Thromboembolic complications remain a major public health burden, making antithrombotic agents one of the most widely prescribed groups of medication, but the treatment is often challenging as it... Show moreThromboembolic complications remain a major public health burden, making antithrombotic agents one of the most widely prescribed groups of medication, but the treatment is often challenging as it at the same time increases risk of bleeding. With nationwide data from Statistics Netherlands, antithrombotic therapy and relevant clinical outcomes were comprehensively examined in the patient population of atrial fibrillation, overall or among those with comorbid cancer. The results suggest the patient population was increasingly receiving anticoagulants, driven by the newly introduced medication- direct oral anticoagulant and guided by the CHA2DS2-VASc score, and meanwhile the patient population experienced fewer ischemic stroke and major bleeding. In spite of these promising changes, suboptimal medication adherence and potential underuse of anticoagulants remain directions for further improvement. Antithrombotic agent use during pregnancy was also examined in the general Dutch pregnant population, which featured a surge in antiplatelet prescriptions, and risk of preeclampsia/eclampsia decreased and several newborn outcomes improved simultaneously. Together, the studies presented in this thesis provide an overview of antithrombotic therapy in the Netherlands in recent years, providing insights for further improving this treatment and relevant patient outcomes. Show less
This thesis addresses potential threats to the validity of observational epidemiological studies. Examples of these potential sources of bias are confounding, missing data, selection bias, and... Show moreThis thesis addresses potential threats to the validity of observational epidemiological studies. Examples of these potential sources of bias are confounding, missing data, selection bias, and measurement error. Although various methods have been developed to mitigate these biases, it is often unclear which methods can be used in which empirical settings. It is also common that issues discussed in methodological studies are overlooked in clinical research. Thus, we investigated problems ofmissing data, selection bias, and measurement error occurring in several specific observational settings and discuss how to optimally handle them. Show less
For part I population-based data from the national cancer registries of Belgium, the Netherlands, Norway, and Sweden was used. In all countries, the use of chemotherapy increased with stage and... Show moreFor part I population-based data from the national cancer registries of Belgium, the Netherlands, Norway, and Sweden was used. In all countries, the use of chemotherapy increased with stage and decreased with age. Also, 30-day and one-year excess mortality decreased over the years for colon and rectal cancer. After surviving the first postoperative year, the survival of surgically treated older patients aligned with their younger counterparts, except for patients with stage III disease. Part II describes the results of the analyses of the RAPIDO trial. DRTF decreased from 30% in the standard-care group to 24% in the experimental group at 3 years after randomisation, mainly due to a decrease in DM, which is probably due to better compliance preoperatively and perhaps due the earlier treatment of micrometastases in the treatment process. Although patients with DM in the experimental group had worse survival compared to patients in the standard-care group, the cumulative probability of overall survival remained comparable for both treatment groups. If the patients with a complete response can be identified during reassessment after neoadjuvant therapy, surgery may be omitted, a W&W after a cCR with an appropriate follow-up has no additional oncological risk in young patients compared to older patients (part III). This opens the door for potential organ preservation. Show less
Breast cancer is a heterogeneous disease with substantial variability in outcome, risk factors and response to treatment. Therefore, a better understanding of the factors influencing breast cancer... Show moreBreast cancer is a heterogeneous disease with substantial variability in outcome, risk factors and response to treatment. Therefore, a better understanding of the factors influencing breast cancer outcome could lead to improved prognostication and better stratification of patients into treatment subgroups. To this end, we investigated the association of hereditary genetic variants and non-genetic breast cancer risk factors with breast cancer outcome, and assessed the evidence of potential differential associations across specific tumor subtypes and patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment. We focused on two breast cancer outcomes, namely survival and risk of developing a second breast cancer in the contralateral breast (contralateral breast cancer).Based on data from a large international cohort of breast cancer patients, we found clear associations of several known lifestyle breast cancer risk factors with survival in breast cancer patients, independently from specific tumor subtype, and of coding hereditary genetic variants in five known breast cancer susceptibility genes with contralateral breast cancer risk. There was also evidence of association of coding hereditary genetic variants in three known breast cancer genes with breast cancer-specific survival (time to death due to breast cancer), although weaker than for contralateral breast cancer risk. These factors could be incorporated into prediction models for breast cancer outcome thereby potentially improving prognostic estimates and breast cancer counseling. In particular, the findings related to contralateral breast cancer risk are relevant to treatment decisions, follow-up and screening of breast cancer patients. Show less
Metabolomics, proteomics, and genomics analyses provide profound insight into human biology and disease pathophysiology. In this thesis, we explored the methodological challenges facing these OMICs... Show moreMetabolomics, proteomics, and genomics analyses provide profound insight into human biology and disease pathophysiology. In this thesis, we explored the methodological challenges facing these OMICs technologies and illustrated their applications in epidemiological studies. In part one, we focused on some of the methodological challenges facing OMICs research. These challenges included handling missing data in metabolomics, measurement agreement between high throughput proteomic measurements with standard clinical measurements, and challenges in developing prediction models using metabolomic data. The second part of this thesis addressed various epidemiological research questions by utilizing genomic data and metabolomics measurements (Metabolon and Nightingale platforms) and using advanced data analysis methods. These studies provided important insights into the associations between metabolites and hepatic triglyceride content, the associations of between the size of cytosine-adenine-guanine nucleotide repeats in the huntingtin gene with metabolomic profile, and the associations of the man-made per- and polyfluoroalkyl substances (PFAS) with metabolite levels. Show less
Stroke is one of the leading causes of disability and death worldwide. Prevention of stroke is therefore essential. Effective prevention should be tailored to the clinical characteristics,... Show moreStroke is one of the leading causes of disability and death worldwide. Prevention of stroke is therefore essential. Effective prevention should be tailored to the clinical characteristics, lifestyle, and environment of the individual, among others. This is also known as precision prevention. An important example illustrating the need for precision prevention is the existence of sex differences in stroke occurrence. In practice, for predicting stroke risk, only traditional risk factors (such as smoking and hypertension) are included, and women-specific risk factors are not yet routinely included. As a result, women with an increased risk of stroke may be missed, which also prevents timely initiation of preventive treatments. In this thesis, I tried to lay the foundation for precision prevention of stroke in women.Part I discussed the pathophysiology underlying women-specific risk factors for stroke, and gender differences in the clinical presentation of stroke. I found that the mechanisms underlying the relationship between women-specific risk factors and stroke, in particular the relationship between migraine and cerebral infarctions, seem to be particularly significant in the childbearing phase of life.In Part II, I described how health data from the EHR can be used to develop prediction models for the risk of myocardial infarction or stroke specifically for women under 50 years of age, and found that women-specific risk factors can add value in the predictions. However, there is still a long way to go to actually implement these models in practice, such as testing them on new datasets, and complying with current laws and regulations for safe application. Show less
A growing body of scientific literature documents a putative role of commensal and pathogenic bacteria in the initiation and progression of cancers. One such bacterium is nontyphoidal Salmonella ... Show moreA growing body of scientific literature documents a putative role of commensal and pathogenic bacteria in the initiation and progression of cancers. One such bacterium is nontyphoidal Salmonella (NTS), which has been associated with colon cancer in a few studies. Yet, a lot is still unknown about the magnitude and underlying mechanisms, including the necessary conditions or ‘prerequisites’, of the potential colon carcinogenesis promoting effects of Salmonella. In this thesis, we performed several complementary analyses based on both experimental and epidemiological study designs. Significant excess risk of NTS infection was observed among several occupational groups including those involving contact with live animals or animal manure and animal-derived food sale. The risk of colon cancer was not elevated in these groups. Also, no clear association between NTS and colon cancer was found in a Danish cohort. Two-fold infection of mouse embryonic fibroblasts (MEFs) with a low dose of NTS was more successful than a single high-dose infection (i.e. more and larger colonies). Substantial variation between NTS isolates was found in their capacity to infect MEFs and to induce cellular transformation, with a tendency towards higher transformation efficiency in isolates originating from people who were diagnosed with colon cancer later in life. Show less
This thesis aims to assess the differences and similarities between autoantibody-positive and autoantibody-negative RA from the start of complaints to the end of the disease. The described research... Show moreThis thesis aims to assess the differences and similarities between autoantibody-positive and autoantibody-negative RA from the start of complaints to the end of the disease. The described research was performed with the ultimate goal to clarify whether autoantibody-negative and autoantibody-positive RA are distinct diseases that require different diagnoses and treatment. Show less
Over the last decades, increasingly so in the last years, epidemiological methods have been refined, making it challenging to keep abreast of all methodological developments. The choice of the data... Show moreOver the last decades, increasingly so in the last years, epidemiological methods have been refined, making it challenging to keep abreast of all methodological developments. The choice of the data analytical method directly influences the interpretation and clinical meaning of results of an analysis, yet it is undesirable that technical considerations define the subject of the investigation. Having a deeper understanding of the impact that data analytical decisions can have on the interpretation of numerical results of a study would help to apply analytical tools that are both suitable and appropriate to answer clinical questions. The aim of this thesis was to investigate the impact of choices regarding the design and statistical analysis of a study on the meaning of its numerical results in two sets of case studies in research into causal effects (Part I) and prediction research (Part II). The thesis concludes with a discussion on the role and importance of clinical research questions and estimands. Clearly defining a clinically relevant estimand ensures that data analytical decisions yield meaningful results. Making targeted research questions central to quantitative clinical research can reduce fallacious confidence in (complex) methods and can add to intelligibility of findings. Show less
A direct comparison of two methods for estimating the treated incidence of schizophrenia: the first-contact design (current standard) vs. an electronic psychiatric case-register (new method). The... Show moreA direct comparison of two methods for estimating the treated incidence of schizophrenia: the first-contact design (current standard) vs. an electronic psychiatric case-register (new method). The assumptions underlying the first-contact design are tested. The causes of 2 to 4-fold difference in estimates are conceptualized in a 3-dimensional model. The model is tested on the Norther European incidence literature. Show less
This thesis describes studies on methods for answering questions about causality, specifically so-called what-if questions, in the presence of methodological obstacles such as confounding, missing... Show moreThis thesis describes studies on methods for answering questions about causality, specifically so-called what-if questions, in the presence of methodological obstacles such as confounding, missing data, and measurement error. Show less
In the last decade, through Clinical Outcome Assessment, and especially measurement of patient-reported outcome measures (PROM)s, we, among others, have initiated a shift in focus from meningioma... Show moreIn the last decade, through Clinical Outcome Assessment, and especially measurement of patient-reported outcome measures (PROM)s, we, among others, have initiated a shift in focus from meningioma tumors to meningioma patients. In various studies we describe an improvement in surgical approaches for skull base meningioma. Nevertheless, patient functioning remains impaired in the long-term. We describe that on average nine years after treatment or diagnosis patients still suffer from participation restrictions in social situations with their friends, family, and at work. Often, at the outpatient clinic, we do not pay enough attention to these problems, especially as patient visits become less frequent in the long-term. Importantly, functioning of patients and their informal caregivers (i.e., close relatives/friends) is strongly interdependent. Moreover, patients and healthcare providers find different outcomes and care processes relevant. This underlines the importance of implementation of PROMs in clinical practice. The studies in this thesis suggest that meningioma care trajectories could benefit from the use of 1) case managers guiding patients and their informal caregivers, 2) implementation of PROMs, and 3) prediction models assisting in the identification of individual patients at high risk of long-term lowered functioning. Ideally, these trajectories should follow the value-based healthcare (VBHC) principles. Show less
The increasing amount and complexity of data over the past decades have given rise to new sorts of questions, also in the field of infectious disease epidemiology. This thesis proposes methods to... Show moreThe increasing amount and complexity of data over the past decades have given rise to new sorts of questions, also in the field of infectious disease epidemiology. This thesis proposes methods to analyze data available at multiple resolution levels and to combine different data types in infectious disease surveillance. Hereby using techniques central to data science. Show less
Due to the increased incidence of breast cancer and improved survival, more women are at risk of developing contralateral breast cancer (CBC). The aim of this thesis was to explore risk factors... Show moreDue to the increased incidence of breast cancer and improved survival, more women are at risk of developing contralateral breast cancer (CBC). The aim of this thesis was to explore risk factors associated with CBC. We observed significant associations for a polygenic risk score of common germline variants (PRS313) and for different adjuvant systemic therapy regimens with (subtype-specific) CBC risk. These factors may be incorporated in CBC risk prediction models together with other known and available risk factors. For support of clinical decision making more biological information is needed to understand CBC development in women with invasive breast cancer and DCIS. As a first step towards implementation of a risk prediction model, we performed an exploratory interview study, which showed that patients had varying preferences for graphical presentation of probabilities in a CBC prediction model. In future studies, the prediction model should be incorporated in a decision support tool and implemented in clinical practice. This tool can then help to better identify women at high risk of CBC who may benefit from prophylactic surgery, while the estimates can also be used to reassure patients who are at low risk of developing CBC. Show less
Despite developments in the prevention of invasive aspergillosis, the incidence rates are up to 10% in high risk groups. Within high risk groups, individual patients with an even higher risks can... Show moreDespite developments in the prevention of invasive aspergillosis, the incidence rates are up to 10% in high risk groups. Within high risk groups, individual patients with an even higher risks can be identified, such as those suffering from relapsed AML. Mortality of IA is high within all populations and is mainly found in the first 30 days after diagnosis. Because of the serious nature of the underlying diseases that predispose for IA, it can be challenging to quantify the contribution of IA to mortality; crude mortality rates cannot distinguish death due to IA-unrelated causes from IA-related death, almost certainly leading to inflation of mortality rates. It can be helpful to assess contributability of IA to death to provide a better understanding of the impact of IA in this vulnerable patient population. Additionally, we have explored the new problem that is posed by the increase of triazoleresistant Aspergillus fungi, resulting in challenges in the application of antifungal therapies. Treatment strategies involving the use of LAmB are becoming more prevalent in areas withhigh resistance rates, but should be applied with care due to concerns of renal toxicity and decreased efficacy against triazole-susceptible isolates when compared to voriconazole. Rational application of PCR could help us to initiate the right therapy sooner, by possibly providing information about the susceptibility of the Aspergillus fungus. Show less
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... Show moreStudies 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. Show less
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... Show moreIn 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. Show less
The prevalence of musculoskeletal complaints in professional musicians is higher compared to the general population (Odds ratio 2.3): point prevalences in the literature range between 9% and 68%;... Show moreThe prevalence of musculoskeletal complaints in professional musicians is higher compared to the general population (Odds ratio 2.3): point prevalences in the literature range between 9% and 68%; year prevalences range between 41% and 93%. Female gender is the most important risk factor. Also among amateur musicians musculoskeletal complaints are frequent, the year prevalence of playing-related is 68%. Female gender, a sudden increase in playing time and playing a string instrument were the main risk factors. Among professional musicians with musculoskeletal complaints, the impact of these complaints on daily functioning is appreciated as more severe, compared non-musicians with musculoskeletal complaints. Also, healthcare usage is higher among musicians with these complaints. Musicians with complaints report worse illness perceptions compared to non-musicians with musculoskeletal complaints. In the last part of this thesis biomechanical aspects of violin playing are evaluated: Violinists with complaints show more activity of the superficial neck and shoulder muscles while playing the instrument, which is hypothesized to be the result of co-contraction. From a biomechanical point of view, playing without a shoulder rest, or with a shoulder rest with minimal height seems favourable, the latter being subjectively most comfortable by the violinists. Show less
Clostridium difficile infection (CDI) was discovered in 1978 as an important cause of antibiotic-associated diarrhoea. CDI became the most common healthcare-associated infection in Northern-America... Show moreClostridium difficile infection (CDI) was discovered in 1978 as an important cause of antibiotic-associated diarrhoea. CDI became the most common healthcare-associated infection in Northern-America and Europe during the antibiotic era, especially after global spread of a fluoroquinoloneresistant ribotype 027 strain in 2003. The rise of CDI urged the use of epidemiological surveillance systems to monitor disease dynamics and rapidly detect outbreaks. However, valid estimations of the infection burden of CDI in Europe were hampered by the heterogeneity and insufficiency of diagnostic algorithms for CDI, lack of standardised typing systems and incomplete surveillance methodologies. This thesis includes two studies conducted within a project named ‘the European CDI Surveillance Network’ focussing on enhancement of CDI surveillance and laboratory capacity for CDI in Europe. In the Netherlands, a sentinel surveillance system monitors the incidence of CDI in hospitals. This thesis describes (spatial) trends in the epidemiology of CDI in the Netherlands, in particular for children and the potentially zoonotic C. difficile ribotype 078. Data of a community-based case-control study was used to apply spatial scan statistics to detect CDI clustering beyond the hospital setting. Finally, this thesis provides directions for future epidemiological surveillance systems of CDI, both in the Netherlands and Europe. Show less
Worldwide, there is an strong rise of cardiometabolic disorders, which mainly comprise obesity, cardiovascular disease (CVD) and type 2 diabetes. Therefore, the development and improvement of... Show moreWorldwide, there is an strong rise of cardiometabolic disorders, which mainly comprise obesity, cardiovascular disease (CVD) and type 2 diabetes. Therefore, the development and improvement of preventive and curative strategies for cardiometabolic disease is eagerly warranted. With the studies describes in this thesis, we aimed to disentangle the interwoven physiological, environmental and genetic factors that determine cholesterol and energy metabolism to increase our understanding of their contribution to cardiometabolic disease risk. The first part of this thesis focussed on the cholesteryl ester transfer protein (CETP). The lipid transfer properties of CETP induce a proatherogenic lipoprotein profile. Therefore, CETP inhibitory molecules have been developed and tested in clinical trials for their capability to improve the lipoprotein profile and reduce CVD risk. To fully understand the role of CETP in CVD, its physiology and biological function should be fully unravelled. The focus of the second part of this thesis was on the role of energy metabolism in cardiometabolic health. Specifically, we aimed to study the association of environmental and genetic factors, which were previously described to influence brown adipose tissue (BAT) activity, with energy expenditure and disease outcomes. Show less
