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
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
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
The fact that most healthcare resources are spend on a small subgroup of patients with an unfavourable prognosis has long been recognized. Therefore change is needed in terms of an improved... Show moreThe fact that most healthcare resources are spend on a small subgroup of patients with an unfavourable prognosis has long been recognized. Therefore change is needed in terms of an improved identification of patients with an unfavourable prognosis, early in their treatment course, which may facilitate proactive approaches to improve outcomes. We discussed two conceptually distinct constructs of predictors of prognosis in order to improve the identification of patients with an unfavourable prognosis. First, the level of control of the chronic condition as a predictor could reflect to some extent the presence of a multitude of other risk factors. Second, information on early treatment response had better predictive ability for long-term outcomes and so acts as a proxy for treatment effectiveness. Treatment effectiveness depends on different aspects e.g. adequateness of initial treatment and/or drugs, the mutual trust between clinician and patient and behavioral aspects such as treatment adherence. Treatment response adds an insight that can be acted upon; guiding personalized decisions in the treatment plan. In conclusion, this thesis leads to improvement of personalized medicine and thereby could increase the efficient use of healthcare resources, with the early identification of patients at risk of an unfavourable prognosis. Show less
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... Show moreThe 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. Show less
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... Show moreThe 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. Show less
The research provides insight into disease behavior in both rural and semi-urban areas in Serengeti in Tanzania. It focuses on the motives and behaviors that patients exhibit when relying on local... Show moreThe research provides insight into disease behavior in both rural and semi-urban areas in Serengeti in Tanzania. It focuses on the motives and behaviors that patients exhibit when relying on local healthcare systems, classified as traditional, transitional or modern. It describes the availability, accessibility and patterns of use of these healthcare systems, in particular how they are embedded in the local cultural heritage. It shows that behavioral patterns are dominated by psycho-social and cultural factors. In addition, background characteristics, intervening factors and situation-dependent factors that influence usage patterns are described, analyzed and explained. The analytical model based on the school of "Ethnoscience" shows where the use of these medical systems is related to the historical, cultural and economic factors that determine the daily lives of the inhabitants. The analysis of the research data provides recommendations for education and training of local middle management staff in support of integrated transcultural public health policy, as initiated by the local government of Serengeti in collaboration with the local training institutions. The findings are used as input for the intended master course in Transcultural Public Health Management in the area, and elsewhere in similar circumstances. Special attention is paid to the local medical knowledge, beliefs and practices of the target population to improve public health. 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
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
Spondyloarthritis comprises a heterogeneous group of distinct disorders including ankylosing spondylitis, non-radiographic axial spondyloarthritis, psoriatic arthritis, arthritis related to... Show moreSpondyloarthritis comprises a heterogeneous group of distinct disorders including ankylosing spondylitis, non-radiographic axial spondyloarthritis, psoriatic arthritis, arthritis related to inflammatory bowel disease and reactive arthritis. Spondyloarthritis is the second most prevalent form of chronic inflammatory arthritis, with an estimated prevalence of about 0.5-1.5%. The studies presented in this thesis cover many aspects related to Spondyloarthritis in Colombia. The following topics were addressed. First, the analyses and performance of the different classification criteria and the factors important in the decision of the rheumatologist to order an MRI or HLA-B27 test in the diagnostic work-up of spondyloarthritis in the context of the clinical rheumatology setting. Second, a better insight was obtained with regard to the presence of comorbidities and risk factors of patients with spondyloarthritis. This included also a case control study to evaluate the relationship between periodontitis and spondyloarthritis. Third, the translation and cross-cultural adaptation to Spanish of the ASAS-HI was performed. Adittionally, the implementation of the domains and instruments of the ASAS core set in clinical trials have been evaluated. Finally, we discuss the potential unmet needs in the field of rheumatology in Colombia and we propose a research agenda for the upcoming years. Show less
C. Caram-Deelder’s thesis explores the potential of secondary data – data that was generated for a different purpose than the research itself - to answer questions regarding safety and efficacy of... Show moreC. Caram-Deelder’s thesis explores the potential of secondary data – data that was generated for a different purpose than the research itself - to answer questions regarding safety and efficacy of blood products. By combining datasets of several hospitals, she demonstrated that receiving red cell transfusions from a female donor who has been pregnant is associated with increased mortality among male patients under the age of 50. Also using data from hospitals she demonstrated that old platelets shorter the time between platelets transfusions, resulting in an increased total number of transfusions on a population level. This increase is, however, unlikely to outweigh the benefit of reduced outdating and wastage. By meta-analysing studies it is shown that old platelets are inferior to fresh platelets for platelet related counts, time between transfusions and the need of additional platelet transfusions. Additionally the thesis discusses the methodological issue of the use of the terms ‘prospective’ and ‘retrospective’ in clinical observational research. These terms are still broadly used in spite of the recommendation to refrain from using them by guidelines and journals’ editorial boards. The usage of the terms was, however, not associated with the quality of the report. Show less
