Showing papers by "Debbie A Lawlor published in 2009"

Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution

Abstract: To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist-hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9x10(-11)) and MSRA (WC, P = 8.9x10(-9)). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6x10(-8)). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.

Genome-Wide Association Scan Meta-Analysis Identifies Three Loci Influencing Adiposity and Fat Distribution

Abstract: Vandervell Foundation and Wellcome Trust (068545/Z/02, GR072960, GR076113, GR069224, 086596/Z/08/Z)

Alanine Aminotransferase, γ-Glutamyltransferase, and Incident Diabetes: The British Women's Heart and Health Study and meta-analysis

Abstract: OBJECTIVE To estimate and compare associations of alanine aminotransferase (ALT) and γ-glutamyltransferase (GGT) with incident diabetes. RESEARCH DESIGN AND METHODS ALT and GGT were studied as determinants of diabetes in the British Women9s Heart and Health Study, a cohort of 4,286 women 60–79 years old (median follow-up 7.3 years). A systematic review and a meta-analysis of 21 prospective, population-based studies of ultrasonography, which diagnosed nonalcoholic fatty liver disease (NAFLD), ALT, and GGT as determinants of diabetes, were conducted, and associations of ALT and GGT with diabetes were compared. RESULTS Ultrasonography-diagnosed NAFLD was associated with more than a doubling in the risk of incident diabetes (three studies). ALT and GGT both predicted diabetes. The fully adjusted hazard ratio (HR) for diabetes per increase in one unit of logged ALT was 1.83 (95% CI 1.57–2.14, I 2 = 8%) and for GGT was 1.92 (1.66–2.21, I 2 = 55%). To directly compare ALT and GGT as determinants of diabetes, the fully adjusted risk of diabetes in the top versus bottom fourth of the ALT and GGT distributions was estimated using data from studies that included results for both markers. For ALT, the HR was 2.02 (1.59–2.58, I 2 = 27%), and for GGT the HR was 2.94 (1.98–3.88, I 2 = 20%), suggesting that GGT may be a better predictor ( P = 0.05). CONCLUSIONS Findings are consistent with the role of liver fat in diabetes pathogenesis. GGT may be a better diabetes predictor than ALT, but additional studies with directly determined liver fat content, ALT, and GGT are needed to confirm this finding.

Associations of Gestational Weight Gain With Offspring Body Mass Index and Blood Pressure at 21 Years of Age Evidence From a Birth Cohort Study

Abstract: Background— Maternal weight gain in pregnancy is positively associated with offspring body mass index (BMI) and obesity risk in childhood, but whether this increased risk extends into adulthood or results in increases in other cardiovascular risk factors such as elevated blood pressure (BP) is unclear. Methods and Results— We used a population-based birth cohort of 2432 individuals (50% male) born in Brisbane, Australia, between 1981 and 1983 to prospectively examine the association between maternal gestational weight gain (GWG) and offspring BMI and BP at 21 years. On average, each mother gained 14.8 kg (SD, 5.1 kg) during her pregnancy. At 21 years of age, offspring mean BMI, systolic BP, and diastolic BP were 24.2 kg/m2 (SD, 4.9 kg/m2), 116.4 mm Hg (SD, 14.5 mm Hg), and 67.7 mm Hg (SD, 8.5 mm Hg), respectively. Offspring BMI was on average 0.3 kg/m2 (95% confidence interval, 0.1 to 0.4 kg/m2) higher for each 0.1-kg/wk greater GWG after adjustment for potential confounding factors. Systolic BP also was ...

Associations of circulating C-reactive protein and interleukin-6 with cancer risk: findings from two prospective cohorts and a meta-analysis.

Abstract: We investigated the associations of circulating C-reactive protein (CRP) and interleukin-6 (IL-6) with cancer risk. We examined the associations of CRP and IL-6 with incident cancer in two prospective cohorts, the British Women’s Heart and Health Study (4,286 women aged 60–80) and the Caerphilly Cohort (2,398 men aged 45–59) using Cox regression and pooled our findings with previous prospective studies’ in fixed and random effects meta-analyses. CRP and IL-6 were associated with some incident cancers in our cohorts, but the numbers of cancer cases were small. In our meta-analyses elevated CRP was associated with an increased overall risk of cancer (random effects estimate (RE): 1.10, 95% CI: 1.02, 1.18) and lung cancer (RE: 1.32, 95% CI: 1.08, 1.61). Its associations with colorectal (RE: 1.09, 95% CI: 0.98, 1.21) and breast cancer risks (RE: 1.10, 95% CI: 0.97, 1.26) were weaker. CRP appeared unrelated to prostate cancer risk (RE: 1.00 0.88, 1.13). IL-6 was associated with increased lung and breast cancer risks and decreased prostate cancer risk, and was unrelated to colorectal cancer risk. Our findings suggest an etiological role for CRP and IL-6 in some cancers. Further large prospective and genetic studies would help to better understand this role.

Gene-centric Association Signals for Lipids and Apolipoproteins Identified via the HumanCVD BeadChip

Abstract: Blood lipids are important cardiovascular disease (CVD) risk factors with both genetic and environmental determinants. The Whitehall II study (n = 5592) was genotyped with the gene-centric HumanCVD BeadChip (Illumina). We identified 195 SNPs in 16 genes/regions associated with 3 major lipid fractions and 2 apolipoprotein components at p 12,500) revealed previously unreported associations of SH2B3 (p 1 mmol/L in LDL cholesterol [∼1 SD of the trait distribution]). These data suggest that multiple common alleles of small effect can make important contributions to individual differences in blood lipids potentially relevant to the assessment of CVD risk. These genes provide further insights into lipid metabolism and the likely effects of modifying the encoded targets therapeutically.

Common mental disorder and obesity: insight from four repeat measures over 19 years: prospective Whitehall II cohort study

Abstract: Objectives To examine potential reciprocal associations between common mental disorders and obesity, and to assess whether dose-response relations exist. Design Prospective cohort study with four measures of common mental disorders and obesity over 19 years (Whitehall II study). Setting Civil service departments in London. Participants 4363 adults (28% female, mean age 44 years at baseline). Main outcome Common mental disorder defined as general health questionnaire “caseness;” overweight and obesity based on Word Health Organization definitions. Results In models adjusted for age, sex, and body mass index at baseline, odds ratios for obesity at the fourth screening were 1.33 (95% confidence interval 1.00 to 1.77), 1.64 (1.13 to 2.36), and 2.01 (1.21 to 3.34) for participants with common mental disorder at one, two, or three preceding screenings compared with people free from common mental disorder (P for trend<0.001). The corresponding mean differences in body mass index at the most recent screening were 0.20, 0.31, and 0.50 (P for trend<0.001). These associations remained after adjustment for baseline characteristics related to mental health and exclusion of participants who were obese at baseline. In addition, obesity predicted future risk of common mental disorder, again with evidence of a dose-response relation (P for trend=0.02, multivariable model). However, this association was lost when people with common mental disorder at baseline were excluded (P for trend=0.33). Conclusions These findings suggest that in British adults the direction of association between common mental disorders and obesity is from common mental disorder to increased future risk of obesity. This association is cumulative such that people with chronic or repeat episodes of common mental disorder are particularly at risk of weight gain.

The association between BMI and mortality using offspring BMI as an indicator of own BMI: large intergenerational mortality study

Abstract: Objectives To obtain valid estimates of the association between body mass index (BMI) and mortality by using offspring BMI as an instrumental variable for own BMI. Design Cohort study based on record linkage, with 50 years of follow-up for mortality. Associations of offspring BMI with all cause and cause specific maternal and paternal mortality were estimated as hazard ratios per standard deviation of offspring BMI. Setting A large intergenerational prospective population based database covering the general population of Sweden. Participants More than one million Swedish parent-son pairs. Results The final dataset analysed contained information on 1 018 012 mother-son pairs (122 677 maternal deaths) and 1 004 617 father-son pairs (242 126 paternal deaths). For some causes of death, the patterns of associations between offspring BMI and mortality were similar to those seen for own BMI and mortality in previous studies. Parental mortality from diabetes, coronary heart disease, and kidney cancer had the strongest positive associations with offspring BMI (for example, hazard ratio (HR) for coronary heart disease per standard deviation increase in offspring BMI for mothers 1.15, 95% CI 1.14 to 1.17 and for fathers 1.10, 1.09 to 1.11). However, in contrast to the inverse association of own BMI with lung cancer and respiratory disease mortality seen in other studies, there was a positive association between offspring BMI and lung cancer mortality in mothers (1.12, 1.09 to 1.15) and fathers (1.03, 1.02 to 1.05) and between offspring BMI and respiratory mortality in mothers (1.05, 1.02 to 1.08) and fathers (1.02, 1.00 to 1.04). Associations of own BMI and offspring BMI with all cause, cardiovascular disease related, and non-cardiovascular disease related mortality were compared in a subset of father-son pairs (n=72 815). When offspring BMI was used as an instrumental variable for paternal BMI, the causal association between BMI and paternal cardiovascular disease mortality (HR per standard deviation of BMI 1.82, 95% CI 1.17 to 2.83) was stronger than that indicated by the directly observed association between own BMI and cardiovascular disease mortality (1.45, 1.31 to 1.61). Conclusions Use of offspring BMI as a predictor of own BMI, a technique that avoids problems of reverse causality, suggests that positive associations of BMI with all cause and cardiovascular mortality may be underestimated in conventional observational studies. Use of offspring BMI instead of own BMI in analyses of respiratory disease and lung cancer mortality, for which previous studies have reported consistent and strong inverse associations with own BMI, suggests that such studies have overstated the apparent adverse consequences of lower BMI with respect to these outcomes.

Physical fitness in relation to transport to school in adolescents: the Danish youth and sports study

Abstract: In many Western countries, there are concerns about declining levels of physical activity in school-aged children. Active transport is one way to increase physical activity in children, but few studies have evaluated whether active transport in school-aged children and adolescents has beneficial effects on fitness and, if so, whether different modes of transport affect different aspects of fitness. In this study, we examined the association of active transport with different aspects of fitness in a representative Danish sample of 545 boys and 704 girls, 15-19 years of age. Physical fitness was assessed through a number of field tests, including a maximal cycle test, dynamic and static strength in different muscle groups, muscle endurance, flexibility and agility. Transport to school was reported as the mode of transport. Almost two-thirds of the population cycled to school. Cyclists had higher aerobic power than both walkers and passive travelers (4.6-5.9%). Isometric muscle endurance (10-16%), dynamic muscle endurance in the abdominal muscles (10%) and flexibility (6%) were also higher in cyclists compared with walkers and passive travelers. Mode of travel was not related to leisure-time sports participation. Our findings suggest that commuter bicycling may be a way to improve health in adolescents.

Family matters: designing, analysing and understanding family based studies in life course epidemiology

Abstract: 1. Why family matters - an introduction SECTION 1: WHAT CAN FAMILY-BASED STUDIES TELL US ABOUT LIFE COURSE EPIDEMIOLOGY? 2. Theoretical underpinning for the use of intergenerational studies in life course epidemiology 3. Theoretical underpinning for the use of sibling studies in life course epidemiology 4. Theoretical underpinning for the use of twin studies in life course epidemiology 5. Discussant chapter: summary of the theoretical approaches to family-based studies in life course epidemiology SECTION 2: THE PRACTICALITIES OF UNDERTAKING FAMILY-BASED STUDIES 6. Theoretical underpinning for the use of intergenerational studies in life birth cohorts: a resource for life course studies 7. Family-based life course studies in low- and middle-income countries 8. Using available family members as proxies to provide information on other family members who are difficult to reach 9. Discussant chapter: the practicalities of undertaking family-based studies SECTION 3: HOW TO UNDERTAKE STATISTICAL ANALYSES OF FAMILY-BASED STUDIES 10. Statistical considerations in intergenerational studies 11. Random effects models for sibling and twin-based studies in life course epidemiology 12. Discussant chapter: statistical considerations in family-based life course studies SECTION 4: USE OF FAMILY-BASED STUDIES IN LIFE COURSE EPIDEMIOLOGY 13. Family-based studies applied to the influence of early life factors on cardiovascular disease 14. How family-based studies have added to the understanding of life course epidemiology of mental health 15. How family-based studies have added to understanding the life course epidemiology of reproductive health 16. Discussant chapter: using family-based designs in life course epidemiology 17. The future of family-based studies in life course epidemiology: challenges and opportunities

Association of the DRD2 gene Taq1A polymorphism and smoking behavior: a meta-analysis and new data

Abstract: Introduction: Many studies have investigated the association of the dopamine type-2 receptor (DRD2) Taq1A polymorphism with tobacco use and cigarette smoking behaviors, but findings remain equivocal. There is a biological basis for considering that this association differs by sex, and differences in subpopulations might explain some of the contradictory evidence.

Physical Activity, Mortality, and Cardiovascular Disease: Is Domestic Physical Activity Beneficial?

Abstract: Intense domestic physical activity (IDPA) is promoted by preventive health campaigns, but this recommendation is not supported by evidence. The authors used data from the 1995, 1998, and 2003 Scottish Health Survey samples and the associated mortality and hospital episode records to determine the independent effects of IDPA on cardiovascular disease (CVD) events and all-cause mortality. The sample comprised 13,726 (6,102 men) CVD-free respondents (>= 35 years). Multivariable survival analysis assessed the relation between IDPA and the risk for CVD (fatal/nonfatal combined) or all-cause mortality. During 8.4 (standard deviation, 3.4) years of follow-up, there were 1,103 deaths (573 among men) and 890 CVD events (521 among men). Participation in IDPA was associated with lower all-cause mortality (men: relative risk = 0.68, 95% confidence interval: 0.50, 0.91; women: relative risk = 0.70, 95% confidence interval: 0.52, 0.93). In both sexes, IDPA was unrelated to the risk for CVD. Total physical activity (including IDPA) was unrelated to fatal/nonfatal CVD, but when domestic activity was excluded from the calculations there was an association (men: relative risk = 0.76, 95% confidence interval: 0.58, 0.98; women: relative risk = 0.68, 95% confidence interval: 0.50, 0.93). These results indicate that IDPA may not offer protection against CVD, but it may protect against all-cause mortality. CVD preventive efforts may need to focus on moderate-to-vigorous-intensity physical activities other than those performed in and around the household.

Height and Site-specific Cancer Risk: A Cohort Study of a Korean Adult Population

Abstract: To evaluate the association between height and risk of cancer in an East Asian, middle-income population, the authors followed up a cohort of 788,789 Koreans (449,214 men and 339,575 women) aged 40-64 years for cancer incidence between 1994 and 2003. Cox proportional hazards regression analysis was used to evaluate the association. Each 5-cm increment in height was associated with 5% and 7% higher risk of all-sites cancer in men and women, respectively, after adjustment for age, body mass index, and behavioral and socioeconomic factors. When the associations were evaluated for site-specific cancers, a positive association was observed for cancer of the colon and thyroid in both men and women. Among gender-specific cancers, prostate cancer was positively associated with height in men. In women, there was a positive association between height and cancers of the breast and ovary, which did not change even after additional adjustment for reproductive factors. Although more clarification is needed for some site-specific cancers, the same positive association of height with cancer in a middle-income Korean population as found in high-income Western populations supports the influence of early life environment on cancer development in adulthood.

Two British women studies replicated the association between the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) and BMI

Abstract: The goal of this study is to investigate the relationship between the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) and body mass index (BMI) in two sizable and well-characterized populations of British women: the British Women's Heart and Health Study (BWHHS) (age 60–79 years) and the mothers from the Avon Longitudinal Study of Parents and Children (age 16–44 years). We genotyped the Val66Met polymorphism (rs6265) in these two populations, and conducted a linear regression analysis to test for an association between this polymorphism and BMI. Both study populations indicated an association between BMI and the Val66Met polymorphism, with individuals carrying the Met–Met genotype having a lower mean BMI than those with the Val–Met or Val–Val genotypes (in the BWHHS): mean BMI difference=−0.911 kg/m2, 95% confidence interval (CI): −1.70 to −0.12, P=0.023; in the mothers from the Avon Longitudinal Study of Parents and Children (ALSPAC): mean BMI difference=−0.57 kg/m2, 95%CI: −1.08 to −0.054, P=0.03). In a pooled analysis of these two studies, together with one further published study that provided data in a suitable format for inclusion in our meta-analysis, we found a pooled difference of −0.76 (95% CI: −1.16, −0.036) for adult women; I2–test for heterogeneity=51%, P=0.13. Our study indicated an association between BDNF and BMI in two general population studies of women. The exact role of BDNF in weight regulation merits further investigation.

Physical Activity, Mortality, and Cardiovascular Disease: Is Domestic Physical Activity Beneficial?The Scottish Health Survey—1995, 1998, and 2003

Abstract: Intense domestic physical activity (IDPA) is promoted by preventive health campaigns, but this recommendation is not supported by evidence. The authors used data from the 1995, 1998, and 2003 Scottish Health Survey samples and the associated mortality and hospital episode records to determine the independent effects of IDPA on cardiovascular disease (CVD) events and all-cause mortality. The sample comprised 13,726 (6,102 men) CVD-free respondents (> or =35 years). Multivariable survival analysis assessed the relation between IDPA and the risk for CVD (fatal/nonfatal combined) or all-cause mortality. During 8.4 (standard deviation, 3.4) years of follow-up, there were 1,103 deaths (573 among men) and 890 CVD events (521 among men). Participation in IDPA was associated with lower all-cause mortality (men: relative risk = 0.68, 95% confidence interval: 0.50, 0.91; women: relative risk = 0.70, 95% confidence interval: 0.52, 0.93). In both sexes, IDPA was unrelated to the risk for CVD. Total physical activity (including IDPA) was unrelated to fatal/nonfatal CVD, but when domestic activity was excluded from the calculations there was an association (men: relative risk = 0.76, 95% confidence interval: 0.58, 0.98; women: relative risk = 0.68, 95% confidence interval: 0.50, 0.93). These results indicate that IDPA may not offer protection against CVD, but it may protect against all-cause mortality. CVD preventive efforts may need to focus on moderate-to-vigorous-intensity physical activities other than those performed in and around the household.

Accuracy of height and weight data from child health records

Abstract: Background: There is limited knowledge of the accuracy of height and weight measurements from child health records, despite widespread use for research and clinical care. We assess the accuracy of such measurements, using research measurements as the gold standard. Methods: We compare height/length and weight measurements from clinics of the Avon Longitudinal Study of Parents and Children with routinely collected child health records within 2 months of the clinic date at age 4 (n = 345), 8 (n = 1051), 12 (n = 139), 18 (n = 649), 25 (n = 183), and 43 months (n = 123). To adjust for age differences at measurement, growth data were converted into standard deviation scores using the UK 1990 growth reference. Results: Mean weight standard deviation score (SDS) differences were ⩽0.08, with mean predicted differences ⩽0.1 kg (eg, mean predicted difference at 8 months −0.011 kg, 95% level of agreement −0.64 to 0.62 kg). Mean height SDS differences were ⩽0.45, with mean predicted differences ⩽0.9 cm (eg, mean predicted difference at 8 months −0.59 cm, 95% level of agreement −3.84 to 2.66 cm). There was indication of lower accuracy at 4 months old (mean predicted height difference at 4 months −0.91 cm, 95% level of agreement −4.61 to 2.79 cm), but this decreased when the age difference between measurements was reduced. Routine measurements slightly overestimated heights of tall children and underestimated those of short children, but otherwise differences were not associated with sex, social class, birth weight, birth length, or maternal anthropometry. Conclusion: Routinely collected child health record height/length and weight data are compatible with no systematic bias, at least in children over 8 months old, supporting their use in clinical practice and research.

Fasting Blood Glucose and the Risk of Stroke and Myocardial Infarction

Abstract: Background— Although diabetes is a well-known risk factor of atherosclerotic cardiovascular diseases, the cardiovascular disease risk of glycemia below the current diabetic threshold remains uncertain. Methods and Results— A total of 652 901 Korean men aged 30 to 64 years from the Korean National Health Insurance System were categorized into 8 groups by fasting blood glucose (FBG) level at baseline and were followed up for cardiovascular diseases occurrence during 1992–2001. Over the follow-up period of 8.8 years, 10 954 stroke and 3766 myocardial infarction events occurred. In age-adjusted analyses, there was evidence of linear associations between FBG and myocardial infarction, ischemic stroke, and intracerebral hemorrhagic stroke. However, with additional adjustment for socioeconomic position, behaviors, and other cardiovascular disease risk factors, the associations with myocardial infarction and intracerebral hemorrhagic stroke were markedly attenuated with increased risk only at the highest FBG leve...

Lactase persistence-related genetic variant: population substructure and health outcomes

Abstract: Lactase persistence is an autosomal-dominant trait that is common in European-derived populations. A basic tendency for lactase persistence to increase from the southeast to the northwest across European populations has been noted, but such trends within countries have not been extensively studied. We genotyped the C/T−13910 variant (rs4988235) that constitutes the putatively causal allele for lactase persistence (T allele representing persistence) in a general population sample of 3344 women aged 60–79 years from 23 towns across Britain. We found an overall frequency of 0.253 for the C (lactase non-persistence) allele, but with considerable gradients of decreasing frequency from the south to the north and from the east to the west of Britain for this allele. Daily sunlight was positively related to C (non-persistence) allele prevalence. However, sunlight exposure and latitude are strongly correlated, and it was not possible to identify which is the primary factor statistically underlying the distribution of lactase persistence. The C/T−13910 variant (rs4988235) was not related to drinking milk or bone health (although drinking milk itself was protective of bone health), and was essentially unrelated to a wide range of other lifestyle, health and demographic characteristics. One exception was general health being rated as being poor or fair, for which there was an odds ratio of 1.38 (1.04, 1.84) for women homozygous for the C allele; on adjustment for latitude and longitude of place of birth, this attenuated to 1.19 (0.87, 1.64). The lactase persistence variant could contribute to the examination of data for the existence of, and then statistical control for, population substructure in genetic association studies.

Genetic variants in the vitamin d receptor are associated with advanced prostate cancer at diagnosis: findings from the prostate testing for cancer and treatment study and a systematic review

Abstract: Low levels of plasma vitamin D have been implicated as a possible risk factor for both prostate cancer incidence and advanced disease, and recent phase II trials suggest that vitamin D supplementation might delay progression of prostate cancer. Common polymorphisms in the vitamin D receptor (VDR) are associated with VDR activity and are therefore potentially useful proxies for assessing whether vitamin D is causally related to advanced prostate cancer. We genotyped five well-known VDR polymorphisms in 1,604 men with prostate cancer from the Prostate Testing for Cancer and Treatment study. Our aim was to examine the association between VDR polymorphisms and cancer stage (localized versus advanced) as well as cancer grade (Gleason score or=7). Moreover, we also carried out a systematic review and meta-analysis of 13 similar studies. As a result of our meta-analysis, we revealed three polymorphisms, BsmI, ApaI, and TaqI, associated with high Gleason score with an overall summary odds ratios (95% confidence intervals) of 1.12 (1.00-1.25; bb versus BB + Bb), 1.25 (1.02-1.53; aa versus AA + Aa), and 0.82 (0.69-0.98; Tt + tt versus TT), respectively. The haplotype analysis revealed that the BsmI (B)-ApaI (A)-TaqI (t) participants compared with BsmI (b)-ApaI (a)-TaqI (T) individuals were less likely to have high Gleason scores (odds ratio, 0.84; 95% confidence interval, 0.71-1.00; P(unadjusted) = 0.050; P(adjusted) = 0.014). Our finding provides some support for the hypothesis that low levels of vitamin D may increase the risk of prostate cancer progression.

Birth cohort studies: past, present and future

Abstract: There is considerable interest in the suggestion that exposures acting in early life, together with those accumulating in adulthood, and even between generations, have long-term consequences for health in adulthood. Potential early-life factors that might impact on adult health, include those acting during (or before) the period of fetal development (such as endocrine disruptors, maternal diet, smoking or alcohol), those in infancy (such as breastor bottle feeding, exposure to moulds and damp) and those acting in childhood and adolescence (such as environmental toxins, diet and levels of physical activity, passive exposure to tobacco smoke and own initiation of smoking and alcohol consumption). Nearly all domains of later health experience, including cardiovascular disease, various cancers, respiratory disease, cognitive decline and psychological health, have been associated with early-life exposures of one kind or another. These research interests began to some extent with the exploration of data from historical birth cohorts and new uses of existing birth cohorts, with the results from those studies providing a stimulus for the revitalization of more historical pregnancy/birth cohorts and the establishment of new ones. Birth cohorts are used for testing a wide range of hypotheses and there is evidence for a marked increase over the last decade in studies that use data from birth cohorts being published. A quick glance through eight recent issues of the International Journal of Epidemiology from April 2008 to June 2009 shows that there is not one without a research paper using data from a birth cohort study and that of the total 270 research papers published in these volumes, 28 (10%) used data from a birth cohort study. In the most recent issue (June 2009), with a special theme on intergenerational influences on health, 7 (33%) of the 21 research papers used data from birth cohort studies. In this August 2009 issue, two papers from recently established birth cohorts in India and South Africa, and a third that uses record linkage to establish a Norwegian birth cohort study, provide further examples. In addition, the photoessay by Ian Beesley and poem by Ian MacMillan provide information on a new birth cohort—the Born in Bradford (BiB) Study. Birth cohorts are expensive and several of the most recent National birth cohorts, including those from Norway, Denmark and the USA, have recruited, or plan to recruit, 100 000 parents and children in order to determine the genetic and life-course influences on childhood health, development and/or common complex diseases in adulthood. In the UK, where there is a strong tradition of national birth cohort studies going back to the 1940s, funding has been earmarked from the Government’s Large Facilities Capital Fund for a new birth cohort commencing around 2012, with the aim of supporting ‘innovative research spanning the interface between the biomedical and social sciences’. The call specification requesting bids for the leadership team of this new cohort stipulates that data collection must be hypothesis driven (http://www.esrcsocietytoday. ac.uk/ESRCInfoCentre/opportunities/current_funding_ opportunities/birthcohort2012.aspx). Given the investment of money and human resources in these new

Hyperglycemia, Type 2 Diabetes, and Depressive Symptoms: The British Whitehall II study

Abstract: OBJECTIVE: To examine the recent suggestion that impaired fasting glucose may protect against depression, whereas a diagnosis of diabetes might then result in depression. RESEARCH DESIGN AND METHODS: Cross-sectional analysis of 4,228 adults (mean age 60.7 years, 73.0% men) who underwent oral glucose tolerance testing and completed the Center for Epidemiologic Studies Depression scale (CES-D). RESULTS: After adjustment for demographic factors, health behaviors, and clinical measurements (BMI, waist circumference, lipid profile, and blood pressure), there was a U-shaped association between fasting glucose and depression (P(curve) = 0.001), with elevated CES-D at low and very high glucose levels. This finding was replicable with 2-h postload glucose (P = 0.11) and A1C (P = 0.007). CONCLUSIONS: The U-shaped association between blood glucose and CES-D, with the lowest depression risk seen among those in the normoglycemic range of A1C, did not support the hypothesized protective effect of hyperglycemia.

Challenges and novel approaches in the epidemiological study of early life influences on later disease.

Abstract: The influence of factors acting during early life on health outcomes of offspring is of considerable research and public health interest. There are, however, methodological challenges in establishing robust causal links, since exposures often act many decades before outcomes of interest, and may also be strongly related to other factors, generating considerable degrees of potential confounding. With respect to pre-natal factors, the degree of confounding can sometimes be estimated by comparing the association between exposures experienced by the mother during pregnancy and outcomes among the offspring with the association of the same exposures experienced by the father during the pregnancy period and offspring outcomes. If the effects are due to an intra-uterine exposure, then maternal exposure during pregnancy should have a clearly greater influence than paternal exposure. If confounding by socio-economic, behavioural or genetic factors generates the association then maternal and paternal pregnancy exposures will be related in the same way with the outcome. For early life exposures it is also possible to compare outcomes in siblings who are concordant or discordant for the exposure, which will reduce the influence of family-level confounding factors. A different approach is that of Mendelian randomization, which utilises genetic variants of known effect that can proxy for modifiable exposures and are also not in general related to potential confounding factors, or influenced by disease. In other settings the use of non-genetic instrumental variables is possible. A series of examples of the application of these approaches are presented and their potentials and limitations discussed. Other epidemiological strategies are briefly reviewed. It is concluded that the naive acceptance of findings utilising conventional epidemiological methods in this setting is misplaced.

Influence of life course socioeconomic position on older women's health behaviors: findings from the British Women's Heart and Health Study.

Abstract: Objectives. We examined the association between health behaviors and socioeconomic status (SES) in childhood and adult life.Methods. Self-reported diet, smoking, and physical activity were determined among 3523 women aged 60 to 79 years recruited from general practices in 23 British towns from 1999 through 2001.Results. The most affluent women reported eating more fruit, vegetables, chicken, and fish and less red or processed meat than did less affluent women. Affluent women were less likely to smoke and more likely to exercise. Life course SES did not influence the types of fat, bread, and milk consumed. Adult SES predicted consumption of all foods considered and predicted smoking and physical activity habits independently of childhood SES. Childhood SES predicted fruit and vegetable consumption independently of adult SES and, to a lesser extent, predicted physical activity. Downward social mobility over the life course was associated with poorer diets and reduced physical activity.Conclusions. Among old...

Evaluating the causal relevance of diverse risk markers: horizontal systematic review

Abstract: Objectives To develop a new methodology to systematically compare evidence across diverse risk markers for coronary heart disease and to compare this evidence with guideline recommendations. Design “Horizontal” systematic review incorporating different sources of evidence. Data sources Electronic search of Medline and hand search of guidelines. Study selection Two reviewers independently determined eligibility of studies across three sources of evidence (observational studies, genetic association studies, and randomised controlled trials) related to four risk markers: depression, exercise, C reactive protein, and type 2 diabetes. Data extraction For each risk marker, the largest meta-analyses of observational studies and genetic association studies, and meta-analyses or individual randomised controlled trials were analysed. Results Meta-analyses of observational studies reported adjusted relative risks of coronary heart disease for depression of 1.9 (95% confidence interval 1.5 to 2.4), for top compared with bottom fourths of exercise 0.7 (0.5 to 1.0), for top compared with bottom thirds of C reactive protein 1.6 (1.5 to 1.7), and for diabetes in women 3.0 (2.4 to 3.7) and in men 2.0 (1.8 to 2.3). Prespecified study limitations were more common for depression and exercise. Meta-analyses of studies that allowed formal Mendelian randomisation were identified for C reactive protein (and did not support a causal effect), and were lacking for exercise, diabetes, and depression. Randomised controlled trials were not available for depression, exercise, or C reactive protein in relation to incidence of coronary heart disease, but trials in patients with diabetes showed some preventive effect of glucose control on risk of coronary heart disease. None of the four randomised controlled trials of treating depression in patients with coronary heart disease reduced the risk of further coronary events. Comparisons of this horizontal evidence review with two guidelines published in 2007 showed inconsistencies, with depression prioritised more in the guidelines than in our review. Conclusions This horizontal systematic review pinpoints deficiencies and strengths in the evidence for depression, exercise, C reactive protein, and diabetes as unconfounded and unbiased causes of coronary heart disease. This new method could be used to develop a field synopsis and prioritise future development of guidelines and research.

Influence of area and individual lifecourse deprivation on health behaviours: findings from the British Women's Heart and Health Study

Abstract: BackgroundVariable findings have been reported on the contribution of census-based measures of area deprivation over and above that of individual socioeconomic position (SEP) on health outcomes. This study aims to examine the association between residence in a deprived area and health behaviours (diet, smoking and physical inactivity), and how this association is influenced by lifecourse SEP of individuals.DesignA population-based longitudinal study of women aged 60-79 years in 1999-2001 recruited from one general practice in each of 23 British towns.MethodsThree thousand five hundred twenty-two women were included in the analyses. Area deprivation scores were derived from postcode for residence and lifecourse SEP scores were calculated using 10 individual level indicators of childhood and adult circumstances. To allow direct comparisons of effect of area deprivation and individual SEP, we standardized both measures by generating relative indices of inequality.ResultsBoth area deprivation and lifecourse S...

Is IQ in Childhood Associated with Suicidal Thoughts and Attempts? Findings from The Mater University Study of Pregnancy and Its Outcomes

Abstract: This study explores associations of IQ at age 14 with adult symptoms of suicidal thoughts and attempts at age 21. Analysis was based on the Mater University Study of Pregnancy and its outcomes, an Australian prospective birth cohort study started in Brisbane Australia in 1981. We assessed associations with suicide thoughts, plans, and attempts. We used two measures of IQ: the Raven's Standard Progressive Matrices and the Wide Range Achievement Test. In multivariable analyses, there was an inverse association between Raven's IQ and suicide thoughts, plans, and attempts, but no strong evidence of an association between the WRAT3 and the three suicidal items. Specific aspects of intelligence may be associated with suicidal thoughts, plans, and attempts.

Alanine aminotransferase, gamma-glutamyltransferase (GGT) and all-cause mortality: results from a population-based Danish twins study alanine aminotransferase, GGT and mortality in elderly twins.

Abstract: Alanine aminotransferase (ALT) and γ-glutamyltransferase (GGT) are widely used markers of liver disease. Limited evidence suggests that ALT is the liver enzyme most closely associated with liver fat content and non-alcoholic fatty liver disease (NAFLD) (1). γ-Glutamyltransferase has long been considered a marker of excessive alcohol intake and more recently has been suggested to reflect oxidative stress (2) and exposure to environmental pollutants (3), as well as NAFLD. Consistent evidence shows that both ALT and GGT are positively associated with the metabolic syndrome (4) and predict incident diabetes (5). γ-Glutamyltransferase also predicts incident coronary heart disease (CHD) and stroke above and beyond established risk factors (6); fewer studies have assessed ALT as a determinant of incident CHD and stroke than GGT, but current evidence suggests a weaker association for ALT than for GGT with CHD and stroke risk. As cardiovascular diseases are a leading cause of mortality, it would be reasonable to hypothesize that liver enzymes predict all-cause mortality. Several population-based cohort studies have examined the association of these liver enzymes with all-cause mortality. Recent analysis of the NHANES-III found that the hazard ratio (HR) among participants with unexplained elevation of ALT (attributed to NAFLD) was 1.37 [95% confidence interval (CI) 0.98, 1.91] compared with other participants (7). Alanine aminotransferase also predicted mortality among participants with a body mass index (BMI) < median (22.7 kg/m2) in a Japanese cohort, but not among participants with a BMI greater than the median (8). Two additional cohort studies found that GGT, but not ALT, predicts all-cause mortality (9, 10). Finally, associations of GGT with all-cause mortality have been found in several prospective cohort studies (11–13). None of these studies, however, controlled for genetic variation as well as fetal and early life exposure, whether genetic or environmental. This may be of consequence because evidence suggests that both genetics (14) and exposures in utero (15), as reflected by birth weight and pre-pubertal exposures, as reflected by leg length (16), are associated with adults levels of ALT and GGT. Here, we studied the associations of ALT and GGT with all-cause mortality using data for twins included in the Danish Twin Registry. The advantage of using twin data is that intra-uterine exposures (genetic and environmental) and shared environmental exposures in early life are inherently controlled for in monozygotic twins, and partially in dizygotic twins (for genetic exposures). We also control for adult lifestyle factors and examine whether potential associations of liver enzymes with mortality can be attributed to pre-existing diabetes and/or cardiovascular diseases.

A Review of Lifetime Risk Factors for Mortality

Abstract: This review was undertaken for the Faculty and Institute of Actuaries as part of their programme to encourage research collaborations between health researchers and actuaries in order to understand better the factors influencing mortality and longevity. The authors presented their findings in a number of linked sessions at the Edinburgh conference (Joining Forces on Mortality and Longevity) in October 2009 and contributed to this overview. The purpose is to review evidence for the impact on adult mortality of characteristics of the individual's lifetime socioeconomic or psychosocial environment or phenotype at the behavioural; multi-system (e.g. cognitive and physical function); or body system level (e.g. vascular and metabolic traits) that may be common risk factors for a number of major causes of death. This review shows there is growing evidence from large studies and systematic reviews that these individual characteristics, measured in pre-adult as well as the adult life, are associated with later mortality risk. The relative contribution of lifetime environment, genetic factors and chance, whether these contributions change with age, and the underlying social and biological pathways are still to be clarified. This review identifies areas where further life course research is warranted.