Results of Observational Studies: Analysis of Findings from the Nurses’ Health Study

Background

The role of observational studies in informing clinical practice is debated, and high profile examples of discrepancies between the results of observational studies and randomised controlled trials (RCTs) have intensified that debate. We systematically reviewed findings from the Nurses’ Health Study (NHS), one of the longest and largest observational studies, to assess the number and strength of the associations reported and to determine if they have been confirmed in RCTs.

Methods

We reviewed NHS publication abstracts from 1978–2012, extracted information on associations tested, and graded the strength of the reported effect sizes. We searched PubMed for RCTs or systematic reviews for 3 health outcomes commonly reported in NHS publications: breast cancer, ischaemic heart disease (IHD) and osteoporosis. NHS results were compared with RCT results and deemed concordant when the difference in effect sizes between studies was ≤0.15.

Findings

2007 associations between health outcomes and independent variables were reported in 1053 abstracts. 58.0% (1165/2007) were statistically significant, and 22.2% (445/2007) were neutral (no association). Among the statistically significant results that reported a numeric odds ratio (OR) or relative risk (RR), 70.5% (706/1002) reported a weak association (OR/RR 0.5–2.0), 24.5% (246/1002) a moderate association (OR/RR 0.25–0.5 or 2.0–4.0) and 5.0% (50/1002) a strong association (OR/RR ≤0.25 or ≥4.0). 19 associations reported in NHS publications for breast cancer, IHD and osteoporosis have been tested in RCTs, and the concordance between NHS and RCT results was low (≤25%).

Conclusions

NHS publications contain a large number of analyses, the majority of which reported statistically significant but weak associations. Few of these associations have been tested in RCTs, and where they have, the agreement between NHS results and RCTs is poor.     

Duration of Adulthood Overweight,Obesity, and Cancer Risk in the Women’s Health Initiative: A Longitudinal Study from the United States

BackgroundHigh body mass index (BMI) has become the leading risk factor of disease burden in high-income countries. While recent studies have suggested that the risk of cancer related to obesity is mediated by time, insights into the dose-response relationship and the cumulative impact of overweight and obesity during the life course on cancer risk remain scarce. To our knowledge, this study is the first to assess the impact of adulthood overweight and obesity duration on the risk of cancer in a large cohort of postmenopausal women.ConclusionsIn summary, this study showed that a longer duration of overweight and obesity is associated with an increased risk of developing several forms of cancer. Furthermore, the degree of overweight experienced during adulthood seemed to play an important role in the risk of developing cancer, especially for endometrial cancer. Although the observational nature of our study precludes inferring causality or making clinical recommendations, our findings suggest that reducing overweight duration in adulthood could reduce cancer risk and that obesity prevention is important from early onset. If this is true, health care teams should recognize the potential of obesity management in cancer prevention and that excess body weight in women is important to manage regardless of the age of the patient.     

Red Blood Cell Fatty Acids and Incident Diabetes Mellitus in the Women’s Health Initiative Memory Study

Context

The relations between dietary and/or circulating levels of fatty acids and the development of type 2 diabetes is unclear. Protective associations with the marine omega-3 fatty acids and linoleic acid, and with a marker of fatty acid desaturase activity delta-5 desaturase (D5D ratio) have been reported, as have adverse relations with saturated fatty acids and D6D ratio.

Objective

To determine the associations between red blood cell (RBC) fatty acid distributions and incident type 2 diabetes.

Design

Prospective observational cohort study nested in the Women’s Health Initiative Memory Study.

Setting

General population.

Subjects

Postmenopausal women.

Main Outcome Measures

Self-reported incident type 2 diabetes.

Results

There were 703 new cases of type 2 diabetes over 11 years of follow up among 6379 postmenopausal women. In the fully adjusted models, baseline RBC D5D ratio was inversely associated with incident type 2 diabetes [Hazard Ratio (HR) 0.88, 95% confidence interval (CI) 0.81–0.95) per 1 SD increase. Similarly, baseline RBC D6D ratio and palmitic acid were directly associated with incident type 2 diabetes (HR 1.14, 95% CI 1.04–1.25; and HR 1.24, 95% CI 1.14–1.35, respectively). None of these relations were materially altered by excluding incident cases in the first two years of follow-up. There were no significant relations with eicosapentaenoic, docosahexaenoic or linoleic acids.

Conclusions

Whether altered fatty acid desaturase activities or palmitic acid levels are causally related to the development of type 2 diabetes cannot be determined from this study, but our findings suggest that proportions of certain fatty acids in RBC membranes are associated with risk for type 2 diabetes.     

Genetic Determinants of Pelvic Organ Prolapse among African American and Hispanic Women in the Women’s Health Initiative

Current evidence suggests a multifactorial etiology to pelvic organ prolapse (POP), including genetic predisposition. We conducted a genome-wide association study of POP in African American (AA) and Hispanic (HP) women from the Women’s Health Initiative Hormone Therapy study. Cases were defined as any POP (grades 1–3) or moderate/severe POP (grades 2–3), while controls had grade 0 POP. We performed race-specific multiple logistic regression analyses between SNPs imputed to 1000 genomes in relation to POP (grade 0 vs 1–3; grade 0 vs 2–3) adjusting for age at diagnosis, body mass index, parity, and genetic ancestry. There were 1274 controls and 1427 cases of any POP and 317 cases of moderate/severe POP. Although none of the analyses reached genome-wide significance (p<5x10^-8), we noted variants in several loci that met p<10⁻⁶. In race-specific analysis of grade 0 vs 2–3, intronic SNPs in the CPE gene (rs28573326, OR:2.14; 95% CI 1.62–2.83; p = 1.0x10^-7) were associated with POP in AAs, and SNPs in the gene AL132709.5 (rs1950626, OR:2.96; 95% CI 1.96–4.48, p = 2.6x10^-7) were associated with POP in HPs. Inverse variance fixed-effect meta-analysis of the race-specific results showed suggestive signals for SNPs in the DPP6 gene (rs11243354, OR:1.36; p = 4.2x10^-7) in the grade 0 vs 1–3 analyses and for SNPs around PGBD5 (rs740494, OR:2.17; p = 8.6x10^-7) and SHC3 (rs2209875, OR:0.60; p = 9.3x10^-7) in the grade 0 vs 2–3 analyses. While we did not identify genome-wide significant findings, we document several SNPs reaching suggestive statistical significance. Further interrogation of POP in larger minority samples is warranted.     

Gene-environment interactions and obesity traits among postmenopausal African-American and Hispanic women in the Women’s Health Initiative SHARe Study

Genome-wide association studies (GWAS) of obesity measures have identified associations with single nucleotide polymorphisms (SNPs). However, no large-scale evaluation of gene-environment interactions has been performed. We conducted a search of gene-environment (G × E) interactions in post-menopausal African-American and Hispanic women from the Women’s Health Initiative SNP Health Association Resource GWAS study. Single SNP linear regression on body mass index (BMI) and waist-to-hip circumference ratio (WHR) adjusted for multidimensional-scaling-derived axes of ancestry and age was run in race-stratified data with 871,512 SNPs available from African-Americans (N = 8,203) and 786,776 SNPs from Hispanics (N = 3,484). Tests of G × E interaction at all SNPs for recreational physical activity (m h/week), dietary energy intake (kcal/day), alcohol intake (categorical), cigarette smoking years, and cigarette smoking (ever vs. never) were run in African-Americans and Hispanics adjusted for ancestry and age at interview, followed by meta-analysis of G × E interaction terms. The strongest evidence for concordant G × E interactions in African-Americans and Hispanics was for smoking and marker rs10133840 (Q statistic P = 0.70, beta = ?0.01, P = 3.81 × 10^?7) with BMI as the outcome. The strongest evidence for G × E interaction within a cohort was in African-Americans with WHR as outcome for dietary energy intake and rs9557704 (SNP × kcal = ?0.04, P = 2.17 × 10^?7). No results exceeded the Bonferroni-corrected statistical significance threshold.     

Replication of genetic loci for sarcoidosis in US black women: data from the Black Women’s Health Study

In the United States, incidence and mortality from sarcoidosis, a chronic, granulomatous disease, are increased in black women. In data from the Black Women’s Health Study, a follow-up of US black women, we assessed two SNPs (rs2076530 and rs9268480) previously identified in the BTNL2 gene (chromosome 6p21), of which rs4424066 and rs3817963 are perfect proxies, to determine if they represent independent signals of disease risk. We also assessed whether local ancestry in four genomic regions previously identified through admixture mapping was associated with sarcoidosis. Finally, we assessed the relation of global percent African ancestry to risk. We conducted a nested case–control study of 486 sarcoidosis cases and 943 age- and geography-matched controls. Both BTNL2 SNPs were associated with risk of sarcoidosis in separate models, but in a combined analysis the increased risk was due to the A-allele of the rs3817963 SNP; each copy of the A-allele was associated with a 40 % increase in risk of sarcoidosis (p = 0.02) and was confirmed by our haplotypic analysis. Local African ancestry around the rs30533 ancestry informative marker at chromosome 5q31 was associated with a 29 % risk reduction (p = 0.01). Therefore, we adjusted our analysis of global African ancestry for number of copies of African alleles in rs30533. Subjects in the highest quintile of percent African ancestry had a 54 % increased risk of sarcoidosis. The present results from a population of African-American women support the role of the BTNL2 gene and the 5q31 locus in the etiology of sarcoidosis, and also demonstrate that percent African ancestry is associated with disease risk.     

Economic Benefits of Investing in Women’s Health: A Systematic Review

Background

Globally, the status of women’s health falls short of its potential. In addition to the deleterious ethical and human rights implications of this deficit, the negative economic impact may also be consequential, but these mechanisms are poorly understood. Building on the literature that highlights health as a driver of economic growth and poverty alleviation, we aim to systematically investigate the broader economic benefits of investing in women’s health.

Methods

Using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, we systematically reviewed health, gender, and economic literature to identify studies that investigate the impact of women’s health on micro- and macroeconomic outcomes. We developed an extensive search algorithm and conducted searches using 10 unique databases spanning the timeframe 01/01/1970 to 01/04/2013. Articles were included if they reported on economic impacts stemming from changes in women’s health (table of outcome measures included in full review,

The Study of Children’s Play within the Context of Cultural-Historical Psychology: Experience and Prospects

The paper reconstructs the history of the problem of mental development using material from children’s play. This study shows how researchers in the school of cultural-historical psychology identified the developmental function of play, established a qualitative leap in its development and attempted to re-create it, beginning with the works of L.S. Vygotsky, then of his followers (the activity-based approach in the interpretation of narrative role-playing: A.N. Leontiev, D.B. Elkonin, N.Ia. Mikhailenko, N.A. Korotkova, etc.), and, finally, of the researchers who studied a specific act of development in play (L.I. El’koninova, T.V. Bazhanova, K.O. Iur’eva). This research presents the view that the concept of the cultural form of play, containing a Challenge (defined by the boundaries of the possibilities of action and by risk) and the subsequent Response is the basis not only of narrative role-playing but also of games with rules, as well as computer games. The Challenge entails action that changes the action situation; it typifies all forms of play, which are supposed to tie together what is disjointed in a child’s daily life into a semantic knot.     

The Relationship of Walking Intensity to Total and Cause-Specific Mortality. Results from the National Walkers’ Health Study

Purpose

Test whether: 1) walking intensity predicts mortality when adjusted for walking energy expenditure, and 2) slow walking pace (≥24-minute mile) identifies subjects at substantially elevated risk for mortality.

Methods

Hazard ratios from Cox proportional survival analyses of all-cause and cause-specific mortality vs. usual walking pace (min/mile) in 7,374 male and 31,607 female recreational walkers. Survival times were left censored for age at entry into the study. Other causes of death were treated as a competing risk for the analyses of cause-specific mortality. All analyses were adjusted for sex, education, baseline smoking, prior heart attack, aspirin use, diet, BMI, and walking energy expenditure. Deaths within one year of baseline were excluded.

Results

The National Death Index identified 1968 deaths during the average 9.4-year mortality surveillance. Each additional minute per mile in walking pace was associated with an increased risk of mortality due to all causes (1.8% increase, P=10^-5), cardiovascular diseases (2.4% increase, P=0.001, 637 deaths), ischemic heart disease (2.8% increase, P=0.003, 336 deaths), heart failure (6.5% increase, P=0.001, 36 deaths), hypertensive heart disease (6.2% increase, P=0.01, 31 deaths), diabetes (6.3% increase, P=0.004, 32 deaths), and dementia (6.6% increase, P=0.0004, 44 deaths). Those reporting a pace slower than a 24-minute mile were at increased risk for mortality due to all-causes (44.3% increased risk, P=0.0001), cardiovascular diseases (43.9% increased risk, P=0.03), and dementia (5.0-fold increased risk, P=0.0002) even though they satisfied the current exercise recommendations by walking ≥7.5 metabolic equivalent (MET)-hours per week.

Conclusions

The risk for mortality: 1) decreases in association with walking intensity, and 2) increases substantially in association for walking pace ≥24 minute mile (equivalent to <400m during a six-minute walk test) even among subjects who exercise regularly.     

Women’s Perceptions and Misperceptions of Male Circumcision: A Mixed Methods Study in Zambia

Women’s perceptions of male circumcision (MC) have implications for behavioral risk compensation, demand, and the impact of MC programs on women’s health. This mixed methods study combines data from the first two rounds of a longitudinal study (n = 934) and in-depth interviews with a subsample of respondents (n = 45) between rounds. Most women correctly reported that MC reduces men’s risk of HIV (64% R1, 82% R2). However, 30% of women at R1, and significantly more (41%) at R2, incorrectly believed MC is fully protective for men against HIV. Women also greatly overestimated the protection MC offers against STIs. The proportion of women who believed MC reduces a woman’s HIV risk if she has sex with a man who is circumcised increased significantly (50% to 70%). Qualitative data elaborate women’s misperception regarding MC. Programs should address women’s informational needs and continue to emphasize that condoms remain critical, regardless of male partner’s circumcision status.     

Innate Immunity Pathways and Breast Cancer Risk in African American and European-American Women in the Women’s Circle of Health Study (WCHS)

African American (AA) women are more likely than European American (EA) women to be diagnosed with early, aggressive breast cancer. Possible differences in innate immune pathways (e.g., inflammatory responses) have received little attention as potential mechanisms underlying this disparity. We evaluated distributions of selected genetic variants in innate immune pathways in AA and EA women, and examined their associations with breast cancer risk within the Women’s Circle of Health Study (WCHS). In stage I of the study (864 AA and 650 EA women) we found that genotype frequencies for 35 of 42 tested SNPs (18 candidate genes) differed between AAs and EAs (corroborated by ancestry informative markers). Among premenopausal AA women, comparing variant allele carriers to non-carriers, reduced breast cancer risk was associated with CXCL5-rs425535 (OR=0.61, P=0.02), while among EA women, there were associations with TNFA-rs1799724 (OR =2.31, P =0.002) and CRP-rs1205 (OR=0.54, P=0.01). For postmenopausal women, IL1B-rs1143627 (OR=1.80, P=0.02) and IL1B-rs16944 (OR=1.85, P =0.02) were associated with risk among EA women, with significant associations for TNFA-rs1799724 limited to estrogen receptor (ER) positive cancers (OR=2.0, P =0.001). However, none of the SNPs retained significance after Bonferroni adjustment for multiple testing at the level of P0.0012 (0.05/42) except for TNFA-rs1799724 in ER positive cancers. In a stage II validation (1,365 AA and 1,307 EA women), we extended evaluations for four SNPs (CCL2-rs4586, CRP-rs1205, CXCL5-rs425535, and IL1RN-rs4251961), which yielded similar results. In summary, distributions of variants in genes involved in innate immune pathways were found to differ between AA and EA populations, and showed differential associations with breast cancer according to menopausal or ER status. These results suggest that immune adaptations suited to ancestral environments may differentially influence breast cancer risk among EA and AA women.     

Food Insecurity and Children’s Mental Health: A Prospective Birth Cohort Study

Food insecurity (which can be defined as inadequate access to sufficient, safe, and nutritious food that meets individuals’ dietary needs) is concurrently associated with children’s psychological difficulties. However, the predictive role of food insecurity with regard to specific types of children’s mental health symptoms has not previously been studied. We used data from the Longitudinal Study of Child Development in Québec, LSCDQ, a representative birth cohort study of children born in the Québec region, in Canada, in 1997–1998 (n = 2120). Family food insecurity was ascertained when children were 1½ and 4½ years old. Children’s mental health symptoms were assessed longitudinally using validated measures of behaviour at ages 4½, 5, 6 and 8 years. Symptom trajectory groups were estimated to identify children with persistently high levels of depression/anxiety (21.0%), aggression (26.2%), and hyperactivity/inattention (6.0%). The prevalence of food insecurity in the study was 5.9%. In sex-adjusted analyses, children from food-insecure families were disproportionately likely to experience persistent symptoms of depression/anxiety (OR: 1.79, 95% CI 1.15–2.79) and hyperactivity/inattention (OR: 3.06, 95% CI 1.68–5.55). After controlling for immigrant status, family structure, maternal age at child’s birth, family income, maternal and paternal education, prenatal tobacco exposure, maternal and paternal depression and negative parenting, only persistent hyperactivity/inattention remained associated with food insecurity (fully adjusted OR: 2.65, 95% CI 1.16–6.06). Family food insecurity predicts high levels of children’s mental health symptoms, particularly hyperactivity/inattention. Addressing food insecurity and associated problems in families could help reduce the burden of mental health problems in children and reduce social inequalities in development.     

Diabetes Mellitus and the Risk of Alzheimer’s Disease: A Nationwide Population-Based Study

Objectives

Possible association between diabetes mellitus (DM) and Alzheimer’s disease (AD) has been controversial. This study used a nationwide population-based dataset to investigate the relationship between DM and subsequent AD incidence.

Methods

Data were collected from Taiwan’s National Health Insurance Research Database, which released a cohort dataset of 1,000,000 randomly sampled people and confirmed it to be representative of the Taiwanese population. We identified 71,433 patients newly diagnosed with diabetes (age 58.74±14.02 years) since January 1997. Using propensity score, we matched them with 71,311 non-diabetic subjects by time of enrollment, age, gender, hypertension, hyperlipidemia, and previous stroke history. All the patients were followed up to December 31, 2007. The endpoint of the study was occurrence of AD.

Results

Over a maximum 11 years of follow-up, diabetic patients experienced a higher incidence of AD than non-diabetic subjects (0.48% vs. 0.37%, p<0.001). After Cox proportional hazard regression model analysis, DM (hazard ratio [HR], 1.76; 95% confidence interval [CI], 1.50–2.07, p<0.001), age (HR, 1.11; 95% CI, 1.10–1.12, p<0.001), female gender (HR, 1.24; 95% CI, 1.06–1.46, p = 0.008), hypertension (HR, 1.30; 95% CI, 1.07–1.59, p = 0.01), previous stroke history (HR, 1.79; 95% CI, 1.28–2.50, p<0.001), and urbanization status (metropolis, HR, 1.32; 95% CI, 1.07–1.63, p = 0.009) were independently associated with the increased risk of AD. Neither monotherapy nor combination therapy with oral antidiabetic medications were associated with the risk of AD after adjusting for underlying risk factors and the duration of DM since diagnosis. However, combination therapy with insulin was found to be associated with greater risk of AD (HR, 2.17; 95% CI, 1.04–4.52, p = 0.039).

Conclusion

Newly diagnosed DM was associated with increased risk of AD. Use of hypoglycemic agents did not ameliorate the risk.     

Women’s Awareness and Knowledge of Abortion Laws: A Systematic Review

Background

Incorrect knowledge of laws may affect how women enter the health system or seek services, and it likely contributes to the disconnect between official laws and practical applications of the laws that influence women’s access to safe, legal abortion services.

Objective

To provide a synthesis of evidence of women’s awareness and knowledge of the legal status of abortion in their country, and the accuracy of women’s knowledge on specific legal grounds and restrictions outlined in a country’s abortion law.

Methods

A systematic search was carried for articles published between 1980–2015. Quantitative, mixed-method data collection, and objectives related to women’s awareness or knowledge of the abortion law was included. Full texts were assessed, and data extraction done by a single reviewer. Final inclusion for analysis was assessed by two reviewers. The results were synthesised into tables, using narrative synthesis.

Results

Of the original 3,126 articles, and 16 hand searched citations, 24 studies were included for analysis. Women’s correct general awareness and knowledge of the legal status was less than 50% in nine studies. In six studies, knowledge of legalization/liberalisation ranged between 32.3% - 68.2%. Correct knowledge of abortion on the grounds of rape ranged from 12.8% – 98%, while in the case of incest, ranged from 9.8% - 64.5%. Abortion on the grounds of fetal impairment and gestational limits, varied widely from 7% - 94% and 0% - 89.5% respectively.

Conclusion

This systematic review synthesizes literature on women’s awareness and knowledge of the abortion law in their own context. The findings show that correct general awareness and knowledge of the abortion law and legal grounds and restrictions amongst women was limited, even in countries where the laws were liberal. Thus, interventions to disseminate accurate information on the legal context are necessary.     

Menopausal Hormone Therapy and Chronic Disease Risk in the Women’S Health Initiative: is Timing Everything?

ObjectiveThis review provides a comprehensive overview of the most recent findings from the Women’s Health Initiative (WHI) hormone therapy (HT) trials and highlights the role of age and other clinical risk factors in risk stratification.MethodsWe review the findings on cardiovascular disease, cancer outcomes, all-cause mortality, and other major endpoints in the two WHI HT trials (conjugated equine estrogens [CEEs, 0.625 mg/day] with or without medroxyprogesterone acetate [MPA, 2.5 mg/day]).ResultsThe hazard ratio (HR) for coronary heart disease (CHD) was 1.18 (95% confidence interval [CI], 0.95 to 1.45) in the CEE + MPA trial and 0.94 (95% CI, 0.78 to 1.14) in the CEE-alone trial. In both HT trials, there was an increased risk of stroke and deep vein thrombosis and a lower risk of hip fractures and diabetes. The HT regimens had divergent effects on breast cancer. CEE + MPA increased breast cancer risk (cumulative HR, 1.28; 95% CI, 1.11 to 1.48), whereas CEE alone had a protective effect (cumulative HR, 0.79; 95% CI, 0.65 to 0.97). The absolute risks of HT were low in younger women (ages 50 to 59 years) and those who were within 10 years of menopause onset. Furthermore, for CHD, the risks were elevated for women with metabolic syndrome or high low-densitylipoprotein cholesterol concentrations but not in women without these risk factors. Factor V Leiden genotype was associated with elevated risk of venous thromboembolism on HT.ConclusionHT has a complex pattern of benefits and risks. Women in early menopause have low absolute risks of chronic disease outcomes on HT. Use of HT for management of menopausal symptoms remains appropriate, and risk stratification will help to identify women in whom benefits would be expected to outweigh risks. (Endocr Pract. 2014;20:1201-1213)