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      Early imaging biomarkers of lung cancer, COPD and coronary artery disease in the general population: rationale and design of the ImaLife (Imaging in Lifelines) Study

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          Abstract

          Lung cancer, chronic obstructive pulmonary disease (COPD), and coronary artery disease (CAD) are expected to cause most deaths by 2050. State-of-the-art computed tomography (CT) allows early detection of lung cancer and simultaneous evaluation of imaging biomarkers for the early stages of COPD, based on pulmonary density and bronchial wall thickness, and of CAD, based on the coronary artery calcium score (CACS), at low radiation dose. To determine cut-off values for positive tests for elevated risk and presence of disease is one of the major tasks before considering implementation of CT screening in a general population. The ImaLife (Imaging in Lifelines) study, embedded in the Lifelines study, is designed to establish the reference values of the imaging biomarkers for the big three diseases in a well-defined general population aged 45 years and older. In total, 12,000 participants will undergo CACS and chest acquisitions with latest CT technology. The estimated percentage of individuals with lung nodules needing further workup is around 1–2%. Given the around 10% prevalence of COPD and CAD in the general population, the expected number of COPD and CAD is around 1000 each. So far, nearly 4000 participants have been included. The ImaLife study will allow differentiation between normal aging of the pulmonary and cardiovascular system and early stages of the big three diseases based on low-dose CT imaging. This information can be finally integrated into personalized precision health strategies in the general population.

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          Most cited references34

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          Annual or biennial CT screening versus observation in heavy smokers: 5-year results of the MILD trial.

          The efficacy and cost-effectiveness of low-dose spiral computed tomography (LDCT) screening in heavy smokers is currently under evaluation worldwide. Our screening program started with a pilot study on 1035 volunteers in Milan in 2000 and was followed up in 2005 by a randomized trial comparing annual or biennial LDCT with observation, named Multicentric Italian Lung Detection. This included 4099 participants, 1723 randomized to the control group, 1186 to biennial LDCT screening, and 1190 to annual LDCT screening. Follow-up was stopped in November 2011, with 9901 person-years for the pilot study and 17 621 person-years for Multicentric Italian Lung Detection. Forty-nine lung cancers were detected by LDCT (20 in biennial and 29 in the annual arm), of which 17 were identified at baseline examination; 63% were of stage I and 84% were surgically resectable. Stage distribution and resection rates were similar in the two LDCT arms. The cumulative 5-year lung cancer incidence rate was 311/100 000 in the control group, 457 in the biennial, and 620 in the annual LDCT group (P=0.036); lung cancer mortality rates were 109, 109, and 216/100 000 (P=0.21), and total mortality rates were 310, 363, and 558/100 000, respectively (P=0.13). Total mortality in the pilot study was similar to that observed in the annual LDCT arm at 5 years. There was no evidence of a protective effect of annual or biennial LDCT screening. Furthermore, a meta-analysis of the four published randomized trials showed similar overall mortality in the LDCT arms compared with the control arm.
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            The presence and progression of emphysema in COPD as determined by CT scanning and biomarker expression: a prospective analysis from the ECLIPSE study.

            Emphysema is a key contributor to airflow limitation in chronic obstructive pulmonary disease (COPD) and can be quantified using CT scanning. We investigated the change in CT lung density in a longitudinal, international cohort of patients with COPD. We also explored the potential relation between emphysema and patient characteristics, and investigated if certain circulating biomarkers were associated with decline in CT lung density. We used a random coefficient model to assess predictors of both CT lung density and its longitudinal change over 3 years in 1928 patients with COPD enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. Lung density was measured for every voxel in the CT scan and after correcting for lung volume was expressed as the density at lowest 15th percentile point of the distribution. This study is registered with ClinicalTrials.gov, number NCT00292552. Lung density at baseline was influenced by age, sex, body-mass index, current smoking status and smoking history, and severity of airflow limitation. The observed decline in lung density was variable (mean decline -1·13 g/L [SE 0·06] per year). The annual decline in lung density was more rapid in women (additional -0·41 [SE 0·14] g/L per year, p=0·003) than men and in current smokers (additional -0·29 [SE 0·14] g/L per year, p=0·047) than in former smokers. Circulating levels of the biomarkers surfactant protein D (SP-D) and soluble receptor for advanced glycation endproduct (sRAGE) were significantly associated with both baseline lung density and its decline over time. This study shows that decline in lung density in COPD can be measured, that it is variable, and related to smoking and gender. We identified potential biochemical predictors of the presence and progression of emphysema. GlaxoSmithKline. Copyright © 2013 Elsevier Ltd. All rights reserved.
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              Evaluation of newer risk markers for coronary heart disease risk classification: a cohort study.

              Whether newer risk markers for coronary heart disease (CHD) improve CHD risk prediction remains unclear. To assess whether newer risk markers for CHD risk prediction and stratification improve Framingham risk score (FRS) predictions. Prospective population-based study. The Rotterdam Study, Rotterdam, the Netherlands. 5933 asymptomatic, community-dwelling participants (mean age, 69.1 years [SD, 8.5]). Traditional CHD risk factors used in the FRS (age, sex, systolic blood pressure, treatment of hypertension, total and high-density lipoprotein cholesterol levels, smoking, and diabetes) and newer CHD risk factors (N-terminal fragment of prohormone B-type natriuretic peptide levels, von Willebrand factor antigen levels, fibrinogen levels, chronic kidney disease, leukocyte count, C-reactive protein levels, homocysteine levels, uric acid levels, coronary artery calcium [CAC] scores, carotid intima-media thickness, peripheral arterial disease, and pulse wave velocity). Adding CAC scores to the FRS improved the accuracy of risk predictions (c-statistic increase, 0.05 [95% CI, 0.02 to 0.06]; net reclassification index, 19.3% overall [39.3% in those at intermediate risk, by FRS]). Levels of N-terminal fragment of prohormone B-type natriuretic peptide also improved risk predictions but to a lesser extent (c-statistic increase, 0.02 [CI, 0.01 to 0.04]; net reclassification index, 7.6% overall [33.0% in those at intermediate risk, by FRS]). Improvements in predictions with other newer markers were marginal. The findings may not be generalizable to younger or nonwhite populations. Among 12 CHD risk markers, improvements in FRS predictions were most statistically and clinically significant with the addition of CAC scores. Further investigation is needed to assess whether risk refinements using CAC scores lead to a meaningful change in clinical outcome. Whether to use CAC score screening as a more routine test for risk prediction requires full consideration of the financial and clinical costs of performing versus not performing the test for both persons and health systems. Netherlands Organization for Health Research and Development (ZonMw).
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                Author and article information

                Contributors
                c.xia@umcg.nl
                m.rook@umcg.nl
                g.j.pelgrim@umcg.nl
                g.sidorenkov@umcg.nl
                h.j.wisselink@umcg.nl
                j.n.van.bolhuis@lifelines.nl
                p.m.a.van.ooijen@umcg.nl
                j.guo@umcg.nl
                m.oudkerk@rug.nl
                h.j.m.groen@umcg.nl
                m.van.den.berge@umcg.nl
                p.van.der.harst@umcg.nl
                h.dijkstra01@umcg.nl
                m.vonder@umcg.nl
                m.a.heuvelmans@umcg.nl
                m.d.dorrius@umcg.nl
                p.p.de.deyn@umcg.nl
                g.h.de.bock@umcg.nl
                a.dotinga@lifelines.nl
                r.vliegenthart@umcg.nl
                Journal
                Eur J Epidemiol
                Eur. J. Epidemiol
                European Journal of Epidemiology
                Springer Netherlands (Dordrecht )
                0393-2990
                1573-7284
                23 April 2019
                23 April 2019
                2020
                : 35
                : 1
                : 75-86
                Affiliations
                [1 ]GRID grid.4494.d, ISNI 0000 0000 9558 4598, Department of Radiology, , University of Groningen, University Medical Center Groningen, ; Hanzeplein 1, 9713 GZ Groningen, The Netherlands
                [2 ]GRID grid.416468.9, ISNI 0000 0004 0631 9063, Martini Hospital Groningen, ; Groningen, The Netherlands
                [3 ]GRID grid.4494.d, ISNI 0000 0000 9558 4598, Department of Epidemiology, , University of Groningen, University Medical Center Groningen, ; Groningen, The Netherlands
                [4 ]Lifelines Cohort Study, Groningen, The Netherlands
                [5 ]GRID grid.4494.d, ISNI 0000 0000 9558 4598, Department of Radiation Therapy, , University of Groningen, University Medical Center Groningen, ; Groningen, The Netherlands
                [6 ]iDNA B.V, Groningen, The Netherlands
                [7 ]GRID grid.4830.f, ISNI 0000 0004 0407 1981, University of Groningen, ; Groningen, The Netherlands
                [8 ]GRID grid.4494.d, ISNI 0000 0000 9558 4598, Department of Pulmonary Diseases, , University of Groningen, University Medical Center Groningen, ; Groningen, The Netherlands
                [9 ]GRID grid.4494.d, ISNI 0000 0000 9558 4598, Department of Cardiology, , University of Groningen, University Medical Center Groningen, ; Groningen, The Netherlands
                [10 ]GRID grid.4494.d, ISNI 0000 0000 9558 4598, Department of Neurology, , University of Groningen, University Medical Center Groningen, Alzheimer Research Center, ; Groningen, The Netherlands
                Author information
                http://orcid.org/0000-0002-7262-3376
                Article
                519
                10.1007/s10654-019-00519-0
                7058676
                31016436
                3175320f-629a-449b-a0f8-124ba9c348e6
                © The Author(s) 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 16 October 2018
                : 10 April 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100011699, Siemens Healthineers;
                Categories
                New Study
                Custom metadata
                © Springer Nature B.V. 2020

                Public health
                cardiovascular disease,chronic obstructive pulmonary disease,general population,imaging biomarkers,low-dose computed tomography,lung cancer

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