Biobanking for epidemiology

Biobanks are a key resource in unravelling the association between genetic background, lifestyle and environmental determinants of the incidence, natural course and treatment response for various complex diseases and health traits. Biobanks are goldmines for epidemiological research, provided that they are set up properly, enable multicentre collaboration, and are available for use by all serious epidemiology groups.     

Ten-year incidence of coronary heart disease in the Honolulu Heart Program. Relationship to biologic and lifestyle characteristics

In 10 years of follow-up of 7705 Japanese men living in Hawaii, aged 45-68 years and judged free of coronary heart disease (CHD) at the initial examination during 1965-1968, a total of 511 new CHD cases were identified: fatal CHD, 139; nonfatal myocardial infarction (MI), 216; acute coronary insufficiency, 55; and uncomplicated angina pectoris (AP), 101. The incidence rate of fatal CHD and nonfatal MI for this cohort is less than half the rate for US whites and approximately twice the rate for Japanese men in Japan. The relationships of 14 biologic and lifestyle characteristics measured at baseline examination to the incidence of total CHD and specific manifestations of CHD were examined in bivariate and multivariate analyses. In bivariate analyses, all variables except heart rate were significantly related to the risk of total CHD after adjustment for age. However, when an independent contribution of each variable to CHD risk was evaluated in multiple logistic analyses in which all other variables were taken into account, the numbers of risk factors retaining significant associations varied by clinical subgroup of CHD. Among the characteristics studied, systolic blood pressure was the most powerful and consistent risk factor for all manifestations except AP. Cigarette smoking showed a similar pattern. Serum cholesterol was significantly associated with fatal CHD and nonfatal MI, but its contribution to CHD risk was less potent than systolic blood pressure or cigarette smoking. Glucose intolerance was strongly associated with fatal CHD, but with no other manifestations of CHD. Alcohol consumption demonstrated a strong protective effect upon fatal CHD and nonfatal MI. Uncomplicated AP was distinguished from other CHD manifestations by the lack of association with most of the known major risk factors for CHD, including blood pressure, serum cholesterol, and cigarette smoking.     

The validity of the routine mortality statistics on coronary heart disease in Finland: comparison with the FINMONICA MI register data for the years 1983-1992. Finnish multinational MONItoring of trends and determinants in CArdiovascular disease

We compared the diagnoses obtained from the routine mortality statistics with the standardized World Health Organization (WHO) MONICA (multinational MONItoring of trends and determinants in CArdiovascular disease) classification in suspect coronary heart disease (CHD) deaths registered in the FINMONICA myocardial infarction (MI) register during 1983-1992. All CHD deaths from routine mortality statistics (International Classification of Diseases codes 410-414) were registered in the MI register. Of the CHD deaths in routine mortality statistics 1.7% in men and 4.8% in women did not fulfill the MONICA criteria for CHD death (P<0.001 for the difference between the sexes). In men 4.7% and in women 7.3% (P=0.004) of the deaths registered in the MI Register and classified as CHD deaths by MONICA criteria had another underlying cause of death than CHD in routine mortality statistics; this proportion increased over time in both sexes (P=0.002 in men and P=0.77 in women). The CHD mortality trends obtained separately from the routine mortality statistics and from the FINMONICA MI Register were very similar. In conclusion, the high CHD mortality in Finland reported by the routine mortality statistics is real. It is possible that some CHD deaths have escaped registration, but the decline seen in the CHD mortality is also real.     

Coronary heart disease mortality trends in men in the post World War II birth cohorts aged 35-44 in Japan, South Korea and Taiwan compared with the United States

BACKGROUND: Since World War II, people in Japan, South Korea, and Taiwan have been exposed to a westernized lifestyle. It is most likely that the post World War II cohorts (1950+) have been more exposed. We hypothesize that there would be an increase in mortality from coronary heart disease (CHD) in men aged 35-44 in these countries. METHODS AND RESULTS: Mortality from CHD in men aged 35-44 in South Korea and Taiwan has recently increased, and in Japan it has decreased. Mortality from CHD in men aged 35-44 is lower in Japan than in either South Korea or Taiwan, and much lower than in the US. National sample data and several epidemiological studies have shown that risk factors for CHD including hypercholesterolaemia and hypertension in the past decade were not much different between young adult men in Japan and the US. Based upon these risk factors, CHD death rates among post World War II cohorts should be similar in Japan and the US. However, the rates are five times higher in the US for men aged 35-44. The majority of deaths in the category of diseases of the heart were from heart failure in men in this age group in Japan; the mortality from heart failure was about three times higher than the mortality from CHD. Heart failure was rarely used in men aged 35-44 in the US. CONCLUSIONS: The continued low mortality rates from CHD in young men in Japan may be an artifact. It is possible that CHD death rates in post World War II birth cohort in Japan are similar to US rates.     

Health sector reform in South Asia: new challenges and constraints

In early 1990s, Jamison, Mosley and others concluded that a profound demographic and consequent epidemiological transition is taking place in developing countries. According to this classical model, by the year 2015, infectious diseases will account for only about 20% of deaths in developing countries as chronic diseases become more pronounced. These impending demographic and epidemiological transitions were to dominate the health sector reform agenda in developing countries. Following an analysis of fertility, mortality and other demographic and epidemiological data from South Asian and other developing countries, the paper argues that the classical model is in need of re-evaluation. A number of new 'challenges' have complicated the classical interplay of demographic and epidemiological factors. These new challenges include continuing population growth in some countries, rapid unplanned urbanization, the HIV/AIDS pandemic in Sub-Saharan Africa (and its impending threat in South Asia), and globalization and increasing marginalisation of developing countries. While the traditional lack of investment in human development makes the developing countries more vulnerable to the vicissitudes of globalization, increasing economic weakness of their governments forces them to retreat further from the social sector. Pockets of poverty and deprivation, therefore, persist giving rise to three simultaneous burdens for South Asia and much of the rest of the developing world: continuing communicable diseases, increasing burden of chronic diseases, and increasing demand for both primary and tertiary levels of health care services. While these complex factors, on the one hand, underscore the need for health sector reform, on the other, they make the task much more difficult and challenging. The paper emphasizes the need to revisit the classical model of demographic and epidemiological transition. It is argued that the health sector in developing countries must be aware of and effectively address these 'new challenges'. Although it has included data from many developing countries, the focus is primarily on South Asia.     

UK Biobank: Current status and what it means for epidemiology

UK Biobank is a very large prospective study which aims to provide a resource for the investigation of the genetic, environmental and lifestyle determinants of a wide range of diseases of middle age and later life. Between 2006 and 2010, over 500,000 men and women aged 40 to 69 years were recruited and extensive data on participants' lifestyles, environment, medical history and physical measures, along with biological samples, were collected. The health of the participants is now being followed long-term, principally through linkage to a wide range of health-related records, with validation and characterisation of health-related outcomes. Further enhancements are also underway to improve phenotype characterisation, including internet-based dietary assessment, biomarker measurements on the baseline blood samples and, in sub-samples of the cohort, physical activity monitoring and proposals for extensive brain and body imaging. UK Biobank is now available for use by all researchers, without exclusive or preferential access, for any health-related research that is in the public interest. The open-access nature of the resource will allow researchers from around the world to conduct research that leads to better strategies for the prevention, diagnosis and treatment of a wide range of life-threatening and disabling conditions.     

Process evaluation of a lifestyle intervention to prevent diabetes and cardiovascular diseases in primary care

Effective, cost-effective, safe, and feasible interventions to improve lifestyle behavior in at-risk populations are needed in primary care. In the Hoorn Prevention Study, the authors implemented a theory-based lifestyle intervention in which trained practice nurses used an innovative combination of motivational interviewing (MI) and problem-solving treatment (PST). This article presents the intervention's reach, effectiveness in terms of process outcomes, adoption, and implementation. Recruitment strategy and participant flow were documented accurately. The effectiveness in terms of determinants of behavioral change was measured using a validated questionnaire. Questionnaires were also used to assess participant satisfaction and compliance, as well as practice nurses' confidence in providing the intervention. Counseling sessions were tape recorded to assess MI, PST, and general counseling competence. The findings indicate that the recruitment strategy was adequate and resulted in a reasonably extensive reach of the target population. Practice nurses were competent and confident in their provision of MI and PST, and participant satisfaction was high. Nevertheless, the number of sessions attended was low, and almost no effects were seen on determinants of behavioral change. The authors conclude that implementing this type of intervention in primary care is feasible, but more is needed to effectively facilitate changes in determinants of lifestyle behavior in this population.     

The impact of medication use in a multicomponent intervention: results from the WISEWOMAN program

PURPOSE: To assess the impact of medication use on improvements in coronary heart disease (CHD) risk among WISEWOMAN participants. DESIGN: Pre-post analysis. SETTING: WISEWOMAN projects operating at the local level in 8 states. SUBJECTS: WISEWOMAN participants with baseline and one-year follow-up data with at least one abnormal risk factor at baseline (N=2385; 24% of women with baseline visits). INTERVENTION: WISEWOMAN provides low-income uninsured women with CHD risk factor screenings, lifestyle interventions, access to medications, and referral services. MEASURES: One-year changes in blood pressure, cholesterol, and 10-year CHD risk by medication status. ANALYSIS: Regression analysis was used to estimate risk factor changes by medication status (newly medicated women, women medicated at baseline, or not medicated women) and quantify the percentage of improvements in risk factors attributed to medication use. RESULTS: Participants experienced statistically significant improvements in systolic (12.6 mm Hg) and diastolic (9.7 mm Hg) blood pressure, total (25.7 mg/dl) and HDL (4.9 mg/dl) cholesterol, and 10-year CHD risk (11.6%). Medication use was responsible for 4% to 5% of the reduction in blood pressure, 32% of the reduction in total cholesterol, 3% of the increase in HDL cholesterol, and 31 % of the reduction in 10-year CHD risk. CONCLUSIONS: Some of the improvements in CHD risk factors can be attributed to medication use; however, the majority of improvements are likely driven by a combination of other factors, including screenings, risk factor counseling, and lifestyle interventions.     

Unique Features of High-Density Lipoproteins in the Japanese: In Population and in Genetic Factors

Despite its gradual increase in the past several decades, the prevalence of atherosclerotic vascular disease is low in Japan. This is largely attributed to difference in lifestyle, especially food and dietary habits, and it may be reflected in certain clinical parameters. Plasma high-density lipoprotein (HDL) levels, a strong counter risk for atherosclerosis, are indeed high among the Japanese. Accordingly, lower HDL seems to contribute more to the development of coronary heart disease (CHD) than an increase in non-HDL lipoproteins at a population level in Japan. Interestingly, average HDL levels in Japan have increased further in the past two decades, and are markedly higher than in Western populations. The reasons and consequences for public health of this increase are still unknown. Simulation for the efficacy of raising HDL cholesterol predicts a decrease in CHD of 70% in Japan, greater than the extent by reducing low-density lipoprotein cholesterol predicted by simulation or achieved in a statin trial. On the other hand, a substantial portion of hyperalphalipoproteinemic population in Japan is accounted for by genetic deficiency of cholesteryl ester transfer protein (CETP), which is also commonly unique in East Asian populations. It is still controversial whether CETP mutations are antiatherogenic. Hepatic Schistosomiasis is proposed as a potential screening factor for historic accumulation of CETP deficiency in East Asia.     

Genetic,Physiological, and Lifestyle Predictors of Mortality in the General Population

Objectives. We investigated the quality of 162 variables, focusing on the contribution of genetic markers, used solely or in combination with other characteristics, when predicting mortality.Methods. In 5974 participants from the Rotterdam Study, followed for a median of 15.1 years, 7 groups of factors including age and gender, genetics, socioeconomics, lifestyle, physiological characteristics, prevalent diseases, and indicators of general health were related to all-cause mortality. Genetic variables were identified from 8 genome-wide association scans (n = 19 033) and literature review.Results. We observed 3174 deaths during follow-up. The fully adjusted model (C-statistic for 15-year follow-up [C_15y] = 0.80; 95% confidence interval [CI] = 0.75, 0.77) predicted mortality well. Most of the additional information apart from age and sex stemmed from physiological markers, prevalent diseases, and general health. Socioeconomic factors and lifestyle contributed meaningfully to mortality risk prediction with longer prediction horizon. Although specific genetic factors were independently associated with mortality, jointly they contributed little to mortality prediction (C_15y = 0.56; 95% CI = 0.55, 0.57).Conclusions. Mortality can be predicted reasonably well over a long period. Genetic factors independently predict mortality, but only modestly more than other risk indicators.In the 20th century, life expectancy at birth increased from 50 years to over 80 years in Western countries.1 Demographers repeatedly predicted that it had reached a ceiling, but life expectancy in record countries continues to rise by an average of 3 months each year.2 Although epidemiological research has identified numerous predictors of mortality, information about their comparative effect sizes and long-term predictive power is sparse. Prior research has often been limited by a short period of follow-up, a limited set of covariates, or a focus on cause-specific mortality. Only a few studies have evaluated the potential for explaining mortality from a broader perspective by jointly analyzing demographic characteristics, lifestyle factors, and indicators of health and disease.3–7 It is still unclear whether genetic information can be used to predict mortality, but recent advances in genomic technology allow for the inclusion of genetic markers in the prediction of mortality.We combined traditional indicators of mortality risk with genetic factors, derived from a meta-analysis of 8 genome-wide association studies and the literature, and associated them with mortality over 15 years of follow-up. Our aims were twofold: first, to identify independent determinants of mortality by analyzing 162 a priori identified risk factors; second, to provide information on the independent and combined potential of genetic markers in predicting mortality.     

Cigarette smoking and coronary heart disease in Puerto Rico

Cigarette smoking habits were assessed in over 9000 men, aged 45–64 years, who participated in a prospective study of coronary heart disease (CHD) in Puerto Rico beginning in 1965. Fewer Puerto Rican men smoked cigarettes, and they smoked fewer cigarettes per day than in comparable studies in the mainland United States. Even in this lower-smoking, low-CHD population, cigarette smoking showed a significant independent association with the incidence of myocardial infarction (MI) over an 8-year period both in the rural and urban areas; however, this association was not statistically significant for other manifestations of CHD. Pipe and cigar smokers had a risk of MI similar to nonsmokers. Those men who used filter cigarettes or who stated that they did not inhale showed the same risk of MI as other cigarette smokers. Ex-smokers had a risk of MI intermediate to that of nonsmokers and current smokers. The risk of MI did not increase with an increase in the number of cigarettes smoked, but the risk of MI in smokers as a group relative to those who had never smoked was 3.4 in the rural area and 2.0 in the urban area. These results emphasize that there is an excess risk of MI in those cigarette smokers who report that they used filter cigarettes, did not inhale, or smoked a small number of cigarettes a day.     

Genetics,lifestyle and environment

UK Biobank is a long-term prospective epidemiology study having recruited and now following the lives of 500,000 people in England, Scotland and Wales, aged 40–69 years when they joined the study (Sudlow et al., PLoS Med 12(3):e1001779, 2015). Participants were recruited by letter and asked to attend one of 22 assessment centres in towns and cities across Britain, where they provided consent, answered detailed questions about their health and lifestyle, had body measures taken and donated blood, urine and saliva. Participants provided consent for the long-term follow-up of their health via medical records, such as general practice and hospital records, cancer and death records. Samples are being stored long term for a wide range of analyses, including genetic. The resource is open to all bona fide scientists from the UK and overseas, academic and industry who register via its access management system. Summary of UK Biobank data can be viewed via its Data Showcase and the resource will be strengthened over time as the results of new analyses and studies are returned, health links and participants provide additional information about themselves. Some will attend full repeat assessment visits. UK Biobank is open for business, and it hopes researchers will find it a valuable tool to improve the health of future generations.     

South Asia symposium on pneumococcal disease and the promise of vaccines – Meeting report

Despite the licensure of the pneumococcal conjugate vaccine (PCV) in the US and other Western countries for over 14 years, as of September 2014 only 4 South Asian countries were using PCV in their universal immunization program. To generate momentum toward addressing this issue a “South Asia symposium on pneumococcal disease and the promise of vaccines” was organized just prior to the 9th international symposium on pneumococci and pneumococcal diseases held in India recently. Leading scientists, program managers, and decision makers including ministry officials from the region participated in the meeting. The participants discussed available data on pneumococcal disease burden in South Asia, surveillance methods, efficacy and safety of pneumococcal conjugate vaccines (PCV), the status of PCV introduction, programmatic challenges in introducing PCV and available data on the impact of PCV in South Asia and globally. There was a strong consensus that available data on disease burden and the global experience with PCV justified the introduction PCV in all Asian countries in order to accelerate the gains in child survival in the region.     

High density lipoprotein cholesterol and incidence of coronary heart disease--the Israeli Ischemic Heart Disease Study.

Using univariate and multivariate analyses, the association between high density lipoprotein (HDL) cholesterol and coronary heart disease (CHD) incidence was investigated. Over 150 cases of myocardial infarction (MI) occurred among 6500 Israeli adult males in a five-year prospective study. At age 50 years and over, there is a significant inverse association between MI incidence and HDL cholesterol. This relationship persists when controlling for risk factors such as age, other cholesterol components, smoking, blood pressure, weight, and diabetes mellitus. Unlike hypercholesterolemia and smoking, the relative risk with HDL cholesterol increases with age above 50. Similar patterns of association occur between HDL cholesterol and angina pectoris incidence, sudden unexpected death and deaths from MI. It is suggested that HDL cholesterol is an independent risk factor for CHD, especially in males over 50, and the implication of this study is that increased HDL cholesterol might play a protective role in the pathogenesis of CHD.     

“A delicate diplomatic situation”: tobacco industry efforts to gain control of the Framingham Study

BackgroundThe Framingham Heart Study (henceforth Framingham) is among the gold standards for epidemiological research. Being a prospective cohort study of 5,000+ men and women, it provided early findings about the causes of coronary heart disease (CHD), following a cohort over the course of 24 years. After US government funding ended, the tobacco industry funded Council for Tobacco Research (CTR) provided continued funding for analyses related to smoking.ObjectiveThis study sought to understand the tobacco industry's motivation and activities in funding Framingham.Study Design and SettingWe analyzed previously undisclosed tobacco industry documents, conducting iterative searches of the Legacy Tobacco Documents Library (http://legacy.library.ucsf.edu/), and assembled a historical case study.ResultsCTR funded Framingham to obtain full access to Framingham data. CTR planned for long-time industry consultant Carl Seltzer to reanalyze them to suggest that tobacco-related morbidity and mortality primarily resulted from “constitutional” factors, such as age or ethnicity. Once data were obtained, CTR terminated funding for the Framingham principal investigator, who disagreed with Seltzer. Seltzer's critical analyses of subsequently published work by the Framingham team created confusion about the association between CHD and cigarette smoking.ConclusionResearchers accepting tobacco industry funding risk losing control of data, analysis, and publication.     

Are genetic tests exceptional? Lessons from a qualitative study on thrombophilia

Policy makers have suggested that information about genetic risk factors, which are associated with low risk and for which preventive strategies exist, should not be considered "exceptional" and should not warrant special safeguards, such as data protection or specialist pre-test counselling. There is scant research on how such risk factors are perceived, and to explore this we conducted qualitative interviews with 42 participants who had undergone testing in the South West of England for a low risk genetic susceptibility to deep vein thrombosis (DVT). Generally the participants, who were mostly women, thought the test was less serious than a genetic test for a predisposition to breast cancer or a non-genetic, diagnostic test for diabetes. They had used the genetic information to reduce their risk of DVTs by avoiding oral contraceptives and hormone replacement therapy but had not changed their lifestyle. Many considered pre-test genetic counselling unnecessary. However, a subgroup of participants, who were often less educated or at a high risk, were distressed and/or confused about thrombophilia and thought pre-test counselling would have been helpful. The findings indicate an emerging interpretation of genetics not as revealing exceptional or "in depth" knowledge about one's health and identity but as occasionally relevant surface information, which participants use to make specific health decisions but not to transform their everyday lives. However, the views of the subgroup indicate that some participants interpret thrombophilia as serious and/or need special support.     

Assessing family history of heart disease in primary care consultations: a qualitative study

BACKGROUND: Current primary prevention guidelines recommend the assessment of family history of coronary heart disease (CHD) to identify at-risk individuals. OBJECTIVE: To examine how clinicians and patients understand and communicate family history in the context of CHD risk assessment in primary care. METHODS: A qualitative study. Patients completed a validated family history questionnaire. Consultations with clinicians were video recorded, and semi-structured interviews conducted with patients after consultation. The participants were 21 primary care patients and seven primary care clinicians (two practice nurses, five GPs). Four practices in South West England. RESULTS: Patients and clinicians usually agreed about the patient's level of risk and how to reduce it. Patients were mostly satisfied with their consultations and having their family history assessed. However, three issues were identified from the consultations which contributed to concerns and unanswered questions for patients. Problems arose when there were few modifiable risk factors to address. Firstly, patients' explanations of their family history were not explored in the consultation. Secondly, the relationship between the patient's family history and their other risk factors, such as smoking or cholesterol, was rarely discussed. Thirdly, clinicians did not explain the integration of family history into the patient's overall cardiovascular disease risk. CONCLUSIONS: Clinicians appeared to lack a rhetoric to discuss family history, in terms of capturing both genetic and environmental factors and its relation to other risk factors. This created uncertainties for patients and carries potential clinical and social implications. There is a need for better guidance for primary care clinicians about family history assessment.     

The search for new risk factors for coronary heart disease: occupational therapy for epidemiologists?

The identification of the proximal causes of coronary heart disease (CHD) during the second half of the 20th century contributed to the prevention of premature CHD and the extension of life expectancy in middle-aged and older people in many wealthy countries. These major CHD risk factors-high blood cholesterol, high blood pressure, cigarette smoking and physical inactivity-satisfy public health criteria of causality. Strong epidemiological evidence suggests that they explain at least 75% of new cases of CHD. However, the search for 'new' or 'emerging' CHD risk factors continues, partly justified by a myth that minimizes the contribution of the major risk factors. The public health criteria of causality were applied to the following proposed new risk factors: thrombotic factors and serum homocysteine levels; infectious agents; early life exposures including prenatal factors; genetic influences; oestrogen deficiency; and the role of the psychosocial environment. None of these factors are as important as the established risk factors for epidemic CHD and their potential contribution for improving population health is limited or unclear. Research into unexplained variations in the occurrence of CHD and into life course influences and socioeconomic inequalities may provide extra leads to effective public health action. Especially important is research on the upstream social and economic determinants of CHD and its major risk factors, on the spread of the CHD epidemic to poorer populations, and into prevention policy and programme effectiveness. Available evidence supports the feasibility and effectiveness of population-wide prevention directed towards increasing the proportion of people at low risk of CHD. The vast majority of the public health effort should be directed to this approach rather than to the high risk individual approach. There is still a major gap between knowledge and action in preventing the CHD epidemics.