http://repub.eur.nl/res/aut/6252/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/39467/ 2013-03-19T00:00:00Z Objective: To retrospectively investigate whether optimisation of volume-doubling time (VDT) cutoff for fast-growing nodules in lung cancer screening can reduce false-positive referrals. Methods: Screening participants of the NELSON study underwent low-dose CT. For indeterminate nodules (volume 50-500 mm3), follow-up CT was performed 3 months after baseline. A negative baseline screen resulted in a regular second-round examination 1 year later. Subjects referred to a pulmonologist because of a fast-growing (VDT <400 days) solid nodule in the baseline or regular second round were included in this study. Histology was the reference for diagnosis, or stability on subsequent CTs, confirming benignity. Mean follow-up of non-resected nodules was 4.4 years. Optimisation of the false-positive rate was evaluated at maintained sensitivity for lung cancer diagnosis with VDT <400 days as reference. Results: Sixty-eight fast-growing nodules were included; 40 % were malignant. The optimal VDT cutoff for the 3-month follow-up CT after baseline was 232 days. This cutoff reduced false-positive referrals by 33 % (20 versus 30). For the regular second round, VDTs varied more among malignant nodules, precluding lowering of the VDT cutoff of 400 days. Conclusion: All malignant fast-growing lung nodules referred after the 3-month follow-up CT in the baseline lung cancer screening round had VDT ≤232 days. Lowering the VDT cutoff may reduce false-positive referrals. Key Points: • Lung nodules are common in CT lung cancer screening, most being benign • Short-term follow-up CT can identify fast-growing intermediate-size lung nodules • Most fast-growing nodules on short-term follow-up CT still prove to be benign • A new volume-doubling time (VDT) cut-off is proposed for lung screening • The optimised VDT cutoff may decrease false-positive case referrals for lung cancer http://repub.eur.nl/res/pub/33254/ 2011-10-26T00:00:00Z Context: Smoking is a major risk factor for both cancer and chronic obstructive pulmonary disease (COPD). Computed tomography (CT)-based lung cancer screening may provide an opportunity to detect additional individuals with COPD at an early stage. Objective: To determine whether low-dose lung cancer screening CT scans can be used to identify participants with COPD. Design, Setting, and Patients: Single-center prospective cross-sectional study within an ongoing lung cancer screening trial. Prebronchodilator pulmonary function testing with inspiratory and expiratory CT on the same day was obtained from 1140 male participants between July 2007 and September 2008. Computed tomographic emphysema was defined as percentage of voxels less than -950 Hounsfield units (HU), and CT air trapping was defined as the expiratory:inspiratory ratio of mean lung density. Chronic obstructive pulmonary disease was defined as the ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC) of less than 70%. Logistic regression was used to develop a diagnostic prediction model for airflow limitation. Main Outcome Measures: Diagnostic accuracy of COPD diagnosis using pulmonary function tests as the reference standard. Results: Four hundred thirty-seven participants (38%) had COPD according to lung function testing. A diagnostic model with CT emphysema, CT air trapping, body mass index, pack-years, and smoking status corrected for overoptimism (internal validation) yielded an area under the receiver operating characteristic curve of 0.83 (95% CI, 0.81-0.86). Using the point of optimal accuracy, the model identified 274 participants with COPD with 85 false-positives, a sensitivity of 63% (95% CI, 58%-67%), specificity of 88% (95% CI, 85%-90%), positive predictive value of 76% (95% CI, 72%-81%); and negative predictive value of 79% (95% CI, 76%-82%). The diagnostic model showed an area under the receiver operating characteristic curve of 0.87 (95% CI, 0.86-0.88) for participants with symptoms and 0.78 (95% CI, 0.76-0.80) for those without symptoms. Conclusion: Among men who are current and former heavy smokers, low-dose inspiratory and expiratory CT scans obtained for lung cancer screening can identify participants with COPD, with a sensitivity of 63% and a specificity of 88%. http://repub.eur.nl/res/pub/31539/ 2011-02-09T00:00:00Z Background: Coronary artery calcification (CAC) has been proposed to be the underlying mechanism of the increased risk of coronary heart disease with reductions in glomerular filtration rate (GFR). Since renal function diminishes with aging we examined the association between GFR and CAC in the Rotterdam Study, a population-based study of elderly individuals. Methods: The study was performed in 1703 subjects without a history of coronary heart disease. GFR was estimated using the modification of diet in renal disease equation. We used analysis of covariance to test for mean differences in CAC between GFR tertiles. Results: The mean CAC scores in the middle and lowest GFR tertile did not significantly differ from the mean CAC score in the highest GFR tertile (geometric mean CAC score 4.1 and 4.3 vs 4.2). In a multivariable model the mean CAC score did also not differ between the GFR tertiles. As the interaction term between age and GFR was significant (P = 0.037), we divided the population in two age categories based on median age of 70 years. Below 70 years, the mean CAC scores did not differ between the GFR tertiles. Above median age, mean CAC score in the lowest GFR tertile was significantly higher than the mean CAC score in the highest tertile in a multivariable model (CAC 4.9 vs 4.5, p = 0.010). Conclusion: In this population-based study we observed that the association between CAC and GFR is modified by age. In participants at least 70 years of age, a decrease in GFR was associated with increased CAC. http://repub.eur.nl/res/pub/25463/ 2009-01-01T00:00:00Z Purpose: To retrospectively determine whether baseline nodule characteristics at 3-month and 1-year volume doubling time (VDT) are predictive for lung cancer in solid indeterminate noncalcified nodules (NCNs) detected at baseline computed tomographic (CT) screening. Materials and Methods: The study, conducted between April 2004 and May 2006, was institutional review board approved. Patient consent was waived for this retrospective evaluation. NCNs between 5 and 10 mm in diameter (n = 891) were evaluated at 3 months and 1 year to assess growth (VDT < 400 days). Baseline assessments were related to growth at 3 months and 1 year by using x2and Mann-Whitney U tests. Baseline assessments and growth were related to the presence of malignancy by using univariate and multivariate logistic regression analyses. Results: At 3 months and at 1 year, 8% and 1% of NCNs had grown, of which 15% and 50% were malignant, respectively. One-year growth was related to morphology (P < .01), margin (P < .0001), location (P < .001), and size (P < .01). All cancers were nonspherical and purely intra-parenchymal, without attachment to vessels, the pleura, or fissures. In nonsmooth unattached nodules, a volume of 130 mm3or larger was the only predictor for malignancy (odds ratio, 6.3; 95% confidence interval [CI]: 1.7, 23.0). After the addition of information on the 3-month VDT, large volume (odds ratio, 4.9; 95% CI: 1.2, 20.1) and 3-month VDT (odds ratio, 15.6; 95% CI: 4.5, 53.5) helped predict malignancy. At 1 year, only the 1-year growth remained (odds ratio, 213.3; 95% CI: 18.7, 2430.9) as predictor for malignancy. Conclusion: In smooth or attached solid indeterminate NCNs, no malignancies were found at 1-year follow-up. In nonsmooth purely intraparenchymal NCNs, size is the main baseline predictor for malignancy. When follow-up data are available, growth is a strong predictor for malignancy, especially at 1-year follow-up. http://repub.eur.nl/res/pub/29797/ 2008-11-01T00:00:00Z Purpose: To evaluate prospectively the value of size, shape, margin and density in discriminating between benign and malignant CT screen detected solid non-calcified pulmonary nodules. Material and methods: This study was institutional review board approved. For this study 405 participants of the NELSON lung cancer screening trial with 469 indeterminate or potentially malignant solid pulmonary nodules (>50 mm3) were selected. The nodules were classified based on size, shape (round, polygonal, irregular) and margin (smooth, lobulated, spiculated). Mean nodule density and nodule volume were automatically generated by software. Analyses were performed by univariate and multivariate logistic regression. Results were presented as likelihood ratios (LR) with 95% confidence intervals (CI). Receiver operating characteristic analysis was performed for mean density as predictor for lung cancer. Results: Of the 469 nodules, 387 (83%) were between 50 and 500 mm3, 82 (17%) >500 mm3, 59 (13%) malignant, 410 (87%) benign. The median size of the nodules was 103 mm3(range 50-5486 mm3). In multivariate analysis lobulated nodules had LR of 11 compared to smooth; spiculated nodules a LR of 7 compared to smooth; irregular nodules a LR of 6 compared to round and polygonal; volume a LR of 3. The mean nodule CT density did not predict the presence of lung cancer (AUC 0.37, 95% CI 0.32-0.43). Conclusion: In solid non-calcified nodules larger than 50 mm3, size and to a lesser extent a lobulated or spiculated margin and irregular shape increased the likelihood that a nodule was malignant. Nodule density had no discriminative power. http://repub.eur.nl/res/pub/30097/ 2008-05-01T00:00:00Z BACKGROUND - The role of coffee in the cardiovascular system is not yet clear. We examined the relation of coffee intake with coronary calcification in a population-based cohort. METHODS AND RESULTS - The study involved 1570 older men and women without coronary heart disease who participated in the Rotterdam Study. Coffee intake was assessed with a semiquantitative food frequency questionnaire. Coronary calcification was detected with electron beam computed tomography. Severe calcification was defined as an Agatson calcium score >400. Sex-specific odds ratios (ORs) with 95% confidence intervals (95% CI) were obtained by logistic regression with adjustment for age, smoking, body mass index, education, and intake of energy and alcohol. In multivariable analysis, coronary calcification in women was significantly reduced for moderate (>3 to 4 cups) and high (>4 cups) coffee intake, compared with a daily intake of 3 cups or less (OR of 0.41 [95% CI: 0.25 to 0.65] and 0.54 [0.33 to 0.87], respectively). The association persisted after additional adjustment for tea and other dietary confounders, and was not modified by smoking. A nonsignificant inverse relationship was also found in men who smoked, whereas in nonsmoking men a direct association was observed. CONCLUSION - The present study suggests a beneficial effect of coffee drinking against coronary calcification, particularly in women. More research is needed to confirm these findings and to clarify possible effect modification by gender and smoking. http://repub.eur.nl/res/pub/36890/ 2007-07-13T00:00:00Z Background: Asymptomatic subjects at intermediate coronary risk may need diagnostic testing for risk stratification. Both measurement of coronary calcium scores and exercise testing are well established tests for this purpose. However, it is not clear which test should be preferred as initial diagnostic test. We evaluated the prevalence of documented coronary artery disease (CAD) according to calcium scores and exercise test results. Methods: Asymptomatic subjects with ST-T changes on a rest ECG were selected from the population based PREVEND cohort study and underwent measurement of calcium scores by electron beam tomography and exercise testing. With calcium scores ≥10 or a positive exercise test, myocardial perfusion imaging (MPS) or coronary angiography (CAG) was recommended. The primary endpoint was documented obstructive CAD (≥50% stenosis). Results: Of 153 subjects included, 149 subjects completed the study protocol. Calcium scores ≥400, 100-399, 10-99 and <10 were found in 16, 29, 18 and 86 subjects and the primary endpoint was present in 11 (69%), 12 (41%), 0 (0%) and 1 (1%) subjects, respectively. A positive, nondiagnostic and negative exercise test was present in 33, 27 and 89 subjects and the primary endpoint was present in 13 (39%), 5 (19%) and 6 (7%) subjects, respectively. Receiver operator characteristics analysis showed that the area under the curve, as measure of diagnostic yield, of 0.91 (95% CI 0.84-0.97) for calcium scores was superior to 0.74 (95% CI 0.64-0.83) for exercise testing (p = 0.004). Conclusion: Measurement of coronary calcium scores is an appropriate initial non-invasive test in asymptomatic subjects at increased coronary risk. http://repub.eur.nl/res/pub/35347/ 2007-07-01T00:00:00Z The female advantage in coronary heart disease occurrence is not completely understood. To characterize gender differences in cardiovascular disease by vascular site, the authors compared degrees of coronary, carotid, peripheral, and aortic atherosclerosis in men and women aged ≥55 years from the population-based Rotterdam Study (Rotterdam, the Netherlands). Data were collected between 1997 and 2000. A subset of 2,013 participants had data on both coronary calcification and one or more measures of extracoronary atherosclerosis, including intima-media thickness (IMT), carotid plaques, ankle-arm index (AAI), and aortic calcification. The multivariable-adjusted male:female odds ratios for calcium score > 1,000 were 7.8 (95% confidence interval (CI): 3.2, 19.3), 5.4 (95% CI: 2.8, 10.2), and 3.0 (95% CI: 1.7, 5.2) in the lowest, middle, and highest age tertiles, respectively. For IMT > 1.0 mm, severe carotid plaques, AAI < 0.90, and severe aortic calcification, ratios did not decline with age. Overall multivariable-adjusted male:female odds ratios for these measures were 2.9 (95% CI: 2.0, 4.1), 2.0 (95% CI: 1.4, 2.8), 0.9 (95% CI: 0.7, 1.3), and 1.0 (95% CI: 0.8, 1.5), respectively. The authors conclude that the gender difference in atherosclerosis is larger in the coronary vessels than in other vascular beds. Remarkably, it is absent in the aorta and the lower-extremity vessels. Factors causing this site-specific gender difference require further investigation. http://repub.eur.nl/res/pub/13867/ 2005-07-26T00:00:00Z BACKGROUND: Coronary calcification detected by electron beam tomography may improve cardiovascular risk prediction. The technique is particularly promising in the elderly because the predictive power of cardiovascular risk factors weakens with age. We investigated the prognostic value of coronary calcification for cardiovascular events and mortality in a general, asymptomatic population of elderly subjects. METHODS AND RESULTS: From 1997 to 2000, electron beam tomography scanning to assess coronary calcification was performed in subjects of the population-based Rotterdam Study. Risk factors were measured by standardized procedures. Coronary calcium scores were available for 1795 asymptomatic participants (mean age, 71 years; range, 62 to 85 years). During a mean follow-up of 3.3 years, 88 cardiovascular events, including 50 coronary events, occurred. The risk of coronary heart disease increased with increasing calcium score. The multivariate-adjusted relative risk of coronary events was 3.1 (95% CI, 1.2 to 7.9) for calcium scores of 101 to 400, 4.6 (95% CI, 1.8 to 11.8) for calcium scores of 401 to 1000, and 8.3 (95% CI, 3.3 to 21.1) for calcium scores >1000 compared with calcium scores of 0 to 100. The predictive value in subjects >70 years of age was similar. Risk prediction based on the cardiovascular risk factors improved when coronary calcification was added. CONCLUSIONS: Coronary calcification is a strong and independent predictor of coronary heart disease, also in the elderly. Coronary calcification improves prediction of coronary events based on cardiovascular risk factors. Risk stratification by assessment of coronary calcification may have an important role in the primary prevention of coronary heart disease events in the elderly. http://repub.eur.nl/res/pub/10277/ 2004-01-01T00:00:00Z AIMS: We examined associations between cardiovascular risk factors and coronary calcification assessed by electron-beam tomography (EBT) in an unselected population of older subjects. METHODS AND RESULTS: The Rotterdam Coronary Calcification Study is a population-based study in subjects > =55 years. Participants underwent EBT scanning. Coronary calcification was quantified according to the Agatston score. Cardiovascular risk factors were assessed 7 years before and concurrently to scanning. We used the first 2013 participants for the present analyses. Risk factors assessed 7 years before scanning were strongly associated with calcium score. Associations with blood pressure and cholesterol attenuated when measured concurrently to scanning. Although the number of risk factors was strongly associated with a high calcium score in asymptomatic subjects, 29% of the men and 15% of the women without risk factors had a high calcium score. CONCLUSIONS: This population-based study in older subjects shows that cardiovascular risk factors are associated with coronary calcification. Associations were stronger for risk factors measured at earlier age. Almost 30% of the men and 15% of the women without risk factors had extensive coronary calcification. http://repub.eur.nl/res/pub/38003/ 2003-03-19T00:00:00Z Already in the eighteenth century, calcification of the coronary artery wall was recognized as being part of the atherosclerotic process.1 However, only after the recent development of electron-beam tomography (EBT), an ultrafast CT technique, it became possible to accurately quantify the amount of coronary calcification noninvasively. Quantitative measures of coronary calcification, detected by EBT, have been found to be closely related to the amount of atherosclerotic plaque in histopathologic investigations.2,3 Furthermore, the calcium score derived from EBT is strongly associated with the extent of angiographically detected coronary artery disease.4,5 Therefore, quantification of coronary calcification using EBT has been proposed as a promising method for noninvasive detection of asymptomatic subjects at high risk of developing coronary heart disease. Studies showing that coronary calcification increases the risk of coronary events have been performed in selected, high-risk populations with small numbers of events.6-10 There are currently no population-based data on the predictive value of coronary calcification. The focus of this thesis is to investigate whether coronary calcification predicts cardiovascular disease in the general population. For this purpose, an epidemiologic study was carried out in the population-based Rotterdam Coronary Calcification Study. The Rotterdam Coronary Calcification Study consists of participants from the Rotterdam Study who underwent EBT scanning of the heart. On the scans, the amount of coronary calcification was computed. Scandata were available for 2013 older adults. In chapter 2, the current knowledge on the pathogenesis, detection and epidemiology of coronary calcification is reviewed. Chapter 3 contains studies on the validation of the scanning and scoring technique. In chapter 4, associations between cardiovascular risk factors and coronary calcification and peripheral atherosclerosis are described. Chapter 5 focuses on the association between coronary calcification and cardiovascular disease. In chapter 6, the main results of the studies described in this thesis are placed in perspective and methodological issues discussed. In addition, this chapter comments on the relevance of the findings and provides suggestions for future research on the topic. http://repub.eur.nl/res/pub/9831/ 2002-01-01T00:00:00Z BACKGROUND AND PURPOSE: Coronary calcification as detected by electron-beam CT measures the atherosclerotic plaque burden and has been reported to predict coronary events. Because atherosclerosis is a generalized process, coronary calcification may also be associated with manifest atherosclerotic disease at other sites of the vascular tree. We examined whether coronary calcification as detected by electron-beam CT is related to the presence of stroke. METHODS: From 1997 onward, subjects were invited to participate in the prospective Rotterdam Coronary Calcification Study and undergo electron-beam CT to detect coronary calcification. The study was embedded in the population-based Rotterdam Study. Calcifications were quantified in a calcium score according to Agatston's method. Calcium scores were available for 2013 subjects (mean age [SD], 71 [5.7] years). Fifty subjects had experienced stroke before scanning. RESULTS: Subjects were 2 times more likely to have experienced stroke when their calcium score was between 101 and 500 (odds ratio [OR], 2.1; 95% CI, 0.9 to 4.7) and 3 times more likely when their calcium score was above 500 (OR, 3.3; 95% CI, 1.5 to 7.2), compared with subjects in the lowest calcium score category (0 to 100). Additional adjustment for cardiovascular risk factors did not materially alter the risk estimates. CONCLUSIONS: In this population-based study, a markedly graded association was found between coronary calcification and stroke. The results suggest that coronary calcification as detected by electron-beam CT may be useful to identify subjects at high risk of stroke. http://repub.eur.nl/res/pub/9842/ 2002-01-01T00:00:00Z Moderate alcohol consumption is associated with a reduced risk of cardiovascular disease. Data on alcohol consumption and atherosclerosis are scarce. To determine the association between alcohol consumption and risk of peripheral arterial disease, the authors carried out a cross-sectional study (1990-1993) in the population-based Rotterdam Study among men and women aged 55 years or over. Data on alcohol consumption and peripheral arterial disease, as measured by the ankle/brachial blood pressure index, were available for 3,975 participants without symptomatic cardiovascular disease. Male drinkers consumed beer, wine, and liquor, while female drinkers consumed predominantly wine and fortified wine types. An inverse relation between moderate alcohol consumption and peripheral arterial disease was found in women but not in men. Because of residual confounding by smoking, analyses were repeated in nonsmokers. In nonsmoking men, odds ratios were 0.86 (95% confidence interval (CI): 0.46, 1.63) for daily alcohol consumption up to and including 10 g, 0.75 (95% CI: 0.37, 1.55) for 11-20 g, and 0.68 (95% CI: 0.35, 1.34) for more than 20 g, compared with nondrinking. In nonsmoking women, corresponding odds ratios were 0.65 (95% CI: 0.48, 0.87), 0.66 (95% CI: 0.42, 1.05), and 0.41 (95% CI: 0.21, 0.77), respectively. In conclusion, an inverse association between alcohol consumption and peripheral arterial disease was found in nonsmoking men and women. http://repub.eur.nl/res/pub/9980/ 2002-01-01T00:00:00Z AIMS: Available data are insufficient to determine the relation between coronary calcification and coronary events in the general population. We cross-sectionally examined the association between coronary calcification and myocardial infarction in the prospective Rotterdam Coronary Calcification Study. METHODS AND RESULTS: From 1997 onwards, subjects were invited for electron-beam computed tomography scanning to detect coronary calcification. The study was embedded in the population-based Rotterdam Study. Calcifications were quantified in a calcium score according to Agatston's method. Calcium scores were available for 2,013 participants with a mean age of 71 years (standard deviation, 5.7 years). A history of myocardial infarction prior to scanning was present in 229 subjects. Compared to subjects in the lowest calcium score category (0-100), the age-adjusted odds ratio for myocardial infarction in subjects in the highest calcium score category (above 2,000) was 7.7 (95% confidence interval, 4.1-14.5) for men, and 6.7 (95% confidence interval, 2.4-19.1) for women. Additional adjustment for cardiovascular risk factors only slightly altered the estimates. The association was observed across all age subgroups, i.e. also in subjects of 70 years and older. CONCLUSION: A strong and graded association was found between coronary calcification and myocardial infarction. The association remained at high ages.