Erratum to: Assessment of predictive performance in incomplete data by combining internal validation and multiple imputation

Abstract Background Missing values are a frequent issue in human studies. In many situations, multiple imputation (MI) is an appropriate missing data handling strategy, whereby missing values are imputed multiple times, the analysis is performed in every imputed data set, and the obtained estimates are pooled. If the aim is to estimate (added) predictive performance measures, such as (change in) the area under the receiver-operating characteristic curve (AUC), internal validation strategies become desirable in order to correct for optimism. It is not fully understood how internal validation should be combined with multiple imputation. Methods In a comprehensive simulation study and in a real data set based on blood markers as predictors for mortality, we compare three combination strategies: Val-MI, internal validation followed by MI on the training and test parts separately, MI-Val, MI on the full data set followed by internal validation, and MI(-y)-Val, MI on the full data set omitting the outcome followed by internal validation. Different validation strategies, including bootstrap und cross-validation, different (added) performance measures, and various data characteristics are considered, and the strategies are evaluated with regard to bias and mean squared error of the obtained performance estimates. In addition, we elaborate on the number of resamples and imputations to be used, and adopt a strategy for confidence interval construction to incomplete data. Results Internal validation is essential in order to avoid optimism, with the bootstrap 0.632+ estimate representing a reliable method to correct for optimism. While estimates obtained by MI-Val are optimistically biased, those obtained by MI(-y)-Val tend to be pessimistic in the presence of a true underlying effect. Val-MI provides largely unbiased estimates, with a slight pessimistic bias with increasing true effect size, number of covariates and decreasing sample size. In Val-MI, accuracy of the estimate is more strongly improved by increasing the number of bootstrap draws rather than the number of imputations. With a simple integrated approach, valid confidence intervals for performance estimates can be obtained. Conclusions When prognostic models are developed on incomplete data, Val-MI represents a valid strategy to obtain estimates of predictive performance measures

Comparison of genetic risk prediction models to improve prediction of coronary heart disease in two large cohorts of the MONICA/KORA study

It is still unclear how genetic information, provided as single-nucleotide polymorphisms (SNPs), can be most effectively integrated into risk prediction models for coronary heart disease (CHD) to add significant predictive value beyond clinical risk models. For the present study, a population-based case-cohort was used as a trainingset (451 incident cases, 1488 noncases) and an independent cohort as testset (160 incident cases, 2749 noncases). The following strategies to quantify genetic information were compared: A weighted genetic risk score including Metabochip SNPs associated with CHD in the literature (GRSMetabo ); selection of the most predictive SNPs among these literature-confirmed variants using priority-Lasso (PLMetabo ); validation of two comprehensive polygenic risk scores: GRSGola based on Metabochip data, and GRSKhera (available in the testset only) based on cross-validated genome-wide genotyping data. We used Cox regression to assess associations with incident CHD. C-index, category-free net reclassification index (cfNRI) and relative integrated discrimination improvement (IDIrel ) were used to quantify the predictive performance of genetic information beyond Framingham risk score variables. In contrast to GRSMetabo and PLMetabo , GRSGola significantly improved the prediction (delta C-index [95% confidence interval]: 0.0087 [0.0044, 0.0130]; IDIrel : 0.0509 [0.0131, 0.0894]; cfNRI improved only in cases: 0.1761 [0.0253, 0.3219]). GRSKhera yielded slightly worse prediction results than GRSGola

Association of Circulating Monocyte Chemoattractant Protein-1 Levels With Cardiovascular Mortality A Meta-analysis of Population-Based Studies

Importance Human genetics and studies in experimental models support a key role of monocyte-chemoattractant protein-1 (MCP-1) in atherosclerosis. Yet, the associations of circulating MCP-1 levels with risk of coronary heart disease and cardiovascular death in the general population remain largely unexplored. Objective To explore whether circulating levels of MCP-1 are associated with risk of incident coronary heart disease, myocardial infarction, and cardiovascular mortality in the general population. Data Sources and Selection Population-based cohort studies, identified through a systematic review, that have examined associations of circulating MCP-1 levels with cardiovascular end points. Data Extraction and Synthesis Using a prespecified harmonized analysis plan, study-specific summary data were obtained from Cox regression models after excluding individuals with overt cardiovascular disease at baseline. Derived hazard ratios (HRs) were synthesized using random-effects meta-analyses. Main Outcomes and Measures: Incident coronary heart disease (myocardial infarction, coronary revascularization, and unstable angina), nonfatal myocardial infarction, and cardiovascular death (from cardiac or cerebrovascular causes). Results The meta-analysis included 7 cohort studies involving 21401 individuals (mean [SD] age, 53.7 [10.2] years;10012 men [46.8%]). Mean (SD) follow-up was 15.3 (4.5) years (326392 person-years at risk). In models adjusting for age, sex, and race/ethnicity, higher MCP-1 levels at baseline were associated with increased risk of coronary heart disease (HR per 1-SD increment in MCP-1 levels: 1.06 [95% CI, 1.01-1.11];P = .01), nonfatal myocardial infarction (HR, 1.07 [95% CI, 1.01-1.13];P = .02), and cardiovascular death (HR, 1.12 [95% CI, 1.05-1.20];P < .001). In analyses comparing MCP-1 quartiles, these associations followed dose-response patterns. After additionally adjusting for vascular risk factors, the risk estimates were attenuated, but the associations of MCP-1 levels with cardiovascular death remained statistically significant, as did the association of MCP-1 levels in the upper quartile with coronary heart disease. There was no significant heterogeneity;the results did not change in sensitivity analyses excluding events occurring in the first 5 years after MCP-1 measurement, and the risk estimates were stable after additional adjustments for circulating levels of interleukin-6 and high-sensitivity C-reactive protein. Conclusions and Relevance: Higher circulating MCP-1 levels are associated with higher long-term cardiovascular mortality in community-dwelling individuals free of overt cardiovascular disease. These findings provide further support for a key role of MCP-1-signaling in cardiovascular disease. Question Are circulating monocyte-chemoattractant protein-1 (MCP-1) levels associated with the risk of cardiovascular disease in the general population? Findings In this meta-analysis of 7 population-based studies involving 21401 individuals who were free of overt cardiovascular disease, higher baseline circulating MCP-1 levels were associated with higher risk of cardiovascular mortality over a follow-up extending beyond 20 years. Meaning By complementing evidence from previous genetic and experimental studies, these results provide additional support for a key role of MCP-1 in cardiovascular disease development. This meta-analysis of 7 population-based cohort studies assesses the association between circulating monocyte-chemoattractant protein-1 levels and risk of cardiovascular disease and death

Immunological and Cardiometabolic Risk Factors in the Prediction of Type 2 Diabetes and Coronary Events: MONICA/KORA Augsburg Case-Cohort Study

BACKGROUND: This study compares inflammation-related biomarkers with established cardiometabolic risk factors in the prediction of incident type 2 diabetes and incident coronary events in a prospective case-cohort study within the population-based MONICA/KORA Augsburg cohort. METHODS AND FINDINGS: Analyses for type 2 diabetes are based on 436 individuals with and 1410 individuals without incident diabetes. Analyses for coronary events are based on 314 individuals with and 1659 individuals without incident coronary events. Mean follow-up times were almost 11 years. Areas under the receiver-operating characteristic curve (AUC), changes in Akaike's information criterion (ΔAIC), integrated discrimination improvement (IDI) and net reclassification index (NRI) were calculated for different models. A basic model consisting of age, sex and survey predicted type 2 diabetes with an AUC of 0.690. Addition of 13 inflammation-related biomarkers (CRP, IL-6, IL-18, MIF, MCP-1/CCL2, IL-8/CXCL8, IP-10/CXCL10, adiponectin, leptin, RANTES/CCL5, TGF-β1, sE-selectin, sICAM-1; all measured in nonfasting serum) increased the AUC to 0.801, whereas addition of cardiometabolic risk factors (BMI, systolic blood pressure, ratio total/HDL-cholesterol, smoking, alcohol, physical activity, parental diabetes) increased the AUC to 0.803 (ΔAUC [95% CI] 0.111 [0.092-0.149] and 0.113 [0.093-0.149], respectively, compared to the basic model). The combination of all inflammation-related biomarkers and cardiometabolic risk factors yielded a further increase in AUC to 0.847 (ΔAUC [95% CI] 0.044 [0.028-0.066] compared to the cardiometabolic risk model). Corresponding AUCs for incident coronary events were 0.807, 0.825 (ΔAUC [95% CI] 0.018 [0.013-0.038] compared to the basic model), 0.845 (ΔAUC [95% CI] 0.038 [0.028-0.059] compared to the basic model) and 0.851 (ΔAUC [95% CI] 0.006 [0.003-0.021] compared to the cardiometabolic risk model), respectively. CONCLUSIONS: Inclusion of multiple inflammation-related biomarkers into a basic model and into a model including cardiometabolic risk factors significantly improved the prediction of type 2 diabetes and coronary events, although the improvement was less pronounced for the latter endpoint

Länderportrait Österreich : Sozialpolitik, Sozialwirtschaft und Soziale Arbeit

Dieser Artikel gibt einen Überblick über aktuelle Rahmenbedingungen, Entwicklungen und Herausforderungen in Sozialpolitik, Sozialwirtschaft und Sozialer Arbeit in Österreich.Original abrufbar unter https://www.socialnet.de/international/de/oesterreich.html.(VLID)295140

Biomarker-defined pathways for incident type 2 diabetes and coronary heart disease: a comparison in the MONICA/KORA study

Background Biomarkers may contribute to our understanding of the pathophysiology of various diseases. Type 2 diabetes (T2D) and coronary heart disease (CHD) share many clinical and lifestyle risk factors and several biomarkers are associated with both diseases. The current analysis aims to assess the relevance of biomarkers combined to pathway groups for the development of T2D and CHD in the same cohort. Methods Forty-seven serum biomarkers were measured in the MONICA/KORA case-cohort study using clinical chemistry assays and ultrasensitive molecular counting technology. The T2D (CHD) analyses included 689 (568) incident cases and 1850 (2004) non-cases from three population-based surveys. At baseline, the study participants were 35-74 years old. The median follow-up was 14 years. We computed Cox regression models for each biomarker, adjusted for age, sex, and survey. Additionally, we assigned the biomarkers to 19 etiological pathways based on information from literature. One age-, sex-, and survey-controlled average variable was built for each pathway. We used the R-PM(2) coefficient of determination to assess the explained disease risk. Results The associations of many biomarkers, such as several cytokines or the iron marker soluble transferrin receptor (sTfR), were similar in strength for T2D and CHD, but we also observed important differences. Lipoprotein (a) (Lp(a)) and N-terminal pro B-type natriuretic peptide (NT-proBNP) even demonstrated opposite effect directions. All pathway variables together explained 49% of the T2D risk and 21% of the CHD risk. The insulin-like growth factor binding protein 2 (IGFBP-2, IGF/IGFBP system pathway) best explained the T2D risk (about 9% explained risk, independent of all other pathway variables). For CHD, the myocardial-injury- and lipid-related-pathways were most important and both explained about 4% of the CHD risk. Conclusions The biomarker-derived pathway variables explained a higher proportion of the T2D risk compared to CHD. The ranking of the pathways differed between the two diseases, with the IGF/IGFBP-system-pathway being most strongly associated with T2D and the myocardial-injury- and lipid-related-pathways with CHD. Our results help to better understand the pathophysiology of the two diseases, with the ultimate goal of pointing out targets for lifestyle intervention and drug development to ideally prevent both T2D and CHD development

Leptin, adiponectin, their ratio and risk of coronary heart disease: results from the MONICA/KORA Augsburg study 1984–2002

OBJECTIVE: Despite modulating a number of metabolic processes linked to atherosclerosis, including glucose regulation, hematopoiesis, fatty acid catabolism and angiogenesis, the potential association of adiponectin and leptin with coronary heart disease is still a matter of controversy. METHODS: We conducted a population-based case-cohort study within the MONICA/KORA Augsburg studies. Serum levels of adipokines were measured in 333 case subjects with incident CHD and 1,728 non-case subjects selected from a source population of 9300 middle-aged men and women. Mean follow-up was 10.8+/-4.6 years. We sought to analyze the association of leptin and adiponectin and their ratio with CHD. RESULTS: After adjustment for various confounding factors the hazard ratios and 95% confidence intervals comparing tertile extremes were 0.79 (0.53-1.17) for leptin (top vs bottom tertile) and 0.87 (0. 62-1.23) for adiponectin (bottom vs top tertile), respectively. Furthermore, the ratio of leptin/adiponectin also showed no association with CHD (HR 1.01 (0.68-1.51)). CONCLUSIONS: The present study reports the association of leptin and adiponectin with incident CHD in a large population-based cohort. In contrast to fairly strong associations previously reported, our findings indicate no clinically relevant association between leptin, adiponectin and their ratio with the risk of CHD after adjustment for potential confounders

The geriatric nutritional risk index predicts increased healthcare costs and hospitalization in a cohort of community-dwelling older adults: results from the MONICA/KORA Augsburg cohort study, 1994–2005

OBJECTIVE: To determine if the Geriatric Nutritional Risk Index (GNRI), an index for the risk of nutrition-related complications, is associated with healthcare costs and risk of hospitalization at baseline and after 10 y. METHODS: Data from a German population-based cohort of 1999 subjects 55 to 74 y of age at baseline were used. Self-reported physician visits, length of hospital stay, and drug intake were used to estimate costs. The GNRI is based on serum albumin values and the discrepancy between real and ideal body weights. Low GNRI values were defined as mean minus 2 times standard deviation. Mean GNRI values were regarded as normal. RESULTS: Low baseline GNRI was consistently associated with increased total costs, probability of hospitalization, inpatient costs, and pharmaceutical costs at baseline and follow-up, after adjustment for socioeconomic characteristics, lifestyle factors, and coexisting conditions. Subjects with low GNRI at baseline had approximately 47% higher total costs, 50% higher risk of hospitalization, 62% higher inpatient costs and 27% higher pharmaceutical costs at follow-up than subjects with normal GNRI values. CONCLUSION: The GNRI risk predicted increased future healthcare costs and higher risk of hospitalization in independent-living older adults. The GNRI is a rapid and low-cost tool that might be routinely used in population-based settings

Intake of Vitamin and Mineral Supplements and Longitudinal Association with HbA1c Levels in the General Non-Diabetic Population--Results from the MONICA/KORA S3/F3 Study.

Lower levels of hemoglobin A1c (HbA1c) are associated with a decreased risk of cardiovascular complications in diabetic and non-diabetic individuals. The aim of the study was to longitudinally investigate the association between the use of 11 vitamins and minerals (vitamins E, C, D, B1, folic acid, carotenoids, calcium, magnesium, zinc, iron, and selenium) and change in HbA1c levels over 10 years in non-diabetic individuals drawn from the general population.Baseline data were available from 4447 subjects included in the population-based "Monitoring of Trends and Determinants in Cardiovascular Diseases" (MONICA) Augsburg S3 survey (1994/95). Follow-up data were derived from 2774 participants in the follow-up survey named "Cooperative Health Research in the Region of Augsburg" (KORA) F3 (2004/05). Vitamin/mineral intake from supplements and medications was assessed in a personal interview, where participants were asked to bring product packages of preparations that had been ingested during the last 7 days prior to the examination. Associations between regular vitamin/mineral intake amounts and HbA1c levels measured at baseline and follow-up were investigated using generalized estimating equation models. For carotenoids, analyses were stratified by smoking status.None of the investigated nutrients except for carotenoids was significantly associated with changes in HbA1c levels after 10 years. Regular intake of carotenoids from supplements and medications in amounts > 6.8 mg/d (upper tertile) was associated with an absolute -0.26% (95% CI: -0.43 to -0.08) lower increase in HbA1c levels compared with no intake of carotenoids. An inverse association was observed in those who never smoked but not in (former) smokers.Larger prospective and intervention studies in non-diabetic/non-smoking individuals are needed to confirm the results and to assess whether the observed associations between carotenoid intake and change in HbA1c levels are causal. If our results are confirmed, high carotenoid intake could be one strategy for the prevention of cardiovascular complications in non-diabetic people

Low levels of serum 25-hydroxyvitamin D are associated with increased risk of myocardial infarction, especially in women: results from the MONICA/KORA Augsburg case-cohort study

Context and Objective: A growing body of evidence suggests that vitamin D deficiency may adversely affect the cardiovascular system. Therefore, we thought to prospectively assess the association between serum 25-hydroxyvitamin D, the most commonly used index of vitamin D status, and incident coronary heart disease. Design, Setting, and Patients: We measured serum levels of 25[OH]D in 1783 healthy middle-aged subjects (964 men, 819 women) in the population-based Monitoring of Trends and Determinants in Cardiovascular Disease/Cooperative Health Research in the Region of Augsburg studies. A total of 298 coronary heart disease cases were identified over a mean follow-up period of 11 yr. Results: After adjustment for age, survey, and season of blood sampling, the hazard ratio (HR) and 95% confidence interval comparing tertile extremes of serum levels of 25[OH]D was 0.32 (0.16-0.65) (P for trend = 0.001) in women and 0.56 (0.38-0.82) (P for trend = 0.005) in men. Further adjustment for traditional cardiovascular risk factors slightly attenuated the association in women [HR 0.39 (0.18-0.84); P for trend = 0.013], whereas it became nonsignificant in men [HR 0.76 (0.49-1.17); P for trend = 0.215]. After additional adjustment for C-reactive protein, IL-6, soluble intercellular adhesion molecule-1, and interferon-&gamma;-inducible protein-10, the association still remained significant in women [HR 0.42 (0.19-0.93); P for trend = 0.028], and it was further reduced in men [HR 0.84 (0.52-1.35); P for trend = 0.461]. Conclusion: Our findings suggest that higher vitamin D levels are associated with decreased risk of coronary heart disease. This effect is more pronounced in women than in men. Further clinical and experimental studies are needed to investigate the sex differences and whether vitamin D supplementation could contribute to the prevention of coronary heart disease