Cohort description

Participants

The H-PEACE study collected data from 91 336 Koreans aged 45.5±11.7 years (50 507 men and 40 829 women) who received a health check-up between October 2003 and December 2014 at the SNUH Gangnam Center (IRB no. H-1311-031-531). We prospectively collected blood samples from 17 455 of those individuals (9396 men and 8059 women) from October 2013 to form the Gene-environmental interaction and phenotype (GENIE) study, a subcohort of the H-PEACE study. Furthermore, we obtained data for genome-wide single-nucleotide polymorphism (SNP) arrays using 6579 donated blood samples. The flow chart of the H-PEACE study subjects is illustrated in figure 1, and the distribution of the participants in Korea in figure 2.

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Figure 1

Study flow diagram of the Health and Prevention Enhancement study.GC, Gangnam Center; GWAS, genome-wide association study; SNUH, Seoul National University Hospital.

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Figure 2

Regional distribution of the Health and Prevention Enhancement study in Korea.

Data collection

The H-PEACE study consists of core and specific variables (tables 1 and 2). The core variables were tests performed in all of the enrolled participants at the regular health check-ups. The specific variables were the tests selectively performed in the participants on request or based on the recommendation of their medical provider according to the participant’s symptoms or disease risk factors. These tests were sophisticated and expensive tests that are rarely used in other cohort profiles. In table 3, we describe the representative test for each variable and its participation rate. The tests performed for the covariables and specific variables are described below. All data were collected as part of the comprehensive health check-ups. The flow diagram of health check-ups in our study is illustrated in figure 3. All study protocols are available on request at our homepage (http://en-healthcare.snuh.org/HPEACEstudy).

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Table 1

Core variables collected at baseline and follow-up in the Health and Prevention Enhancement study from 2003 to 2014

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Table 2

Specific variables* collected at baseline and follow-up in the Health and Prevention Enhancement (H-PEACE) study

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Table 3

Participation rate for the core and specific variables collected in the Health and Prevention Enhancement (H-PEACE) study at baseline

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Figure 3

Flow diagram of health check-ups in the Health and Prevention Enhancement study. CLO, Campylobacter-like organism; DEXA, dual-energy X-ray absorptiometry; MRA, magnetic resonance angiogram; VDRL, venereal disease research laboratory

Structured questionnaires

Self-reported questionnaires were used to obtain socio-demographic data, personal and familial medical history, health-related behaviours (such as smoking status, alcohol consumption, physical activity, dietary behaviour), International Prostate Symptom Score, female reproductive factors and psychological status. Physical activity levels were assessed using the validated Korean version of the International Physical Activity Questionnaire short form and were classified into three categories: inactive, minimally active and health-enhancing physically active (HEPA).20 21 Dietary habits were evaluated using the Mini-Dietary Assessment Index, which was validated in Korean.22 Psychological status was assessed by the Beck Depression Inventory or Quick Inventory of Depressive Symptomatology-Self Report.23

Physical examinations

Blood pressure was measured using sphygmomanometers with patients in a seated position after a resting period. If systolic blood pressure was ≥140 mm Hg or diastolic blood pressure was ≥90 mm Hg after a rest period and two measurements, we recorded the values and calculated their averages. Height (cm), weight (kg), waist circumference (cm) and body fat composition (%) were measured by trained nurses with participants wearing a lightweight hospital gown and in bare feet. Height and weight were measured using digital scales in a standing position. Waist circumference was obtained by measuring the smallest natural waist circumference area, which is around the umbilicus using a non-stretch tape measure, without any pressure to the body surface during measurements. Percentage of body fat and visceral fat area were estimated with a multifrequency bioimpedance analyser with eight-point tactile electrodes (Inbody 720, Biospace, Seoul, Korea). Comprehensive eye examinations (visual acuity, ocular tonometry, slit-lamp test, fundus photography) and hearing tests were also performed.

Laboratory tests

Blood samples from the antecubital vein were collected after at least 10 hours of fasting. The blood parameters assessed included complete blood cell count, fasting blood glucose, glycated haemoglobin, uric acid, blood urea nitrogen, creatinine, total calcium, inorganic phosphorus, glucose, sodium, potassium, chloride, total CO₂, total protein, albumin, total bilirubin, aspartate transaminase, alanine transaminase, gamma-glutamyl transferase , total cholesterol, low-density lipid cholesterol, high-density lipid cholesterol, triglycerides, high-sensitivity C reactive protein concentration, prothrombin time, activated partial thromboplastin time, hepatitis B surface antigen, anti-HBs, HAV Ab IgG, alpha-fetoprotein, cancer antigen 19-9, carcinoembryonic antigen and prostate-specific antigen in men and cancer antigen 125 in women. The laboratory medicine department at the SNUH has been certified by the Korean Society of Laboratory Medicine and participated in the College of American Pathologist’s Survey/Proficiency Testing programme. Urine tests were performed by stick test using spot urine. Semiquantitative variables included pH, protein, glucose, ketone, bilirubin and blood. Stool samples were collected to conduct faecal occult blood tests and parasite assays.

Digital imaging and specific diagnostic variables

Chest X-ray was included as a core variable of the H-PEACE study, which included specific information on diagnostic variables (table 1). First, the GENIE study collected donated blood samples from 17 455 recipients, and genome-wide SNP arrays from 6579 donated blood samples have already been analysed using the Affymetrix platform (Axiom Customized Genome-Wide Human Assay) (table 3). We plan to increase the available genetic information by 2020 using an SNP array. The PLINK program V.1.9 and R statistics V.3.3.0 were used for quality control procedures and data analysis. SNP genotype data combined with clinical data from the H-PEACE study were used to evaluate gene–environment interactions and to define the related phenotypes.

In total, 12 846 participants underwent coronary CT with a coronary calcium score to assess coronary calcification. The calcium score of the coronary artery is a strong predictor of myocardial infarction and sudden cardiac death.24 In addition, 34 771 participants underwent visceral fat CT to measure visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT). The detailed methods used to measure VAT area and SAT area on abdominal fat CT images have been described elsewhere.17 This quantitative assessment of intra-abdominal adipose tissue is considered the gold standard for measuring the amount of visceral fat.25 With advanced imaging techniques including echocardiography, brain MRI/magnetic resonance angiogram, carotid Doppler ultrasound, abdominal ultrasonography and abdominal CT, we elucidated the correlation of visceral obesity with vascular disease using both data in a complementary manner. The core variables of the H-PEACE study including the blood test results, questionnaire findings and depression scores can contribute to determining the correlation between visceral obesity and metabolic phenotype.

We collected ECG reports from 91 197 consecutive recipients to evaluate the incidence and risk factors of atrial fibrillation, a significant risk factor for stroke. The effects of a bundle branch block or atrioventricular block on stroke and cardiac disease were also analysed. Furthermore, we collected Holter monitor results to confirm the ECG reports.

Human papillomavirus (HPV) is known to lead to cervical cancer in women.26 Of the participants in the H-PEACE study, 12 951 women underwent both a liquid-based cervical cytology (SurePath LBC, Becton Dickinson, Franklin Lakes, New Jersey, USA) and an HPV genotyping test using an HPV DNA chip (MyHPV Chip, Biomedlab, Seoul, Korea) for cervical cancer screening.27 We also included the results of gynaecological sonography, as well as venereal disease research laboratory and HIV tests.

WHO considers Helicobacter pylori infection a class I carcinogen for gastric cancer.13 The diagnosis of H. pylori infection was based on the detection of serum H. pylori IgG antibody using a kit (H. pylori-EIA-Well, Radim, Rome, Italy) that was previously validated in a nationwide Korean seroepidemiological study.28 Furthermore, 66 451 recipients had available upper endoscopy data with pathology results. Serum pepsinogen data and eradication history were also collected.

A total of 46 050 participants in the H-PEACE study received a colonoscopy in our centre. All colonoscopies were conducted by board-certified endoscopists, and the average adenoma detection rate in recipients aged 50–70 years was >30%.12 Endoscopes including the CF-H260 and CF-HQ290 series (Olympus, AIZU, Japan) and the EC-450HL5, EC-450WM5 and EC-590ZW series (Fujinon, Saitama, Japan) were used. Histological diagnoses at our centre were determined according to the WHO classification of tumours of the digestive system.29 30 All colonoscopy results and corresponding pathology reports were collected.

We calculated estimated glomerular filtration rate (GFR) using the chronic kidney disease epidemiology collaboration equation and the modification of diet in renal disease formula. We collected GFR data successively to identify the risk factors for chronic kidney disease. We also included spot urine sodium and creatinine ratio and 24-hour urine data including GFR.

Dental exams were conducted in 43 232 participants. Periodontitis is highly prevalent among adults and is one of the most common causes of teeth loss after 40 years.31–33 Furthermore, periodontitis can induce systemic inflammation, as well as masticatory dysfunction and poor nutritional status.32 This is the first cohort study to include a large number of dental exams to evaluate the progression of periodontitis. In this study, 43 232 participants received a dental exam; 33.1% had mild to moderate periodontitis and 2.1% had severe periodontitis. We also included participants’ colonoscopy and coronary CT results, including coronary calcification and colon polyps, to assess the correlation between periodontitis and systemic inflammation.

The presence of osteoporosis was determined using bone densitometry in 26 207 women and 9488 men. We measured bone mineral density (BMD) of the lumbar spine (L1–L4) and femur using dual-energy X-ray absorptiometry (GE Medical, UK). Based on participants’ lowest T scores, normal BMD, osteopenia and osteoporosis were defined as T scores of −1.0 SD and above, −1.0 to −2.5 SDs and −2.5 SDs and below, respectively. In this cohort, 26.6% of the participants who underwent bone densitometry were male. Of those, osteopenia was found in 24.75% and osteoporosis was found in 3.21%. The information collected in this cohort also included hormone levels, oestrogen levels in women and testosterone levels in men.

Findings to date

The baseline characteristics are summarised in table 4, and the morbidity rate of the major outcomes is shown in table 5. The morbidity rates were calculated as the number of findings divided by the number of participants tested. The prevalence of major outcomes (mortality and cancer incidence rate) is provided in table 6. The H-PEACE study has contributed to the research community by publishing >200 articles since the initiation of the data warehouse, HEALTH-WATCH, as a prototype in 2003.8 Our studies have primarily focused on cancer screening and identifying the risk factors and prognosis of metabolic disease.

For subjects with 1–2 adenomas <10 mm in colonoscopy for colon cancer screening, they were classified as a low-risk group having low 5-year colon adenoma incidence rates and were recommended to take further colonoscopic screening test after 5 years. For subjects with advanced adenoma, multiple adenoma ≥3 or larger adenoma sized ≥10 mm in baseline colonoscopy for colon cancer screening, they were classified as a high-risk group having higher incidence rates of advanced adenoma or higher recurrence rates of adenoma and were recommended to take colonoscopic surveillance at 3 years after initial polypectomy.12 This strategy of colonoscopic surveillance has been reflected in the guidelines for colonoscopic surveillance.34 In our study, the colonic adenoma incidence rate was 37%. Our centre performed a previous study on the prevalence and risks of colorectal adenoma in asymptomatic Koreans aged 40–49 years undergoing screening colonoscopies.35 In that study, the prevalence of adenoma was 22.2% in the age group of 40–49 years and 32.8% in the age group of 50–59 years. This finding is quite consistent with that in our cohort. In the paper, we concluded that the prevalence of adenoma in subjects aged 40–49 years was higher than that in previous studies. Male sex and current smoking habits were among the risk factors.

We also examined the quality of colon cancer screening using metrics such as the adenoma detection rate.36 Additionally, we evaluated the influence of image-enhanced endoscopy, such as narrow band imaging and Fuginon Intelligent Color Enhancement, using our cohort data.10 37 38 For gastric cancer screening, the effect of screening endoscopy remains controversial, but population-based screening has been undertaken in Korea and Japan. For participants with intestinal metaplasia in gastroendoscopy, we also classified them into high-risk group and recommended an annual endoscopic screening, based on study results that people with strong risk factors such as male and an older age can quickly find early-staged endoscopically treatable gastric cancer by taking annual gastroendoscopic screening.11 In our cohort, 54% had H. pylori infection and 36% had atrophic gastritis. In a nationwide multicentre study in Korea performed by our centre for the prevalence of H. pylori infection, the seropositive rate of H. pylori was 59.6%.39 This rate is quite consistent with our study result and consequently explains the relatively high percentage of atrophic gastritis that we observed. Gastric mucosa-associated lymphoid tissue lymphomas (MALToma) and suspicious MALToma lesions were also detected in screening endoscopies, and the prevalence of gastric MALToma was high in middle-aged women.40 Active endoscopic screening for gastric cancer had the additional benefit of detecting early-stage MALToma.40 41 Furthermore, we established that small subepithelial tumours that were incidentally found during upper endoscopy screening showed no size change in subsequent follow-up periods.37

Our research focus was not limited to cancer screening. We also examined metabolic diseases such as non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome. Consistent with our results, the population prevalence of NAFLD in Korea is >25%, like that in many Western countries.19 42–44 Although subjects in this cohort are relatively young and lean, lean NAFLD (or non-obese NAFLD) is more common in Asians (including Koreans) than in Western populations. Asians generally have a higher percentage of visceral fat and body fat than people of other races of the same age, sex and even body mass index (BMI).45–47 As visceral obesity is a major risk factor for lean NAFLD, this might have affected the higher prevalence of NAFLD in this cohort, comprising relatively lean subjects.45 In addition, the term ‘fatty liver’ in this paper includes not only NAFLD but also alcoholic fatty liver disease. The proportion of subjects who drink alcohol heavily in this cohort is as high as 37.5% in men, which might affect the high prevalence of fatty livers that we observe.

We reported that metabolic syndrome was an independent risk factor of silent brain infarction using brain MRI data (OR 2.18; 95% CI 1.38 to 5.82, p=0.001).48 The prevalences of metabolic syndrome and its components were higher in subjects with silent brain infarctions than in those without. This is the first study to demonstrate an association between metabolic syndrome and silent brain infarction. This finding might help identify healthy people at increased risk for developing silent brain infarction. We also found an effect of body fat distribution on the incidence of NAFLD and reflux oesophagitis using abdominal fat CT data.9 14 We identified a relationship between NAFLD and the risks of coronary heart disease and arterial stiffness based on coronary CT and the cardio-ankle vascular index (CAVI), respectively.16–19 To elucidate the relationship between NAFLD and the risk of coronary heart disease, we used the coronary artery calcification score as measured by coronary CT. This measurement showed that patients with NAFLD are at increased risk for coronary atherosclerosis (OR 1.28, 95% CI 1.04 to 1.59, p=0.023).17 In the study on the association between NAFLD and arterial stiffness, we used CAVI, a new measurement of arterial stiffness. In an age-adjusted, sex-adjusted and BMI-adjusted model, NAFLD was associated with a 42% increase in the risk for arterial stiffness, and this increased according to the severity of NAFLD.16 The effect of physical activity on NAFLD was also demonstrated using data from the questionnaires.49

The list and number of publications can be requested on our homepage (http://en-healthcare.snuh.org/HPEACEstudy).

Strengths and limitations

This study has several potential limitations as below. First, our study participants are composed of individuals who voluntarily visited our centre and their data collection for the repeated measurements rely on participants’ self-paid. Our system of enrolling cohort members includes a potential selection bias. Second, self-recorded questionnaires are used to obtain the information of risk factors and disease histories before the next visit of study participants to our centre, and this procedure leads to recall bias and response bias. Third, our active follow-up rates in assessing outcome variables and repeatedly measuring risk factors are not high, leading to selection bias. However, since active follow-up rates are increasing every year, at least 87% of follow-up is expected if all subjects are terminated for at least 10-year follow-up. Forth, in our cohort, we used to measure waist circumference as the definition of the smallest area around the belly button below the rib cage and above the hip bone, although the ideal way is to measure the midway between the top of the hip bone and below the rib cage. The former is usually called the natural waist, and we used this former definition for practical reason to reduce intraindividual measurement bias in waist circumference. In health check-up at our centre, a lot of participants (about 100–120 health examinees) every day visit the  centre for health examination and many health technicians and nurses take measurement of waist and hip circumferences. For each participant, there is a very little chance to take measurement of waist at the time of revisit by same nurses met at the time of cohort enrolment. The intraindividual measurement bias in measuring waist circumference may be problematic at our centre and thus we thought that it was necessary to use the most practical and easy waist measurement together with repeated nurse training. We did a small pilot study for measuring waist by the two methods for 10 men and 16 women. The ideal measuring method (midway measurement) has a limit in consuming time and effort due to difficulty in method itself. In spite of short time and smaller effort in measuring waist, the natural waist measuring method showed an excellent agreement (intraclass correlation coefficients=99% in men and 93% in women) with ideal method and there were no shift between obesity groups classified by each method. Fifth, there is no information of cancer histology subtypes for cohort participants ascertained as new cancer development. Individual cancer development in study participants was ascertained with data linkage to the nationwide cancer registry data. Korea cancer registry data include International Classification of Diseases, Tenth Revision code, T-code (Topography) and M-code (Morphology in primary cancer sites). For example, among the stomach cancer types, 51.3% were adenocarcinomas, 22.1% were tubular adenocarcinomas and only 4.9% were histological NOS.50 Future studies will attempt to merge the individual data associations of M-code and T-code. Finally, the definition of a disease status could be changed during the follow-up periods as new guidelines are declared. For instance, guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults opened at November 201751 recommending a new definition for hypertension. This paper was written before the declaration was done. We have the raw data of blood pressure and the definition can be applied to the study population. But for those who had already been under antihypertensive medication at the point of enrolment in our cohort, they had followed the previous guidelines for indication of treatment. This makes it difficult to reclassify these patients according to the new guidelines. In the future follow-up period, we will pay close attention to clearly declare the definition of disease we are applying according to the period of terms.

A major strength of the H-PEACE study is its structured and organised database, which not only includes data widely used in medical check-ups but also data from sophisticated high-quality advanced examinations, such as colonoscopy, brain MRI, abdominal CT and abdominal fat CT. Particularly in our study, comprehensive biomarkers related to NCDs, including cancer antigens and infection markers, were included, which have not been included in the medical check-ups of other cohort profiles. It has only been about 10–15 years since the comprehensive health check-up programme was actively performed in Korea, and in the past decade, a large proportion of people participated in the check-up due to the support from the affiliated company’s welfare policy. This might result in the relatively young population enrolment in our study population. But since the health check-up programme is getting more general, more elderly population is taking the health check-up. New enrolment is another future target study of our centre. Since the enrolled cohort population is relatively young, it is possible to study the preclinical disease stage and its final long-term outcomes. This might be the characteristics of our cohort that we could design a lot of prediction models for the NCD by using data from the preclinical stages. As we obtained a large sample size, we could confirm disease statuses as well as numerous phenotypes of NCDs. Furthermore, the study protocols were conducted and monitored with intensive quality control procedures. Additional strengths include the active and passive follow-ups and the ability to obtain complete data, covering deaths and incidental cancer cases even among those who discontinued visiting our centre. We believe that these data could contribute to active, effective prevention against the development of cancers and NCDs.