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Demetriou C.A.,Cyprus Institute of Neurology and Genetics | Demetriou C.A.,Imperial College London | Chen J.,Mount Sinai School of Medicine | Polidoro S.,Molecular and Genetic Epidemiology Unit | And 47 more authors.
PLoS ONE | Year: 2013

Reproductive factors have been linked to both breast cancer and DNA methylation, suggesting methylation as an important mechanism by which reproductive factors impact on disease risk. However, few studies have investigated the link between reproductive factors and DNA methylation in humans. Genome-wide methylation in peripheral blood lymphocytes of 376 healthy women from the prospective EPIC study was investigated using LUminometric Methylation Assay (LUMA). Also, methylation of 458877 CpG sites was additionally investigated in an independent group of 332 participants of the EPIC-Italy sub-cohort, using the Infinium HumanMethylation 450 BeadChip. Multivariate logistic regression and linear models were used to investigate the association between reproductive risk factors and genome wide and CpG-specific DNA methylation, respectively. Menarcheal age was inversely associated with global DNA methylation as measured with LUMA. For each yearly increase in age at menarche, the risk of having genome wide methylation below median level was increased by 32% (OR:1.32, 95%CI:1.14-1.53). When age at menarche was treated as a categorical variable, there was an inverse dose-response relationship with LUMA methylation levels (OR12-14vs.≤11 yrs:1.78, 95%CI:1.01-3.17 and OR≥15vs.≤11 yrs:4.59, 95%CI:2.04-10.33; P for trend<0.0001). However, average levels of global methylation as measured by the Illumina technology were not significantly associated with menarcheal age. In locus by locus comparative analyses, only one CpG site had significantly different methylation depending on the menarcheal age category examined, but this finding was not replicated by pyrosequencing in an independent data set. This study suggests a link between age at menarche and genome wide DNA methylation, and the difference in results between the two arrays suggests that repetitive element methylation has a role in the association. Epigenetic changes may be modulated by menarcheal age, or the association may be a mirror of other important changes in early life that have a detectable effect on both methylation levels and menarcheal age. © 2013 Demetriou et al.


Agudo A.,Lhospitalet Of Llobregat | Bonet C.,Lhospitalet Of Llobregat | Travier N.,Lhospitalet Of Llobregat | Gonzalez C.A.,Lhospitalet Of Llobregat | And 52 more authors.
Journal of Clinical Oncology | Year: 2012

Purpose: Our aim was to assess the impact of cigarette smoking on the risk of the tumors classified by the International Agency for Research on Cancer as causally associated with smoking, referred to as tobacco-related cancers (TRC). Methods: The study population included 441,211 participants (133,018 men and 308,193 women) from the European Prospective Investigation Into Cancer and Nutrition. We investigated 14,563 participants who developed a TRC during an average follow-up of 11 years. The impact of smoking cigarettes on cancer risk was assessed by the population attributable fraction (AFp), calculated using the adjusted hazard ratios and 95% CI for current and former smokers, plus either the prevalence of smoking among cancer cases or estimates from surveys in representative samples of the population in each country. Results: The proportion of all TRC attributable to cigarette smoking was 34.9% (95% CI, 32.5 to 37.4) using the smoking prevalence among cases and 36.2% (95% CI, 33.7 to 38.6) using the smoking prevalence from the population. The AF p were above 80% for cancers of the lung and larynx, between 20% and 50% for most respiratory and digestive cancers and tumors from the lower urinary tract, and below 20% for the remaining TRC. Conclusion: Using data on cancer incidence for 2008 and our AFp estimates, about 270,000 new cancer diagnoses per year can be considered attributable to cigarette smoking in the eight European countries with available data for both men and women (Italy, Spain, United Kingdom, the Netherlands, Greece, Germany, Sweden, Denmark). © 2012 by American Society of Clinical Oncology.


Huerta J.M.,Murcia Regional Health Council | Huerta J.M.,CIBER ISCIII | Chirlaque M.-D.,Murcia Regional Health Council | Chirlaque M.-D.,CIBER ISCIII | And 23 more authors.
Stroke | Year: 2013

Background and Purpose-: Large-scale prospective epidemiological data testing the association between physical activity (PA) and cerebrovascular diseases (CVDs) are scarce, particularly in Europe. The objective was to assess the risk of CVD according to PA levels in adults. Methods-: We included a total of 13 576 men and 19 416 women aged 29 to 69 years and participating in the European Prospective Investigation into Cancer and Nutrition cohort in Spain, recruited between 1992 and 1996 and followed-up until 2006 to ascertain incident CVD events. The validated European Prospective Investigation into Cancer and Nutrition PA questionnaire was used to assess metabolic equivalent × hours per week dedicated to different types of PA. Hazard ratios of CVD by PA levels were estimated using multivariate Cox regression. Extensive baseline data collected on diet, lifestyle habits, medical history, and anthropometry were available to adjust for. Results-: A total of 210 transient ischemic attacks and 442 stroke cases (80% ischemic, 10% hemorrhagic, 7% subarachnoid hemorrhage, and 3% mixed or unspecified) were registered after 12.3 years of mean follow-up. Recreational activity was inversely associated with risk of CVD in women but not in men. Women walking for ≥3.5 hours per week were at lower risk of stroke than those who did not engage in regular walking. No significant associations were found for other leisure time activities or vigorous PA with CVD in either sex. Conclusions-: Recreational PA of moderate intensity was inversely associated with stroke incidence in women, whereas PA showed no effect on CVD risk in men. Increasing time dedicated to activities such as walking would be expected to help to reduce the stroke burden in women. © 2012 American Heart Association, Inc.


Roman M.,IMIM Hospital del Mar Medical Research Institute | Rue M.,University of Lleida | Sala M.,IMIM Hospital del Mar Medical Research Institute | Sala M.,Autonomous University of Barcelona | And 23 more authors.
PLoS ONE | Year: 2013

Background: Breast cancer incidence has decreased in the last decade, while the incidence of ductal carcinoma in situ (DCIS) has increased substantially in the western world. The phenomenon has been attributed to the widespread adaption of screening mammography. The aim of the study was to evaluate the temporal trends in the rates of screen detected invasive cancers and DCIS, and to compare the observed trends with respect to hormone replacement therapy (HRT) use along the same study period. Methods: Retrospective cohort study of 1,564,080 women aged 45-69 years who underwent 4,705,681 screening mammograms from 1992 to 2006. Age-adjusted rates of screen detected invasive cancer, DCIS, and HRT use were calculated for first and subsequent screenings. Poisson regression was used to evaluate the existence of a change-point in trend, and to estimate the adjusted trends in screen detected invasive breast cancer and DCIS over the study period. Results: The rates of screen detected invasive cancer per 100.000 screened women were 394.0 at first screening, and 229.9 at subsequent screen. The rates of screen detected DCIS per 100.000 screened women were 66.8 at first screen and 43.9 at subsequent screens. No evidence of a change point in trend in the rates of DCIS and invasive cancers over the study period were found. Screen detected DCIS increased at a steady 2.5% per year (95% CI: 1.3; 3.8), while invasive cancers were stable. Conclusion: Despite the observed decrease in breast cancer incidence in the population, the rates of screen detected invasive cancer remained stable during the study period. The proportion of DCIS among screen detected breast malignancies increased from 13% to 17% throughout the study period. The rates of screen detected invasive cancer and DCIS were independent of the decreasing trend in HRT use observed among screened women after 2002. © 2013 Román et al.


Castells X.,Mar Teaching Hospital | Castells X.,CIBER ISCIII | Roman M.,Mar Teaching Hospital | Roman M.,CIBER ISCIII | And 10 more authors.
Cancer Epidemiology | Year: 2013

Background: False-positives are a major concern in breast cancer screening. However, false-positives have been little evaluated as a prognostic factor for cancer detection. Our aim was to evaluate the association of false-positive results with the cancer detection risk in subsequent screening participations over a 17-year period. Methods: This is a retrospective cohort study of 762,506 women aged 45-69 years, with at least two screening participations, who underwent 2,594,146 screening mammograms from 1990 to 2006. Multilevel discrete-time hazard models were used to estimate the adjusted odds ratios (OR) of breast cancer detection in subsequent screening participations in women with false-positive results. Results: False-positives involving a fine-needle aspiration cytology or a biopsy had a higher cancer detection risk than those involving additional imaging procedures alone (OR = 2.69; 95%CI: 2.28-3.16 and OR = 1.81; 95%CI: 1.70-1.94, respectively). The risk of cancer detection increased substantially if women with cytology or biopsy had a familial history of breast cancer (OR = 4.64; 95%CI: 3.23-6.66). Other factors associated with an increased cancer detection risk were age 65-69 years (OR = 1.84; 95%CI: 1.67-2.03), non-attendance at the previous screening invitation (OR = 1.26; 95%CI: 1.11-1.43), and having undergone a previous benign biopsy outside the screening program (OR = 1.24; 95%CI: 1.13-1.35). Conclusion: Women with a false-positive test have an increased risk of cancer detection in subsequent screening participations, especially those with a false-positive result involving cytology or biopsy. Understanding the factors behind this association could provide valuable information to increase the effectiveness of breast cancer screening. © 2012 Elsevier Ltd.


Alberdi R.Z.,Public Health and Planning Directorate | Llanes A.B.F.,Public Health and Planning Directorate | Ortega R.A.,Public Health and Planning Directorate | Exposito R.R.,CIBER ISCIII | And 6 more authors.
European Radiology | Year: 2011

Objectives: To evaluate the effect of radiologist experience on the risk of false-positive results in population-based breast cancer screening programmes. Methods: We evaluated 1,440,384 single-read screening mammograms, corresponding to 471,112 women aged 45-69 years participating in four Spanish programmes between 1990 and 2006. The mammograms were interpreted by 72 radiologists. Results: The overall percentage of false-positive results was 5.85% and that for false-positives resulting in an invasive procedure was 0.38%. Both the risk of false-positives overall and of false-positives leading to an invasive procedure significantly decreased (p<0.001) with greater reading volume in the previous year: OR 0.77 and OR 0.78, respectively, for a reading volume 500-1,999 mammograms and OR 0.59 and OR 0.60 for a reading volume of >14,999 mammograms with respect to the reference category (<500). The risk of both categories of false-positives was also significantly reduced (p<0.001) as radiologists' years of experience increased: OR 0.96 and OR 0.84, respectively, for 1 year's experience and OR 0.72 and OR 0.73, respectively, for more than 4 years' experience with regard to the category of <1 year's experience. Conclusion: Radiologist experience is a determining factor in the risk of a false-positive result in breast cancer screening. © 2011 European Society of Radiology.


Roman R.,Institute Municipal Dinvestigacio Medica Parc Of Salut Mar Barcelona | Roman R.,CIBER ISCIII | Sala M.,Institute Municipal Dinvestigacio Medica Parc Of Salut Mar Barcelona | Sala M.,CIBER ISCIII | And 6 more authors.
Annals of Oncology | Year: 2012

Background: Reducing the false-positive risk in breast cancer screening is important. We examined how the screening-protocol and women's characteristics affect the cumulative false-positive risk. Methods: This is a retrospective cohort study of 1 565 364 women aged 45-69 years who underwent 4 739 498 screening mammograms from 1990 to 2006. Multilevel discrete hazard models were used to estimate the cumulative false-positive risk over 10 sequential mammograms under different risk scenarios. Results: The factors affecting the false-positive risk for any procedure and for invasive procedures were double mammogram reading [odds ratio (OR) = 2.06 and 4.44, respectively], two mammographic views (OR = 0.77 and 1.56, respectively), digital mammography (OR = 0.83 for invasive procedures), premenopausal status (OR = 1.31 and 1.22, respectively), use of hormone replacement therapy (OR = 1.03 and 0.84, respectively), previous invasive procedures (OR = 1.52 and 2.00, respectively), and a familial history of breast cancer (OR = 1.18 and 1.21, respectively). The cumulative false-positive risk for women who started screening at age 50-51 was 20.39% [95% confidence interval (CI) 20.02-20.76], ranging from 51.43% to 7.47% in the highest and lowest risk profiles, respectively. The cumulative risk for invasive procedures was 1.76% (95% CI 1.66-1.87), ranging from 12.02% to 1.58%. Conclusions: The cumulative false-positive risk varied widely depending on the factors studied. These findings are relevant to provide women with accurate information and to improve the effectiveness of screening programs. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Ascunce N.,CIBER ISCIII | Ederra M.,CIBER ISCIII | Delfrade J.,CIBER ISCIII | Baroja A.,Fundacion Rioja Salud | And 4 more authors.
European Radiology | Year: 2012

Objectives: Breast cancer screening is offered to 100% of the target population in Spain and intermediate mammograms (IMs) are sometimes indicated. This study was aimed at analysing the frequency of IMs, the factors determining their recommendation, and their impact on the risk of false-positive results and the detection rate. Methods: Data from 3,471,307 mammograms from Spanish breast cancer screening programmes were included. Results: 3.36% of the mammograms were IMs. The factors associated with the use of IMs were age, initial screening, previous invasive tests, a familial history of breast cancer and use of hormone replacement therapy. In screening episodes with an IM, the probability of a false-positive result was 13.74% (95% CI: 13.43-14.05), almost double that in episodes without IMs (6.02%, 95% CI 5.99-6.05). In young women with previous invasive procedures, a familial history of breast cancer or hormone replacement therapy use who were undergoing their initial screen, this probability was lower when IMs were performed. IMs always increased the detection rate. Conclusions: The factors prompting IMs should be characterised so that radiologists can systematise their recommendations according to the presence of the factors maximising the benefits and minimising the adverse effects of this procedure. Key Points : • Intermediate mammograms in breast screening offer potential benefits but also disadvantages. • Intermediate mammograms increase the false-positive rate except in specific groups. • Intermediate mammograms reduce the false-positive rate in younger women and initial screens. • Intermediate mammograms also reduce false-positive results in women with personal risk factors • Intermediate mammograms increase cancer detection mainly in women without risk factors. © 2011 European Society of Radiology.


Roman R.,Mar Teaching Hospital | Roman R.,Consortium for Biomedical Research in Epidemiology and Public Health | Sala M.,Mar Teaching Hospital | Sala M.,Consortium for Biomedical Research in Epidemiology and Public Health | And 13 more authors.
Breast Cancer Research and Treatment | Year: 2011

False-positive results may influence adherence to mammography screening. The effectiveness of breast cancer screening is closely related to adequate adherence among the target population. The objective of this study was to evaluate how false-positives and women's characteristics affect the likelihood of reattendance at routine breast cancer screening in a sequence of routine screening invitations. We performed a retrospective cohort study of 1,371,218 women aged 45-69 years, eligible for the next routine screening, who underwent 4,545,346 screening mammograms from 1990 to 2006. We estimated the likelihood of attendance at seven sequential screening mammograms. Multilevel discrete time hazard models were used to estimate the effect of false-positive results on reattendance, and the odds ratios (OR) of non-attendance for the women's personal characteristics studied. The overall reattendance rate at the second screening was 81.7% while at the seventh screening was 95.6%. At the second screening invitation reattendance among women with and without a false-positive mammogram was 79.3 vs. 85.3%, respectively. At the fourth and seventh screenings, these percentages were 86.3 vs. 89.9% and 94.6 vs. 96.0%, respectively. The study variables associated with a higher risk of failing to participate in subsequent screenings were oldest age (OR = 8.48; 95% CI: 8.31-8.65), not attending their first screening invitation (OR = 1.12; 95% CI: 1.11-1.14), and previous invasive procedures (OR = 1.09; 95% CI: 1.07-1.10). The risk of non-attendance was lower in women with a familial history of breast cancer (OR = 0.97; 95% CI: 0.96-0.99), and those using hormone replacement therapy (OR = 0.96; 95% CI: 0.94-0.97). In conclusion, reattendance was lower in women with false-positive mammograms than in those with negative results, although this difference decreased with the number of completed screening participations, suggesting that abnormal results in earlier screenings more strongly influence behavior. These findings may be useful in providing women with accurate information and in improving the effectiveness of screening programs. © Springer Science+Business Media, LLC. 2011.


Johnston M.C.,University of Aberdeen | Johnston M.C.,Public Health and Planning Directorate | Ludbrook A.,University of Aberdeen | Jaffray M.A.,University of Aberdeen
Alcohol and Alcoholism | Year: 2012

Aims: To examine the distribution of the costs of alcohol misuse across Scotland in 2009/2010, in relation to deprivation. Methods: A cost of illness approach was used. Alcohol-related harmful effects were assessed for inclusion using a literature review. This was based upon the following categories: direct healthcare costs, intangible health costs, social care costs, crime costs and labour and productivity costs. An analysis of secondary data supplemented by a literature review was carried out to quantify each harmful effect, determine its value and provide an estimate of the distribution by deprivation. The deprivation distributions used were area measures (primarily the Scottish Index of Multiple Deprivation). Results: The overall cost was £7457 million. Two alcohol harmful effects were not included in the overall cost by deprivation due to a lack of data. These were 'children's social work and hearing system' and the criminal justice system costs from 'alcohol-specific offences'. The included alcohol harmful effects demonstrated that 40.41% of the total cost arose from the 20% most deprived areas. The intangible cost category was the largest category (78.65%). Conclusion: The study found that the burden of alcohol harmful effects is greater in deprived groups and these burdens do not simply arise from deprived groups but are also experienced more by these groups. The study was limited by a lack of data availability in certain areas, leading to less-precise cost estimates. © The Author 2012. Medical Council on Alcohol and Oxford University Press. All rights reserved.

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