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1.  Automated Coronary Artery Calcification Scoring in Non-Gated Chest CT: Agreement and Reliability 
PLoS ONE  2014;9(3):e91239.
To determine the agreement and reliability of fully automated coronary artery calcium (CAC) scoring in a lung cancer screening population.
Materials and Methods
1793 low-dose chest CT scans were analyzed (non-contrast-enhanced, non-gated). To establish the reference standard for CAC, first automated calcium scoring was performed using a preliminary version of a method employing coronary calcium atlas and machine learning approach. Thereafter, each scan was inspected by one of four trained raters. When needed, the raters corrected initially automaticity-identified results. In addition, an independent observer subsequently inspected manually corrected results and discarded scans with gross segmentation errors. Subsequently, fully automatic coronary calcium scoring was performed. Agatston score, CAC volume and number of calcifications were computed. Agreement was determined by calculating proportion of agreement and examining Bland-Altman plots. Reliability was determined by calculating linearly weighted kappa (κ) for Agatston strata and intraclass correlation coefficient (ICC) for continuous values.
44 (2.5%) scans were excluded due to metal artifacts or gross segmentation errors. In the remaining 1749 scans, median Agatston score was 39.6 (P25–P75∶0–345.9), median volume score was 60.4 mm3 (P25–P75∶0–361.4) and median number of calcifications was 2 (P25–P75∶0–4) for the automated scores. The κ demonstrated very good reliability (0.85) for Agatston risk categories between the automated and reference scores. The Bland-Altman plots showed underestimation of calcium score values by automated quantification. Median difference was 2.5 (p25–p75∶0.0–53.2) for Agatston score, 7.6 (p25–p75∶0.0–94.4) for CAC volume and 1 (p25–p75∶0–5) for number of calcifications. The ICC was very good for Agatston score (0.90), very good for calcium volume (0.88) and good for number of calcifications (0.64).
Fully automated coronary calcium scoring in a lung cancer screening setting is feasible with acceptable reliability and agreement despite an underestimation of the amount of calcium when compared to reference scores.
PMCID: PMC3953377  PMID: 24625525
2.  Semi-Automatic Quantification of Subsolid Pulmonary Nodules: Comparison with Manual Measurements 
PLoS ONE  2013;8(11):e80249.
Accurate measurement of subsolid pulmonary nodules (SSN) is becoming increasingly important in the management of these nodules. SSNs were previously quantified with time-consuming manual measurements. The aim of the present study is to test the feasibility of semi-automatic SSNs measurements and to compare the results to the manual measurements.
In 33 lung cancer screening participants with 33 SSNs, the nodules were previously quantified by two observers manually. In the present study two observers quantified these nodules by using semi-automated nodule volumetry software. Nodules were quantified for effective diameter, volume and mass. The manual and semi-automatic measurements were compared using Bland-Altman plots and paired T tests. Observer agreement was calculated as an intraclass correlation coefficient. Data are presented as mean (SD).
Semi-automated measurements were feasible in all 33 nodules. Nodule diameter, volume and mass were 11.2 (3.3) mm, 935 (691) ml and 379 (311) milligrams for observer 1 and 11.1 (3.7) mm, 986 (797) ml and 399 (344) milligrams for observer 2, respectively. Agreement between observers and within observer 1 for the semi-automatic measurements was good with an intraclass correlation coefficient >0.89. For observer 1 and observer 2, measured diameter was 8.8% and 10.3% larger (p<0.001), measured volume was 24.3% and 26.5% larger (p<0.001) and measured mass was 10.6% and 12.0% larger (p<0.001) with the semi-automatic program compared to the manual measurements.
Semi-automated measurement of the diameter, volume and mass of SSNs is feasible with good observer agreement. Semi-automated measurement makes quantification of mass and volume feasible in daily practice.
PMCID: PMC3837004  PMID: 24278264
3.  Impact of Cardiovascular Calcifications on the Detrimental Effect of Continued Smoking on Cardiovascular Risk in Male Lung Cancer Screening Participants 
PLoS ONE  2013;8(6):e66484.
Current smokers have an increased cardiovascular disease (CVD) risk compared to ex-smokers due to reversible as well as irreversible effects of smoking. We investigated if current smokers remain to have an increased CVD risk compared to ex-smokers in subjects with a long and intense smoking history. We in addition studied if the effect of smoking continuation on CVD risk is independent of or modified by the presence of cardiovascular calcifications.
The cohort used comprised a sample of 3559 male lung cancer screening trial participants. We conducted a case-cohort study using all CVD cases and a random sample of 10% (n = 341) from the baseline cohort (subcohort). A weighted Cox proportional hazards model was used to estimate the hazard ratios for current smoking status in relation to CVD events.
During a median follow-up of 2.6 years (max. 3.7 years), 263 fatal and non-fatal cardiovascular events (cases) were identified. Age, packyears and cardiovascular calcification adjusted hazard ratio of current smokers compared to former smokers was 1.33 (95% confidence interval 1.00–1.77). In additional analyses that incorporated multiplicative interaction terms, neither coronary nor aortic calcifications modified the association between smoking status and cardiovascular risk (P = 0.08).
Current smokers have an increased CVD risk compared to former smokers even in subjects with a long and intense smoking history. Smoking exerts its hazardous effects on CVD risk by pathways partly independent of cardiovascular calcifications.
PMCID: PMC3688769  PMID: 23840486
4.  Collaborative modeling of the impact of obesity on race-specific breast cancer incidence and mortality 
Obesity affects multiple points along the breast cancer control continuum from prevention to screening and treatment, often in opposing directions. Obesity is also more prevalent in Blacks than Whites at most ages so it might contribute to observed racial disparities in mortality. We use two established simulation models from the Cancer Intervention and Surveillance Modeling Network (CISNET) to evaluate the impact of obesity on race-specific breast cancer outcomes. The models use common national data to inform parameters for the multiple US birth cohorts of Black and White women, including age- and race-specific incidence, competing mortality, mammography characteristics, and treatment effectiveness. Parameters are modified by obesity (BMI of ≥30 kg/m2) in conjunction with its age-, race-, cohort- and time-period-specific prevalence. We measure age-standardized breast cancer incidence and mortality and cases and deaths attributable to obesity. Obesity is more prevalent among Blacks than Whites until age 74; after age 74 it is more prevalent in Whites. The models estimate that the fraction of the US breast cancer cases attributable to obesity is 3.9–4.5 % (range across models) for Whites and 2.5–3.6 % for Blacks. Given the protective effects of obesity on risk among women <50 years, elimination of obesity in this age group could increase cases for both the races, but decrease cases for women ≥50 years. Overall, obesity accounts for 4.4–9.2 % and 3.1–8.4 % of the total number of breast cancer deaths in Whites and Blacks, respectively, across models. However, variations in obesity prevalence have no net effect on race disparities in breast cancer mortality because of the opposing effects of age on risk and patterns of age- and race-specific prevalence. Despite its modest impact on breast cancer control and race disparities, obesity remains one of the few known modifiable risks for cancer and other diseases, underlining its relevance as a public health target.
PMCID: PMC3511695  PMID: 23104221
Simulation modeling; Breast cancer; Disparities; Obesity
5.  Facilitators and barriers to screening for child abuse in the emergency department 
BMC Pediatrics  2012;12:167.
To identify facilitators of, and barriers to, screening for child abuse in emergency departments (ED) through interviews with ED staff, members of the hospital Board, and related experts.
This qualitative study is based on semi-structured interviews with 27 professionals from seven Dutch hospitals (i.e. seven pediatricians, two surgeons, six ED nurses, six ED managers and six hospital Board members). The resulting list of facilitators/barriers was subsequently discussed with five experts in child abuse and one implementation expert. The results are ordered using the Child Abuse Framework of the Dutch Health Care Inspectorate that legally requires screening for child abuse.
Lack of knowledge of child abuse, communication with parents in the case of suspected abuse, and lack of time for development of policy and cases are barriers for ED staff to screen for child abuse. For Board members, lack of means and time, and a high turnover of ED staff are impediments to improving their child abuse policy. Screening can be promoted by training ED staff to better recognize child abuse, improving communication skills, appointing an attendant specifically for child abuse, explicit support of the screening policy by management, and by national implementation of an approved protocol and validated screening instrument.
ED staff are motivated to work according to the Dutch Health Care Inspectorate requirements but experiences many barriers, particularly communication with parents of children suspected of being abused. Introduction of a national child abuse protocol can improve screening on child abuse at EDs.
PMCID: PMC3502173  PMID: 23092228
Child abuse; Emergency department; Screening; Qualitative study
6.  Modeling the impact of population screening on breast cancer mortality in the United States‡ 
Breast (Edinburgh, Scotland)  2011;20(Suppl 3):S75-S81.
Optimal US screening strategies remain controversial. We use six simulation models to evaluate screening outcomes under varying strategies.
The models incorporate common data on incidence, mammography characteristics, and treatment effects. We evaluate varying initiation and cessation ages applied annually or biennially and calculate mammograms, mortality reduction (vs. no screening), false-positives, unnecessary biopsies and over-diagnosis.
The lifetime risk of breast cancer death starting at age 40 is 3% and is reduced by screening. Screening biennially maintains 81% (range 67% to 99%) of annual screening benefits with fewer false-positives. Biennial screening from 50–74 reduces the probability of breast cancer death from 3% to 2.3%. Screening annually from 40 to 84 only lowers mortality an additional one-half of one percent to 1.8% but requires substantially more mammograms and yields more false-positives and over-diagnosed cases.
Decisions about screening strategy depend on preferences for benefits vs. potential harms and resource considerations.
PMCID: PMC3457919  PMID: 22015298
Mammography; Screening; Modeling
7.  Pregnancy and liver adenoma management: PALM-study 
BMC Gastroenterology  2012;12:82.
Hepatocellular adenoma (HCA) in pregnant women requires special considerations because of the risk of hormone induced growth and spontaneous rupture, which may threaten the life of both mother and child. Due to scarcity of cases there is no evidence-based algorithm for the evaluation and management of HCA during pregnancy. Most experts advocate that women with HCA should not get pregnant or advise surgical resection before pregnancy. Whether it is justified to deny a young woman a pregnancy, as the biological behavior may be less threatening than presumed depends on the incidence of HCA growth and the subsequent clinical events during pregnancy.
We aim to investigate the management and outcome of HCA during pregnancy and labor based on a prospectively acquired online database in the Netherlands.
The Pregnancy And Liver adenoma Management (PALM) - study is a multicentre prospective study in three cohorts of pregnant patients. In total 50 pregnant patients, ≥ 18 years of age with a radiologically and/or histologically proven diagnosis of HCA will be included in the study. Radiological diagnosis of HCA will be based on contrast enhanced MRI. Lesions at inclusion must not exceed 5 cm. The study group will be compared to a healthy control group of 63 pregnant patients and a group of 63 pregnant patients with diabetes mellitus without HCA. During their pregnancy HCA patients will be closely monitored by means of repetitive ultrasound (US) at 14, 20, 26, 32 and 38 weeks of gestation and 6 and 12 weeks postpartum. Both control groups will undergo US of the liver at 14 weeks of gestation to exclude HCA lesions in the liver. All groups will be asked to fill out quality of life related questionnaires.
The study will obtain information about the behaviour of HCA during pregnancy, the clinical consequences for mother and child and the impact of having a HCA during pregnancy on the health related quality of life of these young women. As a result of this study we will propose a decision-making model for the management of HCA during pregnancy.
Trial registration
Dutch trial register: NTR3034
PMCID: PMC3503786  PMID: 22748109
8.  What if I don’t treat my PSA-detected prostate cancer? Answers from three natural history models 
Making an informed decision about treating a prostate cancer detected following a routine prostate-specific antigen (PSA) test requires knowledge about disease natural history, such as the chances that it would have been clinically diagnosed in the absence of screening and that it would metastasize or lead to death in the absence of treatment.
We use three independently developed models of prostate cancer natural history to project risks of clinical progression events and disease-specific deaths for PSA-detected cases assuming they receive no primary treatment.
The three models project that 20–33% of men have preclinical onset; of these 38–50% would be clinically diagnosed and 12–25% would die of the disease in the absence of screening and primary treatment. The risk that men under age 60 at PSA detection with Gleason score 2–7 would have been clinically diagnosed in the absence of screening is 67–93% and would die of the disease in the absence of primary treatment is 23–34%. For Gleason score 8–10 these risks are 90–96% and 63–83%.
Risks of disease progression among untreated PSA-detected cases can be nontrivial, particularly for younger men and men with high Gleason scores. Model projections can be useful for informing decisions about treatment.
This is the first study to project population-based natural history summaries in the absence of screening or primary treatment and risks of clinical progression events following PSA detection in the absence of primary treatment.
PMCID: PMC3091266  PMID: 21546365
Comparative modeling; natural history; prostatic neoplasm; PSA screening
9.  Impact of Reduced Tobacco Smoking on Lung Cancer Mortality in the United States During 1975–2000 
Considerable effort has been expended on tobacco control strategies in the United States since the mid-1950s. However, we have little quantitative information on how changes in smoking behaviors have impacted lung cancer mortality. We quantified the cumulative impact of changes in smoking behaviors that started in the mid-1950s on lung cancer mortality in the United States over the period 1975–2000.
A consortium of six groups of investigators used common inputs consisting of simulated cohort-wise smoking histories for the birth cohorts of 1890 through 1970 and independent models to estimate the number of US lung cancer deaths averted during 1975–2000 as a result of changes in smoking behavior that began in the mid-1950s. We also estimated the number of deaths that could have been averted had tobacco control been completely effective in eliminating smoking after the Surgeon General’s first report on Smoking and Health in 1964.
Approximately 795 851 US lung cancer deaths were averted during the period 1975–2000: 552 574 among men and 243 277 among women. In the year 2000 alone, approximately 70 218 lung cancer deaths were averted: 44 135 among men and 26 083 among women. However, these numbers are estimated to represent approximately 32% of lung cancer deaths that could have potentially been averted during the period 1975–2000, 38% of the lung cancer deaths that could have been averted in 1991–2000, and 44% of lung cancer deaths that could have been averted in 2000.
Our results reflect the cumulative impact of changes in smoking behavior since the 1950s. Despite a large impact of changing smoking behaviors on lung cancer deaths, lung cancer remains a major public health problem. Continued efforts at tobacco control are critical to further reduce the burden of this disease.
PMCID: PMC3317881  PMID: 22423009
10.  Race-Specific Impact of Natural History, Mammography Screening and Adjuvant Treatment on Breast Cancer Mortality Rates in the US 
US Black women have higher breast cancer mortality rates than White women despite lower incidence. The aim of this study is to investigate how much of the mortality disparity can be attributed to racial differences in natural history, uptake of mammography screening and use of adjuvant therapy.
Two simulation models use common national race- and age-specific data for incidence, screening and treatment dissemination, stage distributions, survival and competing mortality from 1975 to 2010. Treatment effectiveness and mammography sensitivity are assumed to be the same for both races. We sequentially substituted Black parameters into the White model to identify parameters that drive the higher mortality for Black women in the current time period.
Both models accurately reproduced observed breast cancer incidence, stage and tumor size distributions and breast cancer mortality for White women. The higher mortality for Black women could be attributed to differences in natural history parameters (26–44%), use of adjuvant therapy (11–19%) and uptake of mammography screening (7–8%), leaving 38–46% unexplained.
Black women appear to have benefited less from cancer control advances than White women, with a greater race-related gap in the use of adjuvant therapy than screening. However, a greater portion of the disparity in mortality appears to be due to differences in natural history and undetermined factors.
Breast cancer mortality may be reduced substantially by ensuring that Black women receive equal adjuvant treatment and screening as White women. More research on racial variation in breast cancer biology and treatment utilization is needed.
PMCID: PMC3075821  PMID: 21119071
breast neoplasms; mammography; adjuvant therapy; mortality; healthcare disparities; continental population groups; computer simulation
11.  Interpreting Overdiagnosis Estimates in Population-based Mammography Screening 
Epidemiologic Reviews  2011;33(1):111-121.
Estimates of overdiagnosis in mammography screening range from 1% to 54%. This review explains such variations using gradual implementation of mammography screening in the Netherlands as an example. Breast cancer incidence without screening was predicted with a micro-simulation model. Observed breast cancer incidence (including ductal carcinoma in situ and invasive breast cancer) was modeled and compared with predicted incidence without screening during various phases of screening program implementation. Overdiagnosis was calculated as the difference between the modeled number of breast cancers with and the predicted number of breast cancers without screening. Estimating overdiagnosis annually between 1990 and 2006 illustrated the importance of the time at which overdiagnosis is measured. Overdiagnosis was also calculated using several estimators identified from the literature. The estimated overdiagnosis rate peaked during the implementation phase of screening, at 11.4% of all predicted cancers in women aged 0–100 years in the absence of screening. At steady-state screening, in 2006, this estimate had decreased to 2.8%. When different estimators were used, the overdiagnosis rate in 2006 ranged from 3.6% (screening age or older) to 9.7% (screening age only). The authors concluded that the estimated overdiagnosis rate in 2006 could vary by a factor of 3.5 when different denominators were used. Calculations based on earlier screening program phases may overestimate overdiagnosis by a factor 4. Sufficient follow-up and agreement regarding the chosen estimator are needed to obtain reliable estimates.
PMCID: PMC3132806  PMID: 21709144
breast neoplasms; early detection of cancer; incidence; mammography; mass screening; overdiagnosis; risk
12.  A randomised controlled trial on the effectiveness of bracing patients with idiopathic scoliosis: failure to include patients and lessons to be learnt 
European Spine Journal  2010;19(5):747-753.
Trials often do not succeed in including as many patients as anticipated beforehand. The aim of this paper was to describe why we were not able to include more than a few patients in our randomized controlled treatment trial on the effectiveness of bracing patients with idiopathic scoliosis, and to describe which lessons can be learnt. A pilot study on the willingness to participate in such a trial was conducted amongst 21 patients and their parents. A description of how we prepared and designed this trial, the problems we faced and how we tried to improve the inclusion are given. A total of four patients were included, and 14 refused to participate in an 18-month period. There were a lot less eligible patients than anticipated (40 instead of 100 per year), and the patients’ participation rate was much lower than we had found in our pilot study (21% instead of 70%). The trial failed to include more than a few patients because of an overestimation of the number of eligible patients and because a lot less eligible patients were willing to participate compared to our pilot study. One reason for a low participation rate could be that this trial evaluated a frequently used existing treatment instead of a new treatment, and patients and parents might be afraid of not being treated (despite an intensive secure system for the control arm).
PMCID: PMC2899969  PMID: 20195651
Idiopathic scoliosis; Brace; Randomized controlled trial; Treatment
13.  Detection of child abuse in emergency departments: a multi-centre study 
Archives of Disease in Childhood  2011;96(5):422-425.
This study examines the detection rates of suspected child abuse in the emergency departments of seven Dutch hospitals complying and not complying with screening guidelines for child abuse.
Data on demographics, diagnosis and suspected child abuse were collected for all children aged ≤18 years who visited the emergency departments over a 6-month period. The completion of a checklist of warning signs of child abuse in at least 10% of the emergency department visits was considered to be compliance with screening guidelines.
A total of 24 472 visits were analysed, 54% of which took place in an emergency department complying with screening guidelines. Child abuse was suspected in 52 children (0.2%). In 40 (77%) of these 52 cases, a checklist of warning signs had been completed compared with a completion rate of 19% in the total sample. In hospitals complying with screening guidelines for child abuse, the detection rate was higher (0.3%) than in those not complying (0.1%, p<0.001).
During a 6-month period, emergency department staff suspected child abuse in 0.2% of all children visiting the emergency department of seven Dutch hospitals. The numbers of suspected abuse cases detected were low, but an increase is likely if uniform screening guidelines are widely implemented.
PMCID: PMC3075563  PMID: 21278429
14.  Prostate-Specific Antigen Screening in the United States vs in the European Randomized Study of Screening for Prostate Cancer–Rotterdam 
Dissemination of prostate-specific antigen (PSA) testing in the United States coincided with an increasing incidence of prostate cancer, a shift to earlier stage disease at diagnosis, and decreasing prostate cancer mortality. We compared PSA screening performance with respect to prostate cancer detection in the US population vs in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC–Rotterdam). We developed a simulation model for prostate cancer and PSA screening for ERSPC–Rotterdam. This model was then adapted to the US population by replacing demography parameters with US-specific ones and the screening protocol with the frequency of PSA tests in the US population. We assumed that the natural progression of prostate cancer and the sensitivity of a PSA test followed by a biopsy were the same in the United States as in ERSPC–Rotterdam. The predicted prostate cancer incidence peak in the United States was then substantially higher than the observed prostate cancer incidence peak (13.3 vs 8.1 cases per 1000 man-years). However, the actual observed incidence was reproduced by assuming a substantially lower PSA test sensitivity in the United States than in ERSPC–Rotterdam. For example, for nonpalpable local- or regional-stage cancers (ie, stage T1M0), the estimates of PSA test sensitivity were 0.26 in the United States vs 0.94 in ERSPC–Rotterdam. We conclude that the efficacy of PSA screening in detecting prostate cancer was lower in the United States than in ERSPC–Rotterdam.
PMCID: PMC2831048  PMID: 20142584
15.  Bracing Patients with Idiopathic Scoliosis: Design of the Dutch Randomized Controlled Treatment Trial 
The effectiveness of bracing patients with IS has not yet been convincingly established due to a lack of RCTs. Some authors suggest that their results confirm that bracing is effective; others conclude that the effectiveness of bracing is doubtful or recommend a RCT. The aim of this study was to establish whether bracing patients with idiopathic scoliosis (IS) in an early stage will result in at least 5 degrees less mean progression of the curvature compared to the control group after two years of follow-up.
A randomized controlled trial was designed. Eligible patients are girls and boys in the age group 8–15 years whose diagnosis of IS has been established by an orthopedic surgeon, who have not yet been treated by bracing or surgery, and for whom further growth of physical height is still expected based on medical examination and maturation characteristics (Risser ≤ 2). The Cobb angle of the eligible patient should either be minimally 22 and maximally 29 degrees with established progression of more than 5 degrees, or should be minimally 30 and maximally 35 degrees; established progression for the latter is not necessary. A total of 100 patients will be included in this trial. The intervention group will be treated with full-time Boston brace wear; the control group will not be braced. Every four months, each patient will have a physical and an X-ray examination. The main outcomes will be the Cobb angle two years after inclusion and health-related quality of life.
The results of this trial will be of great importance for the discussion on early treatment for scoliosis. Furthermore, the result will also be important for screening for scoliosis policies.
Trial registration
Nederlands Trialregister ISRCTN36964733
PMCID: PMC2386134  PMID: 18430217
16.  Health-related quality of life in patients with adolescent idiopathic scoliosis after treatment: short-term effects after brace or surgical treatment 
European Spine Journal  2006;16(1):83-89.
For treatment of teenagers with progressive adolescent idiopathic scoliosis in an early stage, two options are generally considered: treatment with a brace or observation followed by surgery if necessary. Many doctors and patients prefer conservative treatment (i.e. brace treatment) to surgical treatment, because surgery of the spine is generally considered a drastic intervention. Because potential differences in health-related quality of life (HRQoL) after treatment between braced and surgically treated patients are not well explored, this study aimed to determine whether short-term differences exist in HRQoL between adolescents treated with a brace or treated surgically. A cross-sectional analysis of HRQoL was made of 109 patients with adolescent idiopathic scoliosis who, after completing treatment, filled out the Dutch SRS-22 Patient Questionnaire. All patients had been treated either with a brace or surgery, or with a brace followed by surgery. Patients treated surgically had significantly higher mean scores in the satisfaction with management domain than those treated with a brace. No other consistent differences in HRQoL were found between patients treated with a brace and patients treated surgically. Gender, curve type and curve size had no relevant effect on HRQoL. We conclude that short-term differences in HRQoL after treatment in adolescent patients with idiopathic scoliosis are negligible and cannot support preference of one treatment above the other.
PMCID: PMC2198892  PMID: 16609857
Quality of life; Adolescent idiopathic scoliosis; Brace; Surgery
18.  Response shift due to diagnosis and primary treatment of localized prostate cancer: a then-test and a vignette study 
Quality of Life Research  2007;16(10):1627-1634.
Whether a prostate cancer diagnosis induces response shift has not been established so far. Therefore, we assessed response shift in men who were diagnosed with localized prostate cancer.
Patients and methods
Out of 3,892 men who completed a questionnaire before screening, 82 were subsequently diagnosed with prostate cancer. Response shift was assessed in 52 (response 63%) by the then-test (EuroQol self-rating of health, Short-Form 36 mental health and vitality) and a novel method: rating of vignettes relating to side effects of prostate cancer treatment (urinary, bowel and erectile dysfunction). Three then-tests were conducted: two referencing pre-diagnosis (measured pre- and post-treatment), and one referencing pre-treatment (measured post-treatment).
Then-test scores of pre-diagnosis health were significantly higher than original scores, indicating a more positive judgement in retrospect. Then-test scores of pre-treatment health were lower than original scores. Especially the vignette on erectile dysfunction was rated less bad after diagnosis versus before (P < 0.001, moderate effect size).
We found evidence for response shift in men who were diagnosed with prostate cancer. Men evaluated urinary, bowel, and erectile dysfunction as less bad after they had become patients who can expect to experience these side effects. The rating of vignettes is a promising additional technique to assess response shift.
PMCID: PMC2062490  PMID: 17917793
Patient-reported outcome; Prostate cancer; Quality of life; Response shift
20.  Overdiagnosis and overtreatment of breast cancer: Microsimulation modelling estimates based on observed screen and clinical data 
Breast Cancer Research  2005;8(1):202.
There is a delicate balance between the favourable and unfavourable side-effects of screening in general. Overdiagnosis, the detection of breast cancers by screening that would otherwise never have been clinically diagnosed but are now consequently treated, is such an unfavourable side effect. To correctly model the natural history of breast cancer, one has to estimate mean durations of the different pre-clinical phases, transition probabilities to clinical cancer stages, and sensitivity of the applied test based on observed screen and clinical data. The Dutch data clearly show an increase in screen-detected cases in the 50 to 74 year old age group since the introduction of screening, and a decline in incidence around age 80 years. We had estimated that 3% of total incidence would otherwise not have been diagnosed clinically. This magnitude is no reason not to offer screening for women aged 50 to 74 years. The increases in ductal carcinoma in situ (DCIS) are primarily due to mammography screening, but DCIS still remains a relatively small proportion of the total breast cancer problem.
PMCID: PMC1413979  PMID: 16524452
21.  Susceptibility to Chronic Mucus Hypersecretion, a Genome Wide Association Study 
PLoS ONE  2014;9(4):e91621.
Chronic mucus hypersecretion (CMH) is associated with an increased frequency of respiratory infections, excess lung function decline, and increased hospitalisation and mortality rates in the general population. It is associated with smoking, but it is unknown why only a minority of smokers develops CMH. A plausible explanation for this phenomenon is a predisposing genetic constitution. Therefore, we performed a genome wide association (GWA) study of CMH in Caucasian populations.
GWA analysis was performed in the NELSON-study using the Illumina 610 array, followed by replication and meta-analysis in 11 additional cohorts. In total 2,704 subjects with, and 7,624 subjects without CMH were included, all current or former heavy smokers (≥20 pack-years). Additional studies were performed to test the functional relevance of the most significant single nucleotide polymorphism (SNP).
A strong association with CMH, consistent across all cohorts, was observed with rs6577641 (p = 4.25×10−6, OR = 1.17), located in intron 9 of the special AT-rich sequence-binding protein 1 locus (SATB1) on chromosome 3. The risk allele (G) was associated with higher mRNA expression of SATB1 (4.3×10−9) in lung tissue. Presence of CMH was associated with increased SATB1 mRNA expression in bronchial biopsies from COPD patients. SATB1 expression was induced during differentiation of primary human bronchial epithelial cells in culture.
Our findings, that SNP rs6577641 is associated with CMH in multiple cohorts and is a cis-eQTL for SATB1, together with our additional observation that SATB1 expression increases during epithelial differentiation provide suggestive evidence that SATB1 is a gene that affects CMH.
PMCID: PMC3979657  PMID: 24714607
22.  Evaluation of Systematic Assessment of Asthma-Like Symptoms and Tobacco Smoke Exposure in Early Childhood by Well-Child Professionals: A Randomised Trial 
PLoS ONE  2014;9(3):e90982.
This study aimed to evaluate the effectiveness of systematic assessment of asthma-like symptoms and environmental tobacco smoke (ETS) exposure during regular preventive well-child visits between age 1 and 4 years by well-child professionals.
Sixteen well-child centres in Rotterdam, the Netherlands, were randomised into 8 centres where the brief assessment form regarding asthma-like symptoms and ETS exposure was used and 8 centres that applied usual care. 3596 and 4179 children (born between April 2002 and January 2006) and their parents visited the intervention and control centres, respectively. At child’s age 6 years, physician-diagnosed asthma ever, wheezing, fractional exhaled nitric oxide (FeNO), airway resistance (Rint), health-related quality of life (HRQOL) and ETS exposure at home ever were measured. Linear mixed models were applied.
No differences in asthma, wheezing, FeNO, Rint or HRQOL measurements between intervention and control group were found using multilevel regression in an intention-to-treat analysis (p>0.05). Children of whom the parents were interviewed by using the brief assessment form at the intervention well-child centres had a decreased risk on ETS exposure at home ever, compared to children who visited the control well-child centres, in an explorative per-protocol analysis (aOR = 0.71, 95% CI:0.59–0.87).
Systematic assessment and counselling of asthma-like symptoms and ETS exposure in early childhood by well-child care professionals using a brief assessment form was not effective in reducing the prevalence of physician-diagnosed asthma ever and wheezing, and did not improve FeNO, Rint or HRQOL at age 6 years. Our results hold some promise for interviewing parents and using information leaflets at well-child centres to reduce ETS exposure at home in preschool children.
Trial Registration ISRCTN15790308.
PMCID: PMC3953324  PMID: 24626147
23.  Genome-wide study identifies two loci associated with lung function decline in mild to moderate COPD 
Human genetics  2012;132(1):79-90.
Accelerated lung function decline is a key COPD phenotype; however its genetic control remains largely unknown.
We performed a genome-wide association study using the Illumina Human660W-Quad v.1_A BeadChip. Generalized estimation equations were used to assess genetic contributions to lung function decline over a 5-year period in 4,048 European-American Lung Health Study participants with largely mild COPD. Genotype imputation was performed using reference HapMap II data. To validate regions meeting genome-wide significance, replication of top SNPs was attempted in independent cohorts. Three genes (TMEM26, ANK3 and FOXA1) within the regions of interest were selected for tissue expression studies using immunohistochemistry.
Measurements and Main Results
Two intergenic SNPs (rs10761570, rs7911302) on chromosome 10 and one SNP on chromosome 14 (rs177852) met genome-wide significance after Bonferroni. Further support for the chromosome 10 region was obtained by imputation, the most significantly associated imputed SNPs (rs10761571, rs7896712) being flanked by observed markers rs10761570 and rs7911302. Results were not replicated in four general population cohorts or a smaller cohort of subjects with moderate to severe COPD; however, we show novel expression of genes near regions of significantly associated SNPS, including TMEM26 and FOXA1 in airway epithelium and lung parenchyma, and ANK3 in alveolar macrophages. Levels of expression were associated with lung function and COPD status.
We identified two novel regions associated with lung function decline in mild COPD. Genes within these regions were expressed in relevant lung cells and their expression related to airflow limitation suggesting they may represent novel candidate genes for COPD susceptibility.
PMCID: PMC3536920  PMID: 22986903
COPD; lung function decline; GWAS; genome wide association; genes; polymorphisms
24.  The prostate cancer conundrum revisited: Treatment changes and prostate cancer mortality declines 
Cancer  2012;118(23):5955-5963.
Prostate cancer mortality rates in the US declined by over 40% between 1991 and 2005. The impact of changes in primary treatment and adjuvant and neoadjuvant hormonal therapy on this decline is unknown.
Application of three independently developed models of prostate cancer natural history and disease detection under common assumptions about treatment patterns, treatment efficacy, and survival in the population. Primary treatment patterns are from the Surveillance, Epidemiology and End Results registry and hormonal therapy frequencies are from the CaPSURE database; treatment efficacies are based on estimates from randomized trials and comparative effectiveness studies of treatment alternatives. The models project prostate cancer mortality without PSA screening and in the presence and absence of treatment benefit. Impact of primary treatment is expressed as a fraction of the difference between observed mortality and projected mortality in the absence of treatment benefit.
The three models project that changes in treatment explain 22–33% of the mortality decline by 2005. These contributions are accounted for mostly by surgery and radiation therapy, which increased in frequency until the 1990s; hormonal therapies contributed little to the mortality decline by 2005. Assuming that treatment benefit is less for older men, changes in treatment explain only 16–23% of the mortality decline by 2005.
Changes in primary treatment explain a minority of the observed decline in prostate cancer mortality. The remainder of the decline is likely due to other interventions, such as PSA screening and advances in the treatment of recurrent and progressive disease.
PMCID: PMC3424303  PMID: 22605665
Computer simulation; mortality; prostatectomy; prostatic neoplasms; radiotherapy; surveillance
25.  Computed Tomography Structural Lung Changes in Discordant Airflow Limitation 
PLoS ONE  2013;8(6):e65177.
There is increasing evidence that structural lung changes may be present before the occurrence of airflow limitation as assessed by spirometry. This study investigated the prevalence of computed tomography (CT) quantified emphysema, airway wall thickening and gas trapping according to classification of airflow limitation (FEV1/FVC <70% and/or < the lower limit of normal (LLN)) in (heavy) smokers.
A total number of 1,140 male former and current smokers participating in a lung cancer screenings trial (NELSON) were included and underwent chest CT scanning and spirometry. Emphysema was quantified by the 15th percentile, air way wall thickening by the square root of wall area for a theoretical airway with 10mm lumen perimeter (Pi10) and gas trapping by the mean lung density expiratory/inspiratory (E/I)-ratio. Participants were classified by entry FEV1/FVC: group 1>70%; group 2<70% but >LLN; and group 370% but FEV1 <80% predicted, were excluded. Multivariate regression analysis correcting for covariates was used to asses the extent of emphysema, airway wall thickening and gas trapping according to three groups of airflow limitation.
Mean (standard deviation) age was 62.5 (5.2) years and packyears smoked was 41.0 (18.0). Group 2 subjects when compared to group 1 had a significantly lower 15th percentile, −920.6 HU versus −912.2 HU; a higher Pi10, 2.87 mm versus 2.57 mm; and a higher E/I-ratio, 88.6% versus 85.6% (all p<0.001).
Subjects with an FEV1/FVC<70%, but above the LLN, have a significant greater degree of structural lung changes on CT compared to subjects without airflow limitation.
PMCID: PMC3681780  PMID: 23785411

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