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Background: In recent years, the use of non- and semi-parametric models which estimate hazard ratios for analysing time-to-event outcomes is continuously criticized in terms of interpretation, technical implementation, and flexibility. Hazard ratios in particular are critically discussed for their misleading interpretation as relative risks and their non-collapsibility. Additive hazard models do not have these drawbacks but are rarely used because they assume a non- or semi-parametric additive hazard which renders computation and interpretation complicated., Methods: As a remedy, we propose a new parametric additive hazard model that allows results to be reported on the original time rather than on the hazard scale. Being an essentially parametric model, survival, hazard and probability density functions are directly available. Parameter estimation is straightforward by maximizing the log-likelihood function., Results: Applying the model to different parametric distributions in a simulation study and in an exemplary application using data from a study investigating medical care to lung cancer patients, we show that the approach works well in practice., Conclusions: Our proposed parametric additive hazard model can serve as a powerful tool to analyze time-to-event outcomes due to its simple interpretation, flexibility and facilitated parameter estimation., (© 2024. The Author(s).)

Background: Meta-analyses are used to summarise the results of several studies on a specific research question. Standard methods for meta-analyses, namely inverse variance random effects models, have unfavourable properties if only very few (2 - 4) studies are available. Therefore, alternative meta-analytic methods are needed. In the case of binary data, the "common-rho" beta-binomial model has shown good results in situations with sparse data or few studies. The major concern of this model is that it ignores the fact that each treatment arm is paired with a respective control arm from the same study. Thus, the randomisation to a study arm of a specific study is disrespected, which may lead to compromised estimates of the treatment effect. Therefore, we extended this model to a version that respects randomisation. The aim of this simulation study was to compare the "common-rho" beta-binomial model and several other beta-binomial models with standard meta-analyses models, including generalised linear mixed models and several inverse variance random effects models., Methods: We conducted a simulation study comparing beta-binomial models and various standard meta-analysis methods. The design of the simulation aimed to consider meta-analytic situations occurring in practice., Results: No method performed well in scenarios with only 2 studies in the random effects scenario. In this situation, a fixed effect model or a qualitative summary of the study results may be preferable. In scenarios with 3 or 4 studies, most methods satisfied the nominal coverage probability. The "common-rho" beta-binomial model showed the highest power under the alternative hypothesis. The beta-binomial model respecting randomisation did not improve performance., Conclusion: The "common-rho" beta-binomial appears to be a good option for meta-analyses of very few studies. As residual concerns about the consequences of disrespecting randomisation may still exist, we recommend a sensitivity analysis with a standard meta-analysis method that respects randomisation., (© 2022. The Author(s).)

Background: Application of mixed meal tolerance tests (MMTT) to measure beta-cell function in long-term studies is limited by modification of the commercial products occurring over time. This study assessed the intra-individual reliability of MMTTs and compared the effects of liquid meals differing in macronutrient composition on the estimation of beta-cell function in type 2 diabetes (T2DM)., Methods: To test the reliability of MMTTs, 10 people with T2DM (age 58 ± 11 years, body mass index 30.0 ± 4.9 kg/m 2 ) received Boost® high Protein 20 g protein three times. For comparing different meals, another 10 persons with T2DM (58 ± 5 years, 31.9 ± 5.3 kg/m 2 ) ingested either Boost® high Protein 20 g protein or the isocaloric Boost® high Protein 15 g protein containing 35% less protein and 18% more carbohydrates. C-peptide, insulin and glucose release were assessed from the incremental area under the concentration time curve (iAUC) and the intra- and inter-individual variation of these parameters from the coefficients of variations (CV)., Results: Repetitive ingestion of one meal revealed intra-individual CVs for the iAUCs of C-peptide, insulin and glucose, which were at least 3-times lower than the inter-individual variation of these parameters (18.2%, 19.7% and 18.9% vs. 74.2%, 70.5% and 207.7%) indicating a good reliability. Ingestion of two different meals resulted in comparable intra-individual CVs of the iAUCs of C-peptide and insulin (16.9%, 20.5%)., Conclusion: MMTTs provide reliable estimation of beta-cell function in people with T2DM. Furthermore, moderate differences in the protein and carbohydrate contents in a standardized liquid meal do not result in relevant changes of C-peptide and insulin responses., Trial Registration: Clinicaltrials.gov, Identifier number: NCT01055093. Registered 22 January 2010 - Retrospectively registered, https://www.clinicaltrials.gov/ct2/show/study/NCT01055093.

Background: Little evidence exists on the impact of diabetes risk scores, e.g. on physicians and patient's behavior, perceived risk of persons, shared-decision making and particularly on patient's health. The aim of this study is to investigate the impact of a non-invasive type 2 diabetes risk prediction model in the primary health care setting as component of routine health checks on change in physical activity., Methods: Parallel group cluster randomized controlled trial including 30 primary care physicians (PCPs) and 300 participants in the region of Düsseldorf and surrounding urban and rural municipalities, West Germany. On cluster level, PCPs will be randomized into intervention or control group using a biased coin minimization technique. Participants in the control group are going to have a routine health check "Check-up 35" which is recommended biannually for all people ≥35 years of age in Germany. In the intervention group, the routine health check is expanded by usage of a non-invasive diabetes risk prediction model (German Diabetes Risk Score). Primary outcome is change in physical activity after 1 year. Secondary outcomes include aspects of targeted counseling, motivation of participant's to change lifestyle, perceived and objectively measured diabetes risk, acceptance of diabetes risk scores, quality of life, depression and anxiety. Patients will be followed over 12 months. Hierarchical or mixed models will be conducted, including a random intercept to adjust for cluster, the respective baseline value, and covariates to compare the groups., Discussion: This pragmatic cluster randomized controlled trial will enhance our knowledge on the clinical impact of diabetes risk scores for the first time in the real-life primary health care setting., Trial Registration: ClinicalTrials.gov NCT03234322 , registered on July 28, 2017.

Background: Screening and detection of cases are a common public health priority for treatable chronic conditions with long subclinical periods. However, the validity of commonly-used metrics from surveillance systems for rates of detection (or case-finding) have not been evaluated., Methods: Using data from a Danish diabetes register and a recently developed illness-death model of chronic diseases with subclinical conditions, we simulate two scenarios of different performance of case-finding. We report different epidemiological indices to assess case-finding in both scenarios and compare the validity of the results., Results: The commonly used ratio of detected cases over total cases may lead to misleading conclusions. Instead, the ratio of undetected cases over persons without a diagnosis is a more valid index to distinguish the quality of case-finding. However, incidence-based measures are preferable to prevalence based indicators., Conclusion: Prevalence-based indices for assessing case-finding should be interpreted with caution. If possible, incidence-based indices should be preferred.

Background: Precise blood pressure (BP) measurements are central for the diagnosis of hypertension in clinical and epidemiological studies. The purpose of this study was to quantify the variability in BP associated with arm side, body position, and successive measurements in the setting of a population-based observational study. Additionally, we aimed to evaluate the influence of different measurement conditions on prevalence of hypertension., Methods: The sample included 967 men and 812 women aged 45 to 83 years at baseline. BP was measured according to a standardized protocol with oscillometric devices including three sitting measurements at left arm, one simultaneous supine measurement at both arms, and four supine measurements at the arm with the higher BP. Hypertension was defined as systolic BP (SBP) ≥140 mmHg and/or diastolic BP (DBP) ≥90 mmHg. Variability in SBP and DBP were analysed with sex-stratified linear covariance pattern models., Results: We found that overall, no mean BP differences were measured according to arm-side, but substantial higher DBP and for men also higher SBP was observed in sitting than in supine position and there was a clear BP decline by consecutive measurement. Accordingly, the prevalence of hypertension depends strongly on the number and scheme of BP measurements taken to calculate the index values., Conclusions: Thus, BP measurements should only be compared between studies applying equal measurement conditions and index calculation. Moreover, the first BP measurement should not be used to define hypertension since it overestimates BP. The mean of second and third measurement offers the advantage of better reproducibility over single measurements.

Background: The German Diabetes Study (GDS) is a prospective longitudinal cohort study describing the impact of subphenotypes on the course of the disease. GDS aims at identifying prognostic factors and mechanisms underlying the development of related comorbidities., Study Design and Methods: The study comprises intensive phenotyping within 12 months after clinical diagnosis, at 5-year intervals for 20 years and annual telephone interviews in between. Dynamic tests, including glucagon, mixed meal, intravenous glucose tolerance and hyperinsulinemic clamp tests, serve to assess beta-cell function and tissue-specific insulin sensitivity. Magnetic resonance imaging and multinuclei spectroscopy allow quantifying whole-body fat distribution, tissue-specific lipid deposition and energy metabolism. Comprehensive analyses of microvascular (nerve, eye, kidney) and macrovascular (endothelial, cardiorespiratory) morphology and function enable identification and monitoring of comorbidities. The GDS biobank stores specimens from blood, stool, skeletal muscle, subcutaneous adipose tissue and skin for future analyses including multiomics, expression profiles and histology. Repeated questionnaires on socioeconomic conditions, patient-reported outcomes as quality of life, health-related behavior as physical activity and nutritional habits are a specific asset of GDS. This study will recruit 3000 patients and a group of humans without familiy history of diabetes. 237 type 1 and 456 type 2 diabetes patients have been already included.

Background: Diabetic individuals have a largely increased risk of lower extremity amputation (LEA) compared with non-diabetic patients. Prior systematic reviews of incidence of LEA have some limitations with respect to lack of consensus in the definition of LEA, level of LEA (all, major, minor), and definition of source population (general population or population with diabetes at risk). The purpose of our review is to evaluate the incidence of LEA in the diabetic population and its differences with regard to sex, ethnicity, age, and regions; to compare the incidence rate (IR) in the diabetic and non-diabetic population; and to investigate time trends., Methods/design: We will perform a systematic literature search in MEDLINE, Embase, Web of Knowledge, and publisher databases such as Journals@OVID and ScienceDirect. We will develop comprehensive systematic search strategies according to established guidelines for meta-analyses of observational studies in epidemiology (the MOOSE group). Two authors will independently screen abstracts and full text of all references on the basis of inclusion criteria with respect to types of study, types of population, and the main outcome. We will exclude studies if they report solely incidences of LEA among persons with diabetes mellitus when referring to the total population (diabetic and non-diabetic) and not exclusively to the diabetic population. Data extraction and assessment of risk of bias will be undertaken by two review authors working independently. We will assess incidence rate (IR) or cumulative incidence (CumI), relative risk of amputations comparing the diabetic to non-diabetic populations, cause of LEA, and type of diabetes. If we find subsets of studies to be homogeneous enough, we will perform meta-analyses for incidence rates by Poisson generalized linear mixed models (GLMM)., Systematic Review Registration: PROSPERO CRD42015017809.

Background: Communication and information in order to reduce anxiety in the intensive care unit (ICU) has been described as area needing improvement. Therefore, the aim of this trial was to evaluate whether a structured information program that intensifies information given in standard care process reduces anxiety in ICU patients., Methods: Multicenter, two-armed, non-blinded, parallel-group randomized controlled trial in hospitals in the cities of Marburg, Halle, and Stuttgart (Germany). The trial was performed in cardiac surgery, general surgery, and internal medicine ICUs. Two-hundred and eleven elective and non-elective ICU patients were enrolled in the study (intervention group, n = 104; control group, n = 107). The experimental intervention comprised a single episode of structured oral information that was given in addition to standard care and covered two main parts: (1) A more standardized part about predefined ICU specific aspects - mainly procedural, sensory and coping information, and (2) an individualized part about fears and questions of the patient. The control group received a non-specific episodic conversation of similar length additional to standard care. Both conversations took place at the beginning of the ICU stay and lasted 10-15 minutes. Study nurses administered both interventions. The primary outcome ICU-related anxiety (CINT-Score, 0-100 pts., higher scores indicate higher anxiety) was assessed after admission to a regular ward., Results: The primary outcome could be measured in 82 intervention group participants and 90 control group participants resulting in mean values of 20.4 (SD 14.4) compared to 20.8 (SD 14.7) and a mean difference of -0.2 (CI 95% -4.5 to 4.1)., Conclusions: A structured information intervention additional to standard care during ICU stay had no demonstrated additional benefit compared to an unspecific communication of similar duration. Reduction of anxiety in ICU patients will probably require more continuous approaches to information giving and communication., Trial Registration: ClinicalTrials.gov NCT00764933.

Background: To examine the all-cause mortality and uveal melanoma specific mortality among newly diagnosed uveal melanoma patients after five years. Furthermore, we assess of the effect of iris colour and having children on 5-year risk of death after diagnosis of uveal melanoma. Therefore, we assess the performance of an individual prediction model of survival from uveal melanoma., Methods: A cohort of 459 patients aged 45 to 79 years with newly diagnosed uveal melanoma was recruited between 2002 and 2004 from the Division of Ophthalmology, University of Essen, Germany. Survival probabilities were estimated by Kaplan-Meier survival analysis. The clinical and histopathological characteristics were obtained from medical records. Iris colour and childbearing history were assessed at baseline by a computer-assisted telephone interview. We used crude and multivariable Cox proportional hazards regression to estimate unadjusted and adjusted hazard ratios (HR) and corresponding 95% confidence intervals (95%CIs) with respect to death from uveal melanoma and death from all causes. We used the Cox model to estimate adjusted probabilities of primary events. For computing Harrell's C statistics, we used a Cox model including the prognostics factors gender, age at diagnosis, ciliary body involvement, largest basal tumour diameter, and iris colour., Results: The 5-year uveal melanoma-specific survival probability was 82.9% (95% CI: 79.1-86.3). Main prognostic factors for the death of uveal melanoma were ciliary body involvement (HR: 1.7 (95% CI:1.0-2.8)), largest basal tumour diameter >15 mm HR: 7.0 (95% CI: 3.5-13.9), light iris colour (HR: 2.3 (95% CI: 0.9-5.8), having children (HR: 0.6 (95% CI: 0.2 - 1.7)), and gender (HR: 0.7 (95% CI: 0.4-1.1)). The value of the bootstrap-corrected C statistics was 0.76 (95% CI: 0.74-0.77)., Conclusion: Beyond the established prognostic factors, light iris colour also appears to be a prognostic factor for death from uveal melanoma.

Background: The area under the receiver operating characteristic (ROC) curve, referred to as the AUC, is an appropriate measure for describing the overall accuracy of a diagnostic test or a biomarker in early phase trials without having to choose a threshold. There are many approaches for estimating the confidence interval for the AUC. However, all are relatively complicated to implement. Furthermore, many approaches perform poorly for large AUC values or small sample sizes., Methods: The AUC is actually a probability. So we propose a modified Wald interval for a single proportion, which can be calculated on a pocket calculator. We performed a simulation study to compare this modified Wald interval (without and with continuity correction) with other intervals regarding coverage probability and statistical power., Results: The main result is that the proposed modified Wald intervals maintain and exploit the type I error much better than the intervals of Agresti-Coull, Wilson, and Clopper-Pearson. The interval suggested by Bamber, the Mann-Whitney interval without transformation and also the interval of the binormal AUC are very liberal. For small sample sizes the Wald interval with continuity has a comparable coverage probability as the LT interval and higher power. For large sample sizes the results of the LT interval and of the Wald interval without continuity correction are comparable., Conclusions: If individual patient data is not available, but only the estimated AUC and the total sample size, the modified Wald intervals can be recommended as confidence intervals for the AUC. For small sample sizes the continuity correction should be used.

Background: As high percentage of mammographic densities complicates the assessment of imaging findings, mammographic density may influence the histopathological evaluation of core-biopsies of the breast. We measured the influence of mammographic density on the inter-observer variability of histopathological findings of breast biopsies., Methods: Histological slides of 695 women who underwent core biopsies of the breast at University of Halle between 2006 and 2008 were evaluated in a blinded fashion by two pathologists using the five levels of the B-categorization scheme (B1-B5). To quantify mammographic density, we used a computer-based threshold method (Madena). We calculated observed and chance-corrected agreements (weighted kappa) and 95% confidence intervals (95% CI) according to four categories of mammographic density (<10%, 10<25%, 25<50%, ≥50%)., Results: The weighted kappa decreased monotonically from 89.6% (95% CI: 85.8%, 93.3%) among women with less than 10% of mammographic density to 80.4% (95% CI: 69.9%, 90.9%) for women with more than 50% of mammographic density, respectively. Results of a kappa regression analysis showed that agreement of pathologists on clinically relevant categories (B1-B2 versus B3-B5) decreased with mammographic density., Conclusions: Mammographic density is a relevant modifier of the agreement between pathologists who assess breast biopsies using the B-categorization scheme. The influence of mammographic density on the inter-observer variability can be explained to some extent by varying prevalences of histological entities across B categories that have typically different inter-observer agreement. Women with high mammographic density are at higher risk of inter-observer variability compared to women with low mammographic density and should possibly undergo a second pathology review.

Background: Human ß-defensins are a family of antimicrobial peptides located at the mucosal surface. Both sequence multi-site variations (MSV) and copy-number variants (CNV) of the defensin-encoding genes are associated with increased risk for various diseases, including cancer and inflammatory conditions such as psoriasis and acute pancreatitis. In a case-control study, we investigated the association between MSV in DEFB104 as well as defensin gene (DEF) cluster copy number (CN), and pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP)., Results: Two groups of PDAC (N=70) and CP (N=60) patients were compared to matched healthy control groups CARLA1 (N=232) and CARLA2 (N=160), respectively. Four DEFB104 MSV were haplotyped by PCR, cloning and sequencing. DEF cluster CN was determined by multiplex ligation-dependent probe amplification.Neither the PDAC nor the CP cohorts show significant differences in the DEFB104 haplotype distribution compared to the respective control groups CARLA1 and CARLA2, respectively.The diploid DEF cluster CN exhibit a significantly different distribution between PDAC and CARLA1 (Fisher's exact test P=0.027), but not between CP and CARLA2 (P=0.867)., Conclusion: Different DEF cluster b CN distribution between PDAC patients and healthy controls indicate a potential protective effect of higher CNs against the disease.

Background: Reduced heart rate variability (HRV), a non-invasive marker of autonomic dysfunction, and an unhealthy lifestyle are associated with an increased morbidity and mortality of cardiovascular diseases (CVD). The autonomic dysfunction is a potential mediator of the association of behavioural risk factors with adverse health outcomes. We studied the association of HRV with behavioural risk factors in an elderly population., Methods: This analysis was based on the cross-sectional data of 1671 participants (age range, 45-83 years) of the prospective, population-based Cardiovascular Disease, Living and Ageing in Halle (CARLA) Study. Physical activity, smoking habits, alcohol consumption and dietary patterns were assessed in standardized interviews. Time and frequency domain measures of HRV were computed from 5-min segments of highly standardized 20-min electrocardiograms. Their association with behavioural risk factors was determined by linear and non-parametric regression modelling., Results: There were only weak and inconsistent associations of higher physical activity, moderate consumption of alcohol, and non-smoking with higher time and frequency domain HRV in both sexes, and no association with dietary pattern. Results changed only marginally by excluding subjects with CVD, diabetes mellitus and use of cardioactive medication., Conclusion: We hypothesized that HRV is associated with behavioural factors and therefore might be a mediator of the effect of behavioural risk factors on CVD, but this hypothesis was not confirmed by our results. These findings support the interpretation that there may be no true causal association of behavioural factors with HRV.

Background: Pain is one of the most frequent and distressing symptoms in cancer patients. For the majority of the patients, sufficient pain relief can be obtained if adequate treatment is provided. However, pain remains often undertreated due to institutional, health care professional and patient related barriers. Patients self management skills are affected by the patients' knowledge, activities and attitude to pain management. This trial protocol is aimed to test the SCION-PAIN program, a multi modular structured intervention to improve self management in cancer patients with pain., Methods: 240 patients with diagnosed malignancy and pain > 3 days and average pain >or= 3/10 will participate in a cluster randomized trial on 18 wards in 2 German university hospitals. Patients from the intervention wards will receive, additionally to standard pain treatment, the SCION-PAIN program consisting of 3 modules: pharmacologic pain management, nonpharmacologic pain management and discharge management. The intervention will be conducted by specially trained oncology nurses and includes components of patient education, skills training and counseling to improve self care regarding pain management beginning with admission followed by booster session every 3rd day and one follow up telephone counseling within 2 to 3 days after discharge. Patients in the control group will receive standard care. Primary endpoint is the group difference in patient related barriers to management of cancer pain (BQII), 7 days after discharge. Secondary endpoints are: pain intensity & interference, adherence, coping and HRQoL., Discussion: The study will determine if the acquired self management skills of the patients continue to be used after discharge from hospital. It is hypothesized that patients who receive the multi modular structured intervention will have less patient related barriers and a better self management of cancer pain., Trial Registration: ClinicalTrials NCT00779597.

Objective: The patch test (PT) with its modification - the strip patch test (SPT) - is the standard in vivo procedure to diagnose an allergic contact dermatitis (ACD). To date, none of the in vitro tests for the diagnosis of ACD fulfils the requirements of an easy, valid and reliable test. To investigate the prediction ability of a flow cytometric assay of CD69 up-regulation on CD4+ CLA+ T cells in nickel-sensitive and non-nickel-sensitive patients., Methods: In a prospective, investigator-blinded, clinical study a total of 85 nickel-sensitive (n = 44; 51.8%) and non-nickel-sensitive patients (n = 41; 48.2%) were enrolled. The association between CD69 up-regulation on CD4+ CLA+ T cells on the one hand and PT, SPT, and clinical history on the other hand was measured. Association is expressed with c statistic values (receiver operating characteristic analysis) and corresponding 95% CIs., Results: The associations were c = 0.57 (95% CI: 0.42-0.72) between CD69 up-regulation and PT, c = 0.49 (95% CI: 0.36-0.62) between CD69 up-regulation and SPT, and c = 0.51 (95% CI: 0.37-0.64) between CD69 up-regulation and clinical history., Conclusions: CD69 up-regulation on CD4+ CLA+ T cells in vitro could not predict neither a positive PT or SPT result nor a positive clinical history to nickel sulfate. The combination of clinical history and patch testing still remains the basis for diagnosing ACD.

Background: ICU stay is often associated with negative experiences for the individual patient. Many patients are disabled and their communication is restricted during the ICU stay. Specific information on procedures, sensations and coping behavior are thought to reduce anxiety on the ICU. Until now information programs to reduce anxiety were mainly delivered preoperatively, completely neglecting informational needs of non-elective ICU patients., Methods: The trial is designed as a prospective multicenter randomized controlled trial in the cities of Marburg, Halle and Stuttgart. Elective and non-elective ICU patients will be included. The trial includes an intervention and a control group on the ICU. The control group receives a trivial conversation without any ICU-specific information. The intervention group receives an information program with specific procedural, sensory and coping information about their ICU stay. Both conversations take place in the ICU and are planned to take about 10 minutes., Discussion: In contrast to former trials on information programs on the ICU-stay our intervention will take place in the ICU itself. This approach will ensure to compensate for memory effects due to anesthesia or preoperative stress. Further the results will be applicable to non-elective ICU-patients., Trial Registration: ClinicalTrials NCT00764933.

Background: Mediastinitis is a rare, but serious complication of cardiac surgery. It has a significant socioeconomic impact and high morbidity. The purpose of this study was to determine pre-, intra-, and postoperative predictors of mediastinitis., Methods and Results: In 1700 consecutive patients, who underwent cardiac surgery in 2001, 49 variables were retrospectively assessed. Forty-five patients (2.65%, 95% CI [1.88; 3.41]) developed postoperative mediastinitis. None of these patients died during their hospitalization. Multivariate analysis identified three of the 49 variables as highly significant independent predictors for the development of mediastinitis: obesity (OR 1.03, 95% CI [1.01; 1.04] p = 0.001), chronic obstructive pulmonary disease (OR 3.30, 95% CI [1.58; 6.88], p = 0.001), and bilateral grafting of the internal mammary artery (OR 3.18, 95% CI [1.20; 8.43] p = 0.02). The model is reliable in terms of its goodness of fit, it also discriminates well. Additionally, univariate analysis identified diabetes mellitus, CCS class and the number of intraoperatively transfused units of fresh frozen plasma as variables with a significant impact., Conclusion: The present study suggests that bilateral IMA grafting, chronic obstructive pulmonary disease and obesity are important predictors of mediastinitis.

Background: The increasing burden of cardiovascular diseases (CVD) in the ageing population of industrialized nations requires an intensive search for means of reducing this epidemic. In order to improve prevention, detection, therapy and prognosis of cardiovascular diseases on the population level in Eastern Germany, it is necessary to examine reasons for the East-West gradient of CVD morbidity and mortality, potential causal mechanisms and prognostic factors in the elderly. Psychosocial and nutritional factors have previously been discussed as possible causes for the unexplained part of the East-West gradient. A reduced heart rate variability appears to be associated with cardiovascular disease as well as with psychosocial and other cardiovascular risk factors and decreases with age. Nevertheless, there is a lack of population-based data to examine the role of heart rate variability and its interaction with psychosocial and nutritional factors regarding the effect on cardiovascular disease in the ageing population. There also is a paucity of epidemiological data describing the health situation in Eastern Germany. Therefore, we conduct a population-based study to examine the distribution of CVD, heart rate variability and CVD risk factors and their associations in an elderly East German population. This paper describes the design and objectives of the CARLA Study., Methods/design: For this study, a random sample of 45-80 year-old inhabitants of the city of Halle (Saale) in Eastern Germany was drawn from the population registry. By the end of the baseline examination (2002-2005), 1750 study participants will have been examined. A multi-step recruitment strategy aims at achieving a 70% response rate. Detailed information is collected on own and family medical history, socioeconomic, psychosocial, behavioural and biomedical factors. Medical examinations include anthropometric measures, blood pressure of arm and ankle, a 10-second and a 20-minute electrocardiogram, a general physical examination, an echocardiogram, and laboratory analyses of venous blood samples. On 200 participants, a 24-hour electrocardiogram is recorded. A detailed system of quality control ensures high data quality. A follow-up examination is planned., Discussion: This study will help to elucidate pathways to CVD involving autonomic dysfunction and lifestyle factors which might be responsible for the CVD epidemic in some populations.