C-reactive protein levels and body mass index: elucidating direction of causation through reciprocal Mendelian randomization.

CONTEXT: The assignment of direction and causality within networks of observational associations is problematic outside randomized control trials, and the presence of a causal relationship between body mass index (BMI) and C-reactive protein (CRP) is disputed. OBJECTIVE: Using reciprocal Mendelian randomization, we aim to assess the direction of causality in relationships between BMI and CRP and to demonstrate this as a promising analytical technique. PARTICIPANTS AND METHODS: The study was based on a large, cross-sectional European study from Copenhagen, Denmark. Genetic associates of BMI (FTO(rs9939609)) and circulating CRP (CRP(rs3091244)) have been used to reexamine observational associations between them. RESULTS: Observational analyses showed a strong, positive association between circulating CRP and BMI (change in BMI for a doubling in log CRP of 1.03 kg m(-2) (95% confidence interval (95% CI): 1.00, 1.07), P<0.0001). Analysis using CRP(rs3091244) to re-estimate the causal effect of circulating CRP on BMI yielded null effects (change in BMI for a doubling in log CRP of -0.24 kg m(-2) (95% CI: -0.58, 0.11), P=0.2). In contrast, analysis using FTO(rs9939609) to assess the causal effect of BMI on circulating CRP confirmed observational associations (ratio of geometric means of CRP per s.d. increase in BMI 1.41 (95% CI: 1.10, 1.80), P=0.006). CONCLUSIONS: Taken together, these data suggest that the observed association between circulating CRP and measured BMI is likely to be driven by BMI, with CRP being a marker of elevated adiposity. More generally, the method of reciprocal randomization has general applicability in determining the direction of causation within inter-correlated networks of metabolic components.

The associations of high levels of C-reactive protein with depression and myocardial infarction in 9258 women and men from the HUNT population study.

BACKGROUND: Elevated levels of circulating C-reactive protein (CRP) have been associated with coronary heart disease and, in some studies, depression. Most studies have been of populations selected by age and/or gender. We investigate these associations with depression, myocardial infarction (MI), or both, in a large general population sample. METHOD: A cross-sectional population study of 9258 women and men aged ≥ 20 years. The study included clinical examination, self-report of MI and depression and factors known to confound their associations. The Hospital Anxiety and Depression Scale was used to assess severity of depressive symptoms. Elevated high sensitive-CRP was defined as values >2.2 mg/l. RESULTS: The association of elevated CRP with depression was attenuated towards the null [from odds ratio (OR) 1.28, p=0.001 to OR 1.08, p=0.388] following extensive adjustment, while associations with MI (adjusted OR 1.42, p=0.032) and co-morbid MI and depression (adjusted OR 2.66, p=0.003) persisted. Confounders associated with elevated CRP levels were smoking (OR 1.66; p<0.001), chronic physical illness (OR 1.34, p<0.001), BMI ≥ 30 (OR 1.13, p<0.001), employment (OR 0.70, p<0.001) and high coffee consumption (OR 0.83, p=0.017). Interaction tests indicated a lower effect of old age (OR 0.54, p<0.001) and smoking (OR 0.63, p<0.001) on elevated CRP levels in women compared with men. CONCLUSIONS: CRP levels were raised in those with MI and co-morbid MI and depression; the positive association with depression was explained by confounding factors. We found new evidence that might help understand gender-specific patterns. Future studies should explore the neurobiological mechanisms underpinning these interrelations and their relevance for treatment of these conditions.

Age- and puberty-dependent association between IQ score in early childhood and depressive symptoms in adolescence.

BACKGROUND: Lower cognitive functioning in early childhood has been proposed as a risk factor for depression in later life but its association with depressive symptoms during adolescence has rarely been investigated. Our study examines the relationship between total intelligence quotient (IQ) score at age 8 years, and depressive symptoms at 11, 13, 14 and 17 years. METHOD: Study participants were 5250 children and adolescents from the Avon Longitudinal Study of Parents and their Children (ALSPAC), UK, for whom longitudinal data on depressive symptoms were available. IQ was assessed with the Wechsler Intelligence Scale for Children III, and self-reported depressive symptoms were measured with the Short Mood and Feelings Questionnaire (SMFQ). RESULTS: Multi-level analysis on continuous SMFQ scores showed that IQ at age 8 years was inversely associated with depressive symptoms at age 11 years, but the association changed direction by age 13 and 14 years (age-IQ interaction, p<0.0001; age squared-IQ interaction, p<0.0001) when a higher IQ score was associated with a higher risk of depressive symptoms. This change in IQ effect was also found in relation to pubertal stage (pubertal stage-IQ interaction, 0.00049

Obesity, overweight and liver disease in the Midspan prospective cohort studies.

OBJECTIVES: To analyse the relationship between body mass index (BMI) and liver disease in men and women. DESIGN: The Midspan prospective cohort studies. PARTICIPANTS: The three studies were: Main study, screened in 1965-1968, workplaces across Scotland, the general population of the island of Tiree and mainland relatives; Collaborative study, conducted from 1970 to 1973, 27 workplaces in Glasgow, Clydebank and Grangemouth; Renfrew/Paisley general population study, screened in 1972-1976. After exclusions there were 16 522 men and 10 216 women, grouped by BMI into under/normal weight (< 25 kg m(-2)), overweight (25 to < 30 kg m(-2)) and obese (>or=30 kg m(-2)). MEASUREMENTS: Relative rates (RRs) of liver disease mortality, subdivided into liver cancer and all other liver disease, by BMI category and per s.d. increase in BMI, followed-up to end 2007. RRs of liver disease from any diagnosis on the death certificate, hospital discharge records or cancer registrations (Collaborative and Renfrew/Paisley studies only 13 027 men and 9328 women). Analyses adjusted for age and study, then other confounders. RESULTS: In total, 146 men (0.9%) and 61 women (0.6%) died of liver disease as main cause. There were strong associations of BMI with liver disease mortality in men (RR per s.d. increase in BMI=1.41 (95% confidence interval 1.21-1.65)). Obese men had more than three times the rate of liver disease mortality than under/normal weight men. Adjustment for other risk factors had very little effect. No substantial or robust associations were observed in women. In all, 325 men (2.5%) and 155 women (1.7%) had liver disease established from any source. Similar positive associations were observed for men, and there was evidence of a relationship in women. CONCLUSIONS: BMI is related to liver disease, although not to liver disease mortality in women. The current rise in overweight and obesity may lead to a continuing epidemic of liver disease.

Early life growth and hemostatic factors: the Barry Caerphilly Growth study.

Associations between early life growth trajectories and a range of adult (aged approximately 25 years) hemostatic factors were assessed in the Barry Caerphilly Growth study (N = 517) in South Wales, 1974-1999. Associations of birth weight, birth length, and weight and height velocities during three periods ("immediate": 0-<5 months, "infant": 5 months-<1 year 9 months, and "childhood": 1 year 9 months-5 years) with adult levels of hemostatic factors were assessed. Birth weight was inversely associated with fibrinogen (beta per 1-unit change in z score = -0.08, 95% confidence interval (CI): -0.15, -0.02). Immediate weight velocity was inversely associated with factor VII (beta = -1.88, 95% CI: -3.84, 0.09), factor VIII (beta = -2.58, 95% CI: -4.07, -0.45), and von Willebrand factor antigen (beta = -4.07, 95% CI: -7.25, -0.89). Birth length was inversely associated with fibrinogen (beta = -0.07, 95% CI: -0.14, -0.01). Evidence was weaker for an inverse association of immediate height velocity with factor VIII (beta = -2.16, 95% CI: -4.62, 0.29) and von Willebrand factor antigen (beta = -2.85, 95% CI: -6.52, 0.81). Childhood height velocity was positively associated with D-dimer (ratio of geometric means = 1.11, 95% CI: 1.01, 1.23). Results support the view that the immediate postnatal period may be particularly important, possibly through impaired liver development and/or infection in early life, in determining cardiovascular disease risk.

Cigarette smoking and site-specific cancer mortality: testing uncertain associations using extended follow-up of the original Whitehall study.

BACKGROUND: The relation between cigarette smoking and several malignancies is still unclear. We examined the association of cigarette smoking with death attributed to 15 cancer sites, 7 of which are regarded as having an uncertain relation with tobacco. PATIENTS AND METHODS: The original Whitehall study is a prospective cohort of 17 363 London-based male government employees (age 40-69 years) who were examined in the late 1960s and then followed up for a maximum of 38 years. RESULTS: Following adjustment for demographic characteristics, risk factors, and prevalent disease, established positive cigarette smoking--cancer gradients were confirmed for carcinoma of the lung, stomach, pancreas, bladder, upper aero-digestive (including oesophagus), and liver, and for myeloid leukaemia. Among the cancers of uncertain relation with smoking, mortality rates for malignancy of the colon, rectum and prostate and for lymphatic leukaemia were elevated in current and/or former smokers. There was essentially no apparent relation between smoking and mortality from carcinoma of the brain or from lymphoma. CONCLUSION: In this study, cigarette smoking appears to be a risk factor for several malignancies of previously unclear association with tobacco use.

Obesity and overweight in relation to liver disease mortality in men: 38 year follow-up of the original Whitehall study.

Obesity has been implicated in the aetiology of liver disease. However, to date, evidence is largely drawn from cross-sectional studies, where interpretation is hampered by reverse causality, and from studies on clinical populations that have limited generalisability. In this prospective cohort study, data on body mass index (BMI) and covariates were collected at baseline on 18 863 male government employees (aged 40-69 years). Respondents were then followed up for a maximum of 38 years of age. Mortality surveillance gave rise to 13 129 deaths, 122 of which were due to liver disease (57 cancers; 65 non-cancers). In age-adjusted analyses, BMI was positively related to total liver disease mortality (hazards ratio per 1 s.d. increase in BMI; 95% confidence interval (CI): 1.36; 1.14, 1.62) in a graded fashion across the weight categories (P-value for trend: 0.01). The magnitude of this association was somewhat stronger for non-cancer liver disease deaths (1.47; 1.16, 1.86) than for cancer liver disease deaths (1.25; 0.96, 1.62). Excluding deaths in the first 10 years of follow-up somewhat strengthened the BMI-non-cancer liver disease association. Adjustment for socioeconomic position, other candidate confounders and mediating factors led to the modest attenuation of these associations. Further investigation in prospective cohort studies with more detailed data on liver disease, for instance using biochemical tests of liver function or hepatic ultrasonography, is warranted.

Life course influence of residential area on cause-specific mortality.

OBJECTIVE: To examine the relative influence of area of residence on mortality risk along the life course in different age groups and to see if this differs for causes known to be related differently to various models of the life course. METHODS: Individual data from the Censuses in 1960, 1970, 1980 and 1990 from Oslo, Norway, were linked to the death register 1990-1998. All male inhabitants living in Oslo in 1990 aged 30-69 years who had lived in Oslo at the three previous Censuses were included. RESULTS: In the youngest age group, area of residence closest to the time of death is most important for violent and psychiatric causes. In older age groups, area of residence at all time points in the period studied seemed to have a similar influence. Cardiovascular deaths were related to earlier as well as later area of residence in both young and old age groups. For violent and psychiatric causes, the most recent area may be the most important. CONCLUSION: This paper explores a research strategy to investigate how the area of residence through the life course influences mortality. The associations seem to vary according to age at, and cause of, death.

Initial experiences of using an automated volumetric measure of breast density: the standard mammogram form.

Limitations of area based measures of breast density have led several research groups to develop volumetric measures of breast density, for use in predicting risk and in epidemiological research. In this paper, we describe our initial experiences using an automated algorithm (standard mammogram form, SMF) to estimate the volume of the breast that is dense from digitized film mammograms. We performed analyses on 3816 mammograms of 626 women, who were part of the Glasgow Alumni Cohort and had mammograms taken within the Scottish Breast Screening Programme between 1989 and 2002. Absolute volume of dense breast tissue (SMF volume) and the percentage of the volume of the breast that is dense (SMF%) were calculated. The median (interquartile range) of SMF volume was 66 cm3 (48 to 98), and of SMF% was 23.4% (18.6 to 29.7). SMF%, but not SMF volume, was positively related to a six category classification (SCC) of visually assigned area-based breast density (increase in ln(SMF%) per category increase in SCC: 0.04% (95% CI: 0.03-0.05). The SMF algorithm produced lower SMF volume for craniocaudal (CC) compared with mediolateral oblique (MLO) views, but CC/MLO differences for SMF% were small. The mean right/left difference for ln(SMF volume) was -0.027 cm3 (95% confidence interval (CI) -0.044 to -0.009) and of ln(SMF%) was 0.005% (95% CI -0.008% to 0.019%). We present these initial data as a background for future analytical work using SMF.

Maternal age in pregnancy and offspring blood pressure in childhood in the Avon Longitudinal Study of Parents and Children (ALSPAC).

Associations between maternal age in pregnancy and offspring blood pressure (BP) at age 7(1/2) were investigated in 7623 singletons from the Avon Longitudinal Study of Parents and Children (ALSPAC). In models adjusted for age and sex there was an inverse relationship between maternal age and BP in children: beta = -0.06 mmHg per year of maternal age (95% CI -0.10 to -0.01, P = 0.02) for systolic BP and beta = -0.04 (95% CI -0.07 to -0.01, P = 0.02) for diastolic BP. However, this association disappeared after adjustment for confounding factors: beta = -0.02 mmHg per year of maternal age (95% CI -0.07 to 0.04, P = 0.5) for systolic BP and beta = -0.03 (95% CI -0.07 to 0.01, P = 0.2) for diastolic BP. We conclude that there is no evidence of a relationship between maternal age in pregnancy and childhood BP in this contemporary birth cohort.

Childhood IQ and all-cause mortality before and after age 65: prospective observational study linking the Scottish Mental Survey 1932 and the Midspan studies.

OBJECTIVES: The objective was to investigate how childhood IQ related to all-cause mortality before and after age 65. DESIGN: The Midspan prospective cohort studies, followed-up for mortality for 25 years, were linked to individuals' childhood IQ from the Scottish Mental Survey 1932. METHODS: The Midspan studies collected data on risk factors for cardiorespiratory disease from a questionnaire and at a screening examination, and were conducted on adults in Scotland in the 1970s. An age 11 IQ from the Scottish Mental Survey 1932, a cognitive ability test conducted on 1921-born children attending schools in Scotland, was found for 938 Midspan participants. The relationship between childhood IQ and mortality risk, adjusting for adulthood socio-economic confounders, was analysed. The effect of adjustment for childhood IQ on the relationship between established risk factors (blood pressure, smoking, height and respiratory function) and mortality was also investigated. RESULTS: For deaths occurring up to age 65, there was a 36% increased risk per standard deviation decrease (15 points) in childhood IQ which was reduced to 29% after adjusting for social class and deprivation category. There was no statistically significant relationship between childhood IQ and deaths occurring after the age of 65. Adjustment for childhood IQ attenuated the risk factor-mortality relationship in deaths occurring up to age 65, but had no effect in deaths occurring after age 65. CONCLUSIONS: Childhood IQ was significantly related to deaths occurring up to age 65, but not to deaths occurring after age 65.

Is the adiposity-associated FTO gene variant related to all-cause mortality independent of adiposity? Meta-analysis of data from 169,551 Caucasian adults.

Previously, a single nucleotide polymorphism (SNP), rs9939609, in the FTO gene showed a much stronger association with all-cause mortality than expected from its association with body mass index (BMI), body fat mass index (FMI) and waist circumference (WC). This finding implies that the SNP has strong pleiotropic effects on adiposity and adiposity-independent pathological pathways that leads to increased mortality. To investigate this further, we conducted a meta-analysis of similar data from 34 longitudinal studies including 169,551 adult Caucasians among whom 27,100 died during follow-up. Linear regression showed that the minor allele of the FTO SNP was associated with greater BMI (n = 169,551; 0.32 kg m(-2) ; 95% CI 0.28-0.32, P < 1 × 10(-32) ), WC (n = 152,631; 0.76 cm; 0.68-0.84, P < 1 × 10(-32) ) and FMI (n = 48,192; 0.17 kg m(-2) ; 0.13-0.22, P = 1.0 × 10(-13) ). Cox proportional hazard regression analyses for mortality showed that the hazards ratio (HR) for the minor allele of the FTO SNPs was 1.02 (1.00-1.04, P = 0.097), but the apparent excess risk was eliminated after adjustment for BMI and WC (HR: 1.00; 0.98-1.03, P = 0.662) and for FMI (HR: 1.00; 0.96-1.04, P = 0.932). In conclusion, this study does not support that the FTO SNP is associated with all-cause mortality independently of the adiposity phenotypes.

Body mass index in young adulthood and cancer mortality: a retrospective cohort study.

STUDY OBJECTIVE: To examine the relation between body mass index (BMI) in young adulthood and subsequent mortality from cancer. DESIGN: Cohort study. SETTING: University of Glasgow student health service. Weight and height were measured by a physician, and used to calculate BMI. PARTICIPANTS: 8335 men and 2340 women who attended the student health service while at university between 1948 and 1968, and who were followed up with the NHS central register. MAIN RESULTS: The main outcome measure was cancer mortality. Three hundred and thirty nine men and 82 women died of cancer during the follow up (mean 41 years). BMI was associated with mortality from all cancers in men and women, although it did not reach conventional statistical significance. The adjusted hazard ratio (HR) (95% CI) per 5 kg/m(2), was 1.22 (0.97 to 1.53) in men and 1.43 (0.95 to 2.16) in women. Two hundred men and 61 women died from cancers not related to smoking. The adjusted HR for mortality from these were 1.36 (1.02 to 1.82) and 1.80 (1.13 to 2.86) respectively. These results are adjusted for height, number of siblings, pulse rate, year of birth, age, smoking, birth order, number of siblings, and age at menarche in women. Site specific analyses, comparing the highest with the lowest quartile of the BMI distribution found increased risks of prostate cancer (n=28) and breast cancer among heavier subjects. No association between BMI and colorectal cancer was found. CONCLUSIONS: BMI in adolescence has lasting implications for risk of cancer mortality in later life. Future research will include measures of BMI throughout the lifecourse, to determine the period of greatest risk of obesity, in terms of cancer mortality.

Associations of height, leg length, and lung function with cardiovascular risk factors in the Midspan Family Study.

BACKGROUND: Taller people and those with better lung function are at reduced risk of coronary heart disease (CHD). Biological mechanisms for these associations are not well understood, but both measures may be markers for early life exposures. Some studies have shown that leg length, an indicator of pre-pubertal nutritional status, is the component of height most strongly associated with CHD risk. Other studies show that height-CHD associations are greatly attenuated when lung function is controlled for. This study examines (1) the association of height and the components of height (leg length and trunk length) with CHD risk factors and (2) the relative strength of the association of height and forced expiratory volume in one second (FEV(1)) with risk factors for CHD. SUBJECTS AND METHODS: Cross sectional analysis of data collected at detailed cardiovascular screening examinations of 1040 men and 1298 women aged 30-59 whose parents were screened in 1972-76. Subjects come from 1477 families and are members of the Midspan Family Study. SETTING: The towns of Renfrew and Paisley in the West of Scotland. RESULTS: Taller subjects and those with better lung function had more favourable cardiovascular risk factor profiles, associations were strongest in relation to FEV(1). Higher FEV(1) was associated with lower blood pressure, cholesterol, glucose, fibrinogen, white blood cell count, and body mass index. Similar, but generally weaker, associations were seen with height. These associations were not attenuated in models controlling for parental height. Longer leg length, but not trunk length, was associated with lower systolic and diastolic blood pressure. Longer leg length was also associated with more favourable levels of cholesterol and body mass index than trunk length. CONCLUSIONS: These findings provide indirect evidence that measures of lung development and pre-pubertal growth act as biomarkers for childhood exposures that may modify an individual's risk of developing CHD. Genetic influences do not seem to underlie height-CHD associations.

Secular changes in blood pressure in childhood, adolescence and young adulthood: systematic review of trends from 1948 to 1998.

One plausible reason for the decline in cardiovascular disease (CVD), and in particular stroke, in the last century is population reductions in blood pressure. Blood pressure tracks from childhood into adulthood, and early-life blood pressure is associated with increased cardiovascular risk but few studies have reported on blood pressure trends among young individuals who are free of CVD and not taking antihypertensive medication. Knowledge of such trends may improve understanding of the causes of hypertension and enhance prevention. We report that declines in blood pressure have been taking place in high-income countries in 5 to 34-year-olds of both sexes and from a range of ethnic groups for at least the last 50 years, indicating that exposures acting in early life are important determinants of blood pressure. Possible explanations for these favourable trends include improvements in early-life diet and there is also intriguing evidence suggesting that blood pressure may be programmed by sodium intake in infancy. Occurring throughout the blood pressure distribution, these trends may have made important contributions to declining CVD rates. There may therefore be scope for intervening in early life to prevent high blood pressure in adulthood, and the downward trends reported in several recent studies suggest that the prevalence of adult hypertension and cardiovascular risk will continue to decline. However, persisting high rates of CVD in the developed world, the impending CVD epidemic in developing countries, along with increasing childhood obesity, and the possibility that favourable blood pressure trends may be plateauing point to the need for enhanced measures to control blood pressure, and for further research to improve understanding of its determinants.

Childhood IQ and cardiovascular disease in adulthood: prospective observational study linking the Scottish Mental Survey 1932 and the Midspan studies.

This study investigated the influence of childhood IQ on the relationships between risk factors and cardiovascular disease (CVD), coronary heart disease (CHD) and stroke in adulthood. Participants were from the Midspan prospective cohort studies which were conducted on adults in Scotland in the 1970s. Data on risk factors were collected from a questionnaire and at a screening examination, and participants were followed up for 25 years for hospital admissions and mortality. 938 Midspan participants were successfully matched with their age 11 IQ from the Scottish Mental Survey 1932, in which 1921-born children attending schools in Scotland took a cognitive ability test. Childhood IQ was negatively correlated with diastolic and systolic blood pressure, and positively correlated with height and respiratory function in adulthood. For each of CVD, CHD and stroke, defined as either a hospital admission or death, there was an increased relative rate per standard deviation decrease (15 points) in childhood IQ of 1.11 (95% confidence interval 1.01-1.23), 1.16 (1.03-1.32) and 1.10 (0.88-1.36), respectively. With events divided into those first occurring before and those first occurring after the age of 65, the relationships between childhood IQ and CVD, CHD and stroke were only seen before age 65 and not after age 65. Blood pressure, height, respiratory function and smoking were associated with CVD events. Relationships were stronger in the early compared to the later period for smoking and FEV1, and stronger in the later compared to the earlier period for blood pressure. Adjustment for childhood IQ had small attenuating effects on the risk factor-CVD relationship before age 65 and no effects after age 65. Adjustment for risk factors attenuated the childhood IQ-CVD relationship by a small amount before age 65. Childhood IQ was associated with CVD risk factors and events and can be considered an important new risk factor.

Association between breast feeding and growth: the Boyd-Orr cohort study.

OBJECTIVE: To investigate the association of breast feeding with height and body mass index in childhood and adulthood. DESIGN: Historical cohort study, based on long term follow up of the Carnegie (Boyd-Orr) survey of diet and health in pre-war Britain (1937-1939). SETTING: Sixteen urban and rural districts in Britain. SUBJECTS: A total of 4999 children from 1352 families were surveyed in 1937-1939. Information on infant feeding and childhood anthropometry was available for 2995 subjects. MAIN OUTCOME MEASURES: Mean differences in childhood and adult anthropometry between breast and bottle fed subjects. RESULTS: Breast feeding was associated with the survey district, greater household income, and food expenditure, but not with number of children in the household, birth order, or social class. In childhood, breast fed subjects were significantly taller than bottle fed subjects after controlling for socioeconomic variables. The mean height difference among boys was 0.20 standard deviation (SD) (95% confidence interval (CI) 0.07 to 0.32), and among girls it was 0.14 SD (95% CI 0.02 to 0.27). Leg length, but not trunk length, was the component of height associated with breast feeding. In males, breast feeding was associated with greater adult height (difference: 0.34 SD, 95% CI 0.13 to 0.55); of the two components of height, leg length (0.26 SD, 95% CI 0.02 to 0.50) was more strongly related to breast feeding than trunk length (0.16 SD, 95% CI -0.04 to 0.35). Height and leg length differences were in the same direction but smaller among adult females. There was no association between breast feeding and body mass index in childhood or adulthood. CONCLUSIONS: Compared with bottle fed infants, infants breast fed in the 1920s and 1930s were taller in childhood and adulthood. As stature is associated with health and life expectancy, the possible long term impact of infant feeding on adult mortality patterns merits further investigation.

Breast density: agreement of measures from film and digital image.

Mammographic density, in particular density from digital images, is increasingly used in breast cancer research. We investigated the concordance between density assigned by the same radiologist to a mammogram film and a digital image of the same mammogram. Two density measures were investigated, Wolfe parenchymal patterns and a six category classification (SCC) system of density. Included in the study were 78 women, 528 mammograms. Crude and weighted Kappa statistics were used to estimate agreement between the density assigned from the film and the image. Kappa for Wolfe measures was 71%, p<0.001 and for SCC measures was 54%, p<0.001. Weighted Kappa values were 79%, p<0.001 and 77%, p<0.001, respectively. There was some evidence to suggest that the digitized image may be assigned a higher Wolfe but not numerical category than the original film, and the magnitude of these differences was small. Neither age nor mammogram view (craniocaudal or mediolateral oblique) were related to the likelihood of agreement of the two density measurements. This evidence justifies the use of digital images in the visual assessment of breast density in research studies.

Folic acid supplementation during pregnancy may protect against depression 21 months after pregnancy, an effect modified by MTHFR C677T genotype.

BACKGROUND/OBJECTIVES: As low folate status has been implicated in depression, high folate intake, in the form of supplements, during pregnancy might offer protection against depression during pregnancy and postpartum. SUBJECTS/METHODS: We examined the association between change in self-reported depressive symptoms (Edinburgh Postnatal Depression Scale) at different timepoints during and following pregnancy and self-reported folic acid supplementation during pregnancy in a prospective cohort of 6809 pregnant women. We also tested whether there was a main effect of methylenetetrahydrofolate reductase (MTHFR) C677T genotype (which influences folate metabolism and intracellular levels of folate metabolites and homocysteine) on change in depression scores, and carried out our analysis of folic acid supplementation and depression stratifying by genotype. RESULTS: We found no strong evidence that folic acid supplementation reduced the risk of depression during pregnancy and up to 8 months after pregnancy. However, we did find evidence to suggest that folic acid supplements during pregnancy protected against depression 21 months postpartum, and that this effect was more pronounced in those with the MTHFR C677T TT genotype (change in depression score from 8 months to 21 months postpartum among TT individuals was 0.66 (95% CI=0.31-1.01) among those not taking supplements, compared with -1.02 (95% CI=-2.22-0.18) among those taking supplements at 18 weeks pregnancy, P(difference)=0.01). CONCLUSIONS: Low folate is unlikely to be an important risk factor for depression during pregnancy and for postpartum depression, but may be a risk factor for depression outside of pregnancy, especially among women with the MTHFR C677T TT genotype.