Snehal M. Pinto Pereira

Full-Field Digital versus Screen-Film Mammography: Comparison within the UK Breast Screening Program and Systematic Review of Published Data

PURPOSE To (a) compare the performance of full-field digital mammography (FFDM), using hard-copy image reading, with that of screen-film mammography (SFM) within a UK screening program (screening once every 3 years) for women aged 50 years or older and (b) conduct a meta-analysis of published findings along with the UK data. MATERIALS AND METHODS The study complied with the UK National Health Service Central Office for Research Ethics Committee guidelines; informed patient consent was not required, since analysis was carried out retrospectively after data anonymization. Between January 2006 and June 2007, a London population-based screening center performed 8478 FFDM and 31 720 SFM screening examinations, with modality determined by the type of machine available at the screening site. Logistic regression was used to assess whether breast cancer detection rates and recall rates differed between screening modalities. For the meta-analysis, random-effects models were used to combine study-specific estimates, if appropriate. RESULTS A total of 263 breast cancers were detected. After adjustment for age, ethnicity, area of residence, and type of referral, there was no evidence of differences between FFDM and SFM in terms of detection rates (0.68 [95% confidence interval {CI}: 0.47, 0.89] vs 0.72 [95% CI: 0.58, 0.85], respectively, per 100 screening mammograms; P = .74), recall rates (3.2% [95% CI: 2.8, 3.6] vs 3.4% [95% CI: 3.1, 3.6]; P = .44), positive predictive value (PPV) of an abnormal mammogram, or characteristics of detected tumors. Meta-analysis of data from eight studies showed a slightly higher detection rate for FFDM, particularly at 60 years of age or younger (pooled FFDM-SFM difference: 0.11 [95% CI: 0.04, 0.18] per 100 screening mammograms), but no clear modality differences in recall rates or PPVs. CONCLUSION Within a routine screening program, FFDM with hard-copy image reading performed as well as SFM in terms of process indicators; the meta-analysis was consistent with FFDM yielding detection rates at least as high as those for SFM.

Sedentary behaviour and biomarkers for cardiovascular disease and diabetes in mid-life: the role of television-viewing and sitting at work.

Background Knowledge of sedentary behaviour associations with health has relied mainly on television-viewing as a proxy and studies with other measures are less common. To clarify whether sedentary behaviour is associated with disease-risk, we examined associations for television-viewing and sitting at work. Methods Using the 1958 British birth cohort (n = 7660), we analysed cross-sectional associations between television-viewing and work sitting (four categories, 0–1 to ≥3 h/d) with total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL)-cholesterol, triglycerides, blood pressure, glycated haemoglobin, fibrinogen, C-reactive protein, hypertension and metabolic syndrome at 45 y. We adjusted for lifestyle and socio-demographic factors and assessed mediation of associations by body mass index (BMI) and diet. We also assessed whether the sedentary indicators are related similarly to factors linked to disease-risk. Results There was a general trend of adverse socio-demographic and lifestyle characteristics with higher h/d television-viewing, but trends in the opposite direction for work sitting. Television-viewing was associated with most biomarkers and associations were mediated by BMI: e.g. for each category increase in television-viewing, HDL-cholesterol in men was lower by 2.3% (95% CI: 1.5%, 3.2%) and, in BMI and diet adjusted analyses, by 1.6% (0.8%, 2.4%); for women, by 2.0% (1.2%, 2.9%) and 0.9% (0.1%, 1.6%) respectively. Few, weaker associations for work sitting were found, in men only: e.g. corresponding values for HDL-cholesterol were 1.2% (0.5%, 1.9%) and 0.9% (0.3%, 1.5%). Odds for metabolic syndrome were elevated by 82% and 33% respectively for men watching television or work sitting for ≥3 vs. 0–1 h/d. Conclusions Associations with cardiovascular disease and diabetes biomarkers in mid-adulthood differed for television-viewing and work sitting. The role of sedentary behaviour may vary by leisure and work domains or the two indicators reflect differing associations with other disease-related influences.

Childhood abuse is associated with methylation of multiple loci in adult DNA.

BackgroundChildhood abuse is associated with increased adult disease risk, suggesting that processes acting over the long-term, such as epigenetic regulation of gene activity, may be involved. DNA methylation is a critical mechanism in epigenetic regulation. We aimed to establish whether childhood abuse was associated with adult DNA methylation profiles.MethodsIn 40 males from the 1958 British Birth Cohort we compared genome-wide promoter DNA methylation in blood taken at 45y for those with, versus those without, childhood abuse (n = 12 vs 28). We analysed the promoter methylation of over 20,000 genes and 489 microRNAs, using MeDIP (methylated DNA immunoprecipitation) in triplicate.ResultsWe found 997 differentially methylated gene promoters (311 hypermethylated and 686 hypomethylated) in association with childhood abuse and these promoters were enriched for genes involved in key cell signaling pathways related to transcriptional regulation and development. Using bisulfite-pyrosequencing, abuse-associated methylation (MeDIP) at the metalloproteinase gene, PM20D1, was validated and then replicated in an additional 27 males. Abuse-associated methylation was observed in 39 microRNAs; in 6 of these, the hypermethylated state was consistent with the hypomethylation of their downstream gene targets. Although distributed across the genome, the differentially methylated promoters associated with child abuse clustered in genome regions of at least one megabase. The observations for child abuse showed little overlap with methylation patterns associated with socioeconomic position.ConclusionsOur observed genome-wide methylation profiles in adult DNA associated with childhood abuse justify the further exploration of epigenetic regulation as a mediating mechanism for long-term health outcomes.

Depressive Symptoms and Physical Activity During 3 Decades in Adult Life: Bidirectional Associations in a Prospective Cohort Study

IMPORTANCE Associations have been documented between physical activity and depressive symptoms, but the direction of this association is unclear. OBJECTIVE To examine whether depressive symptoms are concurrent with physical activity and to examine the direction of the relationship from 23 to 50 years of age. DESIGN, SETTING, AND PARTICIPANTS Participants included members of the 1958 British Birth Cohort, a general population sample of all persons born in England, Scotland, and Wales in a single week in March 1958 who were followed up to 50 years of age (2008). We included approximately 11,000 cohort members with information on depressive symptoms or frequency of physical activity at 23, 33, 42, or 50 years of age. EXPOSURES Depressive symptoms were measured using the Psychological subscale of the Malaise Inventory; frequency of physical activity, by questionnaire. MAIN OUTCOMES AND MEASURES Number of depressive symptoms (on a scale of 0 to 15 items), depression (defined as being in the top 10% for symptoms at 23, 33, 42, or 50 years of age), and frequency of physical activity (times per week). RESULTS At most ages, we found a trend of fewer depressive symptoms with more frequent activity; for example, per higher frequency of activity per week at 50 years of age, the mean number of symptoms was lower by 0.06 (95% CI, -0.09 to -0.04). In longitudinal analyses, activity was associated with fewer symptoms from 23 to 50 years of age (per higher frequency of activity per week, symptoms were lower by 0.06 [95% CI, -0.07 to -0.05]), and the magnitude of association did not vary with age (P=.21 for interaction). Those who were inactive at 23 years of age and remained inactive 5 years later showed no change in symptom level (mean difference, -0.01 [95% CI, -0.04 to 0.02]); those increasing activity to 3 times/wk had a lower mean number of symptoms (mean difference, -0.18 [95% CI, -0.22 to -0.15]). Such differences equate to estimated reductions in odds of depression by 19%. A longitudinal relationship observed between symptoms and activity weakened with age (P<.001 for interaction). Mean activity among those with no symptoms at 23 years of age and 5 years later was higher by 0.60 (95% CI, 0.57-0.64) times/wk; in those with 1 additional depressive symptom, 0.53 (95% CI, 0.49-0.56) times/wk. Activity frequency did not differ among those with no symptoms at 43 years of age who subsequently had 0 or 1 symptom at 48 years of age. Associations for depression were generally similar to those for the full symptom spectrum. CONCLUSIONS AND RELEVANCE The relationship between activity and depressive symptoms was bidirectional, albeit more persistent during adult life in the direction from activity to depressive symptoms. Findings suggest that activity may alleviate depressive symptoms in the general population and, in turn, depressive symptoms in early adulthood may be a barrier to activity.

Localized Fibroglandular Tissue as a Predictor of Future Tumor Location within the Breast

Background: Mammographic density (MD) is a strong marker of breast cancer risk, but it is unclear whether tumors arise specifically within dense tissue. Methods: In 231 British women diagnosed with breast cancer after at least one negative annual screening during a mammographic screening trial, we assessed whether tumor location was related to localized MD 5 years prior to diagnosis. Radiologists identified tumor locations on digitised films. We used a validated algorithm to align serial images from the same woman to locate the corresponding point on the prediagnostic film. A virtual 1 cm square grid was overlaid on prediagnostic films and MD calculated for each square within a womans breast (mean = 271 squares/film). Conditional logistic regression, matching on a womans breast, was used to estimate the odds of a tumor arising in a square in relation to its prediagnostic square-specific MD. Results: Median (interquartile range) prediagnostic MD was 98.2% (46.8%–100%) in 1 cm-squares that subsequently contained the tumor and 41.0% (31.5%–53.9%) for the whole breast. The odds of a tumor arising in a 1 cm-square were, respectively, 6.1 (95% CI: 1.9–20.1), 16.6 (5.2–53.2), and 25.5-fold (8.1–80.3) higher for squares in the second, third, and fourth quartiles of prediagnostic MD relative to those in the lowest quartile within that breast (Ptrend < 0.001). The corresponding odds ratios were 2.3 (1.3–4.0), 3.9 (2.3–6.4), and 4.6 (2.8–7.6) if a 3 cm-square grid was used. Conclusion: Tumors arise predominantly within the radiodense breast tissue. Impact: Localized MD may be used as a predictor of subsequent tumor location within the breast. Cancer Epidemiol Biomarkers Prev; 20(8); 1718–25. ©2011 AACR.

Life course body mass index, birthweight and lipid levels in mid-adulthood: a nationwide birth cohort study.

AIMS Improvement in lipid profiles is an important public health and clinical goal for which a better understanding is needed of biological pathways and influences. Evidence is scant on the role of growth, including trajectories of body mass index (BMI), so we aimed to determine whether particular life stages from birth to adulthood are important for lipid levels in mid-adulthood (45 years). METHODS AND RESULTS In the 1958 British birth cohort (n = 3927 men; 3897 women), weight and height were recorded at: birth (weight only), 7, 11, 16, 23, 33, and 45 years. Birthweight was inversely associated with triglycerides and in women with total- and non-high-density lipoprotein cholesterol; associations were little affected by adjustment for 7-year BMI. Associations between lipids and BMI strengthened with age, e.g. in women, adult (45-year) triglycerides were elevated by 1.54% (95% confidence interval: 0.87-2.21%) and 3.57% (3.29-3.86%), respectively, per kg/m² higher BMI at 11 and 45 years. Body mass index gain was related to lipids, with strongest associations for the interval between 33 and 45 years, where a kg/m² gain in BMI was associated with ~0.6% higher total cholesterol and ~5.3% higher triglycerides. Associations between 45-year BMI and lipids were stronger for those with lowest than highest BMI at younger ages (P for interaction ≤0.05). A long duration of obesity and obesity in childhood but not thereafter were unrelated to adult lipid levels. CONCLUSIONS Our findings from a large population-based cohort highlight detrimental consequences of high adult BMI for lipids as most pronounced for those with a lower BMI at earlier life stages.

Child Neglect and Maltreatment and Childhood-to-Adulthood Cognition and Mental Health in a Prospective Birth Cohort

OBJECTIVE Life-long adverse effects of childhood maltreatment on mental health are well established, but effects on child-to-adulthood cognition and related educational attainment have yet to be examined in the general population. We aimed to establish whether different forms of child maltreatment are associated with poorer cognition and educational qualifications in childhood/adolescence and whether associations persist to midlife, parallel to associations for mental health. METHOD Cognitive abilities at ages 7, 11, and 16 years (math, reading, and general intellectual ability) and 50 years (immediate/delayed memory, verbal fluency, processing speed) were assessed using standardized tests, and qualifications by age 42 were self-reported. Information on childhood maltreatment (neglect and abuse: sexual, physical, psychological, witnessed), cognition, and mental health was available for 8,928 participants in the 1958 British Birth Cohort. RESULTS We found a strong association of child neglect with cognitive deficits from childhood to adulthood. To illustrate, the most neglected 6% of the population (score ≥4) had a 0.60 (95% CI = 0.56-0.68) SD lower cognitive score at age 16 and a 0.28 (95% CI = 0.20-0.36) SD deficit at age 50 years relative to the non-neglected participants (score = 0) after adjustment for confounding factors and mental health, and they also had increased risk of poor qualifications (i.e., none/low versus degree-level). Childhood neglect and all forms of abuse were associated with poorer child-to-adulthood mental health, but abuse was mostly unrelated to cognitive abilities. CONCLUSION The study provides novel data that child neglect is associated with cognitive deficits in childhood/adolescence and decades later in adulthood, independent of mental health, and highlights the lifelong burden of child neglect on cognitive abilities and mental health.

Childhood Maltreatment and BMI Trajectories to Mid-Adult Life: Follow-Up to Age 50y in a British Birth Cohort

Background Childhood maltreatment including abuse and neglect has been associated with adult obesity, but evidence on life-course development of obesity or BMI gain is unclear. We aim to establish whether childhood maltreatments are related to obesity or BMI at different life-stages 7y-50y and to identify possible explanations for associations. Methods Childhood physical, psychological and sexual abuse, neglect and BMI at seven ages were recorded in the 1958 birth cohort (n~15,000). Associations of child maltreatments with BMI at separate ages were tested using linear regression or logistic regression for obesity, and with rate of child-to-adult BMI gain using multilevel models. We adjusted for potential covariates. Results Abuse was reported in ~12% of the population. Abuse was not associated with elevated childhood BMI, but adult associations were observed: i.e. the abused had faster child-adult BMI gain than the non-abused; associations were independent of adult covariates. For physical abuse in both genders there was a positive linear association of ~0.006/y zBMI gain with age after adjustment for all covariates. Similarly, there was a linear association of physical abuse with obesity risk: e.g. among females from a low ORadjusted of 0.34 (0.16,0.71) at 7y to 1.67 (1.25,2.24) at 50y. In females faster zBMI gains with age of ~0.0034/y were observed for sexual abuse and increases in obesity risk were faster: from a low ORadjusted of 0.23 (0.06,0.84) at 7y to 1.34 (0.86,2.10) at 50y. Psychological abuse and neglect associations were less consistent. Conclusions Childhood maltreatment associations with BMI or obesity varied across life: physical and, in females, sexual abuse were associated with faster lifetime BMI gains, which may have detrimental long-term health consequences.

Obesity and risk factors for cardiovascular disease and type 2 diabetes: Investigating the role of physical activity and sedentary behaviour in mid-life in the 1958 British cohort

OBJECTIVE A key public health priority is to minimise obesity-related health consequences. We aim to establish whether physical activity (PA) or less sedentary behaviour ameliorate associations of obesity with biomarkers for cardiovascular disease (CVD) and type 2 diabetes. METHODS Data on obesity (33 y), PA (42 y), TV-viewing and health biomarkers (45 y) are from the 1958 British birth cohort (N=9377). RESULTS Obesity was associated with an adverse biomarker profile for CVD and type 2 diabetes. For PA, men active≥1/week had 1.09% (0.28, 1.90) lower diastolic blood pressure (DBP) than less active men; triglycerides were 2.08% (0.52, 3.64) lower per unit higher PA (on 4-point scale). TV-viewing was independently associated with several biomarkers, e.g. per unit higher TV-viewing (on 4-point scale) DBP was raised by 0.50% (0.09, 0.90) and triglycerides by 3.61% (1.58, 5.64). For both TV-viewing and PA, associations with HbA1c were greatest for the obese (pinteraction≤0.04): compared to a reference value of 5.20 HbA1c% in non-obese men viewing 0-1 h/day, HbA1c% differed little for those viewing>3 h/day; among obese men HbA1c% was 5.36 (5.22, 5.51) and 5.65 (5.53, 5.76), for 0-1 and >3 h/day respectively. For PA in non-obese men, the reduction associated with activity≥1/week was negligible compared to a reference value of 5.20 HbA1c% for those less active; but there was a reduction among obese men, HbA1c% was 5.50 (5.40, 5.59) vs 5.66 (5.55, 5.77) respectively. CONCLUSION Reduced TV-viewing and prevention of infrequent activity have greatest beneficial associations for glucose metabolism among the obese, with benefits for other biomarkers across obese and non-obese groups.

The spatial distribution of radiodense breast tissue: a longitudinal study

IntroductionMammographic breast density is one of the strongest known markers of susceptibility to breast cancer. To date research into density has relied on a single measure (for example, percent density (PD)) summarising the average level of density for the whole breast, with no consideration of how the radiodense tissue may be distributed. This study aims to investigate the spatial distribution of density within the breast using 493 mammographic images from a sample of 165 premenopausal women (~3 medio-lateral oblique views per woman).MethodsEach breast image was divided into 48 regions and the PD for the whole breast (overall PD) and for each one of its regions (regional PD) was estimated. The spatial autocorrelation (Morans I value) of regional PD for each image was calculated to investigate spatial clustering of density, whether the degree of clustering varied between a womans two breasts and whether it was affected by age and other known density correlates.ResultsThe median Morans I value for 165 women was 0.31 (interquartile range: 0.26, 0.37), indicating a clustered pattern. High-density areas tended to cluster in the central regions of the breast, regardless of the level of overall PD, but with considerable between-woman variability in regional PD. The degree of clustering was similar between a womans two breasts (mean within-woman difference in Morans I values between left and right breasts = 0.00 (95% confidence interval (CI) = -0.01, 0.01); P = 0.76) and did not change with aging (mean within-woman difference in I values between screens taken on average 8 years apart = 0.01 (95% CI = -0.01, 0.02); P = 0.30). Neither parity nor age at first birth affected the level of spatial autocorrelation of density, but increasing body mass index (BMI) was associated with a decrease in the degree of spatial clustering.ConclusionsThis study is the first to demonstrate that the distribution of radiodense tissue within the breast is spatially autocorrelated, generally with the high-density areas clustering in the central regions of the breast. The degree of clustering was similar within a womans two breasts and between women, and was little affected by age or reproductive factors although it declined with increasing BMI.