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1.  Personalizing Age of Cancer Screening Cessation Based on Comorbidity: Model estimates of harms and benefits 
Annals of internal medicine  2014;161(2):104-112.
Background
Harms and benefits of cancer screening depend on age and comorbidity, yet reliable estimates are lacking.
Objective
To estimate the harms and benefits of cancer screening by age and comorbidity to inform decisions about screening cessation.
Design
Collaborative modeling with seven well-established cancer simulation models and common data on average and comorbidity level-specific life expectancy from SEER-Medicare.
Setting
US population.
Patients
US cohorts aged 66–90 years in 2010 with average health or one of four comorbidity levels (linked to specific conditions): none, mild, moderate, or severe.
Intervention
Mammography, prostate-specific antigen testing, or fecal immunochemical testing.
Measurements
Lifetime cancer deaths prevented and life-years gained (benefits); false-positive tests and overdiagnosed cancers (harms). For each comorbidity level: the age at which harms and benefits of screening were similar to that for individuals with average health undergoing screening at age 74.
Results
Screening 1000 women with average life expectancy at age 74 for breast cancer resulted in 79–96 (range across models) false-positives, 0.5–0.8 overdiagnosed cancers, and 0.7–0.9 breast cancer deaths prevented. While absolute numbers of harms and benefits differed across cancer sites, the ages at which to cease screening were highly consistent across models and cancer sites when based on harm-benefit ratios comparable to screening average-health individuals at age 74. For individuals with no, mild, moderate, and severe comorbidities, screening until ages of 76, 74, 72, and 66, respectively, resulted in similar harms and benefits as for average-health individuals.
Limitations
Comorbidity only influenced life expectancy.
Conclusion
Comorbidity is an important determinant of harms and benefits of screening. Estimates of screening benefits and harms by comorbidity can inform discussions between providers and their older patients about personalizing decisions about when to stop cancer screening.
Primary Funding Source
National Cancer Institute at the National Institutes of Health
doi:10.7326/M13-2867
PMCID: PMC4160041  PMID: 25023249
2.  Benefits and harms of CT lung cancer screening strategies. A comparative modeling study for the U.S. Preventive Services Task Force 
Annals of internal medicine  2014;160(5):311-320.
Background
The optimal screening policy for lung cancer is unknown.
Objective
To identify efficient CT-screening scenarios where relatively more lung cancer deaths are averted for fewer CT screens.
Design
Comparative modeling study using 5 independent models.
Data Sources
The National Lung Screening Trial, the Prostate, Lung, Colorectal and Ovarian trial, the Surveillance, Epidemiology, and End Results program, and U.S. Smoking History Generator.
Target Population
U.S. cohort born in 1950.
Time Horizon
Cohort followed from ages 45 to 90.
Perspective
Societal.
Intervention
576 scenarios with varying eligibility criteria (age, smoking pack-years, years quit) and screening intervals.
Outcome Measures
Benefits: lung cancer deaths averted or life-years gained; harms: CT-exams, false positives (including biopsy/surgery), overdiagnosed cases, radiation-related deaths.
Results of Best-Case
Annual screening from age 55 through 80 for ever-smokers with at least 30 pack-years and ex-smokers with less than 15 years since quitting was the most advantageous strategy. It would lead to 50% (45 to 54%) of cancers being detected at an early stage (I/II); 575 screens per lung cancer death averted; a 14% (8.2 to 23.5%) lung cancer mortality reduction; 497 lung cancer deaths averted; and 5,250 life-years gained per the 100,000-member cohort. Harms would include 67,550 false-positive tests, 910 biopsies or surgeries for benign lesions and 190 overdiagnosed cancers (3.7%; 1.4 to 8.3%).
Results of Sensitivity Analysis
The number of cancer deaths averted for the scenario varied across models between 177 and 862, and for overdiagnosed cancers between 72 and 426.
Limitations
Scenarios assumed 100% screening adherence. Data derived from trials with short duration were extrapolated to life-time follow-up.
Conclusion
Annual CT screening for lung cancer has a favorable benefit-harm ratio for individuals aged 55 through 80 years with 30 or more pack-year exposure to smoking.
doi:10.7326/M13-2316
PMCID: PMC4116741  PMID: 24379002
3.  Have Preferences of Girls Changed Almost 3 Years after the Much Debated Start of the HPV Vaccination Program in the Netherlands? A Discrete Choice Experiment 
PLoS ONE  2014;9(8):e104772.
Objectives
To assess how girls' preferences have changed almost 3 years after the much debated start of the human papillomavirus (HPV) vaccination program.
Methods
A discrete choice experiment (DCE) was conducted among girls aged 11–15 years who were invited, or were not yet invited, to get vaccinated. A panel latent class model was used to determine girls' preferences for vaccination based on five characteristics: degree of protection against cervical cancer; duration of protection; risk of mild side-effects; age of vaccination; and the number of required doses of the vaccine.
Results
The response rate was 85% (500/592). Most girls preferred vaccination at age 14 years (instead of at age 9 years) and a 2-dose scheme (instead of the current 3-dose scheme). Girls were willing to trade-off 7% (CI: 3.2% to 10.8%) of the degree of protection to have 10% less risk of mild side-effects, and 4% (CI: 1.2% to 5.9%) to receive 2 doses instead of 3 doses. Latent class analyses showed that there was preference heterogeneity among girls, i.e., higher educated girls and HPV vaccinated girls had a higher probability to opt for HPV vaccination at a higher age than lower educated girls or non-vaccinated girls.
Conclusions
Three years after the start of HPV vaccination program the risk of mild side-effects and age at vaccination seem to have become less important. For the Dutch national immunization program, we recommend not to lower the current target age of 12 years. A 2-dose scheme may result in a higher uptake and we recommend that if this scheme is introduced, it needs to receive adequate publicity.
doi:10.1371/journal.pone.0104772
PMCID: PMC4138034  PMID: 25136919
4.  Comparing Benefits from Many Possible Computed Tomography Lung Cancer Screening Programs: Extrapolating from the National Lung Screening Trial Using Comparative Modeling 
PLoS ONE  2014;9(6):e99978.
Background
The National Lung Screening Trial (NLST) demonstrated that in current and former smokers aged 55 to 74 years, with at least 30 pack-years of cigarette smoking history and who had quit smoking no more than 15 years ago, 3 annual computed tomography (CT) screens reduced lung cancer-specific mortality by 20% relative to 3 annual chest X-ray screens. We compared the benefits achievable with 576 lung cancer screening programs that varied CT screen number and frequency, ages of screening, and eligibility based on smoking.
Methods and Findings
We used five independent microsimulation models with lung cancer natural history parameters previously calibrated to the NLST to simulate life histories of the US cohort born in 1950 under all 576 programs. ‘Efficient’ (within model) programs prevented the greatest number of lung cancer deaths, compared to no screening, for a given number of CT screens. Among 120 ‘consensus efficient’ (identified as efficient across models) programs, the average starting age was 55 years, the stopping age was 80 or 85 years, the average minimum pack-years was 27, and the maximum years since quitting was 20. Among consensus efficient programs, 11% to 40% of the cohort was screened, and 153 to 846 lung cancer deaths were averted per 100,000 people. In all models, annual screening based on age and smoking eligibility in NLST was not efficient; continuing screening to age 80 or 85 years was more efficient.
Conclusions
Consensus results from five models identified a set of efficient screening programs that include annual CT lung cancer screening using criteria like NLST eligibility but extended to older ages. Guidelines for screening should also consider harms of screening and individual patient characteristics.
doi:10.1371/journal.pone.0099978
PMCID: PMC4076275  PMID: 24979231
5.  Peptides from the Variable Region of Specific Antibodies Are Shared among Lung Cancer Patients 
PLoS ONE  2014;9(5):e96029.
Late diagnosis of lung cancer is still the main reason for high mortality rates in lung cancer. Lung cancer is a heterogeneous disease which induces an immune response to different tumor antigens. Several methods for searching autoantibodies have been described that are based on known purified antigen panels. The aim of our study is to find evidence that parts of the antigen-binding-domain of antibodies are shared among lung cancer patients. This was investigated by a novel approach based on sequencing antigen-binding-fragments (Fab) of immunoglobulins using proteomic techniques without the need of previously known antigen panels. From serum of 93 participants of the NELSON trial IgG was isolated and subsequently digested into Fab and Fc. Fab was purified from the digested mixture by SDS-PAGE. The Fab containing gel-bands were excised, tryptic digested and measured on a nano-LC-Orbitrap-Mass-spectrometry system. Multivariate analysis of the mass spectrometry data by linear canonical discriminant analysis combined with stepwise logistic regression resulted in a 12-antibody-peptide model which was able to distinguish lung cancer patients from controls in a high risk population with a sensitivity of 84% and specificity of 90%. With our Fab-purification combined Orbitrap-mass-spectrometry approach, we found peptides from the variable-parts of antibodies which are shared among lung cancer patients.
doi:10.1371/journal.pone.0096029
PMCID: PMC4006902  PMID: 24787687
6.  Susceptibility to Chronic Mucus Hypersecretion, a Genome Wide Association Study 
PLoS ONE  2014;9(4):e91621.
Background
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.
Methods
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).
Results
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.
Conclusions
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.
doi:10.1371/journal.pone.0091621
PMCID: PMC3979657  PMID: 24714607
7.  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.
Objectives
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.
Methods
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.
Results
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).
Conclusions
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
Controlled-Trials.com ISRCTN15790308.
doi:10.1371/journal.pone.0090982
PMCID: PMC3953324  PMID: 24626147
8.  Automated Coronary Artery Calcification Scoring in Non-Gated Chest CT: Agreement and Reliability 
PLoS ONE  2014;9(3):e91239.
Objective
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.
Results
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).
Discussion
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.
doi:10.1371/journal.pone.0091239
PMCID: PMC3953377  PMID: 24625525
9.  Genome-wide study identifies two loci associated with lung function decline in mild to moderate COPD 
Human genetics  2012;132(1):79-90.
Rationale
Accelerated lung function decline is a key COPD phenotype; however its genetic control remains largely unknown.
Methods
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.
Conclusions
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.
doi:10.1007/s00439-012-1219-6
PMCID: PMC3536920  PMID: 22986903
COPD; lung function decline; GWAS; genome wide association; genes; polymorphisms
10.  The prostate cancer conundrum revisited: Treatment changes and prostate cancer mortality declines 
Cancer  2012;118(23):5955-5963.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1002/cncr.27594
PMCID: PMC3424303  PMID: 22605665
Computer simulation; mortality; prostatectomy; prostatic neoplasms; radiotherapy; surveillance
11.  Semi-Automatic Quantification of Subsolid Pulmonary Nodules: Comparison with Manual Measurements 
PLoS ONE  2013;8(11):e80249.
Rationale
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.
Methods
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).
Results
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.
Conclusion
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.
doi:10.1371/journal.pone.0080249
PMCID: PMC3837004  PMID: 24278264
12.  NELSON lung cancer screening study 
Cancer Imaging  2011;11(1A):S79-S84.
Abstract
The Dutch-Belgian Randomized Lung Cancer Screening Trial (Dutch acronym: NELSON study) was designed to investigate whether screening for lung cancer by low-dose multidetector computed tomography (CT) in high-risk subjects will lead to a decrease in 10-year lung cancer mortality of at least 25% compared with a control group without screening. Since the start of the NELSON study in 2003, 7557 participants underwent CT screening, with scan rounds in years 1, 2, 4 and 6. In the current review, the design of the NELSON study including participant selection and the lung nodule management protocol, as well as results on validation of CT screening and first results on lung cancer screening are described.
doi:10.1102/1470-7330.2011.9020
PMCID: PMC3266562  PMID: 22185865
Lung cancer; screening; multidetector computed tomography; population; pulmonary nodules; volume measurement
13.  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.
Background
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1371/journal.pone.0066484
PMCID: PMC3688769  PMID: 23840486
14.  Computed Tomography Structural Lung Changes in Discordant Airflow Limitation 
PLoS ONE  2013;8(6):e65177.
Background
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1371/journal.pone.0065177
PMCID: PMC3681780  PMID: 23785411
15.  The impact of PLCO control arm contamination on perceived PSA screening efficacy 
Cancer causes & control : CCC  2012;23(6):827-835.
Purpose
To quantify the extent to which a clinically significant prostate cancer mortality reduction due screening could have been masked by control arm screening (contamination) in the Prostate, Lung, Colorectal, and Ovarian (PLCO) trial.
Methods
We used three independently developed models of prostate cancer natural history to conduct a virtual PLCO trial. Simulated participants underwent pre-trial screening based on population patterns. The intervention arm followed observed compliance during the trial then resumed population screening. A contaminated control arm followed observed contamination during the trial then resumed population screening, while an uncontaminated control arm discontinued screening upon entry. We assumed a clinically significant screening benefit, applied population treatments and survival patterns, and calculated mortality rate ratios relative to the contaminated and uncontaminated control arms.
Results
The virtual trial reproduced observed incidence, including stage and grade distributions, and control arm mortality after 10 years of complete follow-up. Under the assumed screening benefit, the three models found that contamination increased the mortality rate ratio from 0.68–0.77 to 0.86–0.91, increased the chance of excess mortality in the intervention arm from 0–4% to 15–28%, and decreased the power of the trial to detect a mortality difference from 40–70% to 9–25%.
Conclusions
Our computer simulation models indicate that contamination substantially limited the ability of the PLCO to identify a clinically significant screening benefit. While the trial shows annual screening doesn’t reduce mortality relative to population screening, contamination prevents concluding whether screening reduces mortality relative to no screening.
doi:10.1007/s10552-012-9951-8
PMCID: PMC3556907  PMID: 22488488
Computer simulation; early detection of cancer; mortality; prostate-specific antigen; prostatic neoplasms; randomized controlled trial
16.  Diagnosis of chronic obstructive pulmonary disease in lung cancer screening Computed Tomography scans: independent contribution of emphysema, air trapping and bronchial wall thickening 
Respiratory Research  2013;14(1):59.
Background
Beyond lung cancer, screening CT contains additional information on other smoking related diseases (e.g. chronic obstructive pulmonary disease, COPD). Since pulmonary function testing is not regularly incorporated in lung cancer screening, imaging biomarkers for COPD are likely to provide important surrogate measures for disease evaluation. Therefore, this study aims to determine the independent diagnostic value of CT emphysema, CT air trapping and CT bronchial wall thickness for COPD in low-dose screening CT scans.
Methods
Prebronchodilator spirometry and volumetric inspiratory and expiratory chest CT were obtained on the same day in 1140 male lung cancer screening participants. Emphysema, air trapping and bronchial wall thickness were automatically quantified in the CT scans. Logistic regression analysis was performed to derivate a model to diagnose COPD. The model was internally validated using bootstrapping techniques.
Results
Each of the three CT biomarkers independently contributed diagnostic value for COPD, additional to age, body mass index, smoking history and smoking status. The diagnostic model that included all three CT biomarkers had a sensitivity and specificity of 73.2% and 88.%, respectively. The positive and negative predictive value were 80.2% and 84.2%, respectively. Of all participants, 82.8% was assigned the correct status. The C-statistic was 0.87, and the Net Reclassification Index compared to a model without any CT biomarkers was 44.4%. However, the added value of the expiratory CT data was limited, with an increase in Net Reclassification Index of 4.5% compared to a model with only inspiratory CT data.
Conclusion
Quantitatively assessed CT emphysema, air trapping and bronchial wall thickness each contain independent diagnostic information for COPD, and these imaging biomarkers might prove useful in the absence of lung function testing and may influence lung cancer screening strategy. Inspiratory CT biomarkers alone may be sufficient to identify patients with COPD in lung cancer screening setting.
doi:10.1186/1465-9921-14-59
PMCID: PMC3673831  PMID: 23711184
Quantitative CT analysis; Computed Tomography; Pulmonary emphysema; Airway remodeling; Lung cancer screening; Chronic obstructive pulmonary disease; Tobacco smoking
17.  Rate of progression of CT-quantified emphysema in male current and ex-smokers: a follow-up study 
Respiratory Research  2013;14(1):55.
Background
Little is known about the factors associated with CT-quantified emphysema progression in heavy smokers. The objective of this study was to investigate the effect of length of smoking cessation and clinical / demographical factors on the rate of emphysema progression and FEV1-decline in male heavy smokers.
Methods
3,670 male smokers with mean (SD) 40.8 (17.9) packyears underwent chest CT scans and pulmonary function tests at baseline and after 1 and 3 years follow-up. Smoking status (quitted ≥5, ≥1-<5, <1 years or current smoker) was noted. Rate of progression of emphysema and FEV1-decline after follow-up were assessed by analysis of variance adjusting for age, height, baseline pulmonary function and emphysema severity, packyears, years in study and respiratory symptoms. The quitted ≥5 group was used as reference.
Results
Median (Q1-Q3) emphysema severity,<-950 HU, was 8.8 (5.1 – 14.1) and mean (SD) FEV1 was 3.4 (0.73) L or 98.5 (18.5) % of predicted. The group quitted ‘>5 years’ showed significantly lower rates of progression of emphysema compared to current smokers, 1.07% and 1.12% per year, respectively (p<0.001). Current smokers had a yearly FEV1-decline of 69 ml, while subjects quit smoking >5 years had a yearly decline of 57.5 ml (p<0.001).
Conclusion
Quit smoking >5 years significantly slows the rate of emphysema progression and lung function decline.
Trial registration
Registered at http://www.trialregister.nl with trial number ISRCTN63545820.
doi:10.1186/1465-9921-14-55
PMCID: PMC3669040  PMID: 23688060
Chronic obstructive pulmonary disease (COPD); Emphysema; Smoking; Pulmonary function testing
18.  What level of risk tips the balance of benefits and harms to favor screening mammography starting at age 40? 
Annals of internal medicine  2012;156(9):609-617.
Background
In the US biennial screening mammography is recommended for average-risk women aged 50–74 because the benefits outweigh the harms. For women with increased risk starting screening at age 40 may have a similar harm-benefit ratio.
Objective
Determine the threshold relative risk (RR) at which the harm-benefit ratio of screening women aged 40–49 equals that of biennial screening for women aged 50–74.
Design
Comparative modeling study.
Data Sources
Surveillance, Epidemiology, and End Results, Breast Cancer Surveillance Consortium, medical literature.
Target Population
A contemporary cohort of women eligible for routine screening.
Time Horizon
Lifetime.
Perspective
Societal.
Interventions
Mammography screening starting at age 40 vs. 50 with different screening modalities (film, digital) and screening intervals (annual, biennial).
Outcome Measures
Benefits: life-years gained, breast cancer deaths averted; harms: false-positive mammography examinations; and harm-benefit ratios: false positives/life-year gained, false positives/death averted.
Results of Base-Case Analysis
Screening average-risk women aged 50–74 biennially yields the same false positives/life-year gained as biennial screening with digital mammography starting at age 40 for women with a 2-fold increased risk above average (median threshold RR 1.9; range across models 1.5–4.4). The threshold RRs are higher for annual screening with digital mammography(median 4.3; range 3.3–10) and higher when false positives/death averted is used as outcome measure instead of false positives/life-year gained. The harm-benefit ratio for film mammography is more favorable than for digital, because film has a lower false-positive rate.
Results of Sensitivity Analysis
The threshold RRs changed slightly when a more comprehensive measure of harm was used and were relatively insensitive to lower adherence assumptions.
Limitations
Risk was assumed to influence onset of disease without influencing screening performance.
Conclusions
Women aged 40–49 with a 2-fold increased risk have similar harm-benefit ratios for biennial screening mammography as average-risk women aged 50–74. Threshold RRs required for favorable harm-benefit ratios vary by screening modality, interval, and outcome measure.
Primary Funding Source
National Cancer Institute.
doi:10.1059/0003-4819-156-9-201205010-00002
PMCID: PMC3520058  PMID: 22547470
19.  EFFECTS OF MAMMOGRAPHY SCREENING UNDER DIFFERENT SCREENING SCHEDULES: MODEL ESTIMATES OF POTENTIAL BENEFITS AND HARMS 
Annals of internal medicine  2009;151(10):738-747.
Background
Despite trials of mammography and widespread use, optimal screening policy is controversial.
Design and Objective
Six models use common data elements to evaluate US screening strategies.
Data Sources
The models use national data on age-specific incidence, competing mortality, mammography characteristics and treatment effects.
Target Population and Time Horizon
A contemporary population cohort followed over their lifetimes.
Perspective
We use a societal perspective for analysis.
Interventions
We evaluate 20 screening strategies with varying initiation and cessation ages applied annually or biennially.
Outcome Measures
Number of mammograms, breast cancer mortality reduction or life years gained [LYG] (vs. no screening), false positives, unnecessary biopsies and over-diagnosis.
Results of Base Case
The 6 models produce consistent rankings of screening strategies. Screening biennially maintains an average of 81% (range across strategies and models 67–99%) of the benefit of annual screening with almost half the number of false positives. Screening biennially from ages 50 to 69 achieves a median 16.5% (range 15%–23%) breast cancer mortality reduction vs. no screening. Initiating biennial screening at age 40 (vs. 50) reduces mortality by an additional 3% (range 1%–6%), consumes more resources and yields more false positives. Biennial screening after age 69 yields some additional mortality reduction in all models but over-diagnosis increases most substantially at older ages.
Sensitivity Analysis Results
Varying test sensitivity or treatment patterns do not change conclusions.
Limitations
Results do not include morbidity from false positives, knowledge of earlier diagnosis or under-going unnecessary treatment.
Conclusion
Biennial screening achieves most of the benefit of annual screening with less harm. Decisions about the best strategy depend on program and individual objectives and the weight placed on benefits, harms and resource considerations.
doi:10.1059/0003-4819-151-10-200911170-00010
PMCID: PMC3515682  PMID: 19920274
20.  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.
doi:10.1007/s10549-012-2274-3
PMCID: PMC3511695  PMID: 23104221
Simulation modeling; Breast cancer; Disparities; Obesity
21.  Facilitators and barriers to screening for child abuse in the emergency department 
BMC Pediatrics  2012;12:167.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1471-2431-12-167
PMCID: PMC3502173  PMID: 23092228
Child abuse; Emergency department; Screening; Qualitative study
22.  Breast density as indicator for the use of mammography or MRI to screen women with familial risk for breast cancer (FaMRIsc): a multicentre randomized controlled trial 
BMC Cancer  2012;12:440.
Background
To reduce mortality, women with a family history of breast cancer often start mammography screening at a younger age than the general population. Breast density is high in over 50% of women younger than 50 years. With high breast density, breast cancer incidence increases, but sensitivity of mammography decreases. Therefore, mammography might not be the optimal method for breast cancer screening in young women. Adding MRI increases sensitivity, but also the risk of false-positive results. The limitation of all previous MRI screening studies is that they do not contain a comparison group; all participants received both MRI and mammography. Therefore, we cannot empirically assess in which stage tumours would have been detected by either test.
The aim of the Familial MRI Screening Study (FaMRIsc) is to compare the efficacy of MRI screening to mammography for women with a familial risk. Furthermore, we will assess the influence of breast density.
Methods/Design
This Dutch multicentre, randomized controlled trial, with balanced randomisation (1:1) has a parallel grouped design. Women with a cumulative lifetime risk for breast cancer due to their family history of ≥20%, aged 30–55 years are eligible. Identified BRCA1/2 mutation carriers or women with 50% risk of carrying a mutation are excluded. Group 1 receives yearly mammography and clinical breast examination (n = 1000), and group 2 yearly MRI and clinical breast examination, and mammography biennially (n = 1000).
Primary endpoints are the number and stage of the detected breast cancers in each arm. Secondary endpoints are the number of false-positive results in both screening arms. Furthermore, sensitivity and positive predictive value of both screening strategies will be assessed. Cost-effectiveness of both strategies will be assessed. Analyses will also be performed with mammographic density as stratification factor.
Discussion
Personalized breast cancer screening might optimize mortality reduction with less over diagnosis. Breast density may be a key discriminator for selecting the optimal screening strategy for women < 55 years with familial breast cancer risk; mammography or MRI. These issues are addressed in the FaMRIsc study including high risk women due to a familial predisposition.
Trial registration
Netherland Trial Register NTR2789
doi:10.1186/1471-2407-12-440
PMCID: PMC3488502  PMID: 23031619
Breast cancer; Familial risk; Screening; MRI; Breast density; Cost-effectiveness
23.  Modeling the impact of population screening on breast cancer mortality in the United States‡ 
Breast (Edinburgh, Scotland)  2011;20(Suppl 3):S75-S81.
Summary
Objective
Optimal US screening strategies remain controversial. We use six simulation models to evaluate screening outcomes under varying strategies.
Methods
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.
Results
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.
Conclusion
Decisions about screening strategy depend on preferences for benefits vs. potential harms and resource considerations.
doi:10.1016/S0960-9776(11)70299-5
PMCID: PMC3457919  PMID: 22015298
Mammography; Screening; Modeling
24.  Screening for type 2 diabetes in a high-risk population: study design and feasibility of a population-based randomized controlled trial 
BMC Public Health  2012;12:671.
Background
We describe the design and present the results of the first year of a population-based study of screening for type 2 diabetes in individuals at high risk of developing the disease. High risk is defined as having abdominal obesity.
Methods
Between 2006 and 2007, 79,142 inhabitants of two Dutch municipalities aged 40–74 years were approached to participate in screening. Eligible participants had a self-reported waist circumference of ≥80 cm for women and ≥94 cm for men, and no known pre-existing diabetes. Of the respondents (n = 20,578; response rate 26%), 16,135 were abdominally obese. In total, 10,609 individuals gave written informed consent for participation and were randomized into either the screening (n = 5305) or the control arm (n = 5304). Participants in the screening arm were invited to have their fasting plasma glucose (FPG) measured and were referred to their general practitioner (GP) if it was ≥6.1 mmol/L. In addition, blood lipids were determined in the screening arm, because abdominal obesity is often associated with cardiovascular risk factors. Participants in both arms received written healthy lifestyle information. Between-group differences were analyzed with Chi-square tests and logistic regression (categorical variables) and unpaired t-tests (continuous variables).
Results
The screening attendance rate was 84.1%. Attending screening was associated with age at randomization (OR = 1.03, 95% CI 1.02-1.04), being married (OR = 1.57, 95% CI 1.33-1.83) and not-smoking currently (OR = 0.52, 95% CI 0.44-0.62). Of the individuals screened, 5.6% had hyperglycemia, and a further 11.6% had an estimated absolute cardiovascular disease risk of 5% or higher, according to the Systematic Coronary Risk Evaluation risk model. These participants were referred to their GP.
Conclusions
Self-reported home-assessed waist circumference could feasibly detect persons at high risk of hyperglycemia or cardiovascular disease. Continuation of the large-scale RCT is warranted to test the hypothesis that targeted population-based screening for type 2 diabetes leads to a significant reduction in cardiovascular morbidity and mortality.
Trial registration
ISRCTN75983009
doi:10.1186/1471-2458-12-671
PMCID: PMC3497580  PMID: 22900932
Early detection; Screening; Type 2 diabetes; Abdominal obesity; Waist circumference
25.  Pregnancy and liver adenoma management: PALM-study 
BMC Gastroenterology  2012;12:82.
Background
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.
Methods/design
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.
Discussion
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
doi:10.1186/1471-230X-12-82
PMCID: PMC3503786  PMID: 22748109

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