Annual Report Julius Center for Health Sciences and Primary Care

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1 Annual Report 2008 Julius Center for Health Sciences and Primary Care

2 Annual Report 2008 Julius Center for Health Sciences and Primary Care UMC Utrecht

3 The Julius Center for Health Sciences and Primary Care is one of the twelve divisions of the University Medical Center Utrecht (UMC Utrecht). It carries out scientific research, provides education and offers expertise and facilities in the clinical health sciences field. The Center aims to have a leading and acquisitive role in the enlargement and dissemination of knowledge, particularly in the field of health sciences. This is done by carrying out groundbreaking research on four disease-related themes and research methodology, by offering courses for (bio) medical students, researchers and clinicians, and by providing academic primary care. Disciplines represented in the Center are general practice, (clinical) epidemiology, nursing science, medical technology assessment, public health, medical ethics, nutritional sciences and biostatistics. In this annual report the reader will find information on activities, output and finances in Contact information: M. Donkervoort, PhD Policy officer, research strategy Julius Center for Health Sciences and Primary Care University Medical Center Utrecht Visitors: Heidelberglaan 100, Utrecht, The Netherlands Correspondence: Str.6.131, P.O. Box 85500, 3508 GA Utrecht, The Netherlands URL:

4 Contents Introduction 7 Organization 15 Brief History 17 Organizational Structure 17 Research 19 Research Organization 21 Research Themes 32 Collaboration and Affiliations 43 Research Highlights 48 Education 51 Educational Organization 53 General Practice 57 Epidemiology 64 Public Health 74 Biostatistics 77 Medical Humanities 80 Nursing Science 82 Nutritional Science 85 International Activities in Education 87 Patient Care 91 Nutritional Sciences and Dietetics 93 Julius Center Health Care Leidsche Rijn 99 Unit Health Care Innovations 101 3

5 Operational Support 105 Management Support 107 From CTSU to Julius Clinical Research and Research Support 108 Personnel and Finances 119 Personnel, Figures 121 Personnel, Listing 122 Financial Report 132 Research Projects Cardiovascular Diseases 139 Infectious Diseases 149 Cancer 154 Mental Health 157 Theoretical Epidemiology and Biostatistics 161 Miscellaneous 166 Clinical Trial Services Unit / Research Services 170 Data Management 174 Publications PhD Theses 181 International Refereed Publications 183 Professional Publications 212 Books and Book Chapters 216 Nederlandse Samenvatting Annual Report 2008

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8 Introduction Being selected as an AsiaLink PhD fellow is the best thing that ever happened in my career and I am looking forward to making it a success! Nirmala Bhoo Pathy, PhD fellow AsiaLink Programme


10 The Julius Center for Health Sciences and Primary Care has a simple strategy. It endeavors to do everything necessary in order to excel within research and teaching in health sciences. While sometimes our achievements in research may seem to dominate our profile, we are firmly convinced that the fundament on which to build our scientific and health care achievements is high-quality teaching. Teaching medical students about primary care, public health and the principles and methods of patient-oriented research; teaching MSc and PhD fellows how to set up and conduct research projects that have relevance and impact; teaching general practitioners the way to take best care of their patients and set new standards for primary care. Our teaching tries to bring out the best in our students by stimulating the development of their curiosity and talents to learn and to achieve. As William J. Mayo said One of the chief defects in our plan of education is that we give too much attention to developing the memory and too little to developing the mind. We aim to develop the critical minds required by modern health care and clinical research. The present annual report aims to underline the value we place on teaching by showing you some faces and views of those who are at the receiving end. This involves our students, pupils and fellows from the Netherlands and abroad, with a background in medicine and other disciplines. We are privileged to be able to teach this vibrant and ever changing community and are eager to simultaneously benefit from what they are able to teach us. During 2008, our organization underwent several changes that resulted from a reflection on our strategies and organizational insights developed over the previous years. Our line-organization was strengthened and increased and responsibility was given to the coordinators of our five research themes for defining their strategy and budgetary priorities. For several years it has been clear that the success of our clinical trials and Introduction 9

11 the dedicated organization built for it would eventually require a repositioning of these activities relative to the other tasks of the Julius Center. On the one hand, growth and, sometimes, hectic negotiations and business development called for a larger degree of independence and less interference with other priorities in the Center. On the other hand, it was important to maintain the scientific stimulus and output from major, randomized trials and access to its infrastructural resources. After careful consideration, the Management of the Julius Center and the Board of the University Medical Center Utrecht decided to transfer the clinical trial activities to an independent Academic Clinical Research Organization; Julius Clinical Research BV. The links between the Julius Center and Julius Clinical Research BV remain close and the UMC Utrecht is the majority shareholder in the new company. We believe that this is the best way to move forward and to stay at the forefront of international clinical trials while also maintaining the fruitful interaction between the trials and other scientific work in the Center. The merger of the former University Center for Biostatistics in the Julius Center also took place in This reflected the emerging view that Biostatistics in Utrecht needs a more solid scientific foundation and academic home base while maintaining high quality consultation and teaching, not only within the UMC Utrecht but also for other faculties and departments at Utrecht University. To further accentuate the scientific ambitions in the domain of biostatistics, a Chair of Biostatistics has been established at the Julius Center for which candidates are currently being sought. As Biostatistics enters the Julius Center, we see the department of Nursing Science depart. Major changes in the financing of Nursing Sciences educational activities made a reorganization inevitable and it was judged that scientific research by the discipline would benefit 10 Annual Report 2008

12 from a decentralized position within clinical divisions of the UMC Utrecht that have material patient care delivered by nurses. Successes in education and research were continued throughout A record number of students graduated from the general practice vocational training and from the Master of Science program in Epidemiology. The latter program is being organized in conjunction with other UU epidemiologic groups and was positively evaluated in 2008 by the Accreditation Organization of the Netherlands and Flanders. This guarantees the registration of the MSc exam by law and full compliance with quality control standards. Also, in terms of numbers of completed PhD theses, the Julius Center set a new record which will be difficult to beat in the coming years. No less than 39 fellows defended their PhD thesis with a staff member from the Julius center as (co-) supervisor or co-promoter. For the fourth time, the Julius Center s chair, Rick Grobbee, became PhD Supervisor of the Year, passing a total of over 100 PhD fellows whom he has guided successfully towards their theses defense. Professor Yolanda van der Graaf occupied an honorable third position among the University s top supervisors in This year, in terms of simple numbers, staff members from the Julius Center were involved in 400 international scientific publications, 10 of which were in journals with an impact factor above 20; five appeared in the Lancet, four were in the New England Journal of Medicine and one was in the Journal of the American Medical Association (JAMA). Two important prizes, awarded in 2008, emphasized the Julius Center s scientific position. Professor Bert Brunekreef, jointly appointed by the Julius Center and the Institute for Risk Assessment Sciences, Faculty of Veterinary Medicine, received the prestigious Heineken Prize for groundbreaking research in occupational epidemiology. The scientific contributions to clinical epidemiology by Professor Rick Grobbee were Introduction 11

13 recognized with the award of the bi-annual Catharijne Prize and Julius Center s Dr Maroeska Rovers was awarded the Elisabeth von Freyburg medal for most promising young scientist. While listing the successes of individual staff members, the competitive appointment of Dr Yvonne van der Schouw as Professor of Chronic Disease Epidemiology, as part of the UMC Utrecht strategic chairs program, should also be mentioned. The increased efforts of the Julius Center to further improve the quality of its (inter)national teaching activities are exemplified by the publication of the textbook Clinical epidemiology. Principles, methods and applications for clinical research, in This book was written by Rick Grobbee and Arno Hoes and includes contributions by many other staff members from the Center. While the Julius Center values its position in the University Medical Center Utrecht, we are also very conscious of the international nature of our teaching and research. Our emphasis on strong and productive international relations was expressed in 2008 by the establishment of two visiting chairs in Cardiovascular Disease Epidemiology. Dr Stephen MacMahon, from the George Institute for International Health, Sydney, Australia, and Dr Dan Levy, Director Framingham Heart Study, Framingham and Boston University, US, were appointed to take up these positions. Both have been appointed for a period of four years and, during this time, they will regularly visit the Netherlands, provide teaching and stimulate collaborative projects. Finally, as recommended by the board of supervisors of the Prince Claus Chair in Development and Equity, Utrecht University has appointed Professor Irene Agyepong as holder of the Chair until August The Julius Center is pleased to host the Prince Claus Chair for this period and looks forward to collaboration with Professor Agyepong to promote health scientific research and evidence based medicine in Ghana. 12 Annual Report 2008

14 It is customary to highlight academic achievements when introducing the annual report of an academic department such as the Julius Center. However, an important factor in the achievement of any successes is the contribution and dedication by the people in all layers of the organization. First and foremost, the Julius Center wants to be an inspiring and fun place to be. We promote the expression of talent and determination by our staff within the Center as much as outside of it. Perhaps the best example of this attitude is provided by Chantal Boonakker who combines 20 hours of training with 20 hours of PhD work at the Julius Center and who won a bronze medal for her performance at the 2008 Paralympic Games in Beijing. All of us have gifts and competences and, together, they make our Center what it is today. We set our academic standards high and focus on individual results but always remain aware of the value of being part of the larger community of the Julius, of the University Medical Center Utrecht at large and our responsibilities towards science and healthcare in the Netherlands and abroad. The management team of the Julius Center for Health Sciences and Primary Care Yolanda van der Graaf, manager education Diederick E. Grobbee, chair, medical manager Arno W. Hoes, manager research Anne-Marie Laeven, manager business administration Introduction 13

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16 Organization The ratio of We s to I s is the best indicator of the development of a team Jaap Trappenburg, PhD fellow and active member of Julius staff association Introduction 15


18 Brief History The Julius Center was established on 16 December It was founded on the basis of the previous departments of epidemiology and public health and on the clinical epidemiology s hospital unit. It was originally called the Julius Center for Patient Oriented Research. Since then, both its scope and size have markedly increased and this is reflected by the number of disciplines represented within the Julius Center. In 1999 the department of General Practice merged with the department of patientoriented research to become the Julius Center for Patient-Oriented Research and General Practice. In 2002, the department of Nursing Science and the Nutritional Sciences group joined the Center to become the current Julius Center for Health Sciences and Primary Care. In 2008, Biostatistics was added to the center, by integrating the former Center for Biostatistics, to reinforce education and research in this area. Changes in educational financing led to a reorganization of nursing sciences and, as a result, the discipline left the Julius Center at the end of 2008, to be re-allocated at several clinical divisions of the UMC Utrecht. In response to the increasing challenges facing clinical research in the 21st century, the clinical trial unit was incorporated into a private company, Julius Clinical Research, which is dedicated to the performance of large-scale trials. Organizational Structure The organizational structure can be found inside the cover. Organization 17


20 Research Research is like a triathlon; a challenging race with variation requiring perseverance and commitment Margriet de Beus, PhD fellow Julius Center Organization 19


22 Research organization The University Medical Center Utrecht has formulated seven main research themes. These fit into a matrix with four disease-related themes on the horizontal and three methodological themes on the vertical axes. The Julius Center s main contribution to the UMC Utrecht s total body of research is through the research theme Epidemiology. With rare exceptions, all of the Center s research activities can be classified as clinical epidemiological research, i.e. etiologic, diagnostic, prognostic and intervention research with relevance for patient care. Building upon this, the Julius Center contributes to all four disease-related areas of research: cardiovascular disease, infection & immunity, cancer, and mental health. In addition, there are strong links with the UMC Utrecht s other two methodological research themes: Imaging sciences and Genetics. The Julius Center s research activities focus on five research themes, i.e. the same four disease-related areas as the UMC Utrecht (cardiovascular disease, infection & immunity, cancer, and mental health) and one methodological theme (Theoretical Epidemiology & Biostatistics). Within these themes, there is further focus on subfields, such as research on (etiology and prognosis of) diabetes mellitus as part of the cardiovascular disease theme or on the effects of vaccinations within the infection & immunity theme. All five research themes are headed by one research coordinator or two for the largest theme, cardiovascular diseases. Importantly, the research activities of the (clinical or methodological) disciplines represented in the Julius Center (Clinical Epidemiology, General Practice/Primary Care, Public Health, Biostatistics, Medical Technology Assessment, Medical Ethics, Nutritional Sciences and Nursing Sciences) are also incorporated within these five research themes and not separately. Research 21

23 The research methods for all of these disciplines can be broadly characterized as (clinical) epidemiological and this was one of the main reasons for these disciplines being combined within the Julius Center. The research activities can, thus, be represented by a matrix structure, in which the horizontal axis comprises the five research themes and the disciplines are depicted in the vertical axis. The Center s policy is to concentrate its research as much as possible on the matrix s overlapping areas so that each of its disciplines benefit most from the Center s scientific and clinical expertise and the UMC Utrecht s scientific themes as a whole are strengthened. Disciplines Clinical Epidemiology (CE) General Practice (GP) Public Health/MTA/ Ethics (PH/MTA) Biostatistics Nutritional Sciences (Dietetics, DT) Nursing Science (NS) Themes Cardiovascular Diseases Infectious Diseases Cancer Mental Health Theoretical Epidemiology and Biostatistics The Julius Center has a formalized link with the interfacultary Institute for Risk Assessment Sciences (IRAS), environmental and occupational 22 Annual Report 2008

24 epidemiology at UU. This has been embodied by the joint appointment of Prof Bert Brunekreef and honorary appointee Prof Dick Heederik. There is also collaboration with other epidemiological research groups at Utrecht University, in particular with the Pharmaco-epidemiology group (from the Utrecht Institute for Pharmaceutical sciences) and Veterinary Epidemiology groups. Moreover, collaborations were recently strengthened with health/scientific institutions in the vicinity of the University Medical Center, such as the National Institute for Public Health and the Environment (in Dutch: RIVM) and the Municipal Health Authority (in Dutch: GGD) in Utrecht. In addition to the acquisition and conduct of its own research projects, either independently as an institute or in collaboration with other research groups, a major responsibility of the Center is to provide methodological advice and to support clinical research in virtually all of the University Medical Center s departments. Staff members act as consultants for research methods on a range of clinical investigations both within and outside the UMC Utrecht. The Center also plays a pivotal and formal role in the quality assurance of randomized trials performed in the UMC Utrecht. These are important and expanding activities for the Julius Center. For many clinical departments, the intense and continuous interaction with epidemiology has resulted in joint staff appointments, including the departments of anesthesiology, cardiology, cardiothoracic surgery, dermatology, internal medicine, neurology, pediatrics, psychiatry, and radiology. Research 23

25 Cohorts The Julius Center coordinates and participates in several large research cohorts. These cohorts are an important base for research and provide ample opportunities for obtaining financial research support. Moreover, the projects of the GP-network Utrecht and the Utrecht Health Project are intended to create an infrastructure in which research questions on efficacy and effectiveness of health care and effects of (local) health care policy can be answered. The latter is of major importance for increasing the expertise in the areas of health care improvement, extramural health care and general practice. The major cohorts are: ADDITION The ADDITION (Anglo-Danish-Dutch study of Intensive Treatment In people with screen-detected diabetes in primary care)-netherlands cohort consists of 498 patients with screen-detected type 2 diabetes mellitus, diagnosed in during a population screening among 57,000 people in the south-western part of the Netherlands. The initial purpose of the study is to investigate the effects of a multifactorial, intensified treatment on cardiovascular mortality and morbidity in a randomized design. After finishing the trial in 2009, the cohort will be followed up with an investigation into different aspects of the diabetes career of screen-detected diabetes patients. 24 Annual Report 2008

26 AGIS Health database The AGIS Health Database is a registry of a health insurance company and contains all health care procedures carried out in the last ten years involving 1.2 million health insured persons. Data is preserved on health care procedures by all contracted health care providers such as general practitioners, specialists, physiotherapists, pharmacists, midwives and hospitals. Besides data on health care procedures in primary (consultations, referrals, prescriptions) and secondary care (consultations, prescriptions and Diagnostic-Treatment Codes), a number of personal characteristics are documented, such as date of birth and gender. The insured persons are representative of the Dutch population. Data from this large cohort offers opportunities for all kinds of epidemiological research, but the main purpose is to improve knowledge on health care consumption and interaction between primary care, secondary care and public health. Data is also available to support health care management strategies and to evaluate improvements in quality of care. ARYA The Atherosclerosis Risk in Young Adults (ARYA) study is an unselected birth cohort of 750 persons born between 1970 and 1973 in and around the city of Utrecht. Its research focus is on early life determinants of later life cardiovascular disease. At birth, participants had elaborate birth data registered at the Municipal Health Service in Utrecht and they were followed up into young adulthood. In 1999, participants underwent elaborate cardiovascular disease risk profiling, including classical cardiovascular disease risk factors as well as elaborate non-invasive arterial wall measurements. Research 25

27 DOM The DOM cohort (Doorlopend Onderzoek Morbiditeit en Mortaliteit = Ongoing Study on Morbidity and Mortality = Diagnostisch Onderzoek Mammacarcinoom) is a cohort of 50,000 healthy women, living in Utrecht and surroundings. They were recruited from among breast cancer screening participants, aged between 40 and 70 years when recruited between The purpose of the DOM study is to identify risk factors for several chronic diseases, especially (breast) cancer. Baseline measurements included a short medical examination and extensive lifestyle and medical questionnaires. Overnight urine samples were collected and stored at -20 C. Electronic patient records communication disorders All children referred to our tertiary care centre for multidisciplinary evaluation of speech and language problems undergo a structured evaluation by an otolaryngologist, audiologist, speech therapist and a child psychologist. All data is then fed into their electronic patient records. Currently, about 500 children are included. EPIC-NL EPIC-NL is the Dutch contribution to European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC-NL ( is a merger of the Prospect-EPIC cohort (coordinated by the Julius Center) and the MORGEN- EPIC cohort (coordinated by the National Institute of Public Health and the Environment (RIVM), Bilthoven). It is a cohort of over 40,000 men and women from Amsterdam, Doetinchem, Maastricht and Utrecht and surroundings, aged years at recruitment in The purpose of this study is to assess the relationship between nutrition and cancer and other chronic diseases. Participants filled out lifestyle and medical question- 26 Annual Report 2008

28 naires and extensive food frequency questionnaires. Blood samples were taken, fractionated and stored at -196 C for all participants. HNU The HNU (Huisartsen Netwerk Utrecht = Utrecht General Practice Network) was founded in 1989 and is a collaboration between the General Practice department of the Julius Center and around 38 general practitioners working in six primary health care centers in the Utrecht area. Approximately 60,000 patients are enlisted with these centers. Data on all primary care consultations (including the ICPC coded diagnosis), ATC-coded prescriptions and referrals of these patients have been encoded in the database since GPs receive ongoing training in ICPC coding to ensure high quality coding. The primary goal was to set up a network of general practices that could provide valid and detailed routine care data on a primary care cohort for observational studies. Nowadays, the HNU has a large, centralized database containing observational data on the patients enlisted from 1995 up until IJSCO The IJSCO (IJsselstein Screening for Central Obesity to detect metabolic syndrome) cohort consists of 473 people with screen-detected metabolic syndrome (MetS). The screening among approximately 12,000 inhabitants of IJsselstein, years old on July 1st, 2006 and not known to have cardiovascular risk factors, started with self-measurement of waist circumference using a mailed tape measure. People with screen-detected MetS were advised to visit their general practitioner. Approximately half a year after the screening, they were followed by means of data collection from GP s medical records to investigate the normal course of events following screening for MetS. After approximately three years, all patients will be measured again. Research 27

29 Netherlands Amniotic Fluid (NAF) cohort The Netherlands Amniotic Fluid (NAF) cohort is an ongoing birth cohort focusing on the role of amniotic fluid inflammation in relation to respiratory tract infections during the first years of life. Healthy term infants are studied for the NAF study. Data collected at birth comprises: obstetric history, amniotic fluid cytokine measurements, Toll-like receptor responses, genetic polymorphisms and neonatal lung function. During follow-ups, daily respiratory symptoms are noted in a parental log and nasal swabs are taken for virology testing during each respiratory episode during the first year of life. The parents are instructed to take the diary to the general practitioner, who is subsequently asked to report the ICPC diagnosis. Currently, about 500 infants are included. PCR-MN PCR-MN (Psychiatric Case Registry Midden Nederland) is an anonymous psychiatric case registry that contains information on all patients who have been treated in one of the mental health care institutions in the central region of the Netherlands. It is one of the four regional psychiatric registries that are supported by the Ministry of Health. The primary aim of the database is to provide and analyze epidemiological data on mental health care, to provide management support and to improve quality of care. All major institutions for mental health care in the central region of the Netherlands participate in the registry. From 1999 onwards, data (patient characteristics, DSM IV diagnosis, referring centre, type of care) for approximately 120,000 patients with over 380,000 diagnostic codes, who were treated for mental health problems, has been included in the database. 28 Annual Report 2008

30 PIAMA The PIAMA (Prevention and Incidence of Asthma and Mite Allergy) birth cohort includes circa 4,000 children who have been followed for 8 years since birth. It is a multi-centre study including IRAS/Julius Center, National Institute of Public Health and the Environment (RIVM), Erasmus University Medical Center Rotterdam, University Medical Center Groningen and Sanquin/CLB Amsterdam. The study was started in 1996 and its purpose is to investigate the occurrence of asthma and allergy in young children, as well as lifestyle and environmental risk factors for these diseases. At several points in time, data was collected on exposure and health status. Blood samples were collected in a sub sample of the children. PREDICT This is a prospective study in which consecutive general practice attendees in six European countries are recruited and followed up after six and twelve months for the prevalence of depression. The Dutch part is coordinated by the Julius Center. Its purpose is to develop a risk score for use by general practitioners to predict the onset and maintenance of depression. Recruitment was started in 2003 and participants were years old. Over 10,000 participants were included, of which over 1,000 participants were in the Netherlands. PROVIDI PROVIDI is a cohort of ca. 16,000 patients who have undergone a chest multislice Computed Tomography (msct) scan for diagnostic reasons. The purpose of the cohort is to investigate the extent to which unrequested imaging findings are of prognostic relevance for the occurrence of several relevant diseases, other than the diagnostic that the CT was originally indicated for. Research 29

31 SMART The SMART (Second Manifestations of ARTerial diseases) cohort started in It is an ongoing, prospective, single-center cohort study of patients with cardiovascular risk factors or clinically manifest arterial disease. The purpose is to screen these patients for vascular problems elsewhere in the body. Consecutive patients aged 18 to 80 years, referred to the University Medical Center Utrecht (UMCU), with manifest arterial disease or a cardiovascular risk factor underwent vascular screening including a questionnaire, blood chemistry, and ultrasonography. After this screening, all patients fill out a biannual questionnaire in order to collect information on cardiovascular morbidity and mortality as well as diabetes mellitus end-points. SMART includes over 8,200 patients with more than 10 years of follow-up. In 2008, SMART-2 screening commenced. All patients screened in the past have been approached again to take part in this second screening. The aim of this second vascular screening is to study the course of atherosclerosis and vascular risk factors in time and evaluate the impact of a possible earlier treatment. In 2008, more than 200 patients had been screened, according to this SMART-2 protocol. Utrecht Health Project (LRGP) The Utrecht Health Project (or Leidsche Rijn GezondheidsProject (LRGP) is a population study of residents of the Leidsche Rijn, Utrecht area, who have been invited through their GPs working in the academic Primary Healthcare Centers in the area. The purpose of this study is to enable research on the impact of changes in health care policy, developments in community and public health and determinants - e.g. life style, behavioral, biological and genetic - of health and disease during lifetime, as well as quality management of (primary) health care itself. Until now 10,000 (of 25,000) inhabitants have given informed consent, Individual Health Profiles (IGP) have been mad, and blood samples, ECG and spirometry data has been collected 30 Annual Report 2008

32 at recruitment. Follow-up data (on average 5 years now) is collected through continuous linkage with the computerized medical files recorded by trained general practitioners. Data on diagnoses, prescriptions and referrals of all 25,000 inhabitants is encoded in the database and coupled with intake IGP data of those having given informed consent. Whistler Whistler (Wheezing Illnesses Study in LEidsche Rijn) is a satellite cohort of the Utrecht Health Project. Participants are newborns to inhabitants of Leidsche Rijn. Whistler was originally initiated to study early life predictors of (lower tract) respiratory disease in childhood. The focus has now expanded to include cardiovascular disease research questions as well. Recently, the milestone of 2,000 included newborns was reached in Whistler. The ultimate purpose is to follow participants up until adulthood. Extensive descriptions of cohorts and related websites can be found at: Research 31

33 Research Themes Cardiovascular Diseases The Cardiovascular Diseases research line is one of the four diseasebased research lines at the Julius Center, which coincides with the UMC defined, disease-based field of interest; Cardiovascular Disease. It is the Julius Center s largest research line. The research within this line uses approaches that include the full range of epidemiological research methods, such as multi-centered randomized controlled trials to study the effects of preventive and therapeutic interventions and cohort, casecontrol and cross-sectional studies. The research focuses on the causes, diagnosis, prognosis and therapy of common cardiovascular diseases. Cardiovascular research line is centered around several following themes with dedicated staff. 1 Early origins of vascular disease. Within this theme a research programme started in 2008 entitled From biomarker discovery to primary prevention in early life: an UMC Utrecht joint action for the prevention of cardiovascular disease. In this project, highly specialized cardiovascular knowledge is made accessible for primary prevention. In cohorts of children and patients with varying degrees of atherosclerosis markers, of inflammation, fat metabolism, coagulation and immunologic parameters will be measured. The purpose is to stratify people at a young age into high and low risk individual using these measures. The project is coordinated by the Julius Center and conducted in collaboration with the divisions Pediatrics, Heart & Lungs, Internal Medicine & Dermatology, Neurosciences, and Women & Baby. 32 Annual Report 2008

34 2 Endocrinology of vascular disease. Within this theme, in 2008 Dr. Yvonne van der Schouw was appointed Professor of Chronic Disease Epidemiology. This will boost the further development of this research theme to determine the role of menopause (cause or effect) in relation to development of atherosclerosis and cardiovascular disease risk. Furthermore, an important trial on the supplementation of testosterone was published in JAMA in International intervention studies. In 2008 several trials ended with publications in New England Journal of Medicine; one on the relation of tibolone treatment and fracture rate in postmenopausal woman (LIFT) and one on the effect of blood pressure and glucose lowering on vascular risk in patients with type II diabetes (ADVANCE). Furthermore, a multicenter international polypill trial started in 2008 in asymptomatic high risk subjects using a network of international collaborators. 4 Diagnosis and prognosis of vascular disease in primary care. The general practitioner is the gatekeeper within the Dutch health care system. It is of utmost importance, but also sometimes extremely difficult, to arrive at appropriate diagnoses in primary care in order to further improve patient management. Diagnostic studies in primary care are, therefore, an important research topic at the Julius Center, also in the cardiovascular research line. In 2008, the AMUSE (Amsterdam Maastricht Utrecht Study on thromboembolism) study was finalized. The AMUSE study, evaluated the safety and efficiency of using a clinical decision rule including a point-of-care d-dimer assay in patients suspected of deep vein thrombosis of the leg. The study showed that a diagnostic management strategy in primary care by using a simple clinical decision rule and a point-of-care d-dimer Research 33

35 assay reduces the need for referral to secondary care of patients with clinically suspected DVT by almost 50% and is associated with an acceptably low risk for subsequent venous thromboembolic events. The diagnostic prediction rule has been incorporated into the guideline on deep vein thrombosis for general practitioners in The Netherlands. Similar diagnostic studies are ongoing in patients suspected of myocardial infarction/acute coronary syndrome and pulmonary embolism. 5 Vascular complications of type 2 diabetes mellitus in primary care. In 2008, Julius Center investigators showed that it is possible to reduce cardiovascular risk in patients with diabetes within 1 year through intensive multifactor treatment. The study showing this was picked up by ACP Journal Club of the American College of Physicians American Society of Internal Medicine, a medium to help internists keep up to date by abstracting high quality research from key journals of relevance to internal medicine. Care for type 2 diabetes patients is an important task for the general practitioner. Another study showed that it is feasible, safe and effective to organize care by delegating routine diabetes care to a practice nurse, combined with computerized decision support and feedback. Funding was obtained from the Netherlands Organization for Scientific Research to start a study to assess whether reducing the number of visits for diabetes patients from 4 to 2 per year has no adverse effects on health. 6 Prediction of future vascular disease in secondary care. One of the Julius Center s cohorts is the Second Manifestations of ARTerial disease (SMART) cohort. This unique cohort of patients at high risk of cardiovascular disease (CVD) started in All patients referred 34 Annual Report 2008

36 to the University Medical Center in Utrecht (UMC Utrecht) with either a risk factor for CVD (hypertension, hyperlipidemia, diabetes) or clinically manifest vascular disease (ischemic cerebral disease, asymptomatic stenosis of the internal carotid artery, myocardial infarction, angina pectoris, abdominal aortic aneurysm, intermittent claudication) are eligible for inclusion in the study. Patients undergo an extensive screening programme to detect asymptomatic atherosclerotic lesions and to identify risk factors. Then, a multidisciplinary team formulates an evidence-based treatment plan, to reduce the patient s risk of future cardiovascular events. This treatment advice is sent to the patient s general practitioner and to his or her treating hospital specialist. Every 6 months patients are asked to report, by mail, whether they have experienced or received treatment for a vascular event in the last 6 months. In 2008, 5 PhDtheses resulting from the SMART study were defended successfully. One of these evaluated the SMART screening programme. For patients who are not enrolled in a dedicated screening programme, many risk factors are not systematically documented. Screening alone is insufficient however for adequate treatment of these high-risk patients and more intensive monitoring and follow-up is necessary. Another thesis reported on the contribution of vascular diseases in the development of brain atrophy and cognitive decline. In 2008, the SMART-2 project started, in which patients enrolled in SMART are screened for the second time. The main purpose of SMART-2 is to study the course of atherosclerosis and risk factor development over time, and to study effects of the treatment that was initiated on these patients. In 2008 research within the other themes (7) Diagnosis and Prognosis of atherosclerosis, (8) Prevention of complication after cerebral vascular Research 35

37 disease in secondary care and (9) Epidemiology of haemophilia in secondary care was continued with considerable scientific output and success in aquiring grants. Infectious Diseases Infectious diseases research at the Julius Center is centered around four topics: 1 Prevention, diagnosis and prognosis of respiratory tract infections. This research is mainly positioned within the primary care and Ear Nose and Throat areas. An investigation, for example, may take place into the extent to which certain patient characteristics predict an abnormal and serious clinical progression of bronchial infections and what the consequences for treatment and patient advice are. In addition, antibiotic use and indications for prescribing in general practice are being studied, as is the efficacy of prednisone treatment in patients with persistent complaints of sinusitis. This research has been expanded to include the development of asthma and allergy, in relation to exposure to infectious agents and other environmental determinants, both in young children and in occupationally exposed subjects. 2 Efficacy (and cost-effectiveness) of vaccination strategies. In collaboration with the department of Pediatric Immunology, the National Vaccine Institute and pharmaceutical industries, an increasing number of vaccination studies have been executed and are ongoing. In addition to these studies, the role of confounding in determining vaccination efficacy is also investigated. Currently, this research group is heading the CAPITA study, in which 85,000 elderly people will be randomized to an investigational 13-valent conjugate pneumococcal vaccine or placebo to determine the efficacy of this 36 Annual Report 2008

38 vaccine in preventing community-acquired pneumonia caused by vaccine-specific pneumococcal serotypes. 3 Mathematical modeling of infectious diseases. In collaboration with the Mathematical Institute of the University Utrecht and the National Institute of Health and Environment, the dynamics (and prevention of acquisition) of multi-resistant bacteria and influenza within hospitals and the community at large is being investigated, as well as potential effects of interventions. In 2008, intensified collaborations between the National Institute of Health and Environment, the Mathematical Institute, the Veterinary Faculty and the Julius Center resulted in the creation of the Utrecht Center for Infectious Disease Dynamics. 4 The effects of nosocomial infections and transmission of antibioticresistant bacteria on patient outcome. The attributable mortality of ventilator-associated pneumonia is investigated and the Julius Center coordinates an international cluster-randomized trial in European ICUs to determine the efficacy of several approaches to reduce the transmission of antibiotic-resistant bacteria. Cancer Cancer research at the Julius Center has a strong focus on the etiology, early diagnosis and screening of hormone dependant cancer, predominantly in women. Cancer is a serious health threat in the Netherlands, with approximately 30,000 new cases a year in women. In 2008, for the first time, more people died from cancer than from cardiovascular diseases. However, the known causes of cancer barely explain 30% of all cases encountered. An explanation for this rather low percentage may be sought in the fact that environmental and hormonal factors are predominantly studied without any consideration to genetic predisposition. Cancer etiological research within the Julius Center strongly focuses on Research 37

39 the interaction between genes, hormones and lifestyle habits. For the study of genetic determinants or gene-environmental interactions, the Julius Center has access to biological material originating from two large-scale on-going population-based cohorts, DOM and EPIC-NL, which is a merger of the two Dutch cohorts participating in the European Prospective Investigation into Cancer and Nutrition: Prospect-EPIC and Morgen-EPIC. For studies of the optimal (early) diagnostic and (clinical) follow-up procedures in cancer patients, collaboration has been established with clinicians from other departments of the University Medical Center in Utrecht. Examples are the COBRA and MONET studies, both assessing optimal diagnostic and therapeutic procedures in women with nonpalpable breast diseases. Studies to assess quality of life in the daily care of cancer patients also fall into the domain of the cancer research at the Julius Center. There is close cooperation with the Faculty of Medicine s department of epidemiology and public health at Imperial College in London, UK, where the head of the cancer research line at the Julius Center, Petra Peeters, has been appointed Professor for one day/week. Mental Health The Julius Center s psychiatric epidemiology section studies psychiatric disease and related co-morbidity in primary care and the population at large. Mental illness represents a sizeable proportion of the global burden of disease in the general population, but is only partly presented to health care professionals. Major psychiatric disease represents 5% of the prevalent morbidity in primary care, with an annual prevalence of 125 per 1000 patients. A substantial part of minor psychiatric morbidity is presented in relation to somatic disease or functional syndromes or expressed through excessive consultation frequency of unexplained 38 Annual Report 2008

40 functional syndromes. Mental illness - though closely linked to somatic ill-health is traditionally studied in isolation. The psychiatric epidemiology section focuses on the study of somatic - psychiatric comorbidity, with the following themes: 1 The presentation of depression in primary care and its association with somatic disease such as dementia, diabetes, gastro-enterological and vascular disease. 2 Functional disease and somatoform disorders: presentation, determinants and treatment in primary care. 3 Psychiatric morbidity in relation to socio-demographic context and consultation patterns. The common background hypothesis is that somatic and psychiatric disorders share an overlapping etiology and that this overlap has social and psychological as well as physiological components. Our assessments typically aim to characterize individuals at several levels (psychological, physical and physiological). These themes are studied on the various levels at which disorders manifest themselves: - The general population, by using existing and developing sampling frames such as LRGP (Leidsche Rijn Gezondheidsproject), NEMESIS (Netherlands Mental Health Survey and Incidence Study), AGIS health database and others. - Primary health care, in primary care networks such as the Utrecht General Practitioners Network (In Dutch: HNU (Huisartsen Netwerk Utrecht), PREDICT, Utrecht Health Project (in Dutch: Leidsche Rijn Research 39

41 Gezondheids Project) and the database of Emergency Primary Care service in the Gelderse Vallei area. - Populations of people with reported mental illness such as those registered in our psychiatric case registry (PCR-MN). - Populations of people with reported somatic illness, such as samples of cardiovascular compromised patients (SMART), (pre)diabetic patients (UDES), and medication-using people (PHARMO). This approach of studying the phenomenon of somatic psychiatric comorbidity at various levels of the health care system is unique. From a clinical point of view, it will yield information on the etiology and prognosis of somatic-psychiatric co-morbidity and allow preventive interventions. It will also facilitate evaluation of the patient flow through the mental health care system and its effectiveness Most research projects are carried out in collaboration with partners within primary or secondary care health care: primary care physicians, secondary care centers for psychiatry, neurology and gastro-enterology, often in cooperation with other (international) academic centers. Theoretical Epidemiology and Biostatistics Besides more applied studies on improving insights in the etiology, diagnosis, prognosis and therapy of specific disorders, the Julius Center also aims to further develop the theory and methodology of the discipline itself. The section; Theoretical Epidemiology and Biostatistics conducts studies aiming to improve existing methods and develop innovative methods for design and analysis of (clinical) epidemiological studies. The section focuses on the following themes: 40 Annual Report 2008

42 - Developing innovative designs for diagnostic and prognostic (prediction) research. - Developing innovative methods for quantifying the true or added value of (new) diagnostic and prognostic tests or biomarkers in a multivariable clinical context. - Developing innovative methods for validating and updating so-called clinical prediction rules. - Testing and improving methods for dealing with missing values in epidemiologic research. - Investigating innovative methods for meta-analysis and individual patient data-analysis of etiologic and therapeutic studies. - Development of models to combine data from randomized and observational studies including genetic information, for estimating (long term) prognosis according to specific patient characteristics in addition to treatment effects. - Developing and investigating methods for sequential analysis in randomized trials, cumulative meta-analysis, observational epidemiological and genetic studies, to increase their efficiency and safety. - Developing and investigating methods to adjust for confounding in observational studies, like propensity scores and instrumental variables. - Investigating methods for the analysis of longitudinal data. Notably, the improvement of methods for the design and analysis of multivariable diagnostic and prognostic research is unique. Most research in this field focuses on single test or (bio/genetic) marker evaluations, rather than evaluations in a clinical context, accounting for other test results. The methodology for modeling data from randomized and non-randomized studies combined is also in its infancy. This type of Research 41

43 research is situated at the crossroad of clinical epidemiology and medical technology assessment. 42 Annual Report 2008

44 All of the above methodological themes are not only studied on a purely theoretical level, but are also applied by using empirical data from various medical disciplines, notably from our four disease-oriented sections. For example, data is used from the above-mentioned LRGP (Leidsche Rijn Gezondheidsproject), the Predict study and the AMUSE studies on the diagnosis, prognosis and treatment of deep vein thrombosis and pulmonary embolism, as well as from various other large ongoing studies in the UMC Utrecht such as the SMART study. It may be obvious that the results of our methodological studies do not only serve the clinical domains studied, but may serve all medical domains in which diagnosis, prognosis and therapy, for example, are at issue. Most methodological projects are carried out in close collaboration with other clinical departments from the UMC Utrecht. Other epidemiological and (bio) statistical departments from national and international academic centers are also consulted, such as the Utrecht University, Academic Medical Center Amsterdam, Erasmus Medical Center Rotterdam, Dutch National Institute for Health and the Environment, Vanderbilt University (USA), Harvard University (USA), Oxford University (UK), and McGill University (Canada). Research 43

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