the follow-up studies was based on the results of analyses of biological specimens, questionnaire responses, clinical exami-nations, or on age and sex.

Ethics and data protection

Tromsø 6 was approved by the Data Inspectorate of Norway and the Regional Committee of Medical and Health Research Ethics, North Norway. The study complies with the Declaration of Helsinki, International Ethical Guidelines for Biomedical Research Involving Human Subjects and the International Guidelines for Ethical Review of Epidemiological Studies. Participation was voluntary and each subject gave written informed consent prior to participation.

The information folder [14] informed the partici-pants about study objectives, type of information col-lected from each individual, and how the data and biological materials were planned to be used in future research projects. The participants were given a description of all examinations and measurements




Tab

le V

III.

M

easu

rem

ents

and

ana

lyse

s pe

rfor

med

att

enda

nce

day,

and

out

com

e of

the

fee

dbac

k sy

stem

for

dev

iant

tes

t re

sult

s, t

he p

rede

fined

cut

-off

valu

es,

and

type

of

resp

onse

giv

en

duri

ng o

r af

ter

atte

ndan

ce: t

he T

rom

sø S

tudy

: fir

st v

isit

Tro

msø

6.

Mea

sure

men

ts a

nd a

naly

ses

nE

mer

gent

act

ion:

cut

-off

valu

esn

Let

ter

wit

hin

2–3

wee

ks: c

ut-o

ff va

lues

Rec

omm

enda

tion

and

invi

tati

on t

exts

n (%

)

Sys

tolic

blo

od p

ress

urea

12,9

08N

one

<80

yea

rs: S

BP

145

.8+

0.68

*age

All

SB

P ≥

170

mm

Hg

≥80

year

s: N

one

“The

res

ult

may

indi

cate

hig

h sy

stol

ic

bloo

d pr

essu

re. I

f yo

u do

not

see

yo

ur G

P r

egul

arly

for

blo

od p

ress

ure

cont

rol,

plea

se c

onta

ct y

our

GP

.”

856

(6.6

)

Dia

stol

ic b

lood

pre

ssur

ea12

,908

≥120

mm

Hg

in m

easu

rem

ent

2 an

d 3

9<

80 y

ears

: DB

P 9

4.2+

0.32

*age

All

DB

P ≥

100

mm

Hg

≥80

year

s: N

one

“The

res

ult

may

ind

icat

e hi

gh

dia

stol

ic b

lood

pre

ssu

re.

The

res

t of

the

tex

t m

essa

ge a

s ab

ove.

” If

yo

u d

o n

ot s

ee y

our

GP

reg

ula

rly

for

bloo

d p

ress

ure

con

trol

, pl

ease

co

nta

ct y

our

GP

.

316

(2.4

)

Tot

al c

hole

ster

ola

12,8

30N

one

<80

yea

rs: W

omen

≥6.

78–8

mm

ol/l:

M

en ≥

6.26

–8.0

0 m

mol

/lA

ll ≥8

.00

mm

ol/l

≥80

year

s: N

one

“The

res

ult

may

indi

cate

dis

turb

ance

s in

lipi

d m

etab

olis

m g

ivin

g yo

u hi

gh

chol

este

rol.

If y

ou d

o no

t se

e yo

ur

GP

reg

ular

ly f

or t

his

prob

lem

, ple

ase

cont

act

your

GP

wit

hin

six

mon

ths.

”

290

(2.3

)

Non

-fas

ting

glu

cose

b12

,830

>20

mm

ol/l

no d

iabe

tes

6>

11.0

mm

ol/l

wit

h no

dia

bete

sIn

vite

d to

end

ocri

nolo

gist

102

(0.8

)

>25

mm

ol/l

know

n di

abet

es

HbA

1C12

,771

Non

e7.

0 %

wit

h no

dia

bete

sIn

vite

d to

end

ocri

nolo

gist

C

alci

um12

,830

>3,

1 m

mol

/l0

<1.

90 m

mol

/l: >

2.70

mm

ol/l

Invi

ted

to e

ndoc

rino

logi

st23

(0.

17)

Cre

atin

ine

12,8

30>

400

µmol

/l≥7

5 ye

ars:

Wom

en >

135

µmol

/l, M

en

>17

5 µm

ol/l

Rec

omm

ende

d to

vis

it o

wn

GP

for

ne

w t

est

and

cont

rol

201(

1.6)

≥6

3–75

yea

rs: W

omen

>90

µm

ol/l,

M

en >

100

µmol

/l

<

63 y

ears

: Wom

en >

90 µ

mol

/l, M

en

>10

0 µm

ol/l

A

ND

Cys

tati

n-C

>1.

01 m

g/l

H

aem

oglo

bine

12,7

59<

8 g/

dl6

Wom

en <

9.0

g/dl

, >17

.5 g

/dl

Invi

ted

to h

aem

atol

ogis

t11

(0.

09)

M

en <

10 g

/dl,

> 1

8.5

g/dl

W

hite

blo

od c

ells

12,7

55<

1 x

109/

l0

<2.

5×10

9 /l, ≥2

0×10

9 /l

Invi

ted

to h

aem

atol

ogis

t11

(0.

09)

Thr

ombo

cyte

s12

,698

<10

x 1

09/l

0<

80×

109 /

l, >

600×

109 /

lIn

vite

d to

hae

mat

olog

ist

15 (

0.07

)C

reat

ine

kina

se12

,828

≥ 50

00 U

/l3

Wom

en >

420

U/l,

Men

>50

0 U

/lIn

vite

d to

neu

rolo

gist

for

new

tes

t an

d co

ntro

l13

0 (1

.0)

Gam

ma-

glut

amyl

tran

sfer

asec

5426

Non

eW

omen

>15

0 U

/l, M

en >

200

U/l

Invi

ted

to g

astr

oent

erol

ogis

t fo

r ne

w

test

and

con

trol

91 (

1.7)

AS

AT

c54

26N

one

Wom

en >

70 U

/l, M

en >

90 U

/lIn

vite

d to

gas

troe

nter

olog

ist

for

new

te

st a

nd c

ontr

ol

AL

AT

c54

26N

one

Wom

en >

90 U

/l, M

en >

140

U/l

Invi

ted

to g

astr

oent

erol

ogis

t fo

r ne

w

test

and

con

trol

TS

Hd

7212

Non

e>

25 m

IU/l

7–25

mIU

/l, <

0.05

mIU

/lIn

vite

d to

end

ocri

nolo

gist

R

ecom

men

ded

to c

onta

ct o

wn

GP

for

ne

w t

est

and

cont

rol

361

(0.

8)



The sixth survey of the Tromsø Study (Tromsø 6) in 2007–08 77M

easu

rem

ents

and

ana

lyse

sn

Em

erge

nt a

ctio

n: c

ut-o

ff va

lues

nL

ette

r w

ithi

n 2–

3 w

eeks

: cut

-off

valu

esR

ecom

men

dati

on a

nd in

vita

tion

tex

tsn

(%)

Uri

c ac

idd

7211

Non

eW

omen

>60

0 µm

ol/l,

Men

>70

0 µm

ol/l

Rec

omm

ende

d to

con

tact

ow

n G

P f

or

new

tes

t an

d co

ntro

l5

HD

L-c

hole

ster

ola

12,8

27N

one

Non

eN

one

–T

rigl

ycer

ides

12,8

30N

one

Non

eN

one

–C

ysta

tin

C12

,829

Non

eN

one

Non

e–

hsC

RP

b12

,829

Non

eN

one

Non

e–

Vit

amin

D12

,817

Non

eN

one

Non

e–

Fib

rino

gen

12,7

74N

one

Non

eN

one

–P

hosp

hate

12,8

29N

one

Non

eN

one

–In

sulin

mIU

/ld72

10N

one

Non

eN

one

–P

roin

sulin

pm

ol/ld

7205

Non

eN

one

Non

e–

a Res

ult

repo

rted

in le

tter

to

all p

arti

cipa

nts

toge

ther

wit

h he

ight

and

wei

ght.

b Bot

h fir

st a

nd s

econ

d vi

sit.

c The

fir

st 5

426

part

icip

ants

.d S

econ

d vi

sit

only

.A

LA

T, a

lani

ne a

min

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and how they might be used for control and follow-up examinations. The participants consented to the linkage of data from Tromsø 6 to other official regis-ters and information from medical records pending approval from The Regional Committee of Medical and Health Research Ethics. Such registries include the Cancer Registry, the Medical Birth Registry, the Norwegian Prescription Drug Registry, the Causes of Death Registry, the Census Data of Norway, the Family Registry, and the locally organised Tromsø Study disease registries of cardiovascular diseases, fractures, and diabetes which are based on medical records from the University Hospital North Norway, Tromsø.

The Tromsø Study database (EUTRO) is an IT solution designed to protect and manage metadata, data and projects, and is an integral part of a com-plete data lifecycle system. All physical and logical security of the data is in accordance with, and in dia-logue with, the Data Inspectorate. The physical data storage and security is handled by the university’s central IT department. EUTRO is integrated within the NESSTAR WebView tool, which allows research-ers to view and, for approved projects, select their research variables in a web-based platform [17].

Discussion

The attendance rate of 66% in Tromsø 6 is some-what higher than in comparable recent health sur-veys. We observed a decline in attendance over the last 35 years, as found in other comparable health surveys in Norway [18–20] The decline is also well documented internationally [21,22].

Galea et al. [21] summarise some reasons for the increasing refusal to participate during the latest dec-ades. The potential participant may be invited to an increasing number of health-related and other research projects, which may in some cases be con-fused with marketing and unsolicited mail. Other reasons for non-participation comprise an increasing unwillingness to participate when there is no imme-diate benefit for the participant or particularly rele-vant of the participant’s life, a general decrease in volunteerism in society, a growing popular disillu-sionment with research due to contradictory mes-sages and conflicting results from health research and screenings, and an ever-increasing burden on participants due to more time-consuming compre-hensive studies and complex informed consent procedures.

The Tromsø Study has also become more demand-ing for the participants since its commencement in 1974. Due to increasing numbers of sub-projects and several new laws and regulations concerning health T

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research, the information leaflet has increased from one to eight pages. The questionnaires have become considerably larger. However, the 28-page Q2 was answered by 96% of the participants.

We have shown that the attendance rate was higher among those who had taken part in previous surveys than in those who were invited for the first time. This confirms the results from other cohort studies [18].

The attendance rate was lowest among the youngest and the oldest age groups. According to Langhammer et al. [18], the most important reason for non-participation in the 30-year-old subjects was lack of time or an inconvenient time for appoint-ment. This indicates less willingness to spend time and an assumed limited short time benefit for a healthy age group. However, the opening hours at the Tromsø Study site included early evening hours. Langhammer et al. found that the non-participation reason of feeling too ill to attend was of increasing importance with increasing age. Among the 80-year-olds, one-fifth gave this reason for non-participation. This calls for a new recruitment strategy among the oldest participants.

There is a need for more methodological studies on non-response [23]. The main concern is non-response bias, which may threaten the validity of epi-demiological studies. Previous studies have shown that the participants tend to be female, rural resi-dents, living with someone/married, employed, healthier, healthier life style, more educated, and to use strong analgesics and psychotropics less often than non-participants [18,20,24–27]. Our study confirms the somewhat higher education level among the attenders compared to the total Tromsø population. Langhammer et al. [18] reported that non- participants had lower socioeconomic status, higher mortality, and higher prevalence of several chronic diseases, whilst the opposite patterns were found for common problems like musculoskeletal pain, urine incontinence, and headache. Drivsholm et al. [28] found that although the participants were similar to

the background population when comparing them using information from publicly available registers, the 20-year mortality rate was higher in non-participants. Knudsen et al. [19] also concluded that non-partici-pants had poorer health, but that this was disorder dependent. In particular, people with mental disor-ders were overrepresented among the non-participants. The conclusions with regard to the non-response impact on the estimates differ between studies. Tolonen et al. [25] conclude that estimators of popu-lation trends are likely to be biased. Some studies found very modest effects [18,20], while others con-cluded that non-response leads to a bias in preva-lence estimates but does not cause bias in the examined associations [29,30].

The most valuable resource in epidemiological research is the study population’s willingness to participate. Our experience is that motivation for research participation varies and should be addressed and encouraged in different ways. In a future population study, one should consider criti-cally the research profile, the size and complexity of the study, and the relevance to the public. We need to focus on how to get the attention, particularly from those who are invited for the first time. A good relationship with local newspapers and the media is crucial. The localisation of the examination site should be critically considered, an easy access, flex-ible opening hours, short waiting time, and the gen-eral visibility to the public. The oldest eligible might be visited in their homes or nursing homes or bussed to the study site.

Many participants have shown a great interest in their own results. To give something of relevance back to the individual participants in return for their cooperation may be important. Providing informa-tion to the public about how the research data are used is obligatory, and to be more active in the pres-entation of relevant ongoing research to the public may increase the interest and motivation for attend-ance in health research projects.

Table IX. Referrals of participants due to pathological findings: the Tromsø Study: second visit Tromsø 6.

Examination site No eligible No examined Reasons for referral No referrals (n, %)

Lung 7307 6438 Reduced FEV1 (<50% predicted) and/or reduced O2-saturation (<92%)

53 (0.8)

Eye 7307 6826 Inspection of eye photo:treatable eye damage unknown to the participant

69 (1.0)

Carotid artery 7307 7084 50% stenosis or more 281 (4.0)Bone 4251 3727 t-score –2.5 or below 161 (4.3)Heart 2361 2285 Several factors indicating

heart damage203 (8.9)




Concluding remarks

Our paper shows that it is possible to efficiently conduct a quite large population survey and collect research information on behalf of several research groups. The participants were recruited in a con-trolled manner into new follow-up studies, some randomised controlled trials are still in progress, linkage studies are performed, and researchers still follow up groups of participants through new examinations and questionnaires. The inclusion of several follow-up studies into the design has led to a remarkably higher research activity than after pre-vious Tromsø Study surveys. More than 2500 vari-ables are available from the main study alone, most of them can be viewed through the NESSTAR [17], and about 40 PhD students are currently doing research based on the collected data. Tromsø 6 has also provided in-depth health information and estimates of risk factors that are important for monitoring the health of the general population and subgroups of the population.

Funding

Tromsø 6 was supported by the University of Tromsø and by the Northern Norway Regional Health Authority Medical Programme, the Norwegian Research Council, the Norwegian Foundation for Health and Rehabilitation, the Norwegian Diabetes Association, the Norwegian Council on Cardiovascular Disease, the Cancer Registry of Norway, the Odd Berg Group Research Fund. and Troms County Council.

Acknowledgements

We thank the members of the Tromsø 6 Working Group, which besides of the authors consisted of Hans-Henry Jacobsen, Kristin Kanstad, Bente Augdal, Frode Skjold, Tone Osnes, Merete Albertsen, and Nannan Yang. We are grateful for the valuable work of the technical staff of Tromsø 6. Above all, we thank the residents of Tromsø. Their willingness to participate is fundamental to our research.

Conflict of interest

The authors declare that they have no competing interests.

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