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Visceral adipose tissue (VAT) is a strong prognostic factor for cardiovascular disease and a potential target for cardiovascular risk stratification. Because VAT is difficult to measure in clinical practice, we estimated prediction models with predictors routinely measured in general practice and VAT as outcome using ridge regression in 2,501 middle-aged participants from the Netherlands Epidemiology of Obesity study, 2008–2012. Adding waist circumference and other anthropometric measurements on top of the routinely measured variables improved the optimism-adjusted R2 from 0.50 to 0.58 with a decrease in the root-mean-square error (RMSE) from 45.6 to 41.5 cm2 and with overall good calibration. Further addition of predominantly lipoprotein-related metabolites from the Nightingale platform did not improve the optimism-corrected R2 and RMSE. The models were externally validated in 370 participants from the Prospective Investigation of Vasculature in Uppsala Seniors (PIVUS, 2006–2009) and 1,901 participants from the Multi-Ethnic Study of Atherosclerosis (MESA, 2000–2007). Performance was comparable to the development setting in PIVUS (R2 = 0.63, RMSE = 42.4 cm2, calibration slope = 0.94) but lower in MESA (R2 = 0.44, RMSE = 60.7 cm2, calibration slope = 0.75). Our findings indicate that the estimation of VAT with routine clinical measurements can be substantially improved by incorporating waist circumference but not by metabolite measurements.

Aims: To quantify metabolic impairment via a one-factor approach with confirmatory factor analysis (CFA) including MRI-derived visceral and subcutaneous adipose tissues and to associate it with diastolic dysfunction. Methods: In this cross-sectional analysis, 916 participants (53% female, mean age (SD): 56 (6)) underwent abdominal and cardiovascular MRI. With CFA a metabolic-load factor of metabolic-syndrome variables and visceral and subcutaneous adipose tissues was constructed. A piecewise structural equation model approach with adjustment for confounding factors was used to determine associations with left-ventricular diastolic function, cardiac morphology and hemodynamics. Results: Model fitting excluding blood pressure and waist circumference but including visceral and subcutaneous adipose tissues, fasting glucose, HDL-c and triglycerides was used to construct the metabolic-load factor. Evaluating measurement invariance demonstrated sex-specificity. Change in mitral early/late peak filling rate ratio was -0.12 for both males [-0.20; -0.05, p > 0.05] and females [-0.17; -0.07, p > 0.001] per SD of metabolicload factor. Change in deceleration time of mitral early filling was -11.83 ms in females [-17.38; -6.27] per SD of metabolic-load factor. Conclusion: A single latent metabolic-load factor via CFA including MRI-derived adipose tissues increased sensitivity for metabolic impairment obsoleting waist circumference and is associated with a decreased leftventricular diastolic function, more apparent in females than in males.

Background To evaluate the association between crowding and transmission of viral respiratory infectious diseases, we investigated the change in transmission patterns of influenza and COVID-19 before and after a mass gathering event (i.e., carnival) in the Netherlands. Methods Information on individual hospitalizations related to the 2017/2018 influenza epidemic were accessed from Statistics Netherlands. The influenza cases were stratified between non-carnival and carnival regions. Distributions of influenza cases were plotted with time and compared between regions. A similar investigation in the early outbreak of COVID-19 was also conducted using open data from the Dutch National Institute for Public Health and the Environment. Results Baseline characteristics between non-carnival and carnival regions were broadly similar. There were 13,836 influenza-related hospitalizations in the 2017/2018 influenza epidemic, and carnival fell about 1 week before the peak of these hospitalizations. The distributions of new influenza-related hospitalizations per 100,000 inhabitants with time between regions followed the same pattern with a surge of new cases in the carnival region about 1 week after carnival, which did not occur in the non-carnival region. The increase of new cases for COVID-19 in the carnival region exceeded that in the non-carnival region about 1 week after the first case was reported, but these results warrant caution as for COVID-19 there were no cases reported before the carnival and social measures were introduced shortly after carnival. Conclusion In this study, a mass gathering event (carnival) was associated with aggravating the spread of viral respiratory infectious diseases.

Objective. To investigate the association of hand osteoarthritis (OA) and concurrent hand and knee OA with health-related quality of life (HRQOL) in the general population, and in patients consulting a rheumatology outpatient clinic.Methods. In the population-based Netherlands Epidemiology of Obesity (NEO) study, participants were recruited from the greater area of Leiden, the Netherlands. In the Hand OSTeoArthritis in Secondary care (HOSTAS) study, patients with a rheumatologist's diagnosis of hand OA were recruited from a Leiden-based hospital. In both cohorts, hand and knee OA were defined by the American College of Rheumatology clinical criteria. In NEO, self-reported hospital-based specialist consultation for OA was recorded. Physical and mental HRQOL was assessed with normalized Medical Outcomes Study Short Form-36 scores. Associations were analyzed using linear regression, adjusted for age, sex, education, ethnicity, and body mass index.Results. Hand OA alone and concurrent hand and knee OA was present in 8% and 4% of 6334 NEO participants, and in 57% and 32% of 538 HOSTAS patients. In NEO, hand OA alone, and concurrent hand and knee OA, were associated with lower physical component summary (PCS) scores [mean difference -2.4 (95% CI -3.6, -1.3) and -7.7 (95% CI -9.3, -6.2), respectively] compared with no OA. Consulting a specialist was associated with worse PCS scores. In the HOSTAS cohort, mean PCS scores were lower than norm values (-3.5 and -7.9 for hand OA and combined OA, respectively). Mental HRQOL was not clinically relevantly associated in either cohort.Conclusion. Hand OA was associated with reduced physical, but not mental, HRQOL in the general population and hospital patients. Physical HRQOL was further reduced in hospital care, and with concurrent knee OA.

Background Several trials to prevent cardiovascular disease by inhibiting cholesteryl ester transfer protein (CETP) have failed, except Randomized EValuation of the Effects of Anacetrapib through Lipid-modification. Thus far, it is unclear to what extent CETP is causally related to measures of atherosclerosis. Objective The aim of the article was to study the causal relationship between genetically determined CETP concentration and carotid intima-media thickness (cIMT) in a population-based cohort study. Methods In the Netherlands Epidemiology of Obesity study, participants were genotyped, and cIMT was measured by ultrasonography. We examined the relation between a weighted genetic risk score for CETP concentration, based on 3 single-nucleotide polymorphisms that have previously been shown to largely determine CETP concentration and cIMT using Mendelian randomization in the total population and in strata by sex, Framingham 10-year risk, (pre)diabetes, high-density lipoprotein cholesterol, triglycerides, and statin use. Results We analyzed 5655 participants (56% women) with a mean age of 56 (range 44–66) years, body mass index of 26 (range 17–61) kg/m 2 , and serum CETP of 2.47 (range 0.68–5.33) μg/mL. There was no evidence for a causal relation between genetically determined CETP and cIMT in the total population, but associations were differently directed in men (16 μm per μg/mL increase in genetically determined CETP; 95% confidence interval: −8, 39) and women (−8 μm; −25, 9). Genetically determined CETP appeared to be associated with cIMT in normoglycemic men (26 μm; −1, 52) and in (pre)diabetic women (48 μm; −2, 98). Conclusion In this population-based study, there was no causal relation between genetically determined CETP concentration and cIMT in the total population although we observed directionally differing effects in men and women. Stratified results suggested associations in individuals with different cardiometabolic risk factor profiles, which require replication.

Item does not contain fulltext OBJECTIVE: To study the relative contribution of surrogates for mechanical stress and systemic processes with osteoarthritis (OA) in weight-bearing and non-weight-bearing joints. METHODS: The Netherlands Epidemiology of Obesity study is a population-based cohort including 6673 participants (range 45-65 years, 56% women, median body mass index 26 kg/m(2)). Weight (kg) and fat mass (kg) were measured, fat-free mass (kg) was calculated. The metabolic syndrome was defined following the Adult Treatment Panel III criteria. Knee and hand OA were defined according to the American College of Rheumatology clinical criteria.Logistic regression analyses were performed to associate surrogates for mechanical stress (such as weight, fat-free mass) and systemic processes (such as metabolic syndrome) with OA in knees alone, knees and hands or hands alone, adjusted for age, sex, height, smoking, education and ethnicity, and when appropriate for metabolic factors and weight. RESULTS: Knee, knee and hand, and hand OA were present in 10%, 4% and 8% of the participants, respectively. Knee OA was associated with weight and fat-free mass, adjusted for metabolic factors (OR 1.49 (95% CI 1.32 to 1.68) and 2.05 (1.60 to 2.62), respectively). Similar results were found for OA in knees and hands (OR 1.51 (95% CI 1.29 to 1.78) and 2.17 (95% CI 1.52 to 3.10) respectively). Hand OA was associated with the metabolic syndrome, adjusted for weight (OR 1.46 (95% CI 1.06 to 2.02)). CONCLUSIONS: In knee OA, whether or not in co-occurrence with hand OA, surrogates for mechanical stress are suggested to be the most important risk factors, whereas in hand OA alone, surrogates for systemic processes are the most important risk factors.

In contrast to structured, integrated risk assessment in primary care, unstructured risk factor screening outside primary care and corresponding recommendations to consult a general practitioner (GP) are often based on one abnormal value of a single risk factor. This study investigates the advantages and disadvantages of unstructured screening of blood pressure and cholesterol outside primary care.After the baseline visit of the Netherlands Epidemiology of Obesity study (population-based prospective cohort study in persons aged 45-65 years, recruited 2008-2012) all participants received a letter with results of blood pressure and cholesterol, and a recommendation to consult a GP if results were abnormal. Four years after the start of the study, participants received a questionnaire about the follow-up of their results.The study population consisted of 6343 participants, 48% men, mean age 56 years, mean body mass index 30 kg/m(2). Of all participants 66% had an abnormal result and, of these, 49% had a treatment indication based on the risk estimation system SCORE-NL 2006. Of the 25% of the participants who did not consult a GP, 40% had a treatment indication. Of the participants with an abnormal result 19% were worried, of whom 60% had no treatment indication.In this population 51% of the participants with an abnormal result had unnecessarily received a recommendation to consult a GP, and 10% were unnecessarily worried. GPs should be informed about the complete risk assessment, and only participants at intermediate or high risk should receive a recommendation to consult a GP.

Contains fulltext : 137745.pdf (Publisher’s version ) (Open Access) Changes in endothelial glycocalyx are one of the earliest changes in development of cardiovascular disease. The endothelial glycocalyx is both an important biological modifier of interactions between flowing blood and the vessel wall, and a determinant of organ perfusion. We hypothesize that deeper penetration of erythrocytes into the glycocalyx is associated with reduced microvascular perfusion. The population-based prospective cohort study (the Netherlands Epidemiology of Obesity [NEO] study) includes 6,673 middle-aged individuals (oversampling of overweight and obese individuals). Within this cohort, we have imaged the sublingual microvasculature of 915 participants using sidestream darkfield (SDF) imaging together with a recently developed automated acquisition and analysis approach. Presence of RBC (as a marker of microvascular perfusion) and perfused boundary region (PBR), a marker for endothelial glycocalyx barrier properties for RBC accessibility, were assessed in vessels between 5 and 25 microm RBC column width. A wide range of variability in PBR measurements, with a mean PBR of 2.14 microm (range: 1.43-2.86 microm), was observed. Linear regression analysis showed a marked association between PBR and microvascular perfusion, reflected by RBC filling percentage (regression coefficient beta: -0.034; 95% confidence interval: -0.037 to -0.031). We conclude that microvascular beds with a thick ("healthy") glycocalyx (low PBR), reflects efficient perfusion of the microvascular bed. In contrast, a thin ("risk") glycocalyx (high PBR) is associated with a less efficient and defective microvascular perfusion.

The aim of this thesis was to unravel a selection of a multitude of potential causal pathways that may underlie the association between excess body fat and cardiovascular disease, such as adipokines, inflammation, HDL-cholesterol and postprandial triglyceride response, and cholesteryl ester transfer protein (CETP). We showed that hs-CRP and GlycA as measures of inflammation, adiponectin, and leptin are not associated with clinical and subclinical cardiovascular disease in the general population. However, all may be relevant markers of disease risk. Also, postprandial triglyceride excursions, genetically-determined CETP and HDL-cholesterol, while not related with subclinical atherosclerosis in the general population, may be interesting targets to pursue in women and men separately, and in subgroups of individuals at high-cardiovascular risk.

In this thesis, the transition from a population-based approach to individualized therapy for the prevention of VT following lower-leg cast immobilization and knee arthroscopy is discussed.

The prevalence of obesity is increasing worldwide. In particular abdominal obesity is a well-established risk factor for cardiometabolic diseases. The excess risk of abdominal obesity is due to fat in the visceral area and in and around the organs (ectopic fat), such as in the liver. The main aim of this thesis was therefore to study whether lifestyle can reduce the amount of visceral fat and liver fat.Firstly, in a systematic review and meta-analysis of randomized controlled trials, we concluded that a diet high in proteins decreases liver fat compared with a diet high in carbohydrates. A diet high in fat did not lead to changes in liver fat compared with a diet high in carbohydrates. Within fat types, saturated fat leads to more liver fat accumulation than unsaturated fat. Secondly, we studied diet at multiple levels in the Netherlands Epidemiology of Obesity study, which is a population based cohort study of middle-aged men and women with directly assessed measured of adiposity. When studying food groups rather than nutrients, we observed that consumption of sweet snacks are positively associated with liver fat content, also after taking into account total body fat. Likewise, consumption of fruit and vegetables and plant-based fats and oils was associated with less visceral fat. A better adherence to the current Dutch dietary guidelines, as indicated by a higher score on the 15-component Dutch Healthy Diet Index, was associated with less total body fat, less visceral fat and liver fat. The associations with visceral fat and liver fat remained present after taking into account total body fat, indicating that the associations are indeed specific for visceral and liver fat rather than merely representing associations with overall adiposity. Associations were not driven by one component in particular, indicating the importance of an overall healthy diet. When we studied alcohol intake separately, each additional serving of alcoholic beverages per day was also associated with more liver fat. Moreover, replacing one alcoholic serving with one non-alcoholic serving was associated with less liver fat. Replacing the same amount of calories of alcoholic beverages with sugar sweetened beverages was equally associated with liver fat, whereas replacement with milk was associated with less liver fat. Lastly, we observed that objectively measured sedentary time was associated with more total body fat, visceral fat and liver fat. Replacing 30 minutes of sedentary time per day with moderate to vigorous physical activity, but not light physical activity was associated with less total body fat, visceral fat and liver fat. These associations with visceral fat and liver fat disappeared after additional adjustment for total body fat, indicating that there is no extra effect on visceral fat and liver fat beyond effects via total body fat.Results described in this thesis hint towards the importance of considering diet as a whole, instead of separate components, which is in line with the current dietary guidelines. Sedentary behaviour should be replaced with moderate to vigorous physical activity rather than light physical activity. Alcohol should not be replaced with sugar sweetened beverages, but rather with milk, coffee or tea.

Venous thrombosis (VT), the occlusion of the venous system by a blood clot, is a multicausal disorder affecting 1-2 per 1000 individuals annually. The risk of VT and its complications is not equal for all individuals. In addition to clinical or acquired risk factors, genetic variation contributes to the risk of venous thrombosis. So far, variation in seventeen genes, almost all encoding proteins related to hemostasis, have consistently been identified as genetic risk factors for a first venous thrombosis. Evidence from previous genome-wide association studies and family studies suggests that additional genetic risk variants are yet to be discovered. In addition, the extent to which the identified risk variants contribute to recurrence risk is not clear, nor whether different genetic risk factors play a role in recurrence pathophysiology than those involved in a first event. In this thesis, we used various strategies to identify variants across the allele frequency spectrum that are associated with the risk of a first or recurrent venous thrombosis. In addition, we investigated whether previously identified genetic risk variants can be used to improve risk stratification for venous thrombosis and we discussed the potential value of using genetic variation to aid causal inferences in observational research.

Studies in this thesis were performed in a secondary care cohort of patients with hand osteoarthritis. Several factors were investigated for their association with disease status and disease progression after two years. These factors included comorbidity, illness perceptions and MRI-defined inflammatory features such as bone marrow lesions, synovitis and joint effusion. In the MRI studies we found that these MRI-features have a clinically relevant role for their association with pain (at the same moment and after two years) and progression of radiographic damage after two years. In the second part of this thesis we evaluated the clinimetric properties of two new instruments: self-reported painful joint count and semi-automatic joint space width measurements.

In this thesis, the importance of visceral obesity in the relation of obesity with cardiometabolic risk factors (chapter 2) was confirmed and it was shown that in individuals free of known cardiovascular disease clustering of cardiometabolic risk factors is associated with changes in electrocardiographic parameters indicative of subclinical cardiovascular disease (chapter 3). The findings from chapter 3 also point to the importance of the prevention of these metabolic syndrome components, not only in obese, but also in non-obese individuals. Furthermore, both overall and abdominal adiposity were found to be associated with these deleterious changes in electrocardiographic parameters (chapter 4). Borderline Q-waves were associated with a negative cardiovascular risk profile and increased pulse wave velocity and intima-media thickness (chapter 5). Chapter 6 shows that several cardiovascular risk factors were associated with a wider spatial QRS-T angle, which reflects ventricular electrophysiological heterogeneity. Both carotid intima-media thickness, as measure of subclinical atherosclerosis, and pulse wave velocity, as measure of arterial stiffness, were associated with a wider spatial QRS-T angle. In chapter 7, improvement of electrocardiographic detection of left ventricular hypertrophy with conventional electrocardiographic criteria by taking into account body mass index and the spatial QRS-T angle is shown.

In this thesis the risk factors of venous thrombosis will be discussed in the general and particularly the elderly population. The goal of this thesis is to provide insights on risk factors of thrombosis in the elderly population, in order to advance our basic understanding of physiological age-related changes that increase the risk of venous thrombosis and which may ultimately lead to improved personalized interventions. In this chapter firstly background information will be provided on risk factors for venous thrombosis, focussing specifically on age as a risk factor. Secondly, the role of veins and venous valves in the development of venous thrombosis will be discussed and thirdly, global assays as a potential tool to identify patients at high risk for venous thrombosis will be considered. The study populations used in this thesis will discussed, and an outline of this thesis will be provided.

Several studies during the past decade have shown that patients with venous thrombosis have an increased risk of subsequent arterial thrombosis, thus suggesting a link between the two diseases. The aim of this thesis was to investigate the associations of traditional cardiometabolic risk factors with risk of a first and recurrent venous thrombosis. We showed that levels of major lipids, i.e. total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides, were not associated with a first venous thrombosis. In contrast, low levels of apolipoproteins B and A1 were associated with an increased risk of a first event. Regarding recurrence, tests for lipid levels, glucose levels and hematologic variables did not identify patients at an increased risk of recurrent venous thrombosis, and these tests should not be done for this indication nor influence decisions on duration of anticoagulant treatment. In this thesis, we further searched for associations between lipids and hemostatic factors, and found that levels of vitamin K-dependent factors (VKDFs), including factor IX, were associated with triglyceride levels. We hypothesized that this association could be explained by common mechanisms, regulating levels of both VKDFs and triglycerides.

This thesis reports on studies that have investigated the role of several factors on the risk of arterial thrombosis. The thesis is organised in two sections. The first section (Chapters 2-5) deals with risk factors for the first arterial thrombotic event whereas the second section (Chapters 6 and 7) concerns risk factors for recurrence. The investigations touch several aspects of epidemiology, and make use of several observational study designs, encompassing case control, cohort and meta-analysis. Several statistical models were also applied ranging from logistic regression models, Cox proportional hazards time to event regression models as well as non-parametric statistics. Because of the heterogeneous nature, each investigation had specific problems in study design, data collection and analyses. A common line, however, is the haemostatic balance and its markers. Taken together, the findings of this thesis lead to the conclusion that there are differences in the aetiology of the two main forms of arterial thrombosis. Indeed, they support the hypothesis that hypercoagulability plays a greater role in the pathogenesis of ischaemic stroke than in that of myocardial infarction.

The overall goal of this thesis was to identify patients who are at high risk for major bleedings during anticoagulant treatment and to reduce the number of major bleeds. The first part looks into methodology of observational studies. It shows that biases in observational studies may be an explanation why statins seem to have many unintended effects. The second part looks into bleeding complications and shows that patient with three concomitant anticoagulants experience high major bleeding rates. Also, a study was performed in which plasma and DNA of participants was collected, to identify risk factors for major bleeds in the future. The first results show that damage to vessel walls increases the risk of major bleeding. Interventions to reduce the number of bleeding events were to dose nadroparin od instead of bid. In addition, multi-dose drug dispensing may increase adherence of medication. Also, vitamin K1 tablets are easier to ingest and this thesis shows that the tablets are as effective in reducing the INR as the oral solution.

The main objective of this thesis was to unravel relationships between obesity, insulin resistance, hyperglycemia, and atherosclerosis. It is well-established that patients with type 2 diabetes have a 2- to 3-fold increased risk of cardiovascular disease. We investigated whether insulin resistance and hyperglycemia are associated with atherosclerosis and incident cardiovascular disease before the onset of type 2 diabetes. Obesity can be considered as a common cause of both insulin resistance and atherosclerosis. Therefore, we investigated to what extent associations between insulin resistance, hyperglycemia and atherosclerosis were explained by body fat. We further aimed to study the specific role of visceral fat in the development of insulin resistance and atherosclerosis, and directly assessed abdominal subcutaneous and visceral adipose tissue depots.

The pathogenesis of OA is largely unknown; however, several risk factors are known to contribute to disease development. Treatment modalities are currently limited to alleviation of symptoms. In order to develop better treatment modalities, increase of the understanding of the underlying mechanisms leading to OA development may provide targets for disease modification. Furthermore, knowledge regarding appropriate outcome measures that can be applied in OA research has to be increased for adequate assessment of potential treatment effects. Therefore, part I of this thesis describes studies aiming to increase the understanding of mechanisms underlying the association between known risk factors and OA, especially focussing on obesity in relation to OA in weight-bearing and non-weight-bearing joints. Furthermore, it was investigated which specific structural abnormalities on specific locations within the knee joint could best discriminate presence of symptomatic OA, and impact of knee OA and its modifiable or preventable risk on health-related quality of life was evaluated. Part II of this thesis describes two systematic reviews, assessing available instruments for measurement of the domains pain, physical function, patient global assessment and imaging in hand OA in order to enable recommendations for use in clinical trials.

The main objective of this thesis was to study the role of autonomic nervous system (ANS) function in the development of diabetes and cardiovascular disease using an epidemiological approach. Based on earlier studies it has remained unclear whether impaired ANS function is a risk factor for the development of diabetes and cardiovascular disease, or merely a consequence of pre-existing disease. The main conclusions of this thesis are that excess body fat, in particular visceral fat, is associated with activation of the sympathetic nervous system in individuals without diabetes and cardiovascular disease. Furthermore, this thesis showed that impaired ANS function is not a risk factor for the development of diabetes mellitus. The presented studies suggest that insulin resistance precedes the impairment of the ANS. The results from this thesis also show that impaired ANS function is a risk factor for the development of cardiovascular disease in populations without pre-existing cardiovascular disease. Furthermore, individuals with a higher heart rate have higher concentrations of cholesterol and triglycerides in the circulation and a higher intrahepatic triglyceride content, suggesting that an altered lipid metabolism may be a mechanism underlying the association between ANS function and cardiovascular disease.

Venous thrombosis is a disease that occurs in 1-2 per 1000 people per year. At the time of their first venous thrombosis, approximately 50% of women are exposed to reproductive risk factors (oral contraception, postmenopausal hormone therapy, pregnancy and the puerperium). In this thesis, we showed that these women are at particularly high risk of venous thrombosis if they have previously experienced an episode of superficial vein thrombosis, or are over the age of 50 years (Chapters 2 and 3). There is no known male counterpart to female reproductive risk factors. Nevertheless, the incidence of venous thrombosis is approximately similar in men and women. In this thesis we established that, once female reproductive risk factors are taken into account, men have an approximately twofold higher risk of both first and recurrent venous thrombosis than women (Chapters 4 and 5). Further to these findings, in Chapter 6, we reviewed the literature on sex-specific risk factors for venous thrombosis. We hypothesized that sex-specific genetic risk factors, an excess in overweight and smoking, or hypercoagulable changes such as microalbuminuria may explain the higher risk of venous thrombosis in men than in women.

The aim of this thesis was to identify new risk factors for first and recurrent venous thrombosis of both the upper and lower extremity, and assess the incidence of recurrence and mortality after a first venous thrombosis. An overview was provided of the current literature on risk factors and treatment for a first venous thrombosis of the upper extremity (chapter 2). We investigated the association between levels of coagulation factors, blood group and a first venous thrombosis of the upper extremity (chapter 3), and studied risk factors for a recurrent event in patients with a first venous thrombosis of the upper extremity (chapter 4). Furthermore, we studied the association between venous thrombosis and long-term mortality (chapter 5). In this study we found that patients with thrombosis died more of chronic obstructive pulmonary disease (COPD) than expected from population figures. COPD was found to be a risk factor for a first venous thrombosis in chapter 6. We studied the incidence of recurrent venous thrombosis, as well as sex, age and an idiopathic first venous thrombosis as risk factors for recurrence (chapter 7). Body height was studied as a risk factor for both first and recurrent venous thrombosis in combination with mobility (chapter 8).

We investigated the clinical and radiographic disease course of hand osteoarthritis as well as determinants of poor clinical outcome and radiographic progression over a period of six years in 289 patients with hand osteoarthritis. Because these patients had osteoarthritis at multiple joints this enabled us to not only assess the association between progression of osteoarhtiritis in different hand joints groups but also between progression of hand osteoarthritis and osteoarthritis change at the knee. In addition, genetic factors in hand osteoarthritis progression were investigated as well as the influence of illness perceptions. The hand osteoarthritis subsets erosive osteoarthritis and thumb base osteoarthritis are further characterised. In the last part of the thesis the clinimetric properties of a pain score for osteoarthritis and radiographic outcome measures for hand osteoarthritis are evaluated.

Pulmonary embolism is traditionally, since autopsy studies by Virchow in the mid 1800s, thought to originate from embolization of a deep-vein thrombosis, resulting in two clinical manifestations of one disease: venous thrombosis. The incidence of deep-vein thrombosis in the population is twice as high as the incidence of pulmonary embolism, i.e. 1 per 1000 and 0.5 per 1000 person-years respectively. The aim of this thesis was to assess whether pulmonary embolism and deep-vein thrombosis are always the same disease or not, and to answer this question with regard to etiology (genetic and acquired risk factors) and anatomical distribution of thrombi in the veins. We studied this question in two populations: the PEDLAR study and the MEGA case-control study. In the PEDLAR study we assessed the origin of pulmonary embolism using a total body Magnetic Resonance Direct Thrombus Imaging technique. We proposed several mecha nisms for the absence of deep-vein thrombi in more than half of the patients with pulmonary embolism. In addition, we investigated the effect of aging on venous valve thickness. This was performed in an ultrasonography study, with participants from 20 to 80 years old (the aging venous valves study). We hypothesized that part of the increasing incidence in venous thrombosis with age can be explained by increasing valve thickness.

Cardiovascular disease are a leading cause of mortality and morbidity in the Western world. Platelets play an important role in the development of cardiovascular disease, not only in the acute onset of thrombosis after atherosclerotic plaque rupture but also in the initiation and progression of atherosclerosis and plaque formation. In recent years, the awareness has grown that platelet function may vary among individuals and that high platelet reactivity may increase the risk of cardiovascular events. This thesis addresses variation in platelet reactivity in relation to occurrence of cardiovascular events. We show that high platelet reactivity in subjects with cardiovascular disease using aspirin or clopidogrel as well as in antiplatelet drug-na_ve healthy subjects is related to the risk of cardiovascular events. We also revealed several genetic and clinical risk factors of high platelet reactivity. Moreover, we show that the 110-year old antiplatelet drug aspirin has interesting time-dependent pleiotropic effects on various pressor systems underlying blood pressure. As discussed in this thesis, although promising results have been published, routine platelet reactivity testing in daily clinical practice would currently be premature. Future studies are warranted to further investigate the clinical applicability of platelet reactivity testing in subjects at risk for cardiovascular events.

Assessing metabolic risk in dialysis patients, three main aspects are important: a) the pathophysiologic effects of metabolic disturbances as known from the general population are unlikely to completely reverse once patients reach dialysis. b) Specific additional problems related to chronic kidney disease, in particular protein-energy wasting, may act as “competing risk”, overshadow effects and interfere in various hormonal regulations. c) In advanced chronic kidney disease, the pattern and composition of risk is changing. The aim of this thesis is to 1) Detect specific effects of metabolic alterations in dialysis patients 2) Provide explanations for conflicting results in the literature 3) Provide a rationale for novel interventions. In this thesis, the metabolic status of dialysis patients is adressed and its consequences for the decline in residual kidney function, cardiovascular events and survival. The metabolic status includes alterations in nutritional and hormonal status, focussing on: lipid metabolism, diabetes mellitus type 2, obesity, the role of adipokines, specific effects of protein-energy wasting, and Vitamin D status with the clinical consequences. The investigations are performed in two large cohorts of dialysis patients, the 4D and NECOSAD studies (The German Diabetes and Dialysis Study and The Netherlands Cooperative Study on the Adequacy of Dialysis).

The content of this thesis is of two sorts: in one part, three topics about the early origins of adult disease are addressed, preceded by three related methodological studies which form the other part. The thesis starts with a systematic review of the literature about the growth of infants born preterm. Next, three specific methodological issues related to early origins of adult disease studies are addressed. A: the most favorable regression model for analyzing and interpreting the effect of both prenatal and subsequent postnatal growth on adult health outcomes. B: the efficiency of reliability studies in the context of a multi-centre study. And C: the correct and clear assessment of reliability in case of log transformed outcomes. These methods are used ind the second part, in which three topics about the effects of prenatal and early postnatal growth on adult health outcomes are addressed, namely: A the association between birth weight and adult renal function in non-premature subjects. B: The association between birth weight and the adult metabolic syndrome, and its separate components in the same population. And finally, C: the association between early growth and adult body composition in subjects born very preterm.

Although the quality of oral anticoagulant treatment is already high, improvement is important. We performed several studies which all aimed to optimize dosing of vitamin K antagonists and control of anticoagulant treatment. In our double-blind controlled trial comparing a simple dosing algorithm to an algorithm that incorporated the patients__ sensitivity for vitamin K antagonists, we showed that there was no increase in treatment quality. However, the new algorithm was more efficient, as more dosage proposals were generated and accepted. We studied the relationships between maintenance dosages between acenocoumarol, warfarin and phenprocoumon and calculated transition factors. In a prospective cohort study among 220 Italians initiating anticoagulant treatment with acenocoumarol we showed that CYP2C9*3 was associated with a 25% dose-reduction and an increased risk of over-anticoagulation (INR>6) on day 4. Two copies of the VKORC1*2 alleles were associated with a 45% dose-reduction and an increased risk of over-anticoagulation. Instability is a risk factor for developing complications. We studied several methods to reflect instability and investigated which method was best associated with complications. We also investigated determinants of instability. Finally, we present the design and general results of a trial with primary aim to compare the quality of treatment with warfarin to phenprocoumon.