Prognostic Value of Cardiovascular Biomarkers in the Population.

Importance: Identification of individuals at high risk for atherosclerotic cardiovascular disease within the population is important to inform primary prevention strategies. Objective: To evaluate the prognostic value of routinely available cardiovascular biomarkers when added to established risk factors. Design, Setting, and Participants: Individual-level analysis including data on cardiovascular biomarkers from 28 general population-based cohorts from 12 countries and 4 continents with assessments by participant age. The median follow-up was 11.8 years. Exposure: Measurement of high-sensitivity cardiac troponin I, high-sensitivity cardiac troponin T, N-terminal pro-B-type natriuretic peptide, B-type natriuretic peptide, or high-sensitivity C-reactive protein. Main Outcomes and Measures: The primary outcome was incident atherosclerotic cardiovascular disease, which included all fatal and nonfatal events. The secondary outcomes were all-cause mortality, heart failure, ischemic stroke, and myocardial infarction. Subdistribution hazard ratios (HRs) for the association of biomarkers and outcomes were calculated after adjustment for established risk factors. The additional predictive value of the biomarkers was assessed using the C statistic and reclassification analyses. Results: The analyses included 164 054 individuals (median age, 53.1 years [IQR, 42.7-62.9 years] and 52.4% were women). There were 17 211 incident atherosclerotic cardiovascular disease events. All biomarkers were significantly associated with incident atherosclerotic cardiovascular disease (subdistribution HR per 1-SD change, 1.13 [95% CI, 1.11-1.16] for high-sensitivity cardiac troponin I; 1.18 [95% CI, 1.12-1.23] for high-sensitivity cardiac troponin T; 1.21 [95% CI, 1.18-1.24] for N-terminal pro-B-type natriuretic peptide; 1.14 [95% CI, 1.08-1.22] for B-type natriuretic peptide; and 1.14 [95% CI, 1.12-1.16] for high-sensitivity C-reactive protein) and all secondary outcomes. The addition of each single biomarker to a model that included established risk factors improved the C statistic. For 10-year incident atherosclerotic cardiovascular disease in younger people (aged <65 years), the combination of high-sensitivity cardiac troponin I, N-terminal pro-B-type natriuretic peptide, and high-sensitivity C-reactive protein resulted in a C statistic improvement from 0.812 (95% CI, 0.8021-0.8208) to 0.8194 (95% CI, 0.8089-0.8277). The combination of these biomarkers also improved reclassification compared with the conventional model. Improvements in risk prediction were most pronounced for the secondary outcomes of heart failure and all-cause mortality. The incremental value of biomarkers was greater in people aged 65 years or older vs younger people. Conclusions and Relevance: Cardiovascular biomarkers were strongly associated with fatal and nonfatal cardiovascular events and mortality. The addition of biomarkers to established risk factors led to only a small improvement in risk prediction metrics for atherosclerotic cardiovascular disease, but was more favorable for heart failure and mortality.

Association between fatty liver index and blood coagulation markers: a population-based study.

BACKGROUND: Population-based studies investigating the association between blood coagulation markers and non-alcoholic fatty liver disease (NAFLD) are rare. Thus, we aimed to investigate the relationship between the Fatty Liver Index (FLI) as a measure of hepatic steatosis and plasma concentrations of antithrombin III, D-dimer, fibrinogen D, protein C, protein S, factor VIII, activated partial thromboplastin time (aPTT), quick value and international thromboplastin time (INR) in the general population. METHODS: After the exclusion of participants with anticoagulative treatment, 776 participants (420 women and 356 men, aged 54-74 years) of the population-based KORA Fit study with analytic data on hemostatic factors were included in the present analysis. Linear regression models were used to explore the associations between FLI and hemostatic markers, adjusted for sex, age, alcohol consumption, education, smoking status, and physical activity. In a second model, additional adjustments were made for the history of stroke, hypertension, myocardial infarction, serum non-HDL cholesterol levels, and diabetes status. In addition, analyses were stratified by diabetes status. RESULTS: In the multivariable models (with or without health conditions), significantly positive associations with FLI were obtained for plasma concentrations of D-dimers, factor VIII, fibrinogen D, protein C, protein S, and quick value, while INR and antithrombin III were inversely associated. These associations were weaker in pre-diabetic subjects and largely disappeared in diabetic patients. CONCLUSION: In this population-based study, an increased FLI is clearly related to changes in the blood coagulation system, possibly increasing the risk of thrombotic events. Due to a generally more pro-coagulative profile of hemostatic factors, such an association is not visible in diabetic subjects.

[Measuring physical fitness in the German National Cohort-methods, quality assurance, and first descriptive results]. / Messung der körperlichen Fitness in der NAKO Gesundheitsstudie ­ Methoden, Qualitätssicherung und erste deskriptive Ergebnisse.

Physical fitness is defined as an individual's ability to be physically active. The main components are cardiorespiratory fitness (CRF), muscle strength, and flexibility. Regardless of physical activity level, physical fitness is an important determinant of morbidity and mortality.The aim of the current study was to describe the physical fitness assessment methodology in the German National Cohort (NAKO) and to present initial descriptive results in a subsample of the cohort.In the NAKO, hand grip strength (GS) and CRF as physical fitness components were assessed at baseline using a hand dynamometer and a submaximal bicycle ergometer test, respectively. Maximum oxygen uptake (VO2max) was estimated as a result of the bicycle ergometer test. The results of a total of 99,068 GS measurements and 3094 CRF measurements are based on a data set at halftime of the NAKO baseline survey (age 20-73 years, 47% men).Males showed higher values of physical fitness compared to women (males: GS = 47.8 kg, VO2max = 36.4 ml·min-1 · kg-1; females: GS = 29.9 kg, VO2max = 32.3 ml · min-1 · kg-1). GS declined from the age of 50 onwards, whereas VO2max levels decreased continuously between the age groups of 20-29 and ≥60 years. GS and VO2max showed a linear positive association after adjustment for body weight (males ß = 0.21; females ß = 0.35).These results indicate that the physical fitness measured in the NAKO are comparable to other population-based studies. Future analyses in this study will focus on examining the independent relations of GS and CRF with risk of morbidity and mortality.

Muscular Strength is Independently Associated with Cystatin C: The KORA-Age Study.

The purpose of this study was to investigate if there is a link between muscular strength (MS) and markers of chronic kidney disease (CKD) among older adults. The cross-sectional analysis based on 1041 men and women, aged 65-94 years, who participated in the KORA-Age study. Participants underwent an interview and extensive examinations including anthropometric measurements, diseases and drug intake registration, determination of health-related behaviors, collection of blood samples for measurements of cystatin C and maximal muscle strength evaluation. One-Way ANOVA revealed significant differences in both mean cystatin C (1.16±0.37 vs. 1.03±0.29 vs. 0.93±0.24 mg/L, p<0.001) and mean eGFRcysC (63.61±18.61 vs. 72.14±18.92 vs. 79.87±18.19 ml/min/1.73 m2, p<0.05) across thirds of maximal muscular strength (from lowest to highest). MS in the lowest third was significantly associated with increased odds of having elevated cystatin C (OR: 1.70, 95% CI: 1.01-2.85, p=0.043) after controlling for age, gender, fat mass, fat-free mass, alcohol intake, smoking status, number of regularly used medications, multimorbidity status, hs-CRP, telomere length and levels of physical activity. Lower levels of MS are independently associated with higher concentrations of cystatin C and lower eGFRcysC in older individuals. Increasing the levels of muscular strength may be useful to prevent the age-related CKD disease of older adults.

Childhood Trauma and Somatic and Mental Illness in Adulthood.

BACKGROUND: Childhood trauma is associated with somatic and mental illness in adulthood. The strength of the association varies as a function of age, sex, and type of trauma. Pertinent studies to date have mainly focused on individual diseases. In this study, we investigate the association between childhood trauma and a multiplicity of somatic and mental illnesses in adulthood. METHODS: Data from 156 807 NAKO Health Study participants were analyzed by means of logistic regressions, with adjustment for age, sex, years of education, and study site. The Childhood Trauma Screener differentiated between no/minor (n = 115 891) and moderate/severe childhood trauma (n = 40 916). The outcome variables were medical diagnoses of five somatic and two mental health conditions as stated in the clinical history. RESULTS: Persons with childhood trauma were more likely to bear a diagnosis of all of the studied conditions: cancer (odds ratio [OR] = 1.10; 95% confidence interval: [1.05; 1.15]), myocardial infarction (OR = 1.13 [1.03; 1.24]), diabetes (OR = 1.16, [1.10; 1.23]), stroke (OR = 1.35 [1.23; 1.48]), chronic obstructive pulmonary disease (OR = 1.45 [1.38; 1.52]), depression (OR = 2.36 [2.29; 2.43]), and anxiety disorders (OR = 2.08 [2.00; 2.17]). All of these associations were stronger in younger persons, regardless of the nature of childhood trauma. Differences between the sexes were observed only for some of these associations. CONCLUSION: Childhood trauma was associated with a higher probability of developing mental as well as somatic illness in adulthood. As childhood trauma is an element of individual history that the victim has little to no control over, and because the illnesses that can arise in adulthood in association with it are a heavy burden on the affected persons and on society, there is a need for research on these associations and for the development of preventive measures.

Prediction of type 2 diabetes mellitus based on nutrition data.

Numerous predictive models for the risk of type 2 diabetes mellitus (T2DM) exist, but a minority of them has implemented nutrition data so far, even though the significant effect of nutrition on the pathogenesis, prevention and management of T2DM has been established. Thus, in the present study, we aimed to build a predictive model for the risk of T2DM that incorporates nutrition data and calculates its predictive performance. We analysed cross-sectional data from 1591 individuals from the population-based Cooperative Health Research in the Region of Augsburg (KORA) FF4 study (2013-14) and used a bootstrap enhanced elastic net penalised multivariate regression method in order to build our predictive model and select among 193 food intake variables. After selecting the significant predictor variables, we built a logistic regression model with these variables as predictors and T2DM status as the outcome. The values of area under the receiver operating characteristic (ROC) curve, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of our predictive model were calculated. Eleven out of the 193 food intake variables were selected for inclusion in our model, which yielded a value of area under the ROC curve of 0⋅79 and a maximum PPV, NPV and accuracy of 0⋅37, 0⋅98 and 0⋅91, respectively. The present results suggest that nutrition data should be implemented in predictive models to predict the risk of T2DM, since they improve their performance and they are easy to assess.

Correlation between thoracolumbar disc degeneration and anatomical spinopelvic parameters in supine position on MRI.

OBJECTIVE: This study aims to investigate the correlation between spinopelvic parameters in supine position (pelvic incidence (PI), sacral slope (SS), pelvic tilt (PT), lumbar lordosis (LL)), disc degeneration and herniation of the thoracolumbar spine, as well as cardiovascular risk factors and back pain in a southern German cohort from the general population. METHODS: This study is a cross-sectional, case-control study drawn from a prospective cohort of the "Cooperative Health Research in the Region of Augsburg/Kooperative Gesundheitsforschung in der Region Augsburg" study (KORA). In total, 374 participants (mean age 56.4 ± 9.2 years; 57.8% male) from the whole-body MRI cohort (FF4) were included. All participants underwent a standardized whole-body MRI on which disc degeneration of the thoracic and lumbar spine was evaluated using a sequence adapted Pfirrmann score. PI, PT, SS and LL were measured according to the description in the literature, using sagittal imaging. Furthermore, disc bulging and protrusion were assessed. Correlations were estimated by logistic regression models providing odds ratios. RESULTS: Mean PI was 54.0° ± 11.1°, PT 13.0° ± 5.8°, SS 40.2° ± 8.8° and LL 36.2° ± 9.6°. SS was greater in men (p<0.05) and lumbar lordosis in women (p<0.001). PT increased by 0.09° per age-year with rising age. Age was not associated with PI, SS and LL. Neither BMI, hypertension, cholesterol, lipid levels, nor physical activity were associated with PI, PT, SS or LL. Diabetes mellitus negatively correlated with SS (ß = -4.19; 95%CI -7.31-1.06, p<0.01). Smaller spinopelvic parameters (PI, SS and LL) where significantly (p<0.05) correlated with an increased frequency of disc bulging, as well as a local clustering in the lumbar, but not the thoracic spine. CONCLUSION: In conclusion, spinopelvic parameters, measured in supine position, are significantly correlated with disc bulging alone; there is no significant correlation between supine spinopelvic parameters and disc degeneration, back pain or cardiovascular risk factors.

Random Survival Forest in practice: a method for modelling complex metabolomics data in time to event analysis.

BACKGROUND: The application of metabolomics in prospective cohort studies is statistically challenging. Given the importance of appropriate statistical methods for selection of disease-associated metabolites in highly correlated complex data, we combined random survival forest (RSF) with an automated backward elimination procedure that addresses such issues. METHODS: Our RSF approach was illustrated with data from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study, with concentrations of 127 serum metabolites as exposure variables and time to development of type 2 diabetes mellitus (T2D) as outcome variable. Out of this data set, Cox regression with a stepwise selection method was recently published. Replication of methodical comparison (RSF and Cox regression) was conducted in two independent cohorts. Finally, the R-code for implementing the metabolite selection procedure into the RSF-syntax is provided. RESULTS: The application of the RSF approach in EPIC-Potsdam resulted in the identification of 16 incident T2D-associated metabolites which slightly improved prediction of T2D when used in addition to traditional T2D risk factors and also when used together with classical biomarkers. The identified metabolites partly agreed with previous findings using Cox regression, though RSF selected a higher number of highly correlated metabolites. CONCLUSIONS: The RSF method appeared to be a promising approach for identification of disease-associated variables in complex data with time to event as outcome. The demonstrated RSF approach provides comparable findings as the generally used Cox regression, but also addresses the problem of multicollinearity and is suitable for high-dimensional data.

Immunochip analysis identifies association of the RAD50/IL13 region with human longevity.

Human longevity is characterized by a remarkable lack of confirmed genetic associations. Here, we report on the identification of a novel locus for longevity in the RAD50/IL13 region on chromosome 5q31.1 using a combined European sample of 3208 long-lived individuals (LLI) and 8919 younger controls. First, we performed a large-scale association study on 1458 German LLI (mean age 99.0 years) and 6368 controls (mean age 57.2 years) by targeting known immune-associated loci covered by the Immunochip. The analysis of 142 136 autosomal single nucleotide polymorphisms (SNPs) revealed an Immunochip-wide significant signal (PI mmunochip  = 7.01 × 10(-9) ) for the SNP rs2075650 in the TOMM40/APOE region, which has been previously described in the context of human longevity. To identify novel susceptibility loci, we selected 15 markers with PI mmunochip  < 5 × 10(-4) for replication in two samples from France (1257 LLI, mean age 102.4 years; 1811 controls, mean age 49.1 years) and Denmark (493 LLI, mean age 96.2 years; 740 controls, mean age 63.1 years). The association at SNP rs2706372 replicated in the French study collection and showed a similar trend in the Danish participants and was also significant in a meta-analysis of the combined French and Danish data after adjusting for multiple testing. In a meta-analysis of all three samples, rs2706372 reached a P-value of PI mmunochip+Repl  = 5.42 × 10(-7) (OR = 1.20; 95% CI = 1.12-1.28). SNP rs2706372 is located in the extended RAD50/IL13 region. RAD50 seems a plausible longevity candidate due to its involvement in DNA repair and inflammation. Further studies are needed to identify the functional variant(s) that predispose(s) to a long and healthy life.