Clinical Epidemiology

Prof. dr. M.K. Ikram

This research line focuses on the etiology of neuro-degenerative and cerebrovascular diseases, including dementia and Alzheimer’s disease, Parkinson’s disease, ischemic stroke, hemorrhagic stroke, migraine, white matter pathology, microbleeds, and polyneuropathy. The research utilizes a multimodal approach to study causes, determinants, and prognosis of these disease. A particular focus is on interacting pathologies, including vascular disease and neurodegenerative diseases. The research revolves around three main areas: 1) biomarkers, which includes genetics, serum markers, and metabolomics; 2) neuroimaging, which includes conventional as well as advanced magnetic resonance imaging (MRI) (e.g. diffusion tensor imaging, fMRI, perfusion imaging); and 3) subclinical signs and symptoms, including cognition, gait, and activities of daily living.

Research is carried out at the Department of Epidemiology in the setting of the Rotterdam Study and Rotterdam Scan Study. Major collaborations are set up with the departments of Neurology, Radiology & Nuclear Medicine, Neurosciences, Medical Informatics, Internal Medicine, as well as external national and international partners.

Dr. K. Verhamme

The focus is on intended effects of medications, and the effects of medication use under common circumstances in large populations. There are several drug-related research projects in the Rotterdam Study, a large prospective cohort study that is being conducted since 1990 to investigate cardiovascular, locomotor, neurological, and ophthalmological diseases.

Dr. Maryam Kavousi MD PhD FESC

Cardiovascular disease is the most common chronic illness in both developed and developing countries, causing approximately one-third of the total deaths worldwide and the greatest impact on morbidity. The Cardiovascular Disease Epidemiology group aims at interdisciplinary research across several established disciplines within the group and integrates knowledge on all aspects of the cardiovascular disease; including biology, behavior and lifestyle, imaging, risk prediction, prevention, treatment, and prognosis.The large population-based Rotterdam Study, as well as the long-standing collaborations with a number of other large cohort studies around the world, provide a rich environment for the conduct of cutting edge research. Within the group, the following main research teams, working closely and in parallel, are designed to cover the whole spectrum of research on cardiovascular disease:

Subtheme 1: Biomarkers for cardiovascular disease

Within this discipline, current advances in molecular biology and genetics including genomics, epigenomics, transcriptomics and metabolomics are exported from the laboratory to the epidemiology field, allowing a molecular epidemiologic approach towards investigation of clinical and pre-clinical cardiovascular disease. This working theme aims to recognize the importance of molecular and genetic approaches to cardiovascular disease and most importantly, utilize this knowledge to conduct prevention and treatment research that directly improves the health of individuals.

Subtheme 2: Lifestyle factors and primary prevention

Existing and developing knowledge regarding risk factors for cardiovascular disease, especially modifiable risk factors, suggest that it may be possible to curtail the explosion of global disease. To this end, this work theme is focused on evaluating the role of lifestyle factors and interventions for preventing cardiovascular disease among healthy populations.
The research focuses on the individual as well as the collective contribution of lifestyle factors; including physical activity, dietary factors, alcohol consumption, smoking habits, wellbeing, sun exposure and sleep, to the prevention of cardiovascular disease. It also aims to address the lacking knowledge on the interaction of lifestyle factors with genetic, metabolic, and inflammatory markers as well as medications.

Subtheme 3: Cardiovascular risk prediction

Clinical decision making for detection, management and prevention of cardiovascular disease relies on accurate identification of individuals at risk of developing the disease. This research team, working closely with the departments of public health and biostatistics, appreciates the role of emerging markers in cardiovascular disease risk prediction and aims on augmentation of the standard cardiovascular risk scoring systems with novel measures. Enhancements in ascertaining the risk status of individuals for developing cardiovascular disease secure windows of opportunities that could permit early preventive interventions and personalized care.

Subtheme 4: I Cardiovascular imaging (Dr. Daniel Bos)

Cardiovascular imaging research contributes to the understanding of the natural history of cardiovascular disease and the processes leading to the progression and/or stabilization of the disease, as well as the assessment of disease burden and therapeutic efficacy. This research team within the cardiovascular disease epidemiology group works in close collaboration with the departments of cardiology and radiology and focuses on the application of imaging technology to cardiovascular disease prevention. Imaging techniques that are used are CT (vascular calcification, epicardial fat, liver fat), MRI (carotid atherosclerosis) and ultrasound (carotid plaque). Current research projects within this discipline are focused on evaluating associations between various risk factors and vascular structure and function, as well as evaluating the role of non-invasive assessment of sub-clinical atherosclerosis and endothelial function in cardiovascular risk prediction.

Subtheme 5: Cardiovascular disease among women

Although cardiovascular disease continues to be the leading cause of death for both women and men, there are substantial sex and gender differences in the etiology, prevalence, burden, and prognosis of different cardiovascular diseases. Understanding sex- and gender-specific aspects of cardiovascular disease will serve to improve the health of both women and men. This theme focuses on novel and unique aspects of cardiovascular disease in women and gender differences as they relate to clinical practice in the prediction, prevention, diagnosis, treatment, and prognosis of cardiovascular disease. This research team within the cardiovascular disease epidemiology group works in close collaboration with the departments of gynecology and cardiology.

Subtheme 6: Diabetes mellitus

Type 2 diabetes is a serious and common chronic disorder resulting from a complex interplay between genetic, epigenetic, and environmental factors. Within this discipline, contribution of traditional and novel risk markers representative of different pathophysiological pathways to type 2 diabetes is studied. The research covers the whole spectrum of type 2 diabetes; disease development, progression (from normoglycemia to pre-diabetes, to type 2 diabetes, to initiation of insulin therapy), and complications. This will allow for early detection of prediabetes and diabetes, as well as lifestyle and therapeutic interventions as the overarching objectives in preventing and managing type 2 diabetes.

Dr. Annemarie I. Luik

Depression, anxiety and disturbed sleep are leading causes of the global disease burden worldwide. In the past, researchers identified psycho-social risk factors but we now realize that most psychiatric disorders are the result of an interplay between functional and structural brain changes, genes, cognitive and psychological processes and social factors. Our research on common psychiatric disorders is embedded in the Rotterdam Study and Generation R. Main areas of interest are depression, anxiety and sleep, but we also study complicated grief, alcohol abuse, sexuality and happiness. Our aim is not only to explain how biological or social factors cause psychiatric disorders, we also investigate how psychiatric problems or diseases impact on quality of life physical health. Some examples of research questions we are addressing:

• How do symptoms of depression, anxiety, poor sleep and social health cluster? Using clustering and network approaches we take on a more transdiagnostic approach to psychiatric diseases and symptoms.
• Do changes in cortisol and stress, e.g. HPA-axis, reactivity affect sleep? We monitored sleep using both actigraphy and polysomnography and are one of the first to be able to assess these associations over long periods of time.
• Do first-ever and recurrent depression have the same causes? We collected unique data of more than 5000 persons over 10 years with continuous monitoring of depressive symptoms to increase our understanding of depression.
• How is poor sleep related to brain health across the life course? Using brain imaging, questionnaires, actigraphy and polysomnography we aim to disentangle the association between sleep and brain health in children and adults, For this work we collaborate with the population imaging and neuro-epidemiology groups.

Prof. dr. Vincent W.V. Jaddoe, coordinator,

The Generation R Study is a large population-based cohort study from fetal life until young adulthood in 10,000 children. The Generation R Study is a collaborative project in which several departments in the Erasmus MC participate. The study is designed to study growth, development and health in a contemporary population-based multiethnic cohort of urban children from fetal life until young adulthood. The study focuses on four primary areas of research: (1) growth and physical development; (2) behavioral and cognitive development; (3) diseases in childhood; and (4) health and health care for pregnant women and children. Special interest in these areas of research is on identification of early causal pathways leading to both normal and abnormal growth, development and health in childhood and adulthood.

The general aims are:

• To describe normal and abnormal growth, development and health from fetal life until young adult-hood in a multiethnic population-based cohort;
• To identify biological, social and environmental determinants of normal and abnormal growth, development and health from fetal life until adulthood;
• To examine the utilization and effectiveness of cur-rent strategies for prevention and early identification of groups at risk.

Eventually, this study will contribute to the development of strategies for optimizing health and health care for pregnant women and children.

An extensive data and biobank has been generated. With an integrated strategy of basic, clinical and epidemiological research various research questions are addressed focused on growth, development and health from fetal life to young adulthood. MSc student are actively participating in one of the 4 main research programmes in the Generation R Study (www.generationr.nl). A few subthemes are mentioned below.

Subtheme 1: Early growth, obesity and cardiovascular development

Prof. dr. V.W.V. Jaddoe, Prof dr. E.A.P Steegers

This research is embedded in The Generation R Study and focused on envrionmental and genetic exposures related to fetal and postnatal growth, early cardiovascular development, insulin resistance en obesity. We also study risk factors of pregnancy complications in mother and child, such as preeclampsia and preterm birth. Research is performed in closed collaboration between the departments of Pediatrics, Epidemiology, Obstertrics, Pediatric Cardiology and Pediatric Nephrology.

Examples of research topic are:

• Development of growth curves
• Materna life style habits in relation to pregnancy complications
• Genetics of fetal and postnatal growth
• Maternal and childhood nutrition in relation to cardiovascular and metabolic development
• Biomarkers of preeclampsia and pregnancu induced hypertension

MSc student are actively participating in one of the research projects, actively participate in the research Group (data collection, cleaning, scientific meetings) and normally procude one to two papers that will be submitted for publication.

Subtheme 2: Early determinants of respiratory morbidity

Dr L. Duijts

‘Generation R’ is a multidisciplinary project, aimed at recruiting a 10.000 children birth cohort in Rotterdam, with follow-up from the first trimester of pregnancy until 20 years of age. The project wants to establish prospectively the importance of prenatal and early life events for later health, to ultimately improve children’s health and education by defining factors which affect growth and development, and determine risk of disease in order to stimulate preventive strategies.

The prevalence of chronic respiratory symptoms among children of various ethnic minorities in the Netherlands is unknown. In major North-American cities the prevalence of childhood respiratory disease including asthma and allergy is increasing, especially in non-caucasian children. There is evidence that ethnic differences in prevalence cannot only be explained by differences in socio-economic class. In Europe, several birth cohort studies have addressed respiratory morbidity during the first years of life. These have focused on known risk factors for respiratory morbidity, including socioeconomic status, exposure to allergens and pollutants, family history of allergy and/or asthma, and examined relationships with respiratory symptoms. However, few have focused on ethnic differences. In Swedish and German studies differences in atopic disease prevalence were reported between Western European and Turkish immigrant children, suggesting that environmental and genetic factors are involved which may affect the risk of infection, allergy and asthma in different ethnic groups.

In the Netherlands, the ongoing PIAMA study follows a large birth cohort. A relatively high prevalence of respiratory symptoms was found in non-Dutch ethnic groups, which could be largely attributed to socioeconomic differences, suggesting that environmental factors had strong impact on respiratory morbidity in the first 2 years.

However, numbers were small and biased, as only Dutch questionnaires were used. No epidemiologic birth cohort study has specifically been designed to include different ethnic groups by approaching them in their own language, and evaluate the differences in symptomatology together with biological, medical, psychosocial and environmental factors in order to establish and understand differences in respiratory morbidity, especially asthma, and allergy between ethnic groups living in the multicultural urban society.

Question:

Are respiratory morbidity and allergy different between ethnic groups and, if this is the case, can differences be explained by pre- and/or postnatal environmental factors? The project is focused on describing respiratory and allergic morbidity of the Generation R cohort during the first 2 years of life.

Question/aim:

• This project aims to address the impact of ethnicity and environmental factors on respiratory morbidity in the first 2 years of life by answering the following questions:
• Is ethnicity a risk factor for respiratory morbidity and allergy in the first two years of life?
• Do medical consumption (drug prescription, visit to the general physician, hospital admission), perception of disease and quality of life of infants and preschool children with chronic respiratory symptoms and/or allergy differ between ethnic groups?
• To what extent can environmental pre- and postnatal factors explain differences in respiratory morbidity and allergy between ethnic groups?

For a NIHES fellowship, a suitable question will be selected For a NIHES fellowship, a suitable question will be selected and analysis performed of existing databases, in close co-operation with the dept. of pediatrics, epidemiology and public health of the Erasmus MC.

Subtheme 3: Immunological and bacterial determinants of nasopharyngeal carriage of opportunistic pathogens and infections in young children

Dr. M. van Zelm, Prof. H. Hooijkaas

After infection, T and B lymphocytes are able to maturate into highly specific memory lymphocytes, which is the basis for adaptive immunity. The adaptive immune system matures in the first years of life through host pathogen interactions. However, it is unclear how the adaptive immune system in young children is shaped to create highly specific immunity to a wide variety of pathogens. Although the immune system is able to generate strong immunological responses, complete eradication of pathogens is not always achieved.
Several viruses are known to evade clearance and persist in a dormant state. In latency, the virus is not detectable anymore in serum, but antibodies against these viruses are. Common persistent viruses are Epstein-Barr virus (EBV) and Cytomegalovirus (CMV). The prevalence of persistent CMV and EBV infections is estimated to range from ~50% in children to >90% in adults. Reactivation of these viruses when immunity is suppressed can result in major complications, e.g. in transplantation settings, suggesting that these viruses can only be controlled by a constantly active immune system. We hypothesize that this constant viral pressure puts a heavy load on the immune system, and will affect normal immune maturation. One parameter that reflects the maturation of adaptive immunity is the extent of differentiation of lymphocytes in the peripheral blood. We hypothesize that persistent viral infections have adverse effects on the diversity of the broad immune repertoire, thereby impairing immunity to other pathogens.

The aim is to:

• Study determinants of CMV and EBV infection in children at 5 years of age;
• Study the buildup and diversity of the immature adaptive immune system by studying the phenotypic differentiation of lymphocytes in children with and without persistent infections with EBV or CMV at 5 years of age.
• Study the consequences of the diversity of the adaptive immune system for atopic and immune mediated diseases
• Determine how development, diversity, and reactivity of the adaptive immune response in healthy and allergic children, are affected by the intestinal microbiota.

Clinical and scientific relevance for the future: This project will contribute to the detailed understanding of the development of the immune system and their consequences for atopic and immune mediated diseases in children.

Subtheme 4: Behavioral and cognitive research in young children

Prof. dr. Manon H.J. Hillegers, Dr. Pauline W. Jansen

Whereas most somatic disorders are quite rare, behavioural and learning disorders in children are frequent. About one in ten children will develop a mental health disorder and many more have behavioural or cognitive problems that are a burden to child, families and society. Behavioural problems can be caused by social factors (e.g. bullying or poverty), psychological factors (e.g. bad parenting or poor emotion recognition) and biological factors (e.g. genetic variation or altered stress hormones). Aetiological research has demonstrated that many child psychiatric disorders are neurodevelopmental in origin, i.e. they have their onset early in life and affect the functioning of the nervous system. Furthermore, child psychiatric research has been leading the field of gene-environment interaction studies.
This understanding has guided the behavioural and cognitive research in Generation R. We are thus investigating the importance of fetal development for behaviour and cognition later in life, and have assessed neurodevelopment with brain-ultrasound, neurological examinations, and will soon start MRI imaging.

Moreover, we are conducting genome wide analyses and candidate studies to detect genetic risk factors and vulnerabilities. Together with several EUR and external partners we have introduced many innovative child assessments, which are unique to large-scale behavior studies. These include the Strange Situation Procedure, HOME environment assessment, executive function, parent-child interaction tasks or tasks of moral development.
The topics and possible themes for research in Generation R cover a wide area; selected but prototypical questions addressed in the coming years include:

• Do low thyroid hormone or vitamin levels in pregnant women cause cognitive problems in the offspring? (Neurodevelopmental research)
• Does father-child interaction matter in respect to the emotion development of the child? (Med Psychology)
• What do teacher, father and 5-year child self report add to maternal report of behavioural problems? (Methods)
• Do daycare, bullying in kindergarten, television watching or unstructured parenting affect certain children predisposed to behavioural problems? (Social Psychiatry)
• Are altered cortisol secretion patterns cause or consequence of behavioural problems? (Psychobiology)
• Does prenatal cannabis exposure affect the brain development? (Psy. Imaging)
• Can we identify the genetic basis of child resilience to family adversity (Psy.Genetics)

At the department of Dermatology we conduct research on at least nine skin-related conditions (see themes below). The research group is led by Professor Nijsten, the Head of the Department. Our mission is to improve the diagnosis, treatment and outcome of patients with dermatological conditions. We carry out clinical, epidemiological, cost-effectiveness, qualitative and translational research to detect conditions at early stages, improve treatment and prognosis, and change public health policies. We achieve this in close collaboration with national and international researchers.

Subtheme 1: Skin cancer

Contact person: Dr. Marlies Wakkee, dermatologist

Skin cancer is the most common cancer in adulthood in individuals of European descent. The risk of subsequent cancer or multiple cancers is also high, and represents a burden for public health. To improve care for skin cancer patients, we develop risk prediction models for skin cancer, including the prediction of metastatic, multiple and subsequent cancers. These models can be to stratify patients in clinical care according to their cancer risk (e.g., low, high). For this purpose, we conduct epidemiological studies using nation-wide cancer registry data linked to pathology records. In collaboration with other national and international partners, we aim to identify genetic variants involved in the risk skin cancers and develop gene expression signatures to predict metastasis of skin cancer.

We also aim to understand attitudes towards health-care from both patients and health practitioners. For this purpose we conduct qualitative studies.
Technological advances in medicine, such as teledermatology and mobile phone (mHealth) apps using artificial intelligence (AI), may increase the likelihood of early detection of skin cancer to lower its burden on the healthcare system. To investigate the best way to implement mHealth apps in clinical care, we conduct multiple studies using the SkinVision app.
AI is also used in the field of pathology (referred to as pathomics). For this purpose, we also collaborate with bio-informaticians and pathologists to develop AI algorithms using the histopathological slides of skin cancers, which can be used to develop prediction models for skin cancer metastasis.
In the field of dermatological surgery, we investigate the efficacy of Mohs micrographic surgery (MMS) in the context of squamous cell carcinoma (SCC) and other rare cancers.

Subtheme 2: Eczema (Adults and Children)

Contact person: Dr. Dirk-Jan Hijnen (adults), Prof.dr. Suzanne Pasmans (Children)

Atopic Dermatitis (or atopic eczema) is a heterogeneous and complex disease, meaning that both genetic and environmental factors play a role. The clinical picture is ranging from a self-limited condition in childhood to a life-long severe disease with atopic comorbidities (e.g. asthma and allergic rhinitis). In collaboration with other partners (including Generation R), we investigate the role of determinants on the different eczema phenotypes. One of our aims is to improve the care of difficult-to-treat atopic dermatitis in children and adults. In addition, we aim to identify biomarkers that help stratify patients into more homogeneous disease groups (‘endophenotypes’) to predict treatment response. Furthermore, we aim to evaluate the role of genetics, the microbiome, and the skin barrier in disease susceptibility and progression in ‘the atopic march’.

To standardize the treatment of difficult-to-treat eczema, we developed and implemented the personalized integrative multidiscipline treatment (PIM), which combines different medical and psychological specialties to provide the best possible treatment for difficult-to-treat eczema. In various clinical studies we continue to improve on PIM using the evidence-based approach.
We investigate whether Raman spectroscopy can be used to identify biomarkers for atopy and whether this can be used in clinical practice to improve diagnosis, prognosis and treatment of difficult-to-treat eczema. We are also investigating whether stratification of eczema on the NMF biomarker, measured by Raman spectroscopy, can improve the effectiveness and efficiency of systemic treatment with dupilumab or cyclosporine in moderate-to-severe AD. This cohort also offers a unique possibility to a wide range factors in eczema, including blood biomarkers, gut, nose and skin microbiome, and psychological factors.

In the Erasmus MC – Sophia Children’s Hospital, we investigate the Netherton syndrome, congenital nevi, and other rare skin diseases. We have also started an eczema biobank to investigate the efficacy of biologicals and to identify endophenotypes.

We are participating in clinical trials with new targeted treatments (e.g. biologics and JAK inhibitors). In translational research group, we are using multi-omics approaches to define endophenotypes and further unravel the pathogenesis of atopic dermatitis.

Subtheme 3: Needle-free jet injectors

Contact person: Dr. Martijn van Doorn, dermatologist

Keloids and hypertrophic scars are dysregulated immune responses to cutaneous wound healing and can be associated with substantial physical and psychological distress. Current first-line therapy is triamcinolone administered via conventional needle injections, however, this is associated with (severe) pain and frequent recurrences. Intradermal bleomycin administration using energy-based drug delivery techniques, such as electronic pneumatic injection, could be more effective, safer, faster and less painful treatment options for keloids.
Our aim is to improve patient care by evaluating novel methods for drug delivery to the skin for various drugs and dermatological indications. The past three years, we particularly focused on pre-clinical studies to investigate the distribution of needle-free jet injections in ex vivo skin. These studies showed better distribution of injected fluids in ex vivo skin with needle-free jet injections compared to conventional needle injections.

This year we are performing a double-blind, randomized, placebo-controlled study that compares the effect of bleomycin vs. placebo, administered by needle-free intralesional injections in patients with keloids. The coming years, our main focus is to investigate needle free jet injector treatments to treat keloids in adults and children, with different therapeutic specific drugs. Additionally, we want to explore needle free jet injector treatments in other skin diseases, including hypertrophic scars, alopecia areata and recalcitrant warts.

Subtheme 4: Skin barrier function

Contact person: Dr. Gerwin Puppels, fysicus

As every textbook on the teaches, the skin is the barrier between the body and the outside world. It prevents uncontrolled loss of water and keeps chemicals and microorganisms out. The total skin surface area of the adult body is about 2 m2. However, until recent the ability to measure and quantify how well this barrier works, has eluded us. Available methods are indirect, have reproducibility issues, are invasive and/or use conditions that are far from actual in vivo conditions. They leave a lot to wish for.

In close collaboration with RiverD International, a spin-off of the Erasmus University Medical Center, we have developed instrumentation and methodology to non-invasively quantify the in vivo skin penetration and permeation of topically applied products. This is based on Raman spectroscopy, an optical technique, which provides detailed information about both the intrinsic molecular composition of the skin and the penetration of topically applied chemicals; a field of research we have initiated and continue to lead.

This offers the possibility to close a huge gap in our fundamental knowledge of skin barrier function, with many practical applications and avenues to explore:

• Development of an objective quantitative test to determine a person’s skin barrier function
• Elucidation of the relationship between molecular skin composition and skin architecture and skin barrier function
• Investigation of variance in skin barrier function in the general population
• Effects of (daily) skin care habits on skin barrier function
• Investigation of potential correlations between (skin) diseases (or their severity) and skin barrier function; e.g. atopic dermatitis.
• Enabling bioequivalence studies in support of generic topical product development
• Better informed product claims and public discussions: e.g.
  • No, topically applied hyaluronic acid in creams does not hydrate your skin, because it does not penetrate the skin.
  • Yes, there is a legitimate concern about systemic exposure to UV-filters used in sunscreens, because they can penetrate and permeate the skin very easily, unless properly formulated to keep them on the skin.

Subtheme 5: Hiddradenitis Supperativa

Contact person: Prof.dr. Errol Prens, dermatologist//immunologist

Hidradenitis suppurativa (HS) is a chronic, recurrent, auto-inflammatory disease of the axillae and ano-genital body areas, which causes a profound physiological and psychological burden. The physiopathology of HS is still poorly understood. Therefore, we aim to understand the molecular, genetic and microbial basis of disease in collaboration with the rheumatology laboratory and international colleagues. We aim to identify new therapeutic targets and to investigate the efficacy of new medical treatments in the treatment of HS, both clinically, ex vivo and in vitro. In addition, we aim to assess the effect of surgical and laser treatments. We aim to perform studies to identify the determinants of HS, and to assess the impact of HS on patients’ lives.
During the past six years we have conducted clinical, epidemiological and ex vivo research. We have successfully set up set up a registry and biobank since 2016. We have identified new targets for medical therapy through ex vivo experiments. Moreover, in collaboration with other national and international partners, we found evidence for new treatments. In addition, our team has provided crucial input for national and international HS treatment guidelines. Moreover, our team participated in the global effort to standardize outcome measures in HS clinical trials through the HISTORIC initiative, and still leads the Delphi procedure for the ‘time to recurrence’ outcome.

Prof. Guy Brusselle, Prof. Bruno Stricker, prof. dr. Joachim Aerts, . Lies Lahousse

In the Rotterdam Study, clinical epidemiologic studies of the major respiratory diseases in the elderly are performed. The main focus of the respiratory epidemiologic research are obstructive airway diseases encompassing Chronic Obstructive Pulmonary Disease (COPD) and asthma, but also lung cancer is a priority topic for investigation. In COPD, we study the natural history of the disease, the determinants of exacerbations, the association with cardiovascular and cerebrovascular diseases (comorbidities / multimorbidities) as well as the genetic susceptibility in smokers and nonsmokers to develop COPD. In addition, we aim to elucidate the genetic and clinical determinants of lung function measurements in the adult population (both spirometric measures and lung diffusing capacity).

Subtheme 1: Endocrinology, with a focus on thyroidology

The relation between thyroid (dys)function and clinical outcomes of aging

Dr. L. Chaker, Prof. dr. R.P. Peeters

Thyroid hormone is crucial for normal function of practically all organ systems. Overt thyroid dysfunction is related to various clinical outcomes such as cardiovascular disease, osteoporosis, and cognitive decline. Recent studies have shown that even thyroid function within the normal range may also be related to these clinical outcomes.

This research program focuses on the consequences of variations in thyroid function within the context of the Rotterdam Study, a prospective population-based study of age-related disorders that includes 15,000 persons since 1990. In a large number of subjects we can study different thyroid function parameters (TSH, FT4, TPO antibodies) in relation to detailed follow-up data on cardiovascular and metabolic disease, osteoporosis and fracture risk, cognitive decline and dementia, as well as other parameters of aging. Furthermore, we will have a new and cutting-edge method for assessing thyroid hormone metabolites, which will open new revenues for investigating the role of thyroid hormone metabolism in non-communicable diseases.

We study these endpoints in close collaboration with other research groups within the Rotterdam Study but also work together with the Erasmus MC thyroid lab, the Thyroid Study Collaboration and other cohorts within the Charge Consortium. This work has resulted in several important findings and results (Chaker et al, Circulation, 2016, Bano et al. JAMA Intern. Med. 2017, Teumer, Chaker et al, Nat Commun, 2018) concerning the physiology, genetic background and consequences of thyroid function.

Specific subtopics within the research line:

• Thyroid function and cardiovascular complications
  • Myocardial infarction, cardiovascular mortality, heart failure
  • Cardiac function (imaging and non-imaging)
  • Determinants in variations in outcomes (subgroup analyses)
• Thyroid function and bone parameters
  • Osteoporosis and fracture risk
  • Bone geometry and other bone imaging modalities
  • Osteoarthritis
• Thyroid function and neuro-epidemiology and pychiatry
  • Cognitive decline, Alzheimer’s disease and dementia
  • Depression and depressive disorders
  • Cerebrovascular disorders
  • Pre-clinical markers of degenerative disease (functional imaging and biomarkers)
• Determinants and course of thyroid function during aging:
  • Longitudinal changes in thyroid function
  • Risk factors for changes in thyroid function
  • Assessing the frequency and influence of thyroid medication use

Thyroid function and adverse pregnancy outcomes or suboptimal child development

Dr. T.I.M. Korevaar, Prof. dr. R.P. Peeters,

Thyroid hormone plays an important role in the development of early pregnancy as well as fetal growth and development. Over the last two decades it has been shown that even slight alterations in thyroid function may impact on the course of pregnancy and the development of the child. The thyroid group of the Academic Center for Thyroid diseases has contributed to this literature using data from multiple prospective cohorts including Generation R, the SELMA study and we have also founded the Consortium on Thyroid and Pregnancy (https://www.consortiumthyroidpregnancy.org). For example, we have shown that both low and high thyroid function is associated with suboptimal child brain development (Korevaar et al. Lancet D&E 2017, Janssen et al. Lancet D&E 2019), we have identified that thyroid function and/or thyroid antibodies are a risk factor for preterm birth and abnormal birth weight (Korevaar et al. JAMA 2019, Derakhshan et al. Lancet D&E) and we have done work focusing on the differences in the physiology of thyroid function during pregnancy. The latter includes a wide range of potential environmental, genetic and inter,- or intra-individual determinants. We work in close collaboration with various other research groups but also with the Erasmus MC thyroid laboratory. This allows us to form novel research hypotheses based on basic scientific evidence and translate this to novel clinical research projects.

MSc students will be able to have their own, first-author research project of their choice using either the data of Generation R, the data that we have available from other cohorts, or the data collected in the Consortium on Thyroid and Pregnancy, focusing for example on:

• Determinants of thyroid function during pregnancy, such as endocrine disrupting chemicals, genetic factors or other pregnancy hormones (for example hCG)
• Thyroid function and adverse pregnancy outcomes
• Development of bone, cardiovascular or neurocognitive parameters in the child
• Thyroid dysfunction during pregnancy and postpartum maternal health

Subtheme 2: Nephrology

Dr. L. Chaker, Prof. dr. E.J. Hoorn

The kidneys have several important functions, including removing waste products from the human body and regulating fluid balance and electrolyte levels, making them essential for healthy functioning of the human body. A reduced kidney function or chronic kidney disease is a major global health burden and has been previously associated with increased cardiovascular and cerebrovascular mortality, increased mortality and reduced quality of life. Early and precise identification of patients at risk for kidney damage could be beneficial since preventive treatment can slow down kidney damage and reduce cardiovascular morbidity and mortality.

The Rotterdam Study is a large prospective population-based cohort study, including approximately 15,000 middle aged and elderly participants. This cohort study was designed to investigate the determinants and occurrence of cardiovascular, neurological, ophthalmologic, psychiatric, and endocrine diseases. Within the participants of the Rotterdam Study, several assessments of kidney function are available, including different assessments of the estimated glomerular filtration rate and the urine albumin-to-creatinine ratio. Therefore, we are able to link several assessments of kidney function to many available outcomes, including cardiovascular and neurological outcomes. Furthermore data on electrolytes and echocardiographic data on kidney size and structure is also available and several urinary biomarkers are being collected, the association of this data between kidney and cardiovascular outcomes can also be explored.

Prostaglandin E2 (PGE2) is one of these potential biomarkers and plays an important role in kidney physiology and cardiovascular function. The effects of PGE2 are mainly known from the renal effects of non-steroidal anti-inflammatory drugs, that inhibit PGE2 production. Little is known of the relation between urinary PGE2 excretion and kidney damage or cardiovascular health.

Examples of potential projects within the research line:

• Determinants of several assessments of kidney function (e.g. cystatin C)
• Investigating the association of kidney function with:
  • Cardiovascular outcomes, including atrial fibrillation, diabetes mellitus, and atherosclerosis.
  • Neurological outcomes, including stroke, dementia and cognitive function, and Parkinson’s disease.
  • Pulmonary outcomes, including lung function, asthma, and COPD
  • Bone parameters, including osteoporosis, bone density, and bone structure
• Investigating the association of electrolytes with several cardiovascular and neurological outcomes, as well as with bone and endocrine parameters
• Urinary prostaglandin E2
  • Determinants of urinary PGE2
  • The association between urinary PGE2 and several assessments of kidney function
  • PGE2 and cardiovascular outcomes
• Finding predictors for subjects at risk for kidney function decline
  • Using baseline characteristics of included patients
  • Using known markers of kidney function decline such as albuminuria
  • Using urinary parameters including novel biomarkers

Subtheme 3: Clinical immunology

Dr. L. Chaker, Dr. V.A.S.H. Dalm, Prof. dr. P.M. van Hagen, Prof. dr. R.P. Peeters

Within the Rotterdam Study, we have measured serum immunoglobulins (IgA, IgG, and IgM) in nearly 9,000 participants. This provides the unique opportunity to perform a wide range of studies on the association of serum immunoglobulins in middle-aged and elderly individuals from the general population. Serum immunoglobulins play important roles in the immune response against pathogens, but help clear aberrant cells as well. On the other hand, immunoglobulins may be involved in various autoimmune and inflammatory disorders. Currently, little is known about the role of immunoglobulins in population-based settings.

We have recently published a study on factors that influence serum immunoglobulin levels in our cohort of healthy elderly. Also, we are carrying out multiple studies to assess the associations between serum immunoglobulins and various health related outcomes. We have collaborations with many subgroups of the Epidemiology department (e.g. respiratory medicine, cardio-metabolic epidemiology, neuro-epidemiology) and other departments within the Erasmus MC as well.

Master students will be able to perform independent research with prospects of a peer-reviewed publication on one of the following topics:

• Immunoglobulins and depression/depressive disorders and other neuropsychiatric diseases
• Immunoglobulins and risk of cancer and neoplasms
• Multi-omics analyses including genome-wide association study on immunoglobulins

Dr. ir. Trudy Voortman, dr. Jessica Kiefte-de Jong, dr. Kim Braun, dr. Chantal Koolhaas

Projects in this theme are embedded in the Nutrition and Lifestyle group of the department of Epidemiology. Within this group, we aim to evaluate lifestyle factors; including nutrition, physical activity, and body composition, in relation to health across the life course. In close collaboration with other departments, research areas focus on nutrition, physical (in)activity and body composition in relation to cardiovascular health, DNA methylation, inflammation, gut microbiome composition, metabolic health, and several other aspects of health by using data from two prospective cohort studies: The Generation R Study and The Rotterdam Study.

The Generation R Study is a birth cohort of children and their parents who are followed from pregnancy onward. The children are currently 10 to 12 years of age.

The Rotterdam Study is a prospective cohort study of middle-aged and elderly, focusing on determinants of common age-related diseases such as cardiovascular disease, dementia, diabetes, and cancer.

Additionally, by performing systematic reviews and meta-analyses, we create additional knowledge beyond the information present in these cohort studies.

Specific topics within this research line are briefly outlined below:

Nutrition

Nutrition can be measured as dietary intake or nutritional biomarkers. Dietary intake can be measured by use of questionnaires and categorized in intake of individual nutrients, intake of specific foods or food groups, or overall dietary patterns. Nutritional biomarkers can be measured in tissues, such as blood. In The Generation R Study, information on dietary intake is measured through food frequency questionnaires during pregnancy, infancy, and childhood. Information on nutritional biomarkers, including levels of folate, vitamin B12 and vitamin D, is measured in blood during pregnancy, infancy and childhood. In The Rotterdam Study information on dietary intake is collected through food frequency questionnaires at baseline and repeated during follow-up. Nutritional biomarkers, such as levels of folate and vitamin B12, are measured in blood.

Activity (24-hour activity)

The 24-hour cycle of activity includes physical activity, sedentary behavior, and sleep. Whereas sleep is more a psychological factor it can be included in the 24-hour cycle of activity to examine the association between specific patterns of activity and health. For all activity measures, The Rotterdam Study collected information through questionnaires and through accelerometer.

An accelerometer is a device that measures acceleration and that can be used to identify intensity of activity. In The Generation R Study, information on activity is measured through accelerometer in a subset of participants aged 9-12 years.

Physical activity

Physical activity can be measured through questionnaire, or through an objective device called an accelerometer. Most research so far has focused on questionnaire-assessed physical activity, and the association between physical activity measured through accelerometer and health outcomes remains unclear for several domains. For example:

• Is light intensity physical activity – in contrast to moderate-to-vigorous activity – associated with health?
• To what extent are physical activity data assessed by questionnaire and accelerometer correlated?
• Will physical activity measured by questionnaire and accelerometer be associated with similar risk of disease (e.g. CVD/cancer/mortality)?

Sedentary behavior

The official definition of sedentary behavior is any waking behavior characterized by an energy expenditure ≤1.5 metabolic equivalents (METs), while in a sitting, reclining or lying posture. In simple words, sedentary behavior can also be described with the term ‘sitting’. Most research up to date has focused on sedentary behavior assessed by questionnaire, which includes specific contexts of sitting (e.g. watching television or working behind a computer). It remains unclear whether sedentary behavior in every context is associated with worse health.

Additionally, it remains unclear if uninterrupted bouts of sedentary behavior are associated with worse health outcomes compared to interrupted bouts. Questions related to this area are for example: to what extent are sedentary behavior asses by questionnaire and accelerometer correlated; and which factors are associated with the (dis)agreement?

Compositional analysis

The composition of daily activity is restricted to 24 hours. Therefore, by definition, once a person engages in more physical activity, this person will engage in less sedentary behavior and/or sleep. Up to now, this dependency has not often been accounted for in research. By measuring activity during 24-hours with an accelerometer, The Rotterdam Study has the perfect data to analyze activity in a compositional approach. Research questions related to this topic can be for example whether physical activity, sedentary behavior, and sleep are independently associated with incidence of certain diseases.

Body composition

Obesity is an important determinant of several health outcomes. Obesity is often measured as BMI (kg/m2), but this measures is limited regarding prediction of health because it does not take into account body composition. Therefore, detailed measures of body composition may provide better risk prediction for health outcomes. In both The Generation R Study and The Rotterdam Study assessment of detailed body composition (body fat, lean mass, bone mass) was performed with the use of Dual-energy X-ray absorptiometry (DXA).

Dr. Milan Zarchev, dr. Hester van Eeren, dr. Astrid Kamperman

Background – ethnic origin is a factor that interacts in complex ways with other demographic, clinical and social characteristics in the way it impacts risk of suicide. For example, first generation migrants have been found to be less at risk than native controls, whereas second generation migrants have actually been found to be at higher risk (Termorshuizen et al., 2012). Other factors, such as country of origin and psychiatric status were also found to be of relevance when estimating the association. This is not surprising as the minority status of individuals impacts their lived experiences on an individual, interpersonal and societal level. It is therefore hard to argue against considering most clinical and demographic variables as moderators when investigating ethnic origin and risk of suicide.

Yet from a practical point of view, there are too many combinations of variables possible when modeling just second and potentially third order interactions for all scenarios to be investigated. Additionally, most of these interactions might not be of any scientific or clinical interest at all, yet estimating an unbiased association hinges on their identification. Machine learning approaches are exceptionally useful in modelling non-linear interactions between any variables of importance.  Propensity scores as a conditional probability of being part of a defined group, on the other hand, are often used to achieve a balanced distribution of the observed variables (Shiba & Kawahara, 2021). Combining machine learning algorithms with propensity scores allows for the investigation of a specific association of interest, unbiased from all the complex interaction with other variables (Laan & Rose, 2011). As such, this method of analysis is a novel avenue to study complex associations like ethnic origin and suicide risk.

The current project – we would like to use the WebRAAp data generated by the Parnassia group (N=26,133) to assess if machine learning in combination with propensity scores are a feasible method of investigating research questions in large registry datasets. We would like to model the association using the workflow developed for the “tlme” R package (Gruber et al., 2021). If time permits, ideally a more general algorithm will be developed that allows the “tlme” estimator to be integrated quickly into various research projects. For the data collection part of the project, students will work within the iBerry cohort with adolescents at high risk of developing psychopathology.

References

Gruber, S., Laan, M. van der, & Kennedy, C. (2021). tmle: Targeted Maximum Likelihood Estimation (1.5.0.2) [Computer software]. https://CRAN.R-project.org/package=tmle

Laan, M. J. van der, & Rose, S. (2011). Targeted Learning: Causal Inference for Observational and Experimental Data (2011th edition). Springer.

Shiba, K., & Kawahara, T. (2021). Using Propensity Scores for Causal Inference: Pitfalls and Tips. Journal of Epidemiology, 31(8), 457–463. https://doi.org/10.2188/jea.JE20210145

Termorshuizen, F., Wierdsma, A. I., Visser, E., Drukker, M., Sytema, S., Laan, W., Smeets, H. M., & Selten, J.-P. (2012). Psychosis and suicide risk by ethnic origin and history of migration in the Netherlands. Schizophrenia Research, 138(2), 268–273. https://doi.org/10.1016/j.schres.2012.03.035