Mimi Y. Kim

Repeated measures of serum glucose and insulin in relation to postmenopausal breast cancer

Experimental and epidemiological evidence suggests that circulating glucose and insulin may play a role in breast carcinogenesis. However, few cohort studies have examined breast cancer risk in association with glucose and insulin levels, and studies to date have had only baseline measurements of exposure. We conducted a longitudinal study of postmenopausal breast cancer risk using the 6% random sample of women in the Womens Health Initiative clinical trials whose fasting blood samples, provided at baseline and at years 1, 3 and 6, were analyzed for glucose and insulin. In addition, a 1% sample of women in the observational study, who had glucose and insulin measured in fasting blood samples drawn at baseline and in year 3, were included in the analysis. We used Cox proportional hazards models to estimate hazard ratios and 95% confidence intervals for the association of baseline and follow‐up measurements of serum glucose and insulin with breast cancer risk. All statistical tests were 2‐sided. Among 5,450 women with baseline serum glucose and insulin values, 190 incident cases of breast cancer were ascertained over a median of 8.0 years of follow‐up. The highest tertile of baseline insulin, relative to the lowest, was associated with a 2‐fold increase in risk in the total population (multivariable hazard ratio 2.22, 95% confidence interval 1.39–3.53) and with a 3‐fold increase in risk in women who were not enrolled in the intervention arm of any clinical trial (multivariable hazard ratio 3.15, 95% confidence interval 1.61–6.17). Glucose levels showed no association with risk. Analysis of the repeated measurements supported the results of the baseline analysis. These data suggest that elevated serum insulin levels may be a risk factor for postmenopausal breast cancer.

Body Mass Index and Waist Circumference in Relation to Lung Cancer Risk in the Women's Health Initiative

Investigators in several epidemiologic studies have observed an inverse association between body mass index (BMI) and lung cancer risk, while others have not. The authors used data from the Womens Health Initiative to study the association of anthropometric factors with lung cancer risk. Over 8 years of follow-up (1998-2006), 1,365 incident lung cancer cases were ascertained among 161,809 women. Cox proportional hazards models were used to estimate hazard ratios adjusted for covariates. Baseline BMI was inversely associated with lung cancer in current smokers (highest quintile vs. lowest: hazard ratio (HR) = 0.62, 95% confidence interval (CI): 0.42, 0.92). When BMI and waist circumference were mutually adjusted, BMI was inversely associated with lung cancer risk in both current smokers and former smokers (HR = 0.40 (95% CI: 0.22, 0.72) and HR = 0.61 (95% CI: 0.40, 0.94), respectively), and waist circumference was positively associated with risk (HR = 1.56 (95% CI: 0.91, 2.69) and HR = 1.50 (95% CI: 0.98, 2.31), respectively). In never smokers, height showed a borderline positive association with lung cancer. These findings suggest that in smokers, BMI is inversely associated with lung cancer risk and that waist circumference is positively associated with risk.

Smoking and alcohol consumption in relation to risk of triple-negative breast cancer in a cohort of postmenopausal women

PurposeLittle is known about the risk factors for triple-negative breast cancer (TNBC), which has a worse prognosis compared to hormone receptor-positive breast cancer. We examined the association of smoking and alcohol intake with TNBC and estrogen receptor-positive (ER+) breast cancer.MethodsAmong 148,030 women enrolled in the Women’s Health Initiative, 300 TNBC cases and 2,479 ER+ cases were identified over a median of 8.0xa0years of follow-up. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI).ResultsCigarette smoking was not associated with TNBC, whereas drinkers had reduced risk compared to never drinkers. In contrast, both exposures showed slight positive associations with ER+ breast cancer: for women with ≥40 pack-years of smoking, the HR was 1.24, 95% CI 1.06–1.44; for women consuming ≥7 servings of alcohol per week, the HR was 1.26, 95% CI 1.06–1.50. Intakes of wine and hard liquor were also significantly positively associated with ER+ breast cancer.ConclusionsThese findings from a large cohort of postmenopausal women suggest that smoking and alcohol consumption are not associated with increased risk of TNBC, but may be modestly associated with increased risk of ER+ breast cancer.

Longitudinal study of serum carotenoid, retinol, and tocopherol concentrations in relation to breast cancer risk among postmenopausal women.

BACKGROUNDnProspective studies have examined the association of serum and plasma carotenoids and micronutrients and breast cancer; however, to date, studies have only assessed exposure at one point in time.nnnOBJECTIVEnThis study analyzed baseline and repeated serum measurements of carotenoids, retinol, and tocopherols to assess their associations with postmenopausal breast cancer risk.nnnDESIGNnSerum concentrations of alpha-carotene, beta-carotene, beta-cryptoxanthin, lycopene, lutein + zeaxanthin, retinol, alpha-tocopherol, and gamma-tocopherol were measured in a 6% sample of women in the Womens Health Initiative clinical trials at baseline and at years 1, 3, and 6 and in a 1% sample of women in the observational study at baseline and at year 3. The association of baseline compounds and breast cancer risk was estimated by Cox proportional hazards models. In addition, repeated measurements were analyzed as time-dependent covariates. Of 5450 women with baseline measurements, 190 incident cases of breast cancer were ascertained over a median of 8.0 y of follow-up.nnnRESULTSnAfter multivariable adjustment, risk of invasive breast cancer was inversely associated with baseline serum alpha-carotene concentrations (hazard ratio for highest compared with the lowest tertile: 0.55; 95% CI: 0.34, 0.90; P = 0.02) and positively associated with baseline lycopene (hazard ratio: 1.47; 95% CI: 0.98, 2.22; P = 0.06). Analysis of repeated measurements indicated that alpha-carotene and beta-carotene were inversely associated with breast cancer and that gamma-tocopherol was associated with increased risk.nnnCONCLUSIONSnThe present study, which was the first to assess repeated measurements of serum carotenoids and micronutrients in relation to breast cancer, adds to the evidence of an inverse association of specific carotenoids with breast cancer. The positive associations observed for lycopene and gamma-tocopherol require confirmation. This trial was registered at ClinicalTrials.gov as NCT00000611.

Insulin-Like Growth Factor Axis and Risk of Type 2 Diabetes in Women

IGF-I shares structural homology and in vitro metabolic activity with insulin. Laboratory models suggest that IGF-I and its binding proteins IGFBP-1 and IGFBP-2 have potentially beneficial effects on diabetes risk, whereas IGFBP-3 may have adverse effects. We therefore conducted a prospective nested case-control investigation of incident diabetes (n = 742 case subjects matched 1:1 to control subjects) and its associations with IGF-axis protein levels in the Nurses’ Health Study, a cohort of middle-aged women. The median time to diabetes was 9 years. Statistical analyses were adjusted for multiple risk factors, including insulin and C-reactive protein. Diabetes risk was fivefold lower among women with baseline IGFBP-2 levels in the top versus bottom quintile (odds ratio [OR]q5–q1 = 0.17 [95% CI 0.08–0.35]; P trend < 0.0001) and was also negatively associated with IGFBP-1 levels (ORq5–q1 = 0.37 [0.18–0.73]; P trend = 0.0009). IGFBP-3 was positively associated with diabetes (ORq5–q1 = 2.05 [1.20–3.51]; P trend = 0.002). Diabetes was not associated with total IGF-I levels, but free IGF-I and diabetes had a significant association that varied (P interaction = 0.003) by insulin levels above the median (ORq5–q1 = 0.48 [0.26–0.90]; P trend = 0.0001) versus below the median (ORq5–q1 = 2.52 [1.05–6.06]; P trend < 0.05). Thus, this prospective study found strong associations of incident diabetes with baseline levels of three IGFBPs and free IGF-I, consistent with hypotheses that the IGF axis might influence diabetes risk.

Anthropometric factors, physical activity, and risk of Non-Hodgkin's lymphoma in the Women's Health Initiative

BACKGROUNDnIncidence rates of non-Hodgkins lymphoma (NHL) increased substantially in the United States and worldwide during the latter part of the 20th century, but little is known about its etiology. Obesity is associated with impaired immune function through which it may influence the risk of NHL; other factors reflecting energy homeostasis (height, abdominal adiposity, and physical activity) may also be involved.nnnMETHODSnWe examined the association of anthropometric factors and physical activity with risk of NHL and its major subtypes in a large cohort of women aged 50-79 years old who were enrolled at 40 clinical centers in the United States between 1993 and 1998. Over a mean follow-up period of 11 years, 1123 cases of NHL were identified among 158,975 women. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI).nnnRESULTSnHeight at baseline was positively associated with risk of all NHL and with that of diffuse large B-cell lymphoma (HRs(q4vs.q1) 1.19, 95% CI 1.00-1.43 and 1.43, 95% CI 1.01-2.03, respectively). Measures of obesity and abdominal adiposity at baseline were not associated with risk. Hazard ratios for NHL were increased for women in the highest quartile of weight and body mass index at age 18 (HRs(q4vs.q1) 1.29, 95% CI 1.01-1.65 and 1.27, 95% CI 1.01-1.59, respectively). Some measures of recreational physical activity were modestly associated with increased risk of NHL overall, but there were no clear associations with specific subtypes.nnnCONCLUSIONnOur findings regarding anthropometric measures are consistent with those of several previous reports, suggesting that early life influences on growth and immune function may influence the risk of NHL later in life.

Anthropometric factors and physical activity and risk of thyroid cancer in postmenopausal women.

PurposeTo investigate the associations of anthropometric factors and physical activity with risk of thyroid cancer in a large prospective study.MethodsWe examined these associations with risk of incident thyroid cancer in a cohort of 144,319 postmenopausal women enrolled in the Women’s Health Initiative. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CI) for factors of interest with risk of all thyroid cancer (nxa0=xa0294) and of the two major subtypes: papillary (nxa0=xa0245) and follicular thyroid cancer (nxa0=xa032).ResultsAfter adjustment for covariates, measured height at baseline was positively associated with thyroid cancer overall (HR for highest vs. lowest quartile 1.48, 95% CI 1.04–2.13, p for trend 0.02) and with papillary carcinoma (HR 1.49, 95% CI 1.01–2.21, p for trend 0.03, respectively). For each 5xa0cm-increase in height, the HR for all thyroid cancer was 1.15, 95% CI 1.04–1.27 and for papillary thyroid cancer was 1.14, 95% CI 1.03–1.27. In addition, self-reported weight at age 18 was positively associated with risk of papillary thyroid cancer. In contrast, baseline weight, body mass index, waist circumference, hip circumference, waist-hip ratio, weight change from age 18 to baseline, and level of self-reported recreational physical activity were not associated with risk.ConclusionsOur results suggest that attained stature is a risk factor for thyroid cancer in postmenopausal women. This association may reflect the influence of either genetic or environmental factors in early life on risk of thyroid cancer.

Menstrual and reproductive factors, exogenous hormone use, and risk of thyroid carcinoma in postmenopausal women

PurposeTo investigate the association of reproductive factors and hormone therapy, including type of hormone therapy, with risk of thyroid cancer in postmenopausal women.MethodsWe assessed these associations with risk of incident thyroid cancer in a cohort of 145,007 postmenopausal women enrolled in the Women’s Health Initiative. Over 12.7xa0years of follow-up, 296 cases of thyroid cancer were identified, including 243 with papillary thyroid cancer. Cox proportional hazards models were used to estimate hazard ratios and 95xa0% confidence intervals for exposures of interest.ResultsIn both age-adjusted and multivariable-adjusted analyses, menstrual and reproductive factors including age at menarche, age at menopause, age at first birth, age at last live birth, parity, duration of breastfeeding, miscarriages, stillbirths, hysterectomy, bilateral oophorectomy, and use of oral contraceptives were not associated with risk of all thyroid cancer or papillary thyroid cancer. In addition, ever use of menopausal hormone therapy, current or former use, duration of use, and type were not associated with risk.ConclusionWe found little support for associations of reproductive or hormonal factors with risk of developing thyroid cancer. Importantly, our study showed no association of type of hormone therapy used with thyroid cancer risk.

Common scientific and statistical errors in obesity research.

This review identifies 10 common errors and problems in the statistical analysis, design, interpretation, and reporting of obesity research and discuss how they can be avoided. The 10 topics are: 1) misinterpretation of statistical significance, 2) inappropriate testing against baseline values, 3) excessive and undisclosed multiple testing and “P‐value hacking,” 4) mishandling of clustering in cluster randomized trials, 5) misconceptions about nonparametric tests, 6) mishandling of missing data, 7) miscalculation of effect sizes, 8) ignoring regression to the mean, 9) ignoring confirmation bias, and 10) insufficient statistical reporting. It is hoped that discussion of these errors can improve the quality of obesity research by helping researchers to implement proper statistical practice and to know when to seek the help of a statistician.

Attained height, sex, and risk of cancer at different anatomic sites in the NIH-AARP Diet and Health Study

PurposeTo examine the association of adult height with risk of cancer at different anatomic sites in a cohort of men and women.MethodsThe association of self-reported height with subsequent cancer risk was assessed in 288,683 men and 192,514 women enrolled in the National Institutes of Health-AARP Diet and Health Study. After a median follow-up of 10.5xa0years, incident cancer was diagnosed in 51,139 men and 23,407 women. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95xa0% confidence intervals (95xa0% CIs) for the association of height with cancer risk.ResultsAfter adjustment for covariates, height was positively associated with increased risk of all cancers combined in both men [HR10xa0cm increasexa0=xa01.05 (95xa0% CI 1.04–1.06)] and women [HR10xa0cm increasexa0=xa01.08 (95xa0% CI 1.06–1.10)]. Several sites common to men and women showed significant positive associations with height: colon, rectum, kidney, melanoma, and non-Hodgkin’s lymphoma. For other shared sites, the association differed by sex. For still other sites, there was no clear association with height. Positive associations were also observed with cancers of the breast, endometrium, and prostate.ConclusionsDifferent patterns were observed in the height–cancer association by sex. Studies investigating the biological mechanisms underlying the association of height with cancer risk should focus on those sites that show a reproducible association with attained height.