Helmholtz Zentrum Munchen Research Articles

Systemic Biomarkers of Lung Function and FEV <sub>1</sub> Decline Across Multiple Cohorts

Background: Chronic obstructive pulmonary disease (COPD) is a common, complex respiratory disease characterized by airway obstruction and accelerated lung function decline. Our understanding of systemic protein biomarkers associated with COPD remains incomplete. We tested whether aptamer-based protein profiling could identify markers and pathways related to impaired pulmonary function and lung function decline in multiple studies. Methods: We studied 3,827 non-Hispanic/European White participants across six cohort studies with both aptamer-based proteomic and spirometry data. In linear regression models we examined protein associations with baseline FEV1 and FEV1/FVC. In linear mixed effects models we investigated the associations of baseline protein levels with rate of FEV1 decline (mL/year) in 2,636 participants with up to 7 years of follow-up spirometry. Findings: We identified 198 proteins associated with FEV1, twelve of the proteins were also significantly associated with FEV1/FVC, including retinal binding protein 4 FEV1 : β=0·0307, Q= 2·18×10-4; FEV1/FVC: β=0·008, Q =4·0×10-3 ) and bactericidal permeability-increasing protein (FEV1 : β=-0·0280, Q =6·80×10-3; FEV1/FVC: β=0·0050, Q =0·04). We further identified 15 proteins associated with the rate of FEV1 decline ( Q <0·05), including coagulation-related tissue factor and basement membrane-associated nidogen (β=-5·21 mL/year, Q =0·016 and β=-4·90 mL/year, Q =0·020, respectively). Pathways and processes associated with lung function included extracellular matrix organization, coagulation, and angiogenesis. Interpretation: In this study, we identified novel biomarkers and pathways associated with lung function and lung function decline. Additionally, several protein findings support previously reported genetic signals, highlighting the plausibility of certain biologic pathways. These novel proteins might represent disease markers of at-risk individuals and/or novel molecular targets with the potential to modify COPD clinical course. Funding Statement: COPDGene Phase 3: Grant Support and Disclaimer: The project described was supported by Award Number U01 HL089897 and Award Number U01 HL089856 from the National Heart, Lung, and Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health; COPD Foundation Funding: The COPDGene® project is also supported by the COPD Foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, and Sunovion; FHS: This work was supported by R01HL132320 and R01HL133870. The Framingham Heart Study (FHS) acknowledges the support of contracts NO1-HC25195, HHSN268201500001I and 75N92019D00031. KORA: The KORA study was initiated and financed by the Helmholtz Zentrum Munchen – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universitat, as part of LMUinnovativ. This work was also supported by the Comprehensive Pneumology Center Munich (CPC-M) as member of the German Center for Lung Research (DZL). LSC: This work was supported by funding from the State of New Mexico. MESA-TOPMed/MESA Lung Support: Molecular data for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI), with core services provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I) and the TOPMed Data Coordinating Center (3R01HL120393-2S1; contract HHSN268201800001I). Proteomics data for the MultiEthnic Study of Atherosclerosis MESA; phs001416) were generated through the TOPMed MESA Multi-Omics project (HHSN2682015000031/HHSN26800004). The MESA Lung Study is supported by R01-HL077612 and R01-HL093081. SPIROMICS. This work was supported by contracts from the NIH/NHLBI (HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, HHSN268200900020C), grants from the NIH/NHLBI (U01 HL137880 and U24 HL141762), and supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from AstraZeneca/MedImmune; Bayer; Bellerophon Therapeutics; BoehringerIngelheim Pharmaceuticals, Inc.; Chiesi Farmaceutici S.p.A.; Forest Research Institute, Inc.; GlaxoSmithKline; Grifols Therapeutics, Inc.; Ikaria, Inc.; Novartis Pharmaceuticals Corporation; Nycomed GmbH; ProterixBio; Regeneron Pharmaceuticals, Inc.; Sanofi; Sunovion; Takeda Pharmaceutical Company; and Theravance Biopharma and Mylan. Declaration of Interests: None. Ethics Approval Statement: The respective local Institutional Review Boards approved all study protocols and informed consent was obtained from all participants.

Reply: Analysis of the sex ratio at birth in South Africa increased 9 months after the 2010 FIFA World Cup

a Irish Centre for Fetal and Neonatal Translational Research (INFANT), Department of Obstetrics and Gynaecology, University College Cork, Cork, Ireland b Gravida: National Centre for Growth & Development, University of Auckland, Auckland, New Zealand c Division of Epidemiology and Biostatistics, School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa d Academic Department of Paediatrics, Medical School, Mater Dei Hospital, Malta e Helmholtz Zentrum Munchen—German Research Center for Environmental Health, Institute of Computational Biology, Ingolstadter Landstr. 1, D-85764 Neuherberg, Germany

Epigenome-wide association of DNA methylation markers in peripheral blood from Indian Asians and Europeans with incident type 2 diabetes: a nested case-control study

Indian Asians, who make up a quarter of the world's population, are at high risk of developing type 2 diabetes. We investigated whether DNA methylation is associated with future type 2 diabetes incidence in Indian Asians and whether differences in methylation patterns between Indian Asians and Europeans are associated with, and could be used to predict, differences in the magnitude of risk of developing type 2 diabetes. We did a nested case-control study of DNA methylation in Indian Asians and Europeans with incident type 2 diabetes who were identified from the 8-year follow-up of 25 372 participants in the London Life Sciences Prospective Population (LOLIPOP) study. Patients were recruited between May 1, 2002, and Sept 12, 2008. We did epigenome-wide association analysis using samples from Indian Asians with incident type 2 diabetes and age-matched and sex-matched Indian Asian controls, followed by replication testing of top-ranking signals in Europeans. For both discovery and replication, DNA methylation was measured in the baseline blood sample, which was collected before the onset of type 2 diabetes. Epigenome-wide significance was set at p<1 × 10(-7). We compared methylation levels between Indian Asian and European controls without type 2 diabetes at baseline to estimate the potential contribution of DNA methylation to increased risk of future type 2 diabetes incidence among Indian Asians. 1608 (11·9%) of 13 535 Indian Asians and 306 (4·3%) of 7066 Europeans developed type 2 diabetes over a mean of 8·5 years (SD 1·8) of follow-up. The age-adjusted and sex-adjusted incidence of type 2 diabetes was 3·1 times (95% CI 2·8-3·6; p<0·0001) higher among Indian Asians than among Europeans, and remained 2·5 times (2·1-2·9; p<0·0001) higher after adjustment for adiposity, physical activity, family history of type 2 diabetes, and baseline glycaemic measures. The mean absolute difference in methylation level between type 2 diabetes cases and controls ranged from 0·5% (SD 0·1) to 1·1% (0·2). Methylation markers at five loci were associated with future type 2 diabetes incidence; the relative risk per 1% increase in methylation was 1·09 (95% CI 1·07-1·11; p=1·3 × 10(-17)) for ABCG1, 0·94 (0·92-0·95; p=4·2 × 10(-11)) for PHOSPHO1, 0·94 (0·92-0·96; p=1·4 × 10(-9)) for SOCS3, 1·07 (1·04-1·09; p=2·1 × 10(-10)) for SREBF1, and 0·92 (0·90-0·94; p=1·2 × 10(-17)) for TXNIP. A methylation score combining results for the five loci was associated with future type 2 diabetes incidence (relative risk quartile 4 vs quartile 1 3·51, 95% CI 2·79-4·42; p=1·3 × 10(-26)), and was independent of established risk factors. Methylation score was higher among Indian Asians than Europeans (p=1 × 10(-34)). DNA methylation might provide new insights into the pathways underlying type 2 diabetes and offer new opportunities for risk stratification and prevention of type 2 diabetes among Indian Asians. The European Union, the UK National Institute for Health Research, the Wellcome Trust, the UK Medical Research Council, Action on Hearing Loss, the UK Biotechnology and Biological Sciences Research Council, the Oak Foundation, the Economic and Social Research Council, Helmholtz Zentrum Munchen, the German Research Center for Environmental Health, the German Federal Ministry of Education and Research, the German Center for Diabetes Research, the Munich Center for Health Sciences, the Ministry of Science and Research of the State of North Rhine-Westphalia, and the German Federal Ministry of Health.

EPRBioDose 2013: EPR applications and biological dosimetry

The series of EPRBioDose conferences includes both the International Symposium on EPR Dosimetry and Dating (EPR) and the International Conference on Biological Dosimetry (BioDose). EPRBioDose 2013 was jointly organized by Leiden University Medical Center (Leiden, The Netherlands) and the Helmholtz Zentrum Munchen (Munchen, Germany) and was held on 24–28 March 2013 in Leiden. The conference topics covered new aspects of traditional EPR dosimetry applications, retrospective dosimetry with physical and cytogenetic techniques, dosimetry for mass casualty events and technical developments in particularly on automatic analysing systems for biological assays, as well as those applicable for dose assessment in scenarios of mass casualties. The aim of the conference was to share technological advances achieved since the last EPRBioDose conference and to improve the understanding of physical, biophysical and biological processes that can be used in the dosimetry of ionizing radiation. This volume of Radiation and Environmental Biophysics includes fifteen papers that were presented at the conference.

Reply to Little et al.: dose–responses from multi-model inference for the non-cancer disease mortality of atomic bomb survivors

We appreciate the comment by Little et al. (2013) related to the study of Schollnberger et al. (2012) and thank our colleagues for the time they took to deal with our analysis. Little et al. (2013) state ‘‘... there are biological data suggesting [that] many inflammatory endpoints potentially relevant to circulatory disease may be differentially regulated below and above about 0.5 Gy, emphasizing the importance of assessing risks associated with exposures \0.5 Gy.’’ We agree with the statement and take it as a support of our approach to analyze the available data with a variety of models that take several possible dose dependences into account. Little et al. (2013) express a concern ‘‘... that the method of Schollnberger et al. 2012 (multi-model inference, MMI) may not adequately assess the uncertainties in model parameters’’ without elucidating reasons of their concern. However, seemingly to backup their concern, they cite Wang et al. (2012), a paper describing the development of a novel approach to ‘‘adjustment uncertainty’’ (i.e., the uncertainty about which variables should be included in the model to properly adjust for confounding), called Bayesian adjustment for confounding. We will argue below that the pre-conditions on which Wang et al. (2012) built their interesting, though not uncontested (Gutman and Rubin 2012), methodology do not apply to our analysis. When the effect of exposure on outcome is estimated, a proper adjustment for confounding variables is a general concern in epidemiology. A series of papers by Wang et al. (2012), Crainiceanu et al. (2008) and Dominici et al. (2004) addressed this problem for the correlation of air pollution and mortality. A big challenge in air pollution epidemiology is to control for possible confounding by changes in weather parameters such as temperature or humidity, which determine both the concentration of particulate matter in air and have a direct impact on mortality rates, especially among older persons and those with preexisting health conditions. Hence, such covariables are clearly correlated with exposure and outcome and can be considered as true confounders. In our study of the association between circulatory diseases and ionizing radiation, we have adjusted the risk for the main covariables of city c, sex s, age at exposure e and attained age a, for which the correlation with the radiation dose is generally small: see bottom row of the correlation matrix (Table 1), which was calculated from the raw data of LSS Report 13 with follow-up since January 1, 1968 (Preston et al. 2003), the data set that has been analyzed by Schollnberger et al. (2012). Additional adjustment for other covariables such as smoking, alcohol intake, education, type of household occupation, obesity and diabetes mellitus ‘‘had almost no impact on the associations with radiation’’ (see Table 3 and Discussion in Shimizu et al. (2010)). We have not calculated the correlation with exposure for the latter covariables but we expect again small correlations similar to those for c, s, e and a. H. Schollnberger (&) J. C. Kaiser P. Jacob Helmholtz Zentrum Munchen, Department of Radiation Sciences, Institute of Radiation Protection, 85764 Neuherberg, Germany e-mail: schoellnberger@helmholtz-muenchen.de

When genetic screening for your patient with long QT syndrome comes back negative, don’t always take a no for a no

Lia Crotti, MD, PhD, Peter J. Schwartz, MD, FHRS From the Department of Molecular Medicine, Section of Cardiology, University of Pavia, Pavia, Italy, yDepartment of Cardiology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy, zInstitute of Human Genetics, Helmholtz Zentrum Munchen, Neuherberg, Germany, Cardiovascular Genetics Laboratory, Department of Medicine, Hatter Institute for Cardiovascular Research in Africa, University of Cape Town, South Africa, and Department of Family and Community Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia.

German Conference on Chemoinformatics 2010 – organizers' notes

The Chemistry-Information-Computers (CIC) division [1] of the German Chemical Society (GDCh) invited the chemoinformatics and modeling community from the 7th to the 9th November 2010 to Goslar, Germany, to participate in the 6th German Conference on Chemoinformatics (GCC 2010). The international symposium addressed a broad range of modern research topics in the realm of computers and chemistry. The conference focused on recent developments and trends in the fields of • Chemoinformatics and Drug Discovery • Chemical Information, Patents and Databases • Molecular Modeling • Computational Material Science and Nanotechnology In addition, contributions from other research areas of Computational Chemistry were welcome. Similar to other conferences in the Life Science sector the German Conference on Chemoinformatics was faced with a decreasing number of participants in 2010. This is assumed to be mainly caused by travel cost cuts in industry due to the global economic crisis. Nevertheless, a large number of scientists (156 participants, Figure ​Figure1)1) from 18 nations were attracted by the excellent scientific program established by the scientific advisory board and attended the GCC 2010. The large number of attendees from countries other than Germany demonstrates that the conference is an internationally well-established event in the global Chemoinformatics and Modelling community (see Figure ​Figure2A).2A). Despite the travel situation in industry, a good ratio between academic institutes, industry and exhibitors could be achieved (see Figure ​Figure2B2B). Figure 1 Participants of the 6. German Conference on Chemoinformatics, November 7–9, 2010, Goslar, Germany. Figure 2 A) 156 participants from 18 nations attended the GCC2010. Most participants (99) were from Germany followed by 16 attendees from the United Kingdom. Participants from the USA and Switzerland followed on the third position with 6 attendees each. B) 56% ... Traditionally, the conference was opened by a “Free-Software-Session” on Sunday afternoon right before the official conference opening at 5 pm. Six Open Source projects were presented in “Free-Software-Session”. This was the largest number of contributions to this session in the history of the GCC. The audience followed presentations of PostgreSQL (Bayer Business Services), OCHEM (Helmholtz Zentrum Munchen), Knime (University of Konstanz), Indigo & Ketcher (SciTouch), and MosGrid (MosGrid Consortium). The “Chemoinformatics Market Place” took place at the same time and included software tutorials by the Chemical Computing Group (“New Features of MOE 2010”) and BioSolveIT (“Fragment-Based Lead Design in Teams”). The scientific program started with an entertaining and enthralling evening lecture giving by Colleen Fitzpatrick (“Hand in Snow”). In addition, the program of the following two days included plenary lectures of six well known invited speakers from industry and academia (Wolfgang Guba, Roche, Swiss; Andrew R. Leach, GSK, UK; Hans Fraaije, Leiden University, The Netherlands; Jurgen Gmehling, Oldenburg University, Germany; Gerhard Klebe, Marburg University, Germany; Holger Gohlke, Dusseldorf University, Germany), 17 lectures as well as 43 poster presentations. Besides the scientific program a special highlight of the conference were the awards (see Figure ​Figure3).3). In contrast to the last GCC in 2009, two different awards could be handed over for excellent scientific work this year. Prof. Jurgen Gmehling from the University of Oldenburg was presented with the Gmelin-Beilstein-Denkmunze [2] award for his groundbreaking contributions in the field of compound databases and fragment methods for the prediction of chemical properties used in technical chemistry. The laudatory speech was given by Prof. Onken and the award was handed over by the president of the German Chemical Society Prof. Michael Droscher. Furthermore, the FIZ-CHEMIE-Berlin awards [3] took place on Monday afternoon. The CIC division awards this price each year to the best diploma thesis and the best PhD thesis in the field of Computational Chemistry. The price for the PhD thesis was awarded to Dr. Simone Fulle from the group of Prof. Dr. Holger Gohlke, Goethe University of Frankfurt for her dissertation “Constraint counting on RNA and ribosomal structures: Linking flexibility and function”. The award for the best diploma thesis was given to Karen Schomburg from the group of Prof. Matthias Rarey, University of Hamburg for her excellent master thesis with the title “Visualization of molecular subgraph pattern using the example of SMARTS pattern”. Figure 3 FIZ CHEMIE Berlin Awards 2010 and GDCh Gmelin-Beilstein-Denkmunze Award: from left to right, Frank Oellien (Chair of the GDCh-CIC division), Ulfert Onken (Laudatory Gmelin-Beilstein-Denkmunze Award), Karen Schomburg (FIZ CHEMIE Berlin ...

Central pulse pressure and augmentation index in asymptomatic bicuspid aortic valve disease

a Centre of Cardiology and Cardiovascular Surgery, University Hospital Eppendorf, Hamburg, Germany b Department of Medical Biometry and Epidemiology, University Hospital Eppendorf, Hamburg, Germany c Medical Clinic II, University of Lubeck, Germany d Institute of Epidemiology and Social Medicine, University of Muenster, Germany e Helmholtz Zentrum Munchen, German Research Center for Environmental Health (GmbH), Institute of Epidemiology II, Neuherberg, Germany f Institute of Medical Genetics, Charite Universitatsmedizin Berlin, Germany

What should public health research focus on? Comments from a decision analytic perspective

Scientific articles often end with ‘further research is needed…’. However, further research in one specific area consumes resources that could have been needed to address other research questions, or could have been used for public health interventions—and improve health—instead of filling journals. How can the desirability of further applied research be substantiated in the face of scarce resources? While the tools of statistical inference can establish when evidence is insufficient they cannot address whether it is worthwhile to invest scarce resources into an improvement of the evidence base. A methodological alternative is Bayesian cost-effectiveness and value of information (VOI) analysis, which can address decisions on both technology adoption and research priorities in a coherent manner.1 Cost-effectiveness analysis compares the ratio of additional costs and effects of an intervention like a screening program, expressed in the form of an incremental cost-effectiveness ratio (ICER = ΔC/ΔE), to a threshold value. This threshold value, often referred to as λ, represents the incremental value forgone by not using the scarce resources elsewhere. In the context of a controlled budget increase, it represents the willingness to pay for a … Correspondence: Wolf H. Rogowski, Helmholtz Zentrum Munchen, German Research Center for Environmental Health (GmbH), Neuherberg, Germany, tel: +49 89 3187 4128, fax: +49 89 3187 194128, e-mail: rogowski{at}helmholtz-muenchen.de

Economic modelling in public health: a tool of growing relevance

As their colleagues in clinical medicine, decision makers in public health should require the best available evidence in order to set priorities. Decisions on public health intervention need to take into account questions of how many people are at risk, how these people and care givers will respond to different types of interventions, how effective interventions will be for different subgroups and what the costs are linked to all of this? A public health decision—even one that is not taken—is likely to at least implicitly weigh these issues. When looking for an evidence base, it may be difficult or even impossible to identify results from clinical trials that are suitable to cover all above issues. Data on the epidemiologic situation in the target population, on behaviour as well as on health and cost outcomes may be necessary to assess the decision maker’s choices. Models provide an option to synthesize all data within a consistent framework. In order to be … Correspondence: Reiner Leidl, Institute for Health Economics and Health Care Management, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Germany. e-mail: leidl{at}helmholtz-muenchen.de

Late health effects of ionizing radiation: bridging the experimental and epidemiological divide

Knowledge of health risks from chronic or repeated exposures to low-LET radiation with organ doses on the order of 100 mGy or less is of central importance for radiation protection and the safe use of ionizing radiation in medical diagnosis. While it is not yet clear whether the incidence of circulatory diseases is increased after such exposures, there is evidence of an overall elevated risk of cancer. QuantiWcation of site-speciWc cancer risks and their dependences on exposure patterns, age and other factors still needs clariWcation. It can be anticipated that approaches to resolve these questions will involve integration of mechanistic and epidemiological methods. The International Conference on Late Health EVects of Ionizing Radiation which was held in Washington, DC, 4–6 May 2009, was organized to stimulate such interdisciplinary research approaches. This volume includes nine papers based on conference presentations. Recently, radiation-induced genomic instability has been related to cancer incidence in an epidemiological study (Eidemuller et al. 2009). In this volume, StreVer reviews the evidence for the involvement of genomic instability in carcinogenesis and concludes that genetic predisposition for increased radiosensitivity is related to increased genomic instability and cancer predisposition (StreVer 2010). Genomic instability is often assumed to be an early stage in the carcinogenic process. A late step is the progression during which malignant cells develop into clinical symptomatic cancer. In a number of organs, especially thyroid and prostate, dormant or slow-growing tumours often do not develop into clinically relevant tumours. It is an open question how these tumours should be evaluated in assessing cancer risk and latency period. An approach is proposed by Fakir et al. (2010), who address this problem using lung cancer as an example. They developed a mathematical model that takes into account experimental, epidemiological and clinical data to predict latency period and conclude that radiation may be involved in progression from a dormant tumour to a clinically relevant one. Besides mechanistic understanding, precise dosimetry is important in estimating the health impact of radiation exposures. The large amount of autopsy data from Mayak workers is an important source of information on the biokinetics of inhaled plutonium in airways, the deeper lung, and other organs. In one of the conference presentations, Birchall et al. (2010) described how the Mayak autopsy data on lung tissue clearance and retention rates can impact on current International Commission on Radiological Protection (ICRP) biokinetic models of the respiratory tract. Another area where progress in dosimetry can improve epidemiological studies is computational phantoms. Bolch et al. (2010) review emerging techniques for constructing patientspeciWc phantoms, which are expected to become the basis of a new generation of dose reconstruction methods. Recent studies provide some evidence that leukaemia rates are increased after chronic exposures to low-LET radiation with bone marrow doses of approximately 100 mGy. Whether chronic lymphatic leukaemia (CLL) is associated with exposure to ionizing radiation, however, is not clear. Krestinina et al. (2010) present new data on this question. Leukaemia rates among about 30,000 Techa P. Jacob (&) Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Institute of Radiation Protection, 85764 Neuherberg, Germany e-mail: jacob@helmholtz-muenchen.de; jacob@gsf.de

Experimental setup of field lysimeters for studying effects of elevated ozone and below-ground pathogen infection on a plant-soil-system of juvenile beech (Fagus sylvatica L.)

An experiment, focusing on the effects of chronically enhanced O3 regimes on young beech (Fagus sylvatica) and on the microbial rhizosphere community structure, was conducted from November 2002 to August 2006 in eight field lysimeters at the Helmholtz Zentrum Munchen. The instrumentations of the lysimeters enabled the establishment of the water balance in the unsaturated zone and the assessment of the water uptake by plants. Further, the containment provided by the lysimeters made it possible to apply a root rot pathogen infection without contaminating the surrounding soil. A free-air fumigation system allowed to double the O3 concentration in the air above four lysimeters relative to the ambient air. To avoid damage of the leaves the maximum O3 concentration was limited to 150 nL L−1. For nearly 70% of the time the set-point concentration was reached within 10%. In the final harvest the whole soil column was retrieved and a nearly complete data-set of above-ground and below-ground parameters became available.

Preferences, quality of life and public health

According to the PubMed data base, the first review which mentioned ‘quality of life’ (QoL) in its title appeared >30 years ago. Entries of this term currently exceed 100 000. The rise of QoL research has probably been supported by factors, such as increasing prevalence of chronic conditions, increasing life expectancy in older age and a focus on nonsurvival benefits of medical technology. QoL stands for a multidimensional, subjective perception of health by the individual. It is typically measured as a profile, surveying items across dimensions of physical, psychological and social well being, functional health and further aspects such as the existence of pain. QoL captures key components of population health, and QoL profiles are therefore also being studied in public health research. Yet, there are issues with this approach that need to be considered carefully. When comparing QoL between two populations, it may turn out that for one, QoL is better in some items but worse … Correspondence: Reiner Leidl, Institute for Health Economics and Health Care Management, Helmholtz Zentrum Munchen, German Research Center for Environmental Health (GmbH), Postfach 1129, D-85758 Neuherberg, Germany, e-mail: leidl{at}helmholtz-muenchen.de

Promoting economic value in public health

In the pharmaceutical field, the term ‘fourth hurdle’ has become common currency in many health systems. It means that only products that can show their cost-effectiveness will gain unrestricted access to patients. The preceding hurdles of safety, efficacy and quality have existed for several decades and have been harmonized within the European Union years ago. In the early 1990s, Australia and Canada pioneered the integration of cost-effectiveness into the regulation of drug reimbursement; by 2005, a survey identified 10 more European countries to consider this aspect in drug regulation.1 Adding France and Germany leads to at least a dozen European countries going this way today. The emphasis of the ‘fourth hurdle’ is on individual clinical care. ‘Concentrating on drugs and clinical procedures does not really have a great influence on population health’2 Holland criticized … Correspondence: Reiner Leidl, Institute for Health Economics and Health Care Management, Helmholtz Zentrum Munchen, German Research Center for Environmental Health (GmbH), Postfach 1129, D-85758 Neuherberg, Germany, e-mail: leidl{at}helmholtz-muenchen.de

The first international workshop on Systems Radiation Biology: a new approach to solve old questions

Ionizing radiation is ubiquitous and primordial; every living being has always been and will always be exposed to it from natural and man-made sources. Alpha and beta particles, gamma rays, neutrons and muons penetrate our body every second, and life has evolved under this environmental background condition. It is well known that acute irradiation with medium to high doses, i.e. far above the natural level, can cause negative physical health eVects in humans, animals and plants. At low doses of the order of the annual natural exposure, real, potential and perceived irradiations can deWnitely lead to observable mental and social health eVects. Thus, ionizing radiation is one of the few agents capable of aVecting all three aspects of human well-being considered by the World Health Organization. Whether or not small doses can also physically aVect human health is still an open scientiWc question. This has far-ranging consequences in the public attitude, e.g. towards facilities of the nuclear energy cycle and related political decisions. Finding new scientiWc approaches to tackle this old question has been the main aim of the First International Workshop on Systems Radiation Biology, which took place at the GSF-National Research Center for Environment and Health (its new name as of 1 January 2008 is Helmholtz Zentrum Munchen, German Research Center for Environmental Health) in Neuherberg near Munich, from 14 to 16 Febuary 2007. About 80 scientists from 13 countries exchanged and discussed their experience with the research strategy of Systems Biology in their various Welds. In the context of the workshop, “Systems Biology” (SB) is considered to study the various relevant processes and interactions between the components of a complex biological system, and how these give rise to the function, behaviour and reactions of that system after a disturbance. SB is characterized by cycles of (a) theory, (b) in silico modelling and (c) experiments, with the goal to quantitatively describe biological systems (e.g. cell, organs, etc.) and their behaviour. Useful SB experiments and models should in principle aim to provide (a) system-wide and (b) quantitative information that would allow construction and testing of explanatory and generalizing mathematical models to describe the behaviour of biological systems. Only with the help of such approved models, predictions can be made on the general or special behaviour of a living organism, including parameters, variables, etc. beyond the previous experimental evidence. However, presently there are several severe theoretical and experimental problems to identify and include—on a horizontal level—a suYcient number of subsystems (e.g. neighbouring cells) in a theoretical or experimental study. Additionally, it is also diYcult to identify and include them on a vertical level derived (a) from relevant molecules, (b) from their response and behaviour in cell compartments, (c) the fates of these cells, (d) the behaviour of a few cells in terms of the resulting consequences for the whole organ (remember, for example, that each single cell within the lung, which breathes to the beneWt of organismic oxygenation, does not breathe, as was pointed out by M.-H. Barcellos-HoV at the workshop), and (e) from the consequences which might Wnally determine the health status (e.g. free from cancer) of the whole organism. The biochemical and biophysical dynamic networks involved [1] are extremely complex and largely uncharacterized quantitatively. This is in part because of their natural H. G. Paretzke (&) Institute of Radiation Protection, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Ingolstadterstr.1, 85764, Neuherberg, Germany e-mail: paretzke@helmholtz-muenchen.de