Instability of personal human metabotype is linked to all-cause mortality.

Disruption of metabolic homeostasis is an important factor in many diseases. Various metabolites have been linked to higher risk of morbidity and all-cause mortality using metabolomics in large population-based cohorts. In these studies, baseline metabolite levels were compared across subjects to identify associations with health outcomes, implying the existence of 'healthy' concentration ranges that are equally applicable to all individuals. Here, we focused on intra-individual changes in metabolite levels over time and their link to mortality, potentially allowing more personalized risk assessment. We analysed targeted metabolomics data for 134 blood metabolites from 1409 participants in the population-based CARLA cohort at baseline and after four years. Metabotypes of the majority of participants (59%) were extremely stable over time indicated by high correlation between the subjects' metabolite profiles at the two time points. Metabotype instability and, in particular, decrease of valine were associated with higher risk of all-cause mortality in 7.9 years of follow-up (hazard ratio (HR) = 1.5(95%CI = 1.0-2.3) and 0.2(95%CI = 0.1-0.3)) after multifactorial adjustment. Excluding deaths that occurred in the first year after metabolite profiling showed similar results (HR = 1.8(95%CI = 1.1-2.8)). Lower metabotype stability was also associated with incident cardiovascular disease (OR = 1.2(95%CI = 1.0-1.3)). Therefore, changes in the personal metabotype might be a valuable indicator of pre-clinical disease.

Educational status and differences in left ventricular mass and ejection fraction - The role of BMI and parameters related to the metabolic syndrome: A longitudinal analysis from the population-based CARLA cohort.

BACKGROUND AND AIMS: Higher ventricular mass has been reported in non-white US-Americans with low educational status and in socially isolated people. To assess the impact of education on cardiac mass and function in the general population and to identify mediators. METHODS AND RESULTS: Data from a German population-based sample were used (CARLA cohort, n = 1779 at baseline, n = 1436 at the four-year follow-up). Ventricular mass indexed on height (LVMI) and ejection fraction, using Teichholz's formula (EFTZ), were measured. Education was assessed using the ISCED classification. Mediator analyses were performed using the R-macro 'mediation' to compute the average direct effect and the average causal mediated effect after confounder adjustment. Sensitivity analyses for unobserved confounders were performed. Considered mediators were BMI, waist-to-hip ratio, HbA1c, and systolic and diastolic blood pressures. We found differences in LVMI and EFTZ, both at baseline and follow-up, between educational levels in women (lowest vs highest educational level: 15.6 g, 95% CI: -25.7, -5.6), but not in men. Similarly, women (lowest vs highest educational level at baseline: 3.3%, 95% CI: 0.8-5.7), but not men, of higher educational levels had a higher EFTZ of comparable magnitude at baseline and follow-up. Of the considered mediators, BMI explained 55.9% at baseline and 54.1% at follow-up of the educational effect, while other potential mediators had no significant effect. Relations remained constant between baseline and follow-up. CONCLUSIONS: Women with low educational levels tend to have a higher ventricular mass and lower EF, which can be explained by a higher BMI in this group.

Changes in body weight and obesity status in German adults: results of seven population-based prospective studies.

BACKGROUND/OBJECTIVES: The objective of this study was to quantify body weight changes in German adult populations during the past decades. SUBJECTS/METHODS: Longitudinal analysis of seven cohort studies covering different age ranges between 18 and 83 years. Baseline examinations were between 1994 and 2007 and follow-up durations between 4.0 and 11.9 years. For each study, mean change in body weight per year and 10-year change in body mass index (BMI) classification were analyzed. For the middle age group of 45-64 years, meta-analysis was conducted to obtain an overall estimate for Germany. RESULTS: Among men weight gain was highest in the youngest participants and decreased with advancing age. Among women weight gain was on a stable high level among those younger than 45 years and decreased at older age. Within 10 years, 30-40% of middle-aged participants with normal baseline weight became pre-obese or obese and 20-25% of those with pre-obesity at baseline became obese, whereas >80% of persons who were obese at baseline remained obese over time. The estimated average weight change in adults aged 45-64 years was 0.25 (95% confidence interval (CI): 0.18-0.33) kg/year among men and 0.24 (0.17-0.30) kg/year among women. CONCLUSIONS: We could observe a moderate weight gain over the past years in German middle-aged populations of 0.25 kg/year. Obesity prevention needs to be targeted to specific subgroups in the population, especially to younger adults, who seem to be most vulnerable for gaining weight. Obesity intervention needs to be improved, as the majority of obese adults remained obese over time.

Educational level and chronic inflammation in the elderly--the role of obesity: results from the population-based CARLA study.

This study aimed to assess the mediating role of anthropometric parameters in the relation of education and inflammation in the elderly. Cross-sectional data from the population-based CARdio-vascular Disease, Living and Ageing in Halle study were used after excluding subjects with a plasma level of high-sensitive C-reactive protein (hsCRP) above 10 mg L(-1) (916 men/760 women remaining). Education was categorized in accordance with International Standard Classification of Education. As inflammation parameters, the soluble tumour necrosis factor type 1 (sTNF-R1), hsCRP and interleukin 6 (IL-6) were taken into account. Anthropometric parameters were the body mass index (BMI), waist-to-hip ratio (WHR) and waist-to-height ratio (WHeR). We used covariate adjusted mixed models to assess associations. Effect measures were the natural indirect effect (NIE), controlled direct effect and total effect (TE). Education was associated with sTNF-R1, hsCRP and IL-6 in men, and sTNF-R1 and hsCRP in women. Anthropometric parameters correlated with all inflammation parameters after covariate adjustment. BMI and WHeR were strong mediators of educational differences in sTNF-R1 (percentage of NIE of TE: 28% in men; 33% in women) and hsCRP (percentage of NIE of TE: 35% in men; 52% in women), while WHR was the weakest mediator. General obesity mediates roughly one-third of the association of education with chronic inflammation in the elderly.

Association of neighbourhood unemployment rate with incident Type 2 diabetes mellitus in five German regions.

AIM: To analyse the association of neighbourhood unemployment with incident self-reported physician-diagnosed Type 2 diabetes in a population aged 45-74 years from five German regions. METHODS: Study participants were linked via their addresses at baseline to particular neighbourhoods. Individual-level data from five population-based studies were pooled and combined with contextual data on neighbourhood unemployment. Type 2 diabetes was assessed according to a self-reported physician diagnosis of diabetes. We estimated proportional hazard models (Weibull distribution) in order to obtain hazard ratios and 95% CIs of Type 2 diabetes mellitus, taking into account interval-censoring and clustering. RESULTS: We included 7250 participants residing in 228 inner city neighbourhoods in five German regions in our analysis. The incidence rate was 12.6 per 1000 person-years (95% CI 11.4-13.8). The risk of Type 2 diabetes mellitus was higher in men [hazard ratio 1.79 (95% CI 1.47-2.18)] than in women and higher in people with a low education level [hazard ratio 1.55 (95% CI 1.18-2.02)] than in those with a high education level. Independently of individual-level characteristics, we found a higher risk of Type 2 diabetes mellitus in neighbourhoods with high levels of unemployment [quintile 5; hazard ratio 1.72 (95% CI 1.23-2.42)] than in neighbourhoods with low unemployment (quintile 1). CONCLUSIONS: Low education level and high neighbourhood unemployment were independently associated with an elevated risk of Type 2 diabetes mellitus. Studies examining the impact of the residential environment on Type 2 diabetes mellitus will provide knowledge that is essential for the identification of high-risk populations.

Health-related quality of life in women and men with type 2 diabetes: a comparison across treatment groups.

AIM: This study compares health-related quality of life (HRQL) in patients with type 2 diabetes (T2DM) across treatment groups and explores gender differences. METHODS: Four regional surveys (KORA, CARLA, SHIP, DHS) and a national survey (GNHIES98) were pooled at individual level. HRQL was assessed with the SF-12/-36v1. Linear regression models were used to assess the effect of T2DM by treatment type (no medication; oral; oral/insulin combination; insulin) on the physical (PCS-12) and mental summary score (MCS-12) and the SF-6D, controlling for age, sex, study and covariates. We also performed an explanatory analysis of single items. RESULTS: PCS-12 scores and treatment type were associated (P-value 0.006), with lowest values for insulin treatment (-4.44 vs. oral; -4.41 vs. combination). MCS-12 scores were associated with treatment type and gender (P-value <0.012), with lower scores for women undergoing oral (-4.25 vs. men) and combination treatment (-6.99 vs. men). Similar results were observed for SF-6D utilities and single items, related to mental health, social functioning, vitality and role limitation (emotional). Comorbidities were predictors of lower PCS-12 and SF-6D scores. CONCLUSIONS: T2DM treatment impacts differently on physical and mental HRQL and on women and men. Further studies of gender-specific perceptions of T2DM treatment regimens are needed.

Validation of the German Diabetes Risk Score within a population-based representative cohort.

AIM: To validate the German Diabetes Risk Score within the population-based cohort of the Cardiovascular Disease - Living and Ageing in Halle (CARLA) study. METHODS: The sample included 582 women and 719 men, aged 45-83 years, who did not have diabetes at baseline. The individual risk of every participant was calculated using the German Diabetes Risk Score, which was modified for 4 years of follow-up. Predicted probabilities and observed outcomes were compared using Hosmer-Lemeshow goodness-of-fit tests and receiver-operator characteristic analyses. Changes in prediction power were investigated by expanding the German Diabetes Risk Score to include metabolic variables and by subgroup analyses. RESULTS: We found 58 cases of incident diabetes. The median 4-year probability of developing diabetes based on the German Diabetes Risk Score was 6.5%. The observed and predicted probabilities of developing diabetes were similar, although estimation was imprecise owing to the small number of cases, and the Hosmer-Lemeshow test returned a poor correlation (chi-squared = 55.3; P = 5.8*10⁻¹²). The area under the receiver-operator characteristic curve (AUC) was 0.70 (95% CI 0.64-0.77), and after excluding participants ≥66 years old, the AUC increased to 0.77 (95% CI 0.70-0.84). Consideration of glycaemic diagnostic variables, in addition to self-reported diabetes, reduced the AUC to 0.65 (95% CI 0.58-0.71). A new model that included the German Diabetes Risk Score and blood glucose concentration (AUC 0.81; 95% CI 0.76-0.86) or HbA(1c) concentration (AUC 0.84; 95% CI 0.80-0.91) was found to peform better. CONCLUSIONS: Application of the German Diabetes Risk Score in the CARLA cohort did not reproduce the findings in the European Prospective Investigation into Cancer and Nutrition (EPIC) Potsdam study, which may be explained by cohort differences and model overfit in the latter; however, a high score does provide an indication of increased risk of diabetes.

The impact of regional deprivation and individual socio-economic status on the prevalence of Type 2 diabetes in Germany. A pooled analysis of five population-based studies.

AIM: Our objective was to test the hypothesis that the prevalence of Type 2 diabetes increases with increasing regional deprivation even after controlling for individual socio-economic status. METHODS: We pooled cross-sectional data from five German population-based studies. The data set contained information on n = 11,688 study participants (men 50.1%) aged 45-74 years, of whom 1008 people had prevalent Type 2 diabetes (men 56.2%). Logistic multilevel regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI) for diabetes prevalence. We controlled for sex, age and lifestyle risk factors, individual socio-economic status and regional deprivation, based on a new small-area deprivation measure, the German Index of Multiple Deprivation. RESULTS: Adjusted for sex, age, body mass index (BMI), physical activity, smoking status and alcohol consumption, the prevalence of Type 2 diabetes showed a stepwise increase in risk with increasing area deprivation [OR 1.88 (95% CI 1.16-3.04) in quintile 4 and OR 2.14 (95% CI 1.29-3.55) in quintile 5 compared with the least deprived quintile 1], even after controlling for individual socio-economic status. Focusing on individual socio-economic status alone, the risk of having diabetes was significantly higher for low compared with medium or high educational level [OR 1.46 (95% CI 1.24-1.71)] and for the lowest compared with the highest income group [OR 1.53 (95% CI 1.18-1.99)]. CONCLUSION: Regional deprivation plays a significant part in the explanation of diabetes prevalence in Germany independently of individual socio-economic status. The results of the present study could help to target public health measures in deprived regions.

[The German National Cohort]. / Die Nationale Kohorte.

The German National Cohort (GNC) is a joint interdisciplinary endeavour of scientists from the Helmholtz Association, universities and other German research institutes. Its aim is to investigate the development of major chronic diseases (cardiovascular diseases, cancer, diabetes, neurodegenerative psychiatric diseases, pulmonary and infectious diseases), the subclinical stages and functional changes. In 18 study centres across Germany, a representative sample of the general population will be drawn to recruit in total 200,000 men and women aged 20-69 years. In addition to interviews and questionnaires, the baseline assessment includes a series of medical examinations and the collection of a diverse range of biomaterials. In 20% of the participants, an intensified assessment programme is foreseen. Also in 40,000 participants, magnetic resonance imaging of the whole body, heart and brain will be performed. After 5 years, a follow-up examination will be performed in all subjects and active follow-up by postal questionnaires is planned every 2-3 years. The GNC will provide an excellent basis for future population-based epidemiology in Germany and results will help identify new and tailored strategies for prevention, prediction and early detection of major diseases.

[A cohort study investigating risk factors for cardiovascular disease in an urban elderly East-German population (CARLA study)]. / Kohortenstudie zu Risikofaktoren für Herz-Kreislauf-Krankheiten in einer urbanen älteren ostdeutschen Allgemeinbevölkerung (CARLA-Studie).

The CARLA study (Cardiovascular Disease, Living and Ageing in Halle) is a population-based cohort study of the elderly general population of the city of Halle (Saale) aged 45-83 years. The aim is to investigate established cardiovascular risk factors and a reduced heart rate variability (HRV) as indicator of autonomous dysfunction. In total, 1779 probands (812 women and 967 men) were investigated at baseline. Of those, 1436 participants were re-examined at a 4-years follow-up. The corresponding response rates were 64.1% in the baseline and 92% in the follow-up investigation. In the cross-sectional analysis a clear decrease was found in all parameters of HRV with increasing age, but no consistent associations to cardiovascular classical risk factors and diseases could be shown. Compared to other German cohorts a striking risk constellation was found consisting of high prevalence of hypertension, frequent occurrence of central overweight (measured by waist-hip ratio) and high prevalence of diabetes mellitus. These findings will be further scrutinized in the ongoing analyses of the 4-year follow-up and the 10-years follow-up which will start in 2012.

Regional differences in the prevalence of known Type 2 diabetes mellitus in 45-74 years old individuals: results from six population-based studies in Germany (DIAB-CORE Consortium).

AIM: In Germany, regional data on the prevalence of Type 2 diabetes mellitus are lacking for health-care planning and detection of risk factors associated with this disease. We analysed regional variations in the prevalence of Type 2 diabetes and treatment with antidiabetic agents. METHODS: Data of subjects aged 45-74 years from five regional population-based studies and one nationwide study conducted between 1997 and 2006 were analysed. Information on self-reported diabetes, treatment, and diagnosis of diabetes were compared. Type 2 diabetes prevalence estimates (95% confidence interval) from regional studies were directly standardized to the German population (31 December 2007). RESULTS: Of the 11,688 participants of the regional studies, 1008 had known Type 2 diabetes, corresponding to a prevalence of 8.6% (8.1-9.1%). For the nationwide study, a prevalence of 8.2% (7.3-9.2%) was estimated. Prevalence was higher in men (9.7%; 8.9-10.4%) than in women (7.6%; 6.9-8.3%). The regional standardized prevalence was highest in the east with 12.0% (10.3-13.7%) and lowest in the south with 5.8% (4.9-6.7%). Among persons with Type 2 diabetes, treatment with oral antidiabetic agents was more frequently reported in the south (56.9%) and less in the northeast (46.0%), whereas treatment with insulin alone was more frequently reported in the northeast (21.6%) than in the south (16.4%). CONCLUSION: The prevalence of known Type 2 diabetes showed a southwest-to-northeast gradient within Germany, which is in accord with regional differences in the distribution of risk factors for Type 2 diabetes. Furthermore, the treatment with antidiabetic agents showed regional differences.

Health-related quality of life in subjects with and without Type 2 diabetes: pooled analysis of five population-based surveys in Germany.

AIMS: To estimate population values of health-related quality of life (HRQL) in subjects with and without Type 2 diabetes mellitus across several large population-based survey studies in Germany. Systematic differences in relation to age and sex were of particular interest. METHODS: Individual data from four population-based studies from different regions throughout Germany and the nationwide German National Health Interview and Examination Survey (GNHIES98) were included in a pooled analysis of primary data (N = 9579). HRQL was assessed using the generic index instrument SF-36 (36-item Short Form Health Survey) or its shorter version, the SF-12 (12 items). Regression analysis was carried out to examine the association between Type 2 diabetes and the two component scores derived from the SF-36/SF-12, the physical component summary score (PCS-12) and the mental component summary score (MCS-12), as well as interaction effects with age and sex. RESULTS: The PCS-12 differed significantly by -4.1 points in subjects with Type 2 diabetes in comparison with subjects without Type 2 diabetes. Type 2 diabetes was associated with significantly lower MCS-12 in women only. Higher age was associated with lower PCS-12, but with an increase in MCS-12, for subjects with and without Type 2 diabetes. CONCLUSIONS: Pooled analysis of population-based primary data offers HRQL values for subjects with Type 2 diabetes in Germany, stratified by age and sex. Type 2 diabetes has negative consequences for HRQL, particularly for women. This underlines the burden of disease and the importance of diabetes prevention. Factors that disadvantage women with Type 2 diabetes need to be researched more thoroughly.

Longevity of soccer players: an investigation of all German internationals from 1908 to 2006.

Leisure-time physical activity is associated with better health and a reduced risk of all-cause mortality. It is unclear if this association is also present with a high level of physical activity as it is found in professional athletes. In a population-based retrospective cohort study, we compared the survival experience of all soccer players participating for Germany in international matches between 1908 and 2006 to that of the general population. To summarize survival experience, we calculated cumulative relative survival ratios (RSRs) from a life table. We included data of 812 international players, of which 428 (=52.7%) died during follow-up. In all 13 intervals, cumulative observed survival was smaller than cumulative expected survival, resulting in cumulative RSRs being <1. The cumulative RSRs are statistically significantly different from 1 in all but the last interval. This impaired survival experience of the internationals translates into a loss of median residual lifetime of 1.9 years [95% confidence interval: 0.6, 3.2] years at the entry time into the cohort. This loss is mainly driven by the mortality of internationals from the earlier half of the observation period. Reasons for this might be poorer medical care in former times, internationals being killed in action during World War II, and a changing distribution of causes of death during the 20th century.

Ignoring lack of association of heart rate variability with cardiovascular disease and risk factors: response to the manuscript "The relationship of autonomic imbalance, heart rate variability cardiovascular disease risk factors" by Julian F. Thayer, Shelby S. Yamamoto, Jos F. Brosschot.

A reduced heart rate variability (HRV) is a marker of autonomic dysfunction and has been shown to be associated with an increased risk of cardiovascular morbidity and mortality. However, especially regarding the association of HRV with cardiovascular risk factors the literature is rather inconsistent. We therefore critically discuss the review of Thayer et al. concerning the relationship between autonomic imbalance, heart rate variability and cardiovascular disease risk factors.

[Biological markers in epidemiology: concepts, applications, perspectives (part I)]. / Biologische Marker in der Epidemiologie: Begriffe, Anwendungen, Perspektiven (Teil I).

The inclusion of biomarkers in epidemiological research provides new possibilities for exposure assessment and the study of early structural or functional changes and pre-clinical stages of diseases. At the same time issues of validity, reliability, and quality control as well as logistics require special attention. Usually epidemiological studies become more expensive with regard to time and cost. Interdisciplinary collaboration between epidemiology, basic research, and laboratory research is crucial. A prerequisite for this collaboration are agreements on definitions, methods and procedures. The definition of "biomarker" and a description of previous uses of biomarkers in epidemiological studies are presented in the first part of this paper. The second part addresses genetic markers and markers of individual sensitivity and susceptibility. We will end with a discussion about the possible future of biomarkers in epidemiology.

[Biological Markers in Epidemiology: Concepts, applications, Perspectives (Part II)]. / Biologische Marker in der Epidemiologie: Begriffe, Anwendungen, Perspektiven (Teil II).

The first part of this paper outlined terms and definitions in the context of the application of biological markers in epidemiological studies. Cardiovascular epidemiology served as an example for their historical development. The second part focusses on DNA-based biomarkers, practical and methodological dimensions of the use of biomarkers in analytic epidemiological studies as well as requirements in respect of validity and quality assurance. Most genetic polymorphisms have no impact on health. However, some can be used as biomarkers for individual sensitvity to exposures and susceptibility for specific diseases. The Human Genome Project has brought about a quantum leap in the development of genetic markers. The practical implications cannot presently be assessed with certainty. However, present and future research programmes of gene-environment interactions depend on "traditional" epidemiological study designs, methods, and concepts. Ethical principles and data protection requirements apply equally to genetic and molecular epidemiology as do the "Guidelines for Good Epidemiological Practice".