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1.  Nutrition and Physical Activity Cancer Prevention Guidelines, Cancer Risk, and Mortality in the Women's Health Initiative 
Healthy lifestyle behaviors are recommended to reduce cancer risk and overall mortality. Adherence to cancer-preventive health behaviors and subsequent cancer risk has not been evaluated in a diverse sample of postmenopausal women. We examined the association between the American Cancer Society (ACS) Nutrition and Physical Activity Cancer Prevention Guidelines score and risk of incident cancer, cancer-specific mortality, and all-cause mortality in 65,838 postmenopausal women enrolled in the Women’s Health Initiative Observational Study. ACS guidelines scores (0–8 points) were determined from a combined measure of diet, physical activity, body mass index (current and at age 18 years), and alcohol consumption. After a mean follow-up of 12.6 years, 8,632 incident cancers and 2,356 cancer deaths were identified. The highest ACS guidelines scores compared with the lowest were associated with a 17% lower risk of any cancer [HR, 0.83; 95% confidence interval (CI), 0.75–0.92], 22% lower risk of breast cancer (HR, 0.78; 95% CI, 0.67–0.92), 52% lower risk of colorectal cancer (HR, 0.48; 95% CI, 0.32–0.73), 27% lower risk of all-cause mortality, and 20% lower risk of cancer-specific mortality (HR, 0.80; 95% CI, 0.71–0.90). Associations with lower cancer incidence and mortality were generally strongest among Asian, black, and Hispanic women and weakest among non-Hispanic whites. Behaviors concordant with Nutrition and Physical Activity Cancer Prevention Guidelines were associated with lower risk of total, breast, and colorectal cancers and lower cancer-specific mortality in postmenopausal women.
doi:10.1158/1940-6207.CAPR-13-0258
PMCID: PMC4090781  PMID: 24403289
2.  Genome-wide association analysis of red blood cell traits in African Americans: the COGENT Network 
Human Molecular Genetics  2013;22(12):2529-2538.
Laboratory red blood cell (RBC) measurements are clinically important, heritable and differ among ethnic groups. To identify genetic variants that contribute to RBC phenotypes in African Americans (AAs), we conducted a genome-wide association study in up to ∼16 500 AAs. The alpha-globin locus on chromosome 16pter [lead SNP rs13335629 in ITFG3 gene; P < 1E−13 for hemoglobin (Hgb), RBC count, mean corpuscular volume (MCV), MCH and MCHC] and the G6PD locus on Xq28 [lead SNP rs1050828; P < 1E − 13 for Hgb, hematocrit (Hct), MCV, RBC count and red cell distribution width (RDW)] were each associated with multiple RBC traits. At the alpha-globin region, both the common African 3.7 kb deletion and common single nucleotide polymorphisms (SNPs) appear to contribute independently to RBC phenotypes among AAs. In the 2p21 region, we identified a novel variant of PRKCE distinctly associated with Hct in AAs. In a genome-wide admixture mapping scan, local European ancestry at the 6p22 region containing HFE and LRRC16A was associated with higher Hgb. LRRC16A has been previously associated with the platelet count and mean platelet volume in AAs, but not with Hgb. Finally, we extended to AAs the findings of association of erythrocyte traits with several loci previously reported in Europeans and/or Asians, including CD164 and HBS1L-MYB. In summary, this large-scale genome-wide analysis in AAs has extended the importance of several RBC-associated genetic loci to AAs and identified allelic heterogeneity and pleiotropy at several previously known genetic loci associated with blood cell traits in AAs.
doi:10.1093/hmg/ddt087
PMCID: PMC3658166  PMID: 23446634
3.  Correlates of 25-hydroxyvitamin D and breast cancer stage in the Women’s Healthy Eating and Living Study 
Nutrition and cancer  2013;65(2):188-194.
Inverse associations between circulating 25-hydroxyvitamin D [25(OH)D] and breast cancer stage have been reported, thus it is critical to understand the variables that contribute to 25(OH)D levels among women with breast cancer. Among 904 women in the Women’s Healthy Eating and Living Study, plasma 25(OH)D concentrations were measured and data on demographic characteristics, diet, physical activity, and tumor characteristics were collected at study entry. Statistically significant associations with 25(OH)D concentrations were observed for body mass index (BMI), body surface area (BSA), height, smoking, total vitamin D intake, physical activity, and race or ethnicity. Of the correlates of 25(OH)D, BMI, BSA, height, physical activity, and study site were associated with stage of breast cancer; however, concentrations of 25(OH)D were not significantly related to stage. In fully adjusted logistic regression models, the ORs (95% CIs) for the association between vitamin D deficiency and Stage II and III cancers were 0.85 (0.59-1.22) and 1.23 (0.71-2.15), respectively (p-trend=0.59), compared to Stage I. This study confirms previous work regarding the correlates of 25(OH)D concentrations but does not provide support for an association between vitamin D status and breast cancer stage.
doi:10.1080/01635581.2013.756531
PMCID: PMC4041275  PMID: 23441606
4.  Frequency of private spiritual activity and cardiovascular risk in postmenopausal women: the Women’s Health Initiative 
Annals of epidemiology  2013;23(5):239-245.
Purpose
Spirituality has been associated with better cardiac autonomic balance, but its association with cardiovascular risk is not well studied. We examined whether more frequent private spiritual activity was associated with reduced cardiovascular risk in postmenopausal women enrolled in the Women’s Health Initiative Observational Study.
Methods
Frequency of private spiritual activity (prayer, Bible reading, and meditation) was self-reported at year 5 of follow-up. Cardiovascular outcomes were centrally adjudicated, and cardiovascular risk was estimated from proportional hazards models.
Results
Final models included 43,708 women (mean age, 68.9 ± 7.3 years; median follow-up, 7.0 years) free of cardiac disease through year 5 of follow-up. In age-adjusted models, private spiritual activity was associated with increased cardiovascular risk (hazard ratio [HR], 1.16; 95% confidence interval [CI], 1.02–1.31 for weekly vs. never; HR, 1.25; 95% CI, 1.11–1.40 for daily vs. never). In multivariate models adjusted for demographics, lifestyle, risk factors, and psychosocial factors, such association remained significant only in the group with daily activity (HR, 1.16; 95% CI, 1.03–1.30). Subgroup analyses indicate this association may be driven by the presence of severe chronic diseases.
Conclusions
Among aging women, higher frequency of private spiritual activity was associated with increased cardiovascular risk, likely reflecting a mobilization of spiritual resources to cope with aging and illness.
doi:10.1016/j.annepidem.2013.03.002
PMCID: PMC3741666  PMID: 23621989
Women’s health; Cardiovascular diseases; Spirituality
5.  Variants in the Dopamine-4-Receptor Gene Promoter Are Not Associated with Sensation Seeking in Skiers 
PLoS ONE  2014;9(4):e93521.
Sensation seeking is a personality trait that has been associated with disinhibited behaviours including substance use and gambling, but also with high-risk sport practices including skydiving, paragliding, and downhill skiing. Twin studies have shown that sensation seeking is moderately heritable, and candidate genes encoding components involved in dopaminergic transmission have been investigated as contributing to this type of behaviour. To determine whether variants in the regulatory regions of the dopamine-4-receptor gene (DRD4) influenced sport-specific sensation seeking, we analyzed five polymorphisms (−1106T/C, −906T/C, −809G/A, −291C/T, 120-bp duplication) in the promoter region of the gene in a cohort of skiers and snowboarders (n = 599) that represented a broad range of sensation seeking behaviours. We grouped subjects by genotype at each of the five loci and compared impulsive sensation seeking and domain-specific (skiing) sensation seeking between groups. There were no significant associations between genotype(s) and general or domain-specific sensation seeking in the skiers and snowboarders, suggesting that while DRD4 has previously been implicated in sensation seeking, the promoter variants investigated in this study do not contribute to sensation seeking in this athlete population.
doi:10.1371/journal.pone.0093521
PMCID: PMC3972116  PMID: 24691022
6.  Physical Activity Assessment: Biomarkers and Self-Report of Activity-Related Energy Expenditure in the WHI 
American Journal of Epidemiology  2013;177(6):576-585.
We used a biomarker of activity-related energy expenditure (AREE) to assess measurement properties of self-reported physical activity and to determine the usefulness of AREE regression calibration equations in the Women's Health Initiative. Biomarker AREE, calculated as the total energy expenditure from doubly labeled water minus the resting energy expenditure from indirect calorimetry, was assessed in 450 Women's Health Initiative participants (2007–2009). Self-reported AREE was obtained from the Arizona Activity Frequency Questionnaire (AAFQ), the 7-Day Physical Activity Recall (PAR), and the Women's Health Initiative Personal Habits Questionnaire (PHQ). Eighty-eight participants repeated the protocol 6 months later. Reporting error, measured as log(self-report AREE) minus log(biomarker AREE), was regressed on participant characteristics for each instrument. Body mass index was associated with underreporting on the AAFQ and PHQ but overreporting on PAR. Blacks and Hispanics underreported physical activity levels on the AAFQ and PAR, respectively. Underreporting decreased with age for the PAR and PHQ. Regressing logbiomarker AREE on logself-reported AREE revealed that self-report alone explained minimal biomarker variance (R2 = 7.6, 4.8, and 3.4 for AAFQ, PAR, and PHQ, respectively). R2 increased to 25.2, 21.5, and 21.8, respectively, when participant characteristics were included. Six-month repeatability data adjusted for temporal biomarker variation, improving R2 to 79.4, 67.8, and 68.7 for AAFQ, PAR, and PHQ, respectively. Calibration equations “recover” substantial variation in average AREE and valuably enhance AREE self-assessment.
doi:10.1093/aje/kws269
PMCID: PMC3626043  PMID: 23436896
biomakers; measurement error; physical activity; postmenopausal women
7.  A Comparison of Mediterranean-Style and MyPyramid Diets on Weight Loss and Inflammatory Biomarkers in Postpartum Breastfeeding Women 
Journal of Women's Health  2013;22(1):48-57.
Abstract
Background
Of postpartum women, 15%–20% retain≥5 kg of their gestational weight gain, increasing risk for adult weight gain. Postpartum women are also in a persistent elevated inflammatory state. Both factors could increase the risk of obesity-related chronic disease. We hypothesized that breastfeeding women randomized to a Mediterranean-style (MED) diet for 4 months would demonstrate significantly greater reductions in body weight, body fat, and inflammation than women randomized to the U.S. Department of Agriculture's (USDA) MyPyramid diet for Pregnancy and Breastfeeding (comparison diet).
Methods
A randomized, controlled dietary intervention trial was conducted in 129 overweight (body mass index [BMI] 27.2±4.9 kg/m2), mostly exclusively breastfeeding (73.6%) women who were a mean 17.5 weeks postpartum. Dietary change was assessed using a validated Food Frequency Questionnaire (FFQ) before and after intervention as well as plasma fatty acid measures (gas chromatography/flame ionization detector [GC/FID]). Anthropometric measurements and biomarkers of inflammation, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), also were assessed at baseline and 4 months via enzyme-linked immunosorbent assay (ELISA).
Results
Participants in both diet groups demonstrated significant (p<0.001) reductions in body weight (−2.3±3.4 kg and −3.1±3.4 kg for the MED and comparison diets, respectively) and significant (p≤0.002) reductions in all other anthropometric measurements; no significant between-group differences were shown as hypothesized. A significant decrease in TNF-α but not IL-6 was also demonstrated in both diet groups, with no significant between-group difference.
Conclusions
Both diets support the promotion of postpartum weight loss and reduction in inflammation (TNF-α) in breastfeeding women.
doi:10.1089/jwh.2012.3707
PMCID: PMC3546415  PMID: 23276189
8.  MULTIVITAMIN USE AND RISK OF CANCER AND CARDIOVASCULAR DISEASE IN THE WOMEN’S HEALTH INITIATIVE COHORTS 
Archives of internal medicine  2009;169(3):10.1001/archinternmed.2008.540.
Context
Millions of postmenopausal women use multivitamins, often believing that supplements prevent chronic diseases such as cancer and cardiovascular disease.
Objective
To examine associations between multivitamin use and risk of cancer, cardiovascular disease and mortality in postmenopausal women.
Design, Setting and Participants
161,808 participants from the Women’s Health Initiative Clinical Trials (n=68,132 in three overlapping trials of hormone therapy, dietary modification and calcium-vitamin D) or Observational Study (n=93,676). Detailed data were collected on multivitamin use at baseline and follow-up time points. Study enrollment occurred between 1993–1998; women were followed for a median of 8.0 years in the clinical trials and 7.9 years in the observational study. Disease endpoints were collected through 2005.
Outcome Measures
Cancers of the breast (invasive), colon/rectum, endometrium, kidney, bladder, stomach, ovary and lung; cardiovascular disease (myocardial infarction, stroke, venous thrombosis); and total mortality.
Results
41.5% of participants used multivitamins. After a median of 8.0 years of follow-up in the CT and 7.9 years in the OS, 9,619 cases of breast, colorectal, endometrium, kidney, bladder, stomach lung or ovary cancer; 8,751 CVD events and 9,865 deaths were reported. Multivariate-adjusted analyses revealed no association of multivitamins with risk of cancer (breast HR=0.98, 95%CI 0.91–1.05; colorectal HR = 0.99, 95% CI 0.88–1.11; endometrial HR = 1.05, 95%CI= 0.90–1.21; lung HR = 1.0, 95% CI=0.88–1.13; ovary HR = 1.07, 95%CI =0.88–1.29); CVD (MI HR= 0.96, 95%CI= 0.89–1.03; stroke HR = 0.99, 95%CI =0.91–1.07; VT HR = 1.05, 95%CI =0.85–1.29); or mortality (HR = 1.02, 95% CI=0.97–1.07).
Conclusion
After a median follow-up of 8.0 and 7.9 years in the CT and OS, respectively, the WHI cohorts provide convincing evidence that multivitamin use has little or no influence on the risk of common cancers, cardiovascular disease or total mortality in postmenopausal women.
Clinical Trial Registration
clinicaltrials.gov identifier: NCT00000611
doi:10.1001/archinternmed.2008.540
PMCID: PMC3868488  PMID: 19204221
dietary supplements; vitamins; minerals; breast cancer; lung cancer; colon cancer; myocardial infarction; stroke
9.  Weight Loss Is Associated With Increased Serum 25-Hydroxyvitamin D in Overweight or Obese Women 
Obesity (Silver Spring, Md.)  2012;20(11):10.1038/oby.2012.57.
Low circulating concentrations of vitamin D metabolites have been associated with increased risk for several diseases and clinical conditions. Large observational studies and surveys have shown that obesity is independently associated with lower serum 25-hydroxyvitamin D (25(OH)D) concentration. Few studies have examined the effect of weight loss on serum 25(OH)D concentration. The purpose of this study was to prospectively examine the effect of weight loss on serum 25(OH)D concentration. Data were collected from 383 overweight or obese women who participated in a 2-year clinical trial of a weight-loss program, in which 51% (N = 195) lost at least 5% of baseline weight by 24 months, 18% (N = 67) lost 5–10%, and 33% (N = 128) lost >10%. Women who did not lose weight at 24 months had an increase in serum 25(OH)D of 1.9 (9.7) ng/ml (mean (SD)); 25(OH)D increased by 2.7 (9.1) ng/ml for those who lost 5–10% of baseline weight; and 25(OH)D increased by 5.0 (9.2) ng/ml for those who lost >10% of baseline weight (P = 0.014). At baseline, 51% (N = 197) of participants met or exceeded the recommended serum concentration of 20 ng/ml. By study end, 64% (N = 230) of overweight or obese women met this goal, as well as 83% (N = 20) of those whose weight loss achieved a normal BMI. These findings suggest that weight loss, presumably associated with a reduction in body fat, is associated with increased serum 25(OH)D concentration in overweight or obese women.
doi:10.1038/oby.2012.57
PMCID: PMC3849029  PMID: 22402737
10.  VITAMIN C AND ZINC INTAKES ARE RELATED TO BONE MACRO-ARCHITECTURAL STRUCTURE AND STRENGTH IN PREPUBESCENT GIRLS 
Calcified tissue international  2012;91(6):430-439.
Background
The extent to which nutrient intake may influence bone structure and strength during maximum rates of skeletal growth remains uncertain.
Objective
To examine the relationship of dietary intake of micronutrients and bone macro-architectural structure in young girls.
Design
This cross-sectional analysis included baseline data from 363 4th and 6th grade girls enrolled in the Jump-In study. Nutrient intake was assessed using the Harvard Youth/Adolescent Food Frequency Questionnaire. Volumetric BMD (vBMD), bone geometry and strength were measured by peripheral quantitative computed tomography (pQCT). Correlations and regression modeling assessed relations between usual nutrient intake and bone parameters.
Results
In 4th grade girls, metaphyseal and diaphyseal area and circumferences, and diaphyseal strength were associated with vitamin C intake (r = 0.15–0.19; p<0.05). Zinc intake was correlated with diaphyseal vBMD (r = 0.15–0.16; p<0.05). Using multiple linear regression to adjust for important covariates, we observed significant independent associations for vitamin C and zinc with bone parameters. For every mg/d of vitamin C intake trabecular area increased by 11%, cortical strength improved by 14%; and periosteal and endosteal circumferences increased by 5% and 8.6%, respectively. For every mg/d of zinc intake, cortical vBMD increased by <1%. No significant associations were observed in 6th-grade girls.
Conclusion
Results of this study suggests that vitamin C and zinc intake are positively associated with objective measures of bone geometry, size and strength in 4th-grade girls. This indicates potential differences in micronutrient and bone associations at various age-associated stages of bone maturation perhaps indicative of competing hormonal influences.
doi:10.1007/s00223-012-9656-8
PMCID: PMC3496253  PMID: 23076447
peripheral quantitative computed tomography (pQCT); preadolescence; bone mineral density (BMD); bone strength; micronutrient intake; vitamin C
11.  Recreational physical activity, body mass index and survival in women with colorectal cancer 
Cancer causes & control : CCC  2012;23(12):1939-1948.
Background and purpose
Previous studies have shown that physical inactivity and obesity are risk factors for the development of colorectal cancer. However, controversy exists regarding the influence of these factors on survival in colorectal cancer patients. We evaluated the impact of recreational physical activity and body mass index (BMI) before and after colorectal cancer diagnosis on disease-specific mortality and all-cause mortality.
Patients and Methods
This prospective cohort study included 1339 women enrolled in the Women’s Health Initiative study who were diagnosed with colorectal cancer subsequent to study enrolment. BMI and recreational physical activity were measured before cancer diagnosis at study entry (pre-diagnostic) and after diagnosis at study follow-up interviews (post-diagnostic). We used Cox regression to estimate the association between pre- and post-diagnostic exposures and survival after colorectal cancer diagnosis.
Results
Among women diagnosed with colorectal cancer, 265 (13%) deaths occurred during a median study follow-up of 11.9 years, of which 171 (65%) were attributed to colorectal cancer. Compared with women reporting no pre-diagnostic recreational physical activity, those reporting activity levels of ≥18 MET-hours/week had significantly lower colorectal cancer-specific mortality (hazard ratio (HR)=0.68; 95% confidence interval (CI): 0.41–1.13) and all-cause mortality (HR=0.63; 95% CI: 0.42–0.96). Similar inverse associations were seen for post-diagnostic recreational physical activity. Neither pre- nor post-diagnostic BMI were associated with mortality after colorectal cancer diagnosis.
Conclusion
Recreational physical activity before and after CR colorectal cancer C diagnosis, but not BMI, is associated with more favourable survival.
doi:10.1007/s10552-012-0071-2
PMCID: PMC3499635  PMID: 23053793
Physical activity; body mass index; colorectal cancer; survival; postmenopausal
12.  Predictors of Improvement in Cardiometabolic Risk Factors With Weight Loss in Women 
Background
Weight loss is associated with improvements in cardiometabolic risk factors, including serum glucose, insulin, C‐reactive protein, and blood lipids. Few studies have evaluated the long‐term (>18 months) effect of weight loss on these risk factors or sought to identify factors associated with sustained improvements in these measures.
Methods and Results
In 417 overweight/obese women (mean [SD] age, 44 [10] years) participating in a weight loss trial, we sought to identify predictors of weight loss–associated cardiometabolic risk factors after 12 and 24 months of intervention. Total cholesterol (TC), low‐density lipoprotein (LDL)–cholesterol (LDL‐C), high‐density lipoprotein (HDL)–cholesterol, non‐HDL‐cholesterol, triglycerides (TG), insulin, glucose, C‐reactive protein (CRP), and cardiopulmonary fitness were measured at baseline and at 12 and 24 months. After 24 months, significant reductions in body weight, waist circumference, CRP, TC, HDL‐cholesterol, and non‐HDL‐cholesterol were observed (P<0.01). After 24 months, mean TC and non‐HDL‐cholesterol were reduced regardless of the amount of weight lost, whereas reductions in LDL–cholesterol, CRP, insulin, and TG were observed only in those who lost ≥10% body weight. Step‐test performance improved only in those who lost ≥10% body weight after 24 months. Change in weight demonstrated a positive predictive value for change in cholesterol, insulin, glucose, and triglycerides. Baseline level of the biomarker showed the greatest predictive value for follow‐up measures for insulin, cholesterol, glucose, and triglycerides.
Conclusions
Our data extend the results from short‐term weight loss trials and suggest that the magnitude of weight loss and baseline values for risk factors are associated with improvements in cardiometabolic risk factors even after 24 months.
Clinical Trials Registration Information
URL: http://www.clinicaltrials.gov/. Unique identifier: NCT00640900.
doi:10.1161/JAHA.113.000152
PMCID: PMC3886783  PMID: 24351700
lipids; obesity; risk factors; women
13.  Safety and Feasibility of Topical Application of Limonene as a Massage Oil to the Breast 
Journal of cancer therapy  2012;3(5A):10.4236/jct.2012.325094.
Background
Limonene, a major component in citrus oil, has demonstrated anti-cancer effects in preclinical mammary cancer models. However, the effective oral dose translates to a human dose that may not be feasible for chronic dosing. We proposed to evaluate topical application of limonene to the breast as an alternative dosing strategy.
Materials and Methods
We conducted a mouse disposition study to determine whether limonene would be bio available in the mammary tissue after topical application. SKH-1 mice received topical or oral administration of limonene in the form of orange oil every day for 4 weeks. Plasma and mammary pads were collected 4 hrs after the final dosing. We also conducted an exploratory clinical study to evaluate the safety and feasibility of topically applied limonene in the form of orange oil to the breast. Healthy women were recruited to apply orange oil containing massage oil to their breasts daily for four weeks. Safety and feasibility were assessed by reported adverse events, clinical labs, and usage compliance. Pre and post-intervention nipple aspirate fluid (NAF) and plasma were collected for limonene concentration determination.
Results
The mouse disposition study showed that topical and oral orange oil administration resulted in similar mammary tissue disposition of limonene with no clinical signs of toxicity. In the clinical study, the topical application of limonene containing massage oil to the breast was found to be safe with high levels of usage compliance for daily application, although NAF and plasma limonene concentrations were not significantly changed after the massage oil application.
Conclusions
Our studies showed that limonene is bio available in mammary tissue after topical orange oil application in mice and this novel route of administration to the breast is safe and feasible in healthy women.
doi:10.4236/jct.2012.325094
PMCID: PMC3824622  PMID: 24236248
Limonene; Topical Application; Safety
14.  A low-fat dietary pattern and risk of metabolic syndrome in postmenopausal women: The Women’s Health Initiative 
Metabolism: clinical and experimental  2012;61(11):1572-1581.
Objective
Nutrition plays an important role in metabolic syndrome etiology. We examined whether the Women’s Health Initiative (WHI) Dietary Modification Trial influenced metabolic syndrome risk.
Materials/Methods
48,835 postmenopausal women aged 50–79 years were randomized to a low-fat (20% energy from fat) diet (intervention) or usual diet (comparison) for a mean of 8.1 years. Blood pressure, waist circumference and fasting blood measures of glucose, HDL-cholesterol and triglycerides were measured on a subsample (n= 2816) at baseline and years 1, 3 and 6 post-randomization. Logistic regression estimated associations of the intervention with metabolic syndrome risk and use of cholesterol-lowering and hypertension medications. Multivariate linear regression tested associations between the intervention and metabolic syndrome components.
Results
At year 3, but not years 1 or 6, women in the intervention group (vs. comparison) had a non-statistically significant lower risk of metabolic syndrome (OR=0.83, 95% CI 0.59–1.18). Linear regression models simultaneously modeling the five metabolic syndrome components revealed significant associations of the intervention with metabolic syndrome at year 1 (p<0.0001), but not years 3 (p=0.19) and 6 (p=0.17). Analyses restricted to intervention-adherent participants strengthened associations at years 3 (p=0.05) and 6 (p=0.06). Cholesterol-lowering and hypertension medication use was 19% lower at year 1 for intervention vs. comparison group women (OR=0.81, 95% CI 0.60–1.09). Over the entire trial, fewer intervention vs. comparison participants used these medications (26.0% vs. 29.9%), although results were not statistically significant (p=0.89).
Conclusions
The WHI low-fat diet may influence metabolic syndrome risk and decrease use of hypertension and cholesterol-lowering medications. Findings have potential for meaningful clinical translation.
doi:10.1016/j.metabol.2012.04.007
PMCID: PMC3430820  PMID: 22633601
clinical trials; aging; dietary fat; metabolic syndrome
15.  Racial Differences in Colorectal Cancer Incidence and Mortality in the Women’s Health Initiative 
Background
Colorectal cancer (CRC) incidence and mortality rates are higher in African–Americans as compared with other racial/ethnic groups. The women’s health initiative (WHI) study sample was used to determine whether differences in CRC risk factors explain racial/ethnic differences in incidence and mortality.
Methods
The WHI is a longitudinal study of postmenopausal women recruited from 40 centers. Baseline questionnaires were used to collect sociodemographic and health status information. All CRC diagnoses were centrally adjudicated. Cox regression models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for invasive CRC by race/ethnicity.
Results
The study sample included 131,481 (83.7%) White, 14,323 (9.1%) African–American, 6,362 (4.1%) Hispanic, 694 (0.4%) Native American and 4,148 (2.6%) Asian/Pacific Islanders. After a mean follow-up of 10.8 years (SD 2.9), CRC incidence was the highest in African–Americans (annualized rate = 0.14%), followed by Whites and Native Americans (0.12% each), Asian/Pacific Islanders (0.10%), and Hispanics (0.08%). After adjustment for age and trial assignment, Hispanics had a lower risk compared with Whites, HR 0.73 (95% CI: 0.54–0.97) (P = 0.03), and African–Americans had a marginally greater risk, HR 1.16 (95% CI: 0.99–1.34), P = 0.06. Multivariable adjustment attenuated the difference in incidence between African–Americans and Whites (HR 0.99, 95% CI: 0.82–1.20), while strengthening the lower HR for Hispanics (HR 0.68, 95% CI: 0.48–0.97).
Conclusions
African–American/White differences in CRC risk are likely due to sociodemographic/cultural factors other than race.
Impact
A number of modifiable exposures could be a focus for reducing CRC risk in African–Americans.
doi:10.1158/1055-9965.EPI-11-0027
PMCID: PMC3784999  PMID: 21602308
16.  Body Fat and Breast Cancer Risk in Postmenopausal Women: A Longitudinal Study 
Journal of Cancer Epidemiology  2013;2013:754815.
Associations between anthropometric indices of obesity and breast cancer risk may fail to capture the true relationship between excess body fat and risk. We used dual-energy-X-ray-absorptiometry- (DXA-) derived measures of body fat obtained in the Women's Health Initiative to examine the association between body fat and breast cancer risk; we compared these risk estimates with those for conventional anthropometric measurements. The study included 10,960 postmenopausal women aged 50–79 years at recruitment, with baseline DXA measurements and no history of breast cancer. During followup (median: 12.9 years), 503 incident breast cancer cases were diagnosed. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. All baseline DXA-derived body fat measures showed strong positive associations with breast cancer risk. The multivariable-adjusted HR for the uppermost quintile level (versus lowest) ranged from 1.53 (95% CI 1.14–2.07) for fat mass of the right leg to 2.05 (1.50–2.79) for fat mass of the trunk. Anthropometric indices (categorized by quintiles) of obesity (BMI (1.97, 1.45–2.68), waist circumference (1.97, 1.46–2.65), and waist : hip ratio (1.91, 1.41–2.58)) were all strongly, positively associated with risk and did not differ from DXA-derived measures in prediction of risk.
doi:10.1155/2013/754815
PMCID: PMC3649193  PMID: 23690776
17.  Vitamin D and calcium supplementation and one-year change in mammographic density in the Women’s Health Initiative Calcium and Vitamin D Trial 
Background
Calcium and vitamin D may be inversely related to breast cancer risk, in part by affecting mammographic density. However, results from previous, mostly cross-sectional studies have been mixed, and there have been few randomized clinical trials of the effect of calcium and vitamin D supplementation on change in mammographic density.
Methods
We assessed the effect of one year of supplementation on mammographic density in 330 postmenopausal women enrolled in the Women’s Health Initiative Hormone Therapy (HT) and Calcium and Vitamin D (CaD) trials. Women were randomized to receive 1000 mg/day of elemental calcium carbonate plus 400 IU/day of vitamin D3 or placebo.
Results
After approximately one year, mammographic density decreased 2% in the CaD supplementation group and increased 1% in the placebo group (ratio of means = 0.97; 95% confidence interval (CI) = 0.81–1.17). Results suggested potential interaction by HT use (P = 0.08). Among women randomized to HT placebo, the ratio of mean density comparing CaD supplementation and placebo groups was 0.82 (95%CI = 0.61–1.11) vs. 1.16 (95%CI = 0.92–1.45) in women randomized to active HT. In sensitivity analyses limited to women taking ≥80% of study supplements, ratios were 0.67 (95%CI = 0.41–1.07) in women not assigned to HT and 1.07 (95%CI = 0.79–1.47) women assigned to HT.
Conclusions
We observed no overall effect of vitamin D and calcium supplementation on mammographic density after one year.
Impact
Potential interaction between these nutrients and estrogen as related to mammographic density warrants further study.
doi:10.1158/1055-9965.EPI-11-1009
PMCID: PMC3297717  PMID: 22253296
breast; calcium; clinical trial; mammography; vitamin D
18.  Evaluation and Comparison of Food Records, Recalls, and Frequencies for Energy and Protein Assessment by Using Recovery Biomarkers 
American Journal of Epidemiology  2011;174(5):591-603.
The food frequency questionnaire approach to dietary assessment is ubiquitous in nutritional epidemiology research. Food records and recalls provide approaches that may also be adaptable for use in large epidemiologic cohorts, if warranted by better measurement properties. The authors collected (2007–2009) a 4-day food record, three 24-hour dietary recalls, and a food frequency questionnaire from 450 postmenopausal women in the Women’s Health Initiative prospective cohort study (enrollment, 1994–1998), along with biomarkers of energy and protein consumption. Through comparison with biomarkers, the food record is shown to provide a stronger estimate of energy and protein than does the food frequency questionnaire, with 24-hour recalls mostly intermediate. Differences were smaller and nonsignificant for protein density. Food frequencies, records, and recalls were, respectively, able to “explain” 3.8%, 7.8%, and 2.8% of biomarker variation for energy; 8.4%, 22.6%, and 16.2% of biomarker variation for protein; and 6.5%, 11.0%, and 7.0% of biomarker variation for protein density. However, calibration equations that include body mass index, age, and ethnicity substantially improve these numbers to 41.7%, 44.7%, and 42.1% for energy; 20.3%, 32.7%, and 28.4% for protein; and 8.7%, 14.4%, and 10.4% for protein density. Calibration equations using any of the assessment procedures may yield suitable consumption estimates for epidemiologic study purposes.
doi:10.1093/aje/kwr140
PMCID: PMC3202154  PMID: 21765003
bias (epidemiology); biological markers; diet; energy intake; epidemiologic methods; measurement error; nutrition assessment
19.  Improvement in Self-Reported Physical Health Predicts Longer Survival Among Women with a History of Breast Cancer 
Purpose
Physical health-related quality of life scores have been, inconsistently, associated with breast cancer prognosis. This analysis examined whether change in physical health scores were related to outcomes in women with a history of breast cancer.
Methods
2343 breast cancer survivors in a randomized diet trial provided self-reported assessment of physical health-related quality of life at baseline and year 1. Based on change in physical health score, participants were grouped into subpopulations of decreased physical health, no/minimal changes, and increased physical health. Cox regression analysis assessed whether change in physical health (from baseline to year 1) predicted disease-free and overall survival; hazard ratio (HR) was the measure of association.
Results
There were 294 additional breast cancer events and 162 deaths among women followed for 7.3 years. Improvements in physical health were associated with younger age, lower BMI, being employed, not receiving tamoxifen, lower physical activity, and lower baseline physical and mental health. There was no association of change in physical health with additional breast cancer events or mortality among women diagnosed ≤ 2 years before study enrollment. However, among women who entered the study >2 years post diagnosis, the HR for increased compared to decreased physical health was 0.38 (95% CI, 0.16 to 0.85) for all-cause mortality.
Conclusions
These results appear to support testing an intervention to improve physical health in breast cancer patients among patients after the acute stage of treatment.
doi:10.1007/s10549-010-1236-x
PMCID: PMC3306248  PMID: 21042931
breast cancer; physical health; survival; mortality
20.  Physical Activity and Survival in Postmenopausal Women with Breast Cancer: Results from the Women’s Health Initiative 
Although studies have shown that physically active breast cancer survivors have lower all-cause mortality, the association between change in physical activity from before to after diagnosis and mortality is not clear. We examined associations among pre- and postdiagnosis physical activity, change in pre- to postdiagnosis physical activity, and all-cause and breast cancer–specific mortality in post-menopausal women. A longitudinal study of 4,643 women diagnosed with invasive breast cancer after entry into the Women’s Health Initiative study of postmenopausal women. Physical activity from recreation and walking was determined at baseline (prediagnosis) and after diagnosis (assessed at the 3 or 6 years post-baseline visit). Women participating in 9 MET-h/wk or more (~3 h/wk of fast walking) of physical activity before diagnosis had a lower all-cause mortality (HR = 0.61; 95% CI, 0.44–0.87; P = 0.01) compared with inactive women in multivariable adjusted analyses. Women participating in ≥9 or more MET-h/wk of physical activity after diagnosis had lower breast cancer mortality (HR = 0.61; 95% CI, 0.35–0.99; P = 0.049) and lower all-cause mortality (HR = 0.54; 95% CI, 0.38–0.79; P < 0.01). Women who increased or maintained physical activity of 9 or more MET-h/wk after diagnosis had lower all-cause mortality (HR = 0.67; 95% CI, 0.46–0.96) even if they were inactive before diagnosis. High levels of physical activity may improve survival in postmenopausal women with breast cancer, even among those reporting low physical activity prior to diagnosis. Women diagnosed with breast cancer should be encouraged to initiate and maintain a program of physical activity.
doi:10.1158/1940-6207.CAPR-10-0295
PMCID: PMC3123895  PMID: 21464032
21.  Nutrient Intake and Anemia Risk in the WHI Observational Study 
Background
Nutritional anemia among post-menopausal women is preventable; recent data on prevalence are limited.
Objective
To investigate the association between nutrient intakes and anemia prevalence, in relation to both incidence and persistence, in a longitudinal sample of post-menopausal women. We hypothesized that anemia prevalence, incidence and persistence would be greater among women reporting lower intake of B12, folate and iron.
Design
Prospective cohort analysis.
Participants/setting
Observational Cohort of the Women’s Health Initiative(WHI-OS) including 93,676 postmenopausal women, age 50 to 79 years, were recruited across the United States at 40 clinical study sites. Women were enrolled between 1993 and 1998; data collection for these analyses continued through 2000.
Main outcome measures
Anemia was defined as a blood hemoglobin concentration of <12.0 mg/dL. Persistent anemia was defined as anemia present at each measurement time point. Diet was assessed by food frequency questionnaire for iron, folate, B12, red meat and cold breakfast cereal; inadequacies were based on dietary reference intakes for women over age 50 years.
Statistical analysis
Descriptive statistics (mean and standard deviation) were used to characterize the population demographics, anemia rates and diet. Unconditional logistic regression was used to investigate associations between diet and incident and persistent anemia. Associations are presented as odds ratio (OR) and 95% confidence intervals (CI).
Results
Anemia was identified in 3,979 women or 5.5% of the cohort. Inadequate intakes of multiple anemia-associated nutrients were less frequent in non-Hispanic whites (7.4%) than other race/ethnic groups (inadequacies demonstrated in 14.6 to 16.3% of sample). Age, body mass index and smoking were associated with anemia. Women with anemia reported lower intakes of energy, protein, folate, B12, iron, vitamin C and red meat. Multiple (more than a single nutrient) dietary deficiencies were associated with a 21% greater risk of persistent anemia (OR-1.21, 95% CI: 1.05–1.41) and three deficiencies resulted in a 44% increase in risk for persistent anemia (OR-1.44, 95% CI: 1.20–1.73).
Conclusion
Inadequate nutrient intake, a modifiable condition, is associated with greater risk for anemia in post-menopausal women participating in the WHI-OS. Efforts to identify and update incidence estimates for anemia-associated nutrient deficiencies in aging women should be undertaken.
doi:10.1016/j.jada.2011.01.017
PMCID: PMC3066454  PMID: 21443985
anemia; diet; aging
22.  Dietary Intake, Supplement Use, and Survival Among Women Diagnosed with Early Stage Breast Cancer 
Nutrition and cancer  2011;63(3):327-333.
Background
Previous studies examining the relationship between micronutrient intakes and survival following diagnosis of breast cancer have reported mixed results. This may be partly due to considerable variance in amounts of micronutrients consumed from diet and supplements across studies.
Methods
Early stage breast cancer survivors (n=3081) completed four 24-hour dietary and supplement recalls at the baseline assessment (1995 to 2000) and were followed for a median of 9.0 years. Mean micronutrient intakes were compared to dietary reference intakes (DRI) to assess micronutrient adequacy for both users and non-users of supplements. Cox regressions were performed to assess whether intakes of selected micronutrients were associated with all-cause mortality.
Results
412 deaths occurred between baseline and August 2009. Among these women, more supplement users had adequate micronutrient intakes than non-users for 15 out of 17 micronutrients. Less than 10% of supplement users (< 2% of non-supplement users) reported levels that exceeded the tolerable upper limit for each micronutrient except magnesium. After adjusting for age, tumor characteristics, and health status variables, micronutrient intakes were not significantly associated with all-cause mortality.
Conclusion
Dietary supplements may improve overall micronutrient intakes of breast cancer survivors. However, vitamin and mineral intakes were not associated with all-cause mortality.
doi:10.1080/01635581.2011.535957
PMCID: PMC3078826  PMID: 21391124
dietary intake; supplement use; breast cancer survival
23.  Poor Physical Health Predicts Time to Additional Breast Cancer Events and Mortality in Breast Cancer Survivors 
Psycho-Oncology  2011;20(3):252-259.
Background
Health-related quality of life (HRQOL) has been hypothesized to predict time to additional breast cancer events and all-cause mortality in breast cancer survivors.
Methods
Women with early stage breast cancer (n=2967) completed the SF-36 (mental and physical health-related quality of life) and standardized psychosocial questionnaires to assess social support, optimism, hostility, and depression prior to randomization into a dietary trial. Cox regression was performed to assess whether these measures of quality of life and psychosocial functioning predicted time to additional breast cancer events and all-cause mortality; hazard ratios were the measure of association.
Results
There were 492 additional breast cancer events and 301 deaths occurred over a median 7.3 years (range: 0.01–10.8 years) of follow-up. In multivariate models, poorer physical health was associated with both decreased time to additional breast cancer events and all-cause mortality (p trend=0.005 and 0.004, respectively), while greater hostility predicted additional breast cancer events only (p trend=0.03). None of the other psycho-social variables predicted either outcome. The hazard ratios comparing persons with poor (bottom two quintiles) to better (top three quintiles) physical health were 1.42 (95% CI: 1.16, 1.75) for decreased time to additional breast cancer events and 1.37 (95% CI: 1.08, 1.74) for all-cause mortality. Potentially modifiable factors associated with poor physical health included higher BMI, lower physical activity, lower alcohol consumption, and more insomnia (p<0.05 for all).
Conclusion
Interventions to improve physical health should be tested as a means to increase time to additional breast cancer events and mortality among breast cancer survivors.
doi:10.1002/pon.1742
PMCID: PMC3297415  PMID: 20878837
physical health; breast cancer; oncology; survival
24.  Green Tea Improves Metabolic Biomarkers, not Weight or Body Composition: A Pilot Study in Overweight Breast Cancer Survivors 
Background
Overweight status after breast cancer treatment may increase a woman’s risk for recurrent disease and/or early onset cardiovascular disease. Green tea has been proposed to promote weight loss and favourably modify glucose, insulin and blood lipids. This pilot study tested the effect of daily decaffeinated green tea consumption for 6 months on weight and body composition, select metabolic parameters, and lipid profiles in overweight breast cancer survivors.
Methods
The effect of daily decaffeinated green tea intake on weight, body composition and changes in resting metabolic rate, energy intake, glucose, insulin, HOMA-IR, and lipids was evaluated in overweight breast cancer survivors. Participants had a mean weight of 80.2 kg; BMI 30.1 kg/m2; and body fat 46.4%. Participants (N=54) were randomised to 960 mL decaffeinated green or placebo tea daily for 6 months.
Results
Average tea intake among study completers (N=39) was 5952 ± 1176 mL/week and was associated with a significant reduction in energy intake (P =0.02). Change in body weight of −1.2 kg (green tea) versus + 0.2 kg (placebo) suggests a weight change effect, but was not statistically significant. Decaffeinated green tea intake was associated with elevated HDL levels (P=0.003) and non-significant improvements in the HOMA-IR (−1.1±5.9: green tea; +3.2±7.2: herbal) and the HDL/LDL ratio.
Conclusions
Intake of decaffeinated green tea for 6 months was associated with a slight reduction in body weight and improved HDL and glucose homeostasis in overweight breast cancer survivors.
doi:10.1111/j.1365-277X.2010.01078.x
PMCID: PMC2966548  PMID: 20807303
green tea; overweight; breast cancer survivors
25.  The Relationship Between Incidence of Fractures and Anemia in Older Multiethnic Women 
Objectives
The purpose of this study was to prospectively examine the relationship between anemia and incident fractures of the hip, spine and all skeletal sites in women from diverse racial and ethnic backgrounds enrolled in the Women's Health Initiative (WHI) Observational Study and Clinical Trials.
Design
Prospective cohort study.
Setting
40 WHI clinical centers across the US.
Participants
Postmenopausal women (n = 160,080), mean age 63.2 (SD: 7.2) years, were recruited and followed for an average of 7.8 years.
Measurements
Anemia was defined as hemoglobin levels at baseline less than 12 g/dL. All fractures were self-reported. Hip fractures were further confirmed by trained physicians using medical records.
Results
Among the participants 8,739 women (5.5%) were anemic. The age-adjusted incidence rate of hip fractures per 10,000 person years were 21.4 in women with anemia and 15.0 in women without anemia; a higher incidence rate for spine or all fractures in anemic women was also observed. After multiple covariates were included in the Cox proportional hazards models, significant increased fracture risk associated with anemia still existed as demonstrated by the hazards ratios (95% confidence interval) of fractures associated with anemia being 1.38 (1.13–1.68), 1.30 (1.09–1.55) and 1.07 (1.01–1.14) for hip, spine and all-types respectively. No significant racial/ethnic difference was found in these relationships.
Conclusion
A significantly increased fracture risk was observed in multi-ethnic postmenopausal women with anemia. Given the high prevalence of anemia in the elderly population, it is important to better understand the relationship and mechanisms linking anemia to fracture risk.
doi:10.1111/j.1532-5415.2010.03183.x
PMCID: PMC3058294  PMID: 21143442
fracture risk; anemia; hemoglobin; prospective studies

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