Large trans-ethnic meta-analysis identifies AKR1C4 as a novel gene associated with age at menarche.

STUDY QUESTION: Does the expansion of genome-wide association studies (GWAS) to a broader range of ancestries improve the ability to identify and generalise variants associated with age at menarche (AAM) in European populations to a wider range of world populations? SUMMARY ANSWER: By including women with diverse and predominantly non-European ancestry in a large-scale meta-analysis of AAM with half of the women being of African ancestry, we identified a new locus associated with AAM in African-ancestry participants, and generalised loci from GWAS of European ancestry individuals. WHAT IS KNOWN ALREADY: AAM is a highly polygenic puberty trait associated with various diseases later in life. Both AAM and diseases associated with puberty timing vary by race or ethnicity. The majority of GWAS of AAM have been performed in European ancestry women. STUDY DESIGN, SIZE, DURATION: We analysed a total of 38 546 women who did not have predominantly European ancestry backgrounds: 25 149 women from seven studies from the ReproGen Consortium and 13 397 women from the UK Biobank. In addition, we used an independent sample of 5148 African-ancestry women from the Southern Community Cohort Study (SCCS) for replication. PARTICIPANTS/MATERIALS, SETTING, METHODS: Each AAM GWAS was performed by study and ancestry or ethnic group using linear regression models adjusted for birth year and study-specific covariates. ReproGen and UK Biobank results were meta-analysed using an inverse variance-weighted average method. A trans-ethnic meta-analysis was also carried out to assess heterogeneity due to different ancestry. MAIN RESULTS AND THE ROLE OF CHANCE: We observed consistent direction and effect sizes between our meta-analysis and the largest GWAS conducted in European or Asian ancestry women. We validated four AAM loci (1p31, 6q16, 6q22 and 9q31) with common genetic variants at P < 5 × 10-7. We detected one new association (10p15) at P < 5 × 10-8 with a low-frequency genetic variant lying in AKR1C4, which was replicated in an independent sample. This gene belongs to a family of enzymes that regulate the metabolism of steroid hormones and have been implicated in the pathophysiology of uterine diseases. The genetic variant in the new locus is more frequent in African-ancestry participants, and has a very low frequency in Asian or European-ancestry individuals. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Extreme AAM (<9 years or >18 years) were excluded from analysis. Women may not fully recall their AAM as most of the studies were conducted many years later. Further studies in women with diverse and predominantly non-European ancestry are needed to confirm and extend these findings, but the availability of such replication samples is limited. WIDER IMPLICATIONS OF THE FINDINGS: Expanding association studies to a broader range of ancestries or ethnicities may improve the identification of new genetic variants associated with complex diseases or traits and the generalisation of variants from European-ancestry studies to a wider range of world populations. STUDY FUNDING/COMPETING INTEREST(S): Funding was provided by CHARGE Consortium grant R01HL105756-07: Gene Discovery For CVD and Aging Phenotypes and by the NIH grant U24AG051129 awarded by the National Institute on Aging (NIA). The authors have no conflict of interest to declare.

Variability in sleep disturbance, physical activity and quality of life by level of depressive symptoms in women with Type 2 diabetes.

AIMS: To examine (1) the prevalence of depressive symptoms in women with Type 2 diabetes, (2) the associations between depressive symptoms and the following dependent variables: sleep disturbance; physical activity; physical health-related; and global quality of life, and (3) the potential moderating effects of antidepressants and optimism on the relationship between depressive symptoms and dependent variables. METHODS: Participants in the Women's Health Initiative who had Type 2 diabetes and data on depressive symptoms (N=8895) were included in the analyses. In multivariable linear regression models controlling for sociodemographic, medical and psychosocial covariates, we examined the main effect of depressive symptoms, as well as the interactions between depressive symptoms and antidepressant use, and between depressive symptoms and optimism, on sleep disturbance, physical activity, physical health-related quality of life; and global quality of life. RESULTS: In all, 16% of women with Type 2 diabetes reported elevated depressive symptoms. In multivariable analyses, women with depressive symptoms had greater sleep disturbance (P<0.0001) and lower global quality of life (P<.0001). We found evidence of significant statistical interaction in the models for quality-of-life outcomes: the increased risk of poor physical health-related quality of life associated with antidepressant use was stronger in women without vs with depressive symptoms, and the association between greater optimism and higher global quality of life was stronger in women with vs without depressive symptoms. CONCLUSIONS: To improve health behaviours and quality of life in women with Type 2 diabetes, sociodemographic and medical characteristics may identify at-risk populations, while psychosocial factors including depression and optimism may be important targets for non-pharmacological intervention.

The impact of birth weight on cardiovascular disease risk in the Women's Health Initiative.

BACKGROUND AND AIMS: Cardiovascular disease (CVD) is among the leading causes of morbidity and mortality worldwide. Traditional risk factors predict 75-80% of an individual's risk of incident CVD. However, the role of early life experiences in future disease risk is gaining attention. The Barker hypothesis proposes fetal origins of adult disease, with consistent evidence demonstrating the deleterious consequences of birth weight outside the normal range. In this study, we investigate the role of birth weight in CVD risk prediction. METHODS AND RESULTS: The Women's Health Initiative (WHI) represents a large national cohort of post-menopausal women with 63,815 participants included in this analysis. Univariable proportional hazards regression analyses evaluated the association of 4 self-reported birth weight categories against 3 CVD outcome definitions, which included indicators of coronary heart disease, ischemic stroke, coronary revascularization, carotid artery disease and peripheral arterial disease. The role of birth weight was also evaluated for prediction of CVD events in the presence of traditional risk factors using 3 existing CVD risk prediction equations: one body mass index (BMI)-based and two laboratory-based models. Low birth weight (LBW) (<6 lbs.) was significantly associated with all CVD outcome definitions in univariable analyses (HR = 1.086, p = 0.009). LBW was a significant covariate in the BMI-based model (HR = 1.128, p < 0.0001) but not in the lipid-based models. CONCLUSION: LBW (<6 lbs.) is independently associated with CVD outcomes in the WHI cohort. This finding supports the role of the prenatal and postnatal environment in contributing to the development of adult chronic disease.

Ethnic differences in the relationship between birth weight and type 2 diabetes mellitus in postmenopausal women.

AIM: The objective of this study is to examine the relationship between self-reported birth weight and the adult occurrence of type 2 diabetes mellitus in a large multi-ethnic population of women. METHODS: Baseline data from the Women's Health Initiative Observational Study [n=75,993] was used to examine the association between participant birth weight category and prevalent type 2 diabetes mellitus. Models were adjusted for age, ethnicity, body mass index and other pertinent risk factors. Sub-analyses were performed stratifying by ethnicity. RESULTS: There was a strong inverse association between birth weight and type 2 diabetes mellitus with a birth weight of <6 pounds (lbs) (OR: 1.16, 95% CI: 1.01, 1.33) significantly associated with an increased risk of type 2 diabetes mellitus and a birth weight of ≥10 lbs (OR: 0.72, 95% CI: 0.57, 0.92) associated with a decreased risk of type 2 diabetes mellitus compared to women who reported their birth weight between 7 and 8 lbs 15 ounces (oz). Stratifying by ethnicity, the inverse association between birth weight and type 2 diabetes mellitus was only apparent in White women, but not Black, Hispanic or Asian women. CONCLUSION: Lower birth weight was associated with increased T2D risk in American White and Black post-menopausal women.

Participatory planning of interventions to mitigate human-wildlife conflicts.

Conservation of wildlife is especially challenging when the targeted species damage crops or livestock, attack humans, or take fish or game. Affected communities may retaliate and destroy wildlife or their habitats. We summarize recommendations from the literature for 13 distinct types of interventions to mitigate these human-wildlife conflicts. We classified eight types as direct (reducing the severity or frequency of encounters with wildlife) and five as indirect (raising human tolerance for encounters with wildlife) interventions. We analyzed general cause-and-effect relationships underlying human-wildlife conflicts to clarify the focal point of intervention for each type. To organize the recommendations on interventions we used three standard criteria for feasibility: cost-effective design, wildlife specificity and selectivity, and sociopolitical acceptability. The literature review and the feasibility criteria were integrated as decision support tools in three multistakeholder workshops. The workshops validated and refined our criteria and helped the participants select interventions. Our approach to planning interventions is systematic, uses standard criteria, and optimizes the participation of experts, policy makers, and affected communities. We argue that conservation action generally will be more effective if the relative merits of alternative interventions are evaluated in an explicit, systematic, and participatory manner.

Postmenopausal hormone therapy and subclinical cerebrovascular disease: the WHIMS-MRI Study.

OBJECTIVE: The Women's Health Initiative Memory Study (WHIMS) hormone therapy (HT) trials reported that conjugated equine estrogen (CEE) with or without medroxyprogesterone acetate (MPA) increases risk for all-cause dementia and global cognitive decline. WHIMS MRI measured subclinical cerebrovascular disease as a possible mechanism to explain cognitive decline reported in WHIMS. METHODS: We contacted 2,345 women at 14 WHIMS sites; scans were completed on 1,424 (61%) and 1,403 were accepted for analysis. The primary outcome measure was total ischemic lesion volume on brain MRI. Mean duration of on-trial HT or placebo was 4 (CEE+MPA) or 5.6 years (CEE-Alone) and scans were conducted an average of 3 (CEE+MPA) or 1.4 years (CEE-Alone) post-trial termination. Cross-sectional analysis of MRI lesions was conducted; general linear models were fitted to assess treatment group differences using analysis of covariance. A (two-tailed) critical value of alpha = 0.05 was used. RESULTS: In women evenly matched within trials at baseline, increased lesion volumes were significantly related to age, smoking, history of cardiovascular disease, hypertension, lower post-trial global cognition scores, and increased incident cases of on- or post-trial mild cognitive impairment or probable dementia. Mean ischemic lesion volumes were slightly larger for the CEE+MPA group vs placebo, except for the basal ganglia, but the differences were not significant. Women assigned to CEE-Alone had similar mean ischemic lesion volumes compared to placebo. CONCLUSIONS: Conjugated equine estrogen-based hormone therapy was not associated with a significant increase in ischemic brain lesion volume relative to placebo. This finding was consistent within each trial and in pooled analyses across trials.

Prevalence of dementia in the United States: the aging, demographics, and memory study.

AIM: To estimate the prevalence of Alzheimer's disease (AD) and other dementias in the USA using a nationally representative sample. METHODS: The Aging, Demographics, and Memory Study sample was composed of 856 individuals aged 71 years and older from the nationally representative Health and Retirement Study (HRS) who were evaluated for dementia using a comprehensive in-home assessment. An expert consensus panel used this information to assign a diagnosis of normal cognition, cognitive impairment but not demented, or dementia (and dementia subtype). Using sampling weights derived from the HRS, we estimated the national prevalence of dementia, AD and vascular dementia by age and gender. RESULTS: The prevalence of dementia among individuals aged 71 and older was 13.9%, comprising about 3.4 million individuals in the USA in 2002. The corresponding values for AD were 9.7% and 2.4 million individuals. Dementia prevalence increased with age, from 5.0% of those aged 71-79 years to 37.4% of those aged 90 and older. CONCLUSIONS: Dementia prevalence estimates from this first nationally representative population-based study of dementia in the USA to include subjects from all regions of the country can provide essential information for effective planning for the impending healthcare needs of the large and increasing number of individuals at risk for dementia as our population ages.

National estimates of the quantity and cost of informal caregiving for the elderly with dementia.

OBJECTIVE: Caring for the elderly with dementia imposes a substantial burden on family members and likely accounts for more than half of the total cost of dementia for those living in the community. However, most past estimates of this cost were derived from small, nonrepresentative samples. We sought to obtain nationally representative estimates of the time and associated cost of informal caregiving for the elderly with mild, moderate, and severe dementia. DESIGN: Multivariable regression models using data from the 1993 Asset and Health Dynamics Study, a nationally representative survey of people age 70 years or older (N = 7,443). SETTING: National population-based sample of the community-dwelling elderly. MAIN OUTCOME MEASURES: Incremental weekly hours of informal caregiving and incremental cost of caregiver time for those with mild dementia, moderate dementia, and severe dementia, as compared to elderly individuals with normal cognition. Dementia severity was defined using the Telephone Interview for Cognitive Status. RESULTS: After adjusting for sociodemographics, comorbidities, and potential caregiving network, those with normal cognition received an average of 4.6 hours per week of informal care. Those with mild dementia received an additional 8.5 hours per week of informal care compared to those with normal cognition (P < .001), while those with moderate and severe dementia received an additional 17.4 and 41.5 hours (P < .001), respectively. The associated additional yearly cost of informal care per case was 3,630 dollars for mild dementia, 7,420 dollars for moderate dementia, and 17,700 dollars for severe dementia. This represents a national annual cost of more than 18 billion dollars. CONCLUSION: The quantity and associated economic cost of informal caregiving for the elderly with dementia are substantial and increase sharply as cognitive impairment worsens. Physicians caring for elderly individuals with dementia should be mindful of the importance of informal care for the well-being of their patients, as well as the potential for significant burden on those (often elderly) individuals providing the care.

Changes in driving patterns and worsening depressive symptoms among older adults.

OBJECTIVES: This study examined whether changes in driving patterns-driving cessation and reduction-have negative consequences for the depressive symptoms of older Americans and whether these consequences are mitigated for people with a spouse who drives. METHODS: The project used data from 3 waves of the Asset and Health Dynamics Among the Oldest Old (AHEAD) study. Depressive symptoms were assessed with an abbreviated Center for Epidemiologic Studies-Depression scale. Using 2 models, the project examined how driving cessation and reduction that occurred between Waves 1 and 2 contributed to increases in depressive symptoms between Waves 2 and 3. The first model included the entire sample (N = 5,239), and the second model focused on drivers only (n = 3,543). A third model added interaction terms to the analysis to consider whether respondents who stopped driving but had a spouse who drove were less at risk of worsening depressive symptoms. RESULTS: Respondents who stopped driving had greater risk of worsening depressive symptoms. Drivers who restricted their driving distances before the study began also had greater risk of worsening depressive symptoms, but seemingly less so than the respondents who stopped driving altogether. For respondents who stopped driving, having a spouse available to drive them did not mitigate the risk of worsening symptoms. DISCUSSION: Changes in driving patterns can be deleterious for older people's depressive symptoms. Initiatives for assisting older people should focus on strategies that help them retain driving skills, that prepare them for the possible transition from driver to ex-driver, and that ensure that they have access to mental health therapies if driving changes are imminent.

Persistent, consistent, widespread, and robust? Another look at recent trends in old-age disability.

OBJECTIVE: The purpose of this study was to provide new evidence on disability trends among elderly persons from 1982 to 1996. METHODS: The sample includes 124,949 participants aged 70 and older in the 1982-1996 National Health Interview Surveys. Logistic analysis was used to estimate the trend in disability prevalence after controlling for various sociodemographic factors. RESULTS: We found that: (a) the prevalence of disability has declined, but the gains did not persist throughout the entire period or accelerate over time; (b) only routine care disability has declined, whereas more severe personal care disability shows no improvements; (c) estimates are robust to the exclusion of the nursing home population but may be sensitive to growth in the assisted living population; (d) estimates of decline in disability prevalence are fairly consistent across five national surveys; (e) gains have been concentrated among the most educated elderly persons; and (f) gains in education appear to be an important confounder of the improvements. DISCUSSION: Evidence from several surveys using various measures indicates that disability has declined among elderly persons. Determining the causes of the improvements should be a high priority in future research efforts.

Consumption of carrageenan and other water-soluble polymers used as food additives and incidence of mammary carcinoma.

This study examined the hypothesis that the increasing incidence of mammary carcinoma in the USA in the twentieth century may be related to the consumption of carrageenan and possibly other water-soluble polymers. Widely used as food additives in the Western diet, the water-soluble polymers, also known as gums, are generally regarded as inert. However, the gum carrageenan which is comprised of linked, sulfated galactose residues has potent biological activity and undergoes acid hydrolysis to poligeenan, an acknowledged carcinogen. A time-trend analysis using age-adjusted incidence data and consumption data from established sources tested the hypothesis that increased consumption of the gums may be associated with increased incidence of mammary carcinoma. Correlations were determined using Pearson and Spearman correlation coefficients, incorporating lag intervals of 10 to 35 years. This analysis demonstrated that increasing consumption of several gums correlates positively with increased incidence of breast carcinoma.

Blood transfusions and risk of non-Hodgkin's lymphoma subtypes and chronic lymphocytic leukemia.

Allogeneic blood transfusion has been suggested as a risk factor for non-Hodgkin's lymphoma (NHL), possibly specific to certain NHL subtypes, or chronic lymphocytic leukemia (CLL). Self-reported transfusion history and risk of NHL subtypes and CLL were examined in a cohort of 37,934 older Iowa women, using data from a questionnaire mailed in 1986. Through 1997, 229 cases of NHL and 57 cases of CLL in the cohort were identified through linkage to the Iowa Surveillance, Epidemiology and End Results Cancer REGISTRY: Women who reported ever receiving a blood transfusion were at increased risk for all NHLs [age adjusted relative risk (RR), 1.6; 95% confidence interval (CI), 1.2-2.1). On the basis of the Working Formulation classification, blood transfusion was positively associated with low-grade NHL (RR, 2.7; 95% CI, 1.7-4.5) but not with intermediate-grade NHL (RR, 1.1; 95% CI, 0.7-1.6); there were only 8 cases of high-grade NHL. Blood transfusion was positively associated with follicular (RR, 2.8; 95% CI, 1.6-5.1) and small lymphocytic (RR, 3.4; 95% CI, 1.5-7.9) NHL subtypes but not with diffuse NHL (RR, 1.0; 95% CI, 0.7-1.5). There was also a positive association with CLL (RR, 1.7; 95% CI, 1.0-3.0). Finally, transfusion was associated with nodal (RR, 1.8; 95% CI, 1.3-2.5) but not extranodal (RR, 1.2; 95% CI, 0.7-2.1) NHL. Further adjustment for marital status, farm residence, diabetes, alcohol use, smoking, and red meat and fruit consumption did not alter these associations. In conclusion, prior blood transfusion was associated with NHL and CLL, and the strongest associations were seen for low-grade NHL, particularly follicular and small lymphocytic NHL.

Linked linear amplification: a new method for the amplification of DNA.

BACKGROUND: Linked Linear Amplification (LLA) is a new nucleic acid amplification method that uses multiple cycles of primer extension reactions. The presence of nonreplicable elements in LLA primers renders primer extension products unusable as templates for further amplification, leading to linear accumulation of products. Through the use of nested primers, linear reactions can be "linked", providing total amplification yields comparable to those obtained by PCR. METHODS: The LLA model predicts (a) that amplification yield will approach that of PCR as the number of primers increases and (b) that the unique composition of LLA products will give lower carryover amplification efficiency compared with PCR. To test these hypotheses, the human ss-globin gene was amplified by 10-, 14-, or 18-primer LLA and the yield was compared with PCR. Carryover contamination was simulated by reamplifying a dilution series of LLA or PCR products. To demonstrate the clinical utility of the method, LLA coupled with allele-specific oligonucleotide (ASO) capture was used to detect the factor V Leiden mutation in a panel of 111 DNA samples. RESULTS: Fourteen- and 18-primer LLA gave amplification yields comparable to PCR. However, LLA carryover amplification efficiency was four orders of magnitude lower than that of PCR. The LLA-ASO assay detected the correct factor V Leiden genotype in all 111 samples. CONCLUSIONS: LLA is a robust target amplification method that is comparable to PCR in yield. However, LLA is more resistant to false results caused by carryover amplicon contamination.

Bridging epidemiology and demography: theories and themes.

Epidemiology and demography, although both encumbering several theoretical constructs, are generally applied, problem-solving disciplines concerned with the nature and trajectories of defined groups. There are differences between the two disciplines in substantive interests and methodological traditions, however both have comprehensive perspectives and both are deeply concerned with the health, social, and economic well-being of human populations. One way to promote productive interdisciplinary research is to apply or develop scientific theories that exploit the complementary interests and methods of the two disciplines. Several candidate theories and themes are suggested here, including (1) the life course approach as applied to the biology of longevity; (2) the "modernized" Malthusian dilemma; (3) the demographic transition within developing countries; (4) the theory of evolution and its social and biological implications; (5) reciprocal effects of ecological and environmental characteristics on population health and well-being; and (6) systems theory as an approach to population complexity. Other approaches to fostering interdisciplinary investigation between these disciplines include joint course work, specifically targeted research funding initiatives and collaborative development of new population theory. The latter may be particularly important from several perspectives: uniting disciplines to jointly approach common and important scientific problems, providing existing frameworks with which to generate new scientific questions, and promoting enhanced scientific rigor by more tightly linking methods with hypotheses.

Advocacy in epidemiology and demography.

This paper is a summary of a panel discussion at the Conference on Epidemiology and Demography held at Georgetown University, in Washington D.C. on February 8-9, 2001. The participants were Al Hermalin, Linda Martin, Mike Stoto, Robert Wallace, Douglas Weed, and Rose Li (who chaired the session). A list of questions similar to the section headings in this paper was prepared in advance of the conference, and each of the participants was asked to address specific issues, although the presentations typically covered a range of topics. This summary also includes comments from the floor.

Memory complaint in a community sample aged 70 and older.

OBJECTIVES: The ability of older people to estimate their own memory, often referred to as "metamemory," has been evaluated in previous studies with conflicting reports regarding accuracy. Some studies have suggested that an older person's metamemory is mostly accurate, whereas others have demonstrated little relationship between memory complaint and actual impairment. This study examines memory complaint in a large national sample of older people aged > or = 70. DESIGN: A longitudinal cohort study with two waves of data collection spaced 2 years apart. SETTING: A nationwide random sample of community-dwelling older persons. PARTICIPANTS: A total of 5,444 community-dwelling persons aged > or = 70 and their spouses. MEASUREMENTS: Participants were asked if they believed their memory was excellent, very good, good, fair, or poor. They were then administered a cognitive assessment derived from the Mini-Mental Status Exam. RESULTS: In general, people's assessment of their memory corresponded with their actual performance on cognitive measures. However, large portions of the sample inaccurately assessed their memory skills. People who reported depressive symptoms and had impairment in activities of daily living were more likely to state that their memory was impaired, although they performed very well on cognitive measures. CONCLUSIONS: The conditions that skew people's self-assessment are the ones most likely to bring them into contact with healthcare professionals. This may give clinicians the general impression that older people cannot assess their own cognitive skills. However, poor metamemory appears to be a characteristic of a specific subgroup of older persons, not necessarily characteristic of the general population.