Int. J. Epidemiol. Advance Access published December 24, 2015 International Journal of Epidemiology, 2015, 1–9 doi: 10.1093/ije/dyv310 Cohort Profile

Cohort Profile

Timo E. Strandberg,1* Veikko Salomaa,2 Arto Y. Strandberg,1 Hannu Vanhanen,3 Seppo Sarna,4 Kaisu Pitka¨la¨,1 Kirsi Rantanen,1 Salla Savela,5 Tuula Pienima¨ki,5 Emmi Huohvanainen,5 Sari Stenholm,6 Katri Ra¨ikko¨nen,7 Reijo S. Tilvis,1 Pentti J. Tienari1 and Jussi Huttunen 8 1

University of Helsinki and Helsinki University Central Hospital, 2National Institute for Health and Welfare, Helsinki, 3Kela, Social Security Institution of Finland, 4University of Helsinki, Department of Public Health, 5University of Oulu, Centre for Life Course Health Research, 6University of Turku, Department of Public Health, 7University of Helsinki, Department of Psychology and 8Finnish Medical Association Duodecim, Helsinki, Finland *Corresponding author. University of Helsinki, Geriatrics, Haartmaninkatu 4, PO Box 340, FIN-00029 Helsinki, Finland. E-mail: [email protected] This paper is dedicated to the memories of Professor Tatu A Miettinen and Dr. Torger Kumlin. Accepted 23 October 2015

Why was the cohort set up? The Helsinki Businessmen Study (HBS) was originally a convenience cohort of executives and businessmen (n ¼ 3490) who participated in health check-ups during the 1960s,1–6 but since the beginning of the 1970s it has developed into a clinical-epidemiological, longitudinal study. Follow-up time of the cohort currently spans up to 50 years. Median age at first visit was 42 years (interquartile range 38 to 45, range 31 to 54 years). By 2015 the oldest participants have reached 96 years of age (range 81 to 96 years). Consequently, HBS is among the longest follow-up studies in the world. It may well be seen as a ‘life-course’ study, where midlife characteristics can be related to variables in very old age, and various long-term trajectories can be distinguished. At first, the main focus was on cardiovascular diseases (CVD) and their prevention,4 but during the 2000s, with ageing of the cohort, the emphasis has gradually shifted to geriatric medicine with a life-course dimension.7–15 An important focus of the study is to examine how midlife risk factors affect health-related quality of life (HRQoL),

well-being, cognitive function, frailty and disability in old age.16–32 HBS is located with the primary investigator at the University of Helsinki. It has had ad hoc funding from various foundations, and from the Finnish ‘EVO-Valtion tutkimusrahoitus’ (project funding from the Finnish state to medical research in hospitals).

Who is in the cohort? How often have they been followed up? A flow diagram of the design and development of HBS is shown in Figure 1. The study has been registered as ClinicalTrials.gov identifier: NCT02526082. Between 1964 and 1973, the Finnish Institute of Occupational Health in Helsinki, at that time managed by a private foundation, provided voluntary health check-up services and health examinations by physicians for the personnel of private companies. These ‘director or ‘manager’ examinations were primarily targeted at people (usually men) in executive positions [coronary heart disease (CHD)

C The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association V

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Cohort Profile: The Helsinki Businessmen Study (HBS)

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3490 men born between 1919 and 1934 participated in health check-ups Cumulative dead, n (%)

1886 sick, dead not willing to participate, not responded or no risk factors

68 (1.9)

1043 refused or not responded

563 clinical disease or medication

593 lowrisk control

1964-73 clinical and laboratory examinations

1604 willing to participate in prevention trial, clinically healthy but with high risk of CVD

Postal questionnaire, laboratory examinations in 1972-73; clinical and laboratory examinations in 1974-75; randomization of healthy men with high risk into intervention and control groups

610 high-risk control

Groups defined in 1974-75 (n = 3309 in current database, forming the baseline cohort for later examinations)

612 high-risk intervention

5-year multifactorial prevention trial in 1974-80 including 1815 men Not included

540

580

575

End of intervention, clinical and laboratory examinations in 1979-80

335 (9.6)

Not included

Not included

489

456

454

Postal questionnaire, laboratory examinations in 1986. Response rate 81.9%. Follow-up from national registries started (mortality, cause of death, drug reimbursement, hospital discharge)

577 (16.5)

No contact

No contact

No contact

No contact

No contact

Mortality of the groups defined in 1974 from national registers through 1992

1023 (29.3)

379

254

447

406

377

Postal questionnaire survey in 2000. Response rate 81.5%

1258 (36.0)

263

186

329

296

286

Postal questionnaire in 2002-03; clinical and laboratory examinations in a random subcohort of 651 men. Response rate 66.3%

1408 (40.3)

131

88

157

141

129

Postal questionnaire 2005 to a random subcohort in order to compare HRQoL questionnaires

1589 (45.5)

219

132

291

239

239

Postal questionnaire 2007. Response rate 65.1%

1971 (56.5)

186

98

243

198

182

Postal questionnaire in 2010-11; clinical and laboratory examinations in a random subcohort of 521 men. Response rate 67.8%

2177 (62.4)

..

..

..

..

..

Postal questionnaire in 2014, not yet analysed

2293 (65.7)

..

..

..

..

..

Postal questionnaire in 2015, not yet analysed; long-term analyses of the prevention trial

Figure 1. Flow diagram of the Helsinki Businessmen Study (HBS) from 1964 to 2015.

was considered to be a ‘manager’s disease’ at that time33]. The examinations included measurements of those CVD risk factors which were at that time considered to be important (i.e. body mass index (BMI), blood pressure, serum cholesterol and triglycerides, oral 1-h postload glucose tolerance test, smoking status, recalled weight at age of 25 years), as well as resting and exercise electrocardiograms (ECGs). Participants were also given health advice on diet, exercise and other lifestyle factors relevant to CVD by a physician, and contemporary drug treatments were used as appropriate. At baseline, a cohort of 3490 men, who were without CVD or other serious diseases, was identified. Approximately half of them were living in the Helsinki metropolitan area, the other half in other parts of Finland. The cohort was socioeconomically homogeneous; the participants were professionally active White men belonging

to the highest social strata. The current database includes information about 3309 (94.8% of all) men. Their clinical characteristics are shown in Table 1. Due to administrative changes during the 1970s (the Institute of Occupational Health became a public institute owned by the Finnish State in 1978), the service to private companies was discontinued. Aware that the cohort data would be lost, a physician of the Institute enquired of physicians at the Second Department of Medicine, University of Helsinki Central Hospital, whether the cohort could be used for scientific research. This was the starting point of clinical-epidemiological studies of the HBS. From the beginning, the HBS has had two objectives: (i) to examine the possibilities of primary prevention of CVD; and (ii) to conduct a longitudinal study of CVD epidemiology developing into a life-course study. Both study branches have run in parallel.

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Not included

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Table 1. Clinical characteristics of the HBS participants during the 1960s Value, IQ range or SD in parenthesis, no. available

Age at first visit, median (IQ range), range Year of birth 1919–23, n 1924–29, n 1930–34, n Weight, kg (SD) Height, m (SD) BMI, kg/m2, (SD) BMI at 25 years, kg/m2 (SD) Ever smokers, % Blood pressure, mmHg (SD) systolic diastolic Serum lipids, mmol/l (SD) cholesterola triglycerides 1-h glucose tolerance test, mmol/l (SD)

42 (38–45), 31–54

971 1493 845 81.2 (10.4), 3254 177.0 (6.0), 3282 25.9 (2.9), 3229 22.8 (2.2), 2603 59.2, 3308 136.0 (16.2), 3266 86.4 (10.6), 3266 6.6 (1.2), 3277 1.6 (0.9), 1415 (1.9), 2759

IQ, interquartile; SD, standard deviation; BMI, body mass index. a Converted to modern values.

Five-year primary prevention trial during 1974–80 Because of the ‘manager’s disease’ status33 and because several modifiable risk factors of CHD had been identified, the cohort was seen as an ideal population for a multifactorial CHD prevention trial. Several multifactorial prevention studies, such as the large American Multiple Risk Factor Intervention trial (MRFIT),were started during the 1970s.34 Planning of the prevention trial was initiated in 1971 with the goal of finding clinically healthy men, who were at high risk of CVD, for a 5-year multifactorial prevention trial. In 1972–73, a postal questionnaire and a request for laboratory examinations were sent to 3490 men who were born between 1919 and 1934 and who had attended health check-ups in 1964–73. This initial survey yielded 1604 men who were interested in participating, free of clinical CHD (as assessed by the Rose and Blackburn questionnaire, and normal ECG), had no serious disease nor regular medications but had at least one of the following risk factors: hypertension, hyperlipidaemia, overweight, smoking or impaired glucose tolerance. Exclusion criteria for the prevention trial are shown in Table 2.3 The primary prevention trial was a 5-year randomized and controlled multifactorial primary prevention study performed between 1974 and 1980.3,4 It included 1222 men who had a high-risk profile of CVD (at least one of

Table 2. Baseline exclusion criteria for the prevention trial Hypertension  SBP >¼2 mmHg and/or DBP >¼ 115 mm Hg  medication for hypertension  secondary hypertension Cardiovascular diseases  history of myocardial infarction  typical angina pectoris  ECG changes (Minnesota code) indicative of CHD, conduction disturbances, meaningful rhythm disturbances  cardiomyopathies  valve defects  heart failure (clinical, medication) Cerebrovascular diseases  history of stroke  clinical neurological deficits Renal diseases  insufficiency (serum creatinine >¼ 150 umol/l  disease (proteinuria, other pathological urine findings, pathological urography) Metabolic diseases  drug treatment for diabetes  fasting glucose >¼ 10 mmol/l  drug treatment for hyperlipidaemia Cancer Psychiatric diseases  psychosis, serious neurosis  alcoholism SBP, systolic blood pressure; DBP, diastolic blood pressure,

traditional CVD risk factors, average 2.1) but who did not meet the exclusion criteria in Table 2. There were 612 men in the intervention and 610 men in the control group. In addition, a ‘low-risk’ control group (men who did not have risk factors as defined in the trial, n ¼ 593) was identified. Formalities such as trial registration were rudimentary at that time, but the design and purpose of the trial were explained to the participants, and all men gave oral consent and volunteered to take part in the trial. The multifactorial intervention consisted of both intensive lifestyle modification (diet, exercise, smoking, alcohol) and contemporary drug treatment (using mostly diuretics and beta-blockers for hypertension, clofibrate and probucol for hyperlipidaemia). Control groups were in usual care.

Life-course epidemiological study—phases 1964–99 The first epidemiological study among the HBS cohort was on the predictive value of resting and exercise ECG taken during 1964–72 with respect to incidence of CHD. The study included 2821 men with a follow-up (average 5.9 years) of 2446 men. The results have been published only

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Characteristics

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Life-course epidemiological study—phases 2000 onwards In 1999, plans were made for the closer follow-up of the total original cohort. Approval for this was granted by the ethical committee of the Department of Medicine, Helsinki University Central Hospital. Ethical approval was later granted for clinical examinations, including genetic studies. The follow-up study was planned to consist of register data (mortality, causes of death, morbidity, drug reimbursement), postal questionnaires and clinical studies. All postal surveys have included questions about anthropometry, lifestyle, diseases, medications, well-being and healthrelated quality of life (HRQoL) using the RAND-36 (SF-36) instrument; other topics in surveys have varied. The first questionnaire survey was performed in 2000 with a response rate of 81%. The surveys have been repeated in 2002–03, 2005, 2007, 2010–11, 2014 and 2015. In addition, random subgroups have been invited to clinical and

laboratory studies (including genetic samples) in 2002–03 and 2010–11. Clinical studies have focused on key geriatric topics: functional status, cognition, frailty and disability. A clinical study is being planned for 2015–16 with a special reference to active and healthy ageing (‘successful ageing’).

What has been measured? In the early phases and in connection with the prevention trial, focus was on CVD risk factors, medications, mortality and morbidity. In addition, some case-control studies were performed. In the life-course part, measurements have focused, besides on mortality and morbidity, on HRQoL, function, frailty, cognition and genetic studies. Broad categories of measurements at different phases of the HBS are listed in Table 3. The cohort has been linked to the following national registers: the Finnish Population Information System, Statistics Finland (cause of death register), Hospital Discharge Register and Drug Reimbursement Register (at the Social Insurance Institution of Finland). HBS has had cooperation with various study groups, especially for genetic measurements.

What has it found? Key findings and publications Primary prevention trial The trial was operationally successful and led to a clear reduction of CVD risk in the intervention group as compared with the control group. Despite a 46% reduction of total CVD risk in the intervention group as compared with the high-risk control group during the trial in 1974–80, benefit was not observed—contrary to the hypothesis—in terms of mortality or CHD. However, the incidence of stroke was reduced in the intervention group as compared with the high-risk control group The low-risk control group had the fewest number of clinical events overall.4 A clinical and questionnaire follow-up study of the three groups participating in the prevention trial was performed in 1986 (i.e. 6–7 years post-trial), which showed that risk factor differences—except for BMI—between the intervention and high-risk control groups had largely levelled off.36 A national register-based follow-up for mortality and causes of death through 1989 (i.e. 10 years post-trial) in the intervention and control groups unexpectedly showed that all-cause and especially cardiac mortality was increased in the intervention group as compared with highrisk controls. The controversial results were published in JAMA in 19854 and post-trial results 1991.5 The results

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in Finnish2 and showed that especially T-wave changes predicted CHD. In conjunction with the preparations for the prevention trial in 1974–75, five groups of men were identified (Figure 1). As well as the three groups in the prevention trial, also included were an ‘unhealthy’ group of men who had a clinical disease or signs of CHD on ECG or who received regular medication for a risk factor such as hypertension or hyperlipidaemia, and a ‘refused’ group, i.e. persons who were not willing to participate in the prevention trial. The latter group consisted of both low-risk and highrisk men. Between 1974 and 1999, the focus was on the low-risk and high-risk groups and the follow-up of the prevention trial.5–8,35,36 Questionnaires as well as clinical and laboratory data were collected from these groups in 1979–804 and 1985.36 In addition, the whole baseline population was followed up for mortality.6 In the mid 1980s, baseline and follow-up risk factor data were transferred into a common digital database. An important addition to the data was the inclusion of the Finnish personal identification number (PIN), which is the key element to national register follow-up. With this transition, the PIN and at least some baseline risk factor data could be retrieved for 3309 men, forming the basis for later epidemiological studies (94% of the initial 3490). Exercise ECG data could not be retrieved, but the original resting ECGs from 1974–75 are available but largely unanalysed. Observational follow-up of the cohort for mortality and causes of death using national registers had been started after 1986, and mortality results of the whole baseline population were published in 1995.6

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Table 3. Measurement in different phases of the HBS Phase

Measurements

Baseline 1964–73 (median 1968)

MMSE, Mini Mental State Examination; SPPB, Short Physical Performance Battery.

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Anthropometric measurements: weight, height Smoking status Blood pressure Fasting blood samples taken, cholesterol, triglycerides (1969 onwards) assayed 1-h post-load glucose test Follow-up Anthropometric measurements: weight, height, recalled weight at 25 years 1974–75 (those respond- Resting ECG Self-rated health, self-rated fitness ing to questionnaire) Amount of work, sleep and vacation Dietary survey of fat and sugar consumption Detailed exercise data in a subgroup Quantitative smoking status Type and amount of alcohol consumption Blood pressure by nurse and physician Fasting blood samples taken, cholesterol, triglycerides, glucose assayed 1-h post-load glucose test Division in groups according to CVD risk and presence of signs of CHD (Rose and Blackburn questionnaires, ECG), other serious diseases or regular medications Follow-up Anthropometric measurements: weight, height 1979–80 (only high-risk Quantitative smoking status groups and low-risk Type and amount of alcohol consumption group) Blood pressure Fasting blood samples taken, cholesterol, HDL-cholesterol, triglycerides, glucose assayed 1-h post-load glucose test Follow-up Weight 1986 (only high-risk Quantitative smoking status groups and low-risk Type and amount of alcohol consumption group) Blood pressure Fasting blood samples taken, cholesterol, HDL-cholesterol, triglycerides, glucose, non-cholesterol sterols assayed Simple questionnaire of diet and physical activity Follow-up Questionnaire only: self-reported diseases and medications, weight, physical activity, quantitative smoking status, 2000 type and amount of alcohol consumption, RAND-36 health-related quality of life, frailty status assessed Follow-up Questionnaire only: self-reported diseases and medications, weight, physical activity, quantitative smoking status, 2002–03 type and amount of alcohol consumption, RAND-36 health-related quality of life, frailty status assessed. MMSE, laboratory markers related to CVD, non-cholesterol sterols in a random subgroup Blood samples taken for genetic studies, which have included leukocyte telomere length analysis by Southern blotting and gene markers for cognition [APOE2/3/4 þ APOE-promotor -219*G/T (rs405509), carrier status of TYROBP/DAP12 deletion (homozygocity causes Nasu-Hakola disease, a rare dementing disorder), APP*A673T (protecting from Alzheimer disease), C9ORF72 hexanucleotide repeat (this repeat expansion is the most common genetic defect for amyotrophic lateral sclerosis and frontotemporal degeneration in Finland] Follow-up Questionnaire only: self-reported diseases and medications, weight, physical activity, quantitative smoking status, 2007 type and amount of alcohol consumption, RAND-36 health-related quality of life Follow-up Questionnaire only: self-reported diseases and medications, weight, physical activity, quantitative smoking status, 2010 type and amount of alcohol consumption, RAND-36 health-related quality of life Follow-up MMSE, laboratory markers related to CVD, factors related to frailty (walk speed, grip strength, SPPB) in a random 2011 subgroup. Inbody measurements in a subgroup Follow-up Questionnaire only: self-reported diseases and medications, weight, physical activity, quantitative smoking status, 2014 type and amount of alcohol consumption, RAND-36 health-related quality of life Follow-up Questionnaire only: self-reported diseases and medications, weight, physical activity, quantitative smoking status, 2015 type and amount of alcohol consumption, RAND-36 health-related quality of life Ongoing All participants are flagged with register data sources providing morbidity and mortality and causes of death (with narrative death certificates) since baseline and drug reimbursement data through 2007

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raised wide international discussion in both medical journals and the lay press.37–40 Thus far, explanations of this adverse result have not surfaced; for example, cholesterol lowering, or the lower HDL cholesterol induced by probucol treatment in the intervention group, did not explain the adverse result.35 Psychological stress associated with the guidance for lifestyle changes in the intervention group has been hypothesized to be an explanatory factor.5,34 Long-term follow-up and new analyses of baseline factors in a hypothesisgenerating manner are ongoing.

Among men participating in the prevention trial, some case-control studies were performed to analyse new predictors of CVD41,42 and effects of medications like probucol43 used in the prevention trial. Long-term analyses showed that glucose intolerance predicts hypertension.44 A notable finding was that—despite the unexpected intervention trial results between the high-risk groups— low CVD risk at baseline was nevertheless associated with lowest mortality. Furthermore, the ‘refused’, nonparticipating group had higher mortality than the groups which participated in the prevention trial.6 Subsequently, the life-course part of the HBS has observed several long-term relationships between midlife variables and endpoints gathered during the long followup and in old age. These results are briefly summarized in Table 4. An important finding has been that midlife CVD risk (smoking, physical inactivity, hypertension, hyperlipidaemia, impaired glucose tolerance) has long-term adverse effects not only on mortality but also on well-being, HRQoL, function, cognition, and risk of frailty in old age. For example, the association of midlife weight status and old-age frailty is shown in Figure 2.

Adjusted odds ratio

8 7

Prefrail

Frail 6.3 (2.3, 17.8)

6 5 4 2.9 (1.5,5.7)

3 1. 4 (1.02,1.8)

1.9 (1.1,3.3)

2 1 0 BMI 25-29

BMI >29

Weight status in midlife Figure 2. Association of midlife weight status and old age prefrailty and frailty. Normal weight (BMI < 25 kg/m2) as referent and adjusted for age, comorbidity index in old age and midlife systolic blood pressure, triglycerides, 1-h glucose, resting pulse rate and smoking. Odds ratio was calculated using multinomial logistic regression analysis. Adapted from reference 28.

Table 4. Important results of the HBS life-course study Endpoint

Results

References

Long-term (> 20 years) mortality from midlife to old age Mortality in old age

Predicted by midlife cholesterol, blood pressure, BMI (‘the lower the better’), 1-h post-load glucose Predicted by constant overweight and weight loss after midlife, but not by normal weight over the life course Adversely affected by midlife smoking, weight gain up to midlife, midlife high cholesterol, high blood pressure and elevated 1-h glucose as well as overall CVD risk in midlife Adversely affected by high CVD risk in midlife Predicted by overweight, physical inactivity and high CVD risk in midlife Predicted by overweight, smoking and high cholesterol in midlife Midlife CVD risk and cholesterol predict worse cognition in old age

6–13

HRQoL in old age

Psychological well-being in old age Frailty in old age Shorter telomeres in old age Cognitive function in old age

27, 30 12, 16–19, 21,22, 24, 26,31

20 27–30 45–47 23, 32

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‘Life-course’ epidemiological study

The results also dispute the presence of an ‘obesity paradox’ or ‘old-age paradoxes’ and indicate that lifetime normal weight is the best option for active and healthy ageing. In fact, weight gain up to midlife has a graded, adverse effect on HRQoL in old age. The results also suggest that ‘the lower the better’ paradigm holds true as far as cholesterol and blood pressure are concerned. On the other hand, results from this homogeneous cohort do not support the notion that moderate alcohol consumption would be beneficial for health; on the contrary, it was associated with shorter telomeres in old age than among those who did not consume alcohol.45 Also, higher levels of other midlife risk factors such as BMI, smoking and cholesterol have been related to shorter telomere length in old age.46,47

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The HBS investigators have also contributed data on height, BMI, glucose and diabetes to the studies of the Emerging Risk Factors Collaboration.48–51

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Helsinki Businessmen Study (HBS) profile in a nutshell • The Helsinki Businessmen Study (HBS) is a pro-

What are the main strengths and weaknesses?

spective, observational study especially investigating

The strengths of the HBS include the long follow-up from early middle age to old age, thus approaching a life-course study. The mortality follow-up is also reliable, using the individual PIN and national registers.52 The response rate is good to satisfactory during different phases of the study, and the high socioeconomic status of the participants probably gives credence to the self-reported data. The homogeneity of the cohort (White men from the highest social strata in a homogeneous Nordic country) also reduces confounding factors when studying biological mechanisms. The homogeneity of the cohort is also a limitation as to the generalizability of the HBS results. An eternal limitation of long-term studies is that the cohort has lived in a world different from today’s society. For example, only a tiny fraction of the HBS cohort were overweight or obese when they were 25 years of age, which is very different from the situation today, and this must be taken into account when extrapolating the results. The men were also given health advice during the manager examinations in the 1960s, and part of the cohort (intervention group) had more intense treatment in the prevention trial during the 1970s. These points may affect generalizability, although we have aimed to control for the intervention group membership in epidemiological analyses. The response rate has been decreasing with the cohort getting older, more disabled and cognitively impaired, and complete retrieval of institutionalization data has not been possible. However, collection of narrative death certificates and drug reimbursement data helps to narrow this gap. The biomarker battery from midlife is limited, mainly due to a freezer failure during the 1990s, which has prevented later analyses of modern biomarkers. Limited funding has also prevented extensive studies of the total cohort in old age, use of more sophisticated equipment and biomarker and genetic analyses.

morbidity as well as health-related quality of life

Collaboration in data analysis and publication is possible through specific research proposals sent to the primary investigator [[email protected]] or individual HBS investigators. A full list of publications can be found at [http://www.gernet.fi/artikkelit/1463/helsinki-business men-study-hbs-summary-and-bibliography].

(HRQoL), frailty and function in old age. • The HBS was originally a convenience cohort of

male executives and businessmen (born 1919–34, n ¼ 3490) who participated in voluntary health checkups in Helsinki during the 1960s. • During the 1970s, the HBS has developed into a clin-

ical-epidemiological longitudinal study. The original focus has been on the prevention of cardiovascular diseases, and during the 1970s some of men (n ¼ 1815, of these 612 were in the intervention group) participated in a multifactorial prevention trial. • Since the year 2000, the emphasis has shifted to

geriatrics, with regular postal questionnaire surveys with good response rates. Clinical and laboratory studies have been performed in random subcohorts in 2002–03 (n ¼ 651) and 2011 (n ¼ 521). Latest postal survey was performed in 2015 when 2293 had died. • The dataset comprises a wide range of phenotypic

and environmental measures, biological samples, genetic information and linkage to health and administrative records. • The HBS has participated in the Emerging Risk

Factors Collaboration. The data can be accessed via the HBS investigators [ClinicalTrials.gov identifier: NCT02526082].

Funding This work was initially funded by the Academy of Finland and various foundations throughout the decades, most recently by the Sohlberg Foundation, the Jahnsson Foundation and Gustav V och Victoria Frimurarestiftelse. Funding has also been provided by the Helsinki University Central Hospital the Oulu University Hospital (VTR/EVOfunding), the Academy of Finland grants no. 286294 and no. 294154, and Paulon Sa¨a¨tio¨ (grant to prof. Timo Strandberg).

Acknowledgement We would like to thank all HBS participants for their valuable contribution to this study. The original HBS study group included: Tatu A. Miettinen (deceased), Torger Kumlin (deceased), Jussi Huttunen, Vesa Naukkarinen, Seppo Mattila, Timo Strandberg, Seppo Sarna, Veikko Salomaa and Hannu Vanhanen. The second phase included: Arto Y. Strandberg, Tuula Pienima¨ki, Kaisu Pitka¨la¨, Kirsi Rantanen, Salla Savela, Sari Stenholm, Reijo S Tilvis, Emmi Huohvanainen, Katri Ra¨ikko¨nen and Pentti J Tienari.

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Can I get hold of the data? Where can I find out more?

the midlife influences on long-term mortality and

8 Conflict of interest: The authors report no relevant conflict of interest for this work.

References

16. Strandberg TE, Strandberg A, Salomaa VV, Pitka¨la¨ K, Miettinen TA. Impact of midlife weight change on mortality and quality of life in old age. Prospective cohort study. Int J Obes Relat Metab Disord 2003;27:950–54. 17. Strandberg AY, Strandberg TE, Salomaa VV, Pitka¨la¨ K, Miettinen TA. Alcohol consumption, 29-y total mortality, and quality of life in men in old age. Am J Clin Nutr 2004;80:1366–71. 18. Strandberg A, Strandberg TE, Salomaa VV, Pitka¨la¨ K, Ha¨ppo¨la¨ O, Miettinen TA. A follow-up study found that cardiovascular risk in middle age predicted mortality and quality of life in old age. J Clin Epidemiol 2004;57:415–21. 19. Strandberg TE, Strandberg A, Rantanen K, Salomaa VV, Pitka¨la¨ K, Miettinen TA. Low cholesterol, mortality, and quality of life in old age during a 39-year follow-up. J Am Coll Cardiol 2004;44:1002–08. 20. Strandberg TE, Strandberg AY, Pitka¨la¨ KH, Salomaa VV, Tilvis RS, Miettinen TA. Cardiovascular risk in midlife and psychological well-being among older men. Arch Intern Med 2006;166:2266–71. 21. Strandberg TE, Strandberg A, Salomaa VV, Pitka¨la¨ K, Tilvis RS, Miettinen TA. The association between weight gain up to midlife, 30-year mortality, and quality of life in older men. Arch Intern Med 2007;167:2260–61. 22. Strandberg TE, Strandberg AY, Salomaa VV, Pitka¨la¨ K, Tilvis RS, Miettinen TA. Alcoholic beverage preference, 29-year mortality, and quality of life in men in old age. J Gerontol A Biol Sci Med Sci 2007;62:213–18. 23. Rantanen K, Ylikoski R, Ha¨ppo¨la¨ O, Strandberg TE. Higher cardiovascular risk in midlife is associated with worse cognitive function 29 years later, in old age. J Am Geriatr Soc 2008;56:2152–53. 24. Strandberg AY, Strandberg TE, Pitka¨la¨ K, Salomaa VV, Tilvis RS, Miettinen TA. The effect of smoking in midlife on healthrelated quality of life in old age: a 26-year prospective study. Arch Intern Med 2008;168:1968–74. 25. Sirola J, Strandberg AY, Pitka¨la¨ KH et al. Weight change after middle age and disability in older men. J Am Geriatr Soc 2010;58:189–90. 26. Savela SL, Koistinen P, Tilvis RS et al. Physical activity at midlife and health-related quality of life in older men. Arch Intern Med 2010;170:1171–72. 27. Sirola J, Pitkala KH, Tilvis RS, Miettinen TA, Strandberg TE. Definition of frailty in older men according to questionnaire data (RAND-36/SF-36): The Helsinki Businessmen Study. J Nutr Health Aging 2011;15:783–87. 28. Strandberg TE, Sirola J, Pitka¨la¨ KH, Tilvis RS, Strandberg AY, Stenholm S. Association of midlife obesity and cardiovascular risk with old age frailty: a 26-year follow-up of initially healthy men. Int J Obes (Lond) 2012;36:1153–57. 29. Savela SL, Koistinen P, Stenholm S et al. Leisure-time physical activity in midlife is related to old age frailty. J Gerontol A Biol Sci Med Sci 2013;68:1433–38. 30. Strandberg TE, Stenholm S, Strandberg AY, Salomaa VV, Pitka¨la¨ KH, Tilvis RS. The ‘obesity paradox,’ frailty, disability, and mortality in older men: a prospective, longitudinal cohort study. Am J Epidemiol 2013;178:1452–60.

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Cohort Profile: The Helsinki Businessmen Study (HBS).

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