Katherine D. Henderson

Body-mass index and mortality among 1.46 million white adults.

BACKGROUND A high body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) is associated with increased mortality from cardiovascular disease and certain cancers, but the precise relationship between BMI and all-cause mortality remains uncertain. METHODS We used Cox regression to estimate hazard ratios and 95% confidence intervals for an association between BMI and all-cause mortality, adjusting for age, study, physical activity, alcohol consumption, education, and marital status in pooled data from 19 prospective studies encompassing 1.46 million white adults, 19 to 84 years of age (median, 58). RESULTS The median baseline BMI was 26.2. During a median follow-up period of 10 years (range, 5 to 28), 160,087 deaths were identified. Among healthy participants who never smoked, there was a J-shaped relationship between BMI and all-cause mortality. With a BMI of 22.5 to 24.9 as the reference category, hazard ratios among women were 1.47 (95 percent confidence interval [CI], 1.33 to 1.62) for a BMI of 15.0 to 18.4; 1.14 (95% CI, 1.07 to 1.22) for a BMI of 18.5 to 19.9; 1.00 (95% CI, 0.96 to 1.04) for a BMI of 20.0 to 22.4; 1.13 (95% CI, 1.09 to 1.17) for a BMI of 25.0 to 29.9; 1.44 (95% CI, 1.38 to 1.50) for a BMI of 30.0 to 34.9; 1.88 (95% CI, 1.77 to 2.00) for a BMI of 35.0 to 39.9; and 2.51 (95% CI, 2.30 to 2.73) for a BMI of 40.0 to 49.9. In general, the hazard ratios for the men were similar. Hazard ratios for a BMI below 20.0 were attenuated with longer-term follow-up. CONCLUSIONS In white adults, overweight and obesity (and possibly underweight) are associated with increased all-cause mortality. All-cause mortality is generally lowest with a BMI of 20.0 to 24.9.

Associations of Insulin Resistance and Adiponectin With Mortality in Women With Breast Cancer

PURPOSE Overweight or obese breast cancer patients have a worse prognosis compared with normal-weight patients. This may be attributed to hyperinsulinemia and dysregulation of adipokine levels associated with overweight and obesity. Here, we evaluate whether low levels of adiponectin and a greater level of insulin resistance are associated with breast cancer mortality and all-cause mortality. PATIENTS AND METHODS We measured glucose, insulin, and adiponectin levels in fasting serum samples from 527 women enrolled in the Health, Eating, Activity, and Lifestyle (HEAL) Study, a multiethnic, prospective cohort study of women diagnosed with stage I-IIIA breast cancer. We evaluated the association between adiponectin and insulin and glucose levels (expressed as the Homeostatic Model Assessment [HOMA] score) represented as continuous measures and median split categories, along with breast cancer mortality and all-cause mortality, using Cox proportional hazards models. RESULTS Increasing HOMA scores were associated with reduced breast cancer survival (hazard ratio [HR], 1.12; 95% CI, 1.05 to 1.20) and reduced all-cause survival (HR, 1.09; 95% CI, 1.02 to 1.15) after adjustment for possible confounders. Higher levels of adiponectin (above the median: 15.5 μg/mL) were associated with longer breast cancer survival (HR, 0.39; 95% CI, 0.15 to 0.95) after adjustment for covariates. A continuous measure of adiponectin was not associated with either breast cancer-specific or all-cause mortality. CONCLUSION Elevated HOMA scores and low levels of adiponectin, both associated with obesity, were associated with increased breast cancer mortality. To the best of our knowledge, this is the first demonstration of the association between low levels of adiponectin and increased breast cancer mortality in breast cancer survivors.

Long-Term Exposure to Constituents of Fine Particulate Air Pollution and Mortality: Results from the California Teachers Study

Background Several studies have reported associations between long-term exposure to ambient fine particulate matter (PM) and cardiovascular mortality. However, the health impacts of long-term exposure to specific constituents of PM2.5 (PM with aerodynamic diameter ≤ 2.5 μm) have not been explored. Methods We used data from the California Teachers Study, a prospective cohort of active and former female public school professionals. We developed estimates of long-term exposures to PM2.5 and several of its constituents, including elemental carbon, organic carbon (OC), sulfates, nitrates, iron, potassium, silicon, and zinc. Monthly averages of exposure were created using pollution data from June 2002 through July 2007. We included participants whose residential addresses were within 8 and 30 km of a monitor collecting PM2.5 constituent data. Hazard ratios (HRs) were estimated for long-term exposure for mortality from all nontraumatic causes, cardiopulmonary disease, ischemic heart disease (IHD), and pulmonary disease. Results Approximately 45,000 women with 2,600 deaths lived within 30 km of a monitor. We observed associations of all-cause, cardiopulmonary, and IHD mortality with PM2.5 mass and each of its measured constituents, and between pulmonary mortality and several constituents. For example, for cardiopulmonary mortality, HRs for interquartile ranges of PM2.5, OC, and sulfates were 1.55 [95% confidence interval (CI), 1.43–1.69], 1.80 (95% CI, 1.68–1.93), and 1.79 (95% CI, 1.58–2.03), respectively. Subsequent analyses indicated that, of the constituents analyzed, OC and sulfates had the strongest associations with all four outcomes. Conclusions Long-term exposures to PM2.5 and several of its constituents were associated with increased risks of all-cause and cardiopulmonary mortality in this cohort. Constituents derived from combustion of fossil fuel (including diesel), as well as those of crustal origin, were associated with some of the greatest risks. These results provide additional evidence that reduction of ambient PM2.5 may provide significant public health benefits.

Disparities in reconstruction rates after mastectomy: patterns of care and factors associated with the use of breast reconstruction in Southern California.

BackgroundMany factors influence whether breast cancer patients undergo reconstruction after mastectomy. We sought to determine the patterns of care and variables associated with the use of breast reconstruction in Southern California.Materials and MethodsPostmastectomy reconstruction rates were determined from the California Office of Statewide Health Planning and Development (OSHPD) inpatient database from 2003 to 2007. International Classification of Disease-9 codes were used to identify patients undergoing reconstruction after mastectomy. Changes in reconstruction rates were examined by calendar year, age, race, type of insurance, and type of hospital using a chi-square test. Univariate and multivariate odds ratios (OR) with 95% confidence intervals (95% CI) were estimated for relative odds of immediate reconstruction versus mastectomy only.ResultsIn multivariate analysis, calendar year, age, race, type of insurance, and type of hospital were statistically significantly associated with use of reconstruction. The proportion of patients undergoing reconstruction rose from 24.8% in 2003 to 29.2% in 2007. Patients with private insurance were 10 times more likely to undergo reconstruction than patients with Medi-Cal insurance (OR 9.95, 95% CI 8.46–11.70). African American patients were less likely (OR 0.58, 95% CI 0.46–0.73) and Asian patients one-third as likely (OR 0.37, 95% CI 0.29–0.47) to undergo reconstruction as Caucasians patients Most reconstructive procedures were performed at teaching hospitals and designated cancer centers.ConclusionsAlthough the rate of postmastectomy reconstruction is increasing, only a minority of patients undergo reconstruction. Age, race, type of insurance, and type of hospital appear to be significant factors limiting the use of reconstruction.

Genetic determinants of pubertal timing in the general population

Puberty is an important developmental stage during which reproductive capacity is attained. The timing of puberty varies greatly among healthy individuals in the general population and is influenced by both genetic and environmental factors. Although genetic variation is known to influence the normal spectrum of pubertal timing, the specific genes involved remain largely unknown. Genetic analyses have identified a number of genes responsible for rare disorders of pubertal timing such as hypogonadotropic hypogonadism and Kallmann syndrome. Recently, the first loci with common variation reproducibly associated with population variation in the timing of puberty were identified at 6q21 in or near LIN28B and at 9q31.2. However, these two loci explain only a small fraction of the genetic contribution to population variation in pubertal timing, suggesting the need to continue to consider other loci and other types of variants. Here we provide an update of the genes implicated in disorders of puberty, discuss genes and pathways that may be involved in the timing of normal puberty, and suggest additional avenues of investigation to identify genetic regulators of puberty in the general population.

Pregnancy-related factors and the risk of breast carcinoma in situ and invasive breast cancer among postmenopausal women in the California Teachers Study cohort

IntroductionAlthough pregnancy-related factors such as nulliparity and late age at first full-term pregnancy are well-established risk factors for invasive breast cancer, the roles of these factors in the natural history of breast cancer development remain unclear.MethodsAmong 52,464 postmenopausal women participating in the California Teachers Study (CTS), 624 were diagnosed with breast carcinoma in situ (CIS) and 2,828 with invasive breast cancer between 1995 and 2007. Multivariable Cox proportional hazards regression methods were used to estimate relative risks associated with parity, age at first full-term pregnancy, breastfeeding, nausea or vomiting during pregnancy, and preeclampsia.ResultsCompared with never-pregnant women, an increasing number of full-term pregnancies was associated with greater risk reduction for both breast CIS and invasive breast cancer (both P trend < 0.01). Women having four or more full-term pregnancies had a 31% lower breast CIS risk (RR = 0.69, 95% CI = 0.51 to 0.93) and 18% lower invasive breast cancer risk (RR = 0.82, 95% CI = 0.72 to 0.94). Parous women whose first full-term pregnancy occurred at age 35 years or later had a 118% greater risk for breast CIS (RR = 2.18, 95% CI = 1.36 to 3.49) and 27% greater risk for invasive breast cancer (RR = 1.27, 95% CI = 0.99 to 1.65) than those whose first full-term pregnancy occurred before age 21 years. Furthermore, parity was negatively associated with the risk of estrogen receptor-positive (ER+) or ER+/progesterone receptor-positive (PR+) while age at first full-term pregnancy was positively associated with the risk of ER+ or ER+/PR+ invasive breast cancer. Neither of these factors was statistically significantly associated with the risk of ER-negative (ER-) or ER-/PR- invasive breast cancer, tests for heterogeneity between subtypes did not reach statistical significance. No clear associations were detected for other pregnancy-related factors.ConclusionsThese results provide some epidemiologic evidence that parity and age at first full-term pregnancy are involved in the development of breast cancer among postmenopausal women. The role of these factors in risk of in situ versus invasive, and hormone receptor-positive versus -negative breast cancer merits further exploration.

Risk factors for surgically removed fibroids in a large cohort of teachers.

OBJECTIVE To describe reproductive and lifestyle correlates of surgically confirmed fibroids. DESIGN Prospective cohort study. SETTING The California Teachers Study, an ongoing prospective study of more than 133,000 female teachers and school administrators identified through the California State Teachers Retirement System. PATIENT(S) California Teachers Study cohort members, reporting no previous history of fibroids, were ascertained prospectively for surgical diagnosis of fibroids using hospital patient discharge records. MAIN OUTCOME MEASURE(S) Multivariable Cox proportional hazards regression methods were used to assess the association of self-reported menstrual, reproductive, and lifestyle characteristics with fibroids, using ages at the start and end of follow-up (in months) to define time on study. Hazard rate ratios, presented as relative risks (RR) with 95% confidence intervals (CI), were estimated. RESULT(S) The strongest risk factor we identified was African-American race/ethnicity, as compared to non-Latina white women. We observed a reduced risk of fibroids for postmenopausal women in comparison to premenopausal women, but use of hormone replacement therapies (regardless of formulation) were associated with an increased risk. Other risk factors included race, a family history of fibroids, being overweight, and drinking alcohol, Smoking and diabetes were associated with a decreased risk of fibroids. CONCLUSION(S) These observations provide a more detailed epidemiologic profile of women with surgically managed fibroids.

Passive Smoking and Risk of Breast Cancer in the California Teachers Study

Background: Although recent reviews have suggested active smoking to be a risk factor for breast cancer, the association with passive smoke exposure remains controversial. This risk association was explored in a large prospective study of women, the California Teachers Study. Methods: Detailed lifetime information on passive smoke exposure by setting (home, work, or social) and by age of exposure was collected in 1997 from 57,523 women who were lifetime nonsmokers and had no history of breast cancer. In the ensuing decade, a total of 1,754 women were diagnosed with invasive breast cancer. Cox proportional hazards models were fit to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) associated with several lifetime passive smoke exposure metrics. Results: For all breast cancer, measures of higher lifetime passive smoking intensity and duration were associated with nonstatistically significant HRs of 1.11 to 1.14. For postmenopausal women, HRs for lifetime low, medium, and high cumulative exposure were 1.17 (95% CI, 0.91-1.49), 1.19 (95% CI, 0.93-1.53), and 1.26 (95% CI, 0.99-1.60). For women exposed in adulthood (age ≥20 years), risk was elevated at the highest level of cumulative exposure (HR, 1.18; 95% CI, 1.00-1.40), primarily among postmenopausal women (HR, 1.25; 95% CI, 1.01-1.56). A statistically significant dose response was detected when analysis was restricted to women with moderate to high levels of passive smoke exposure. Conclusion: These results suggest that cumulative exposures to high levels of sidestream smoke may increase breast cancer risk among postmenopausal women who themselves have never smoked tobacco products. (Cancer Epidemiol Biomarkers Prev 2009;18(12):3389–98)

Long-Term and Recent Recreational Physical Activity and Survival After Breast Cancer: The California Teachers Study

Introduction: Long-term physical activity is associated with lower breast cancer risk. Little information exists on its association with subsequent survival. Methods: California Teachers Study cohort members provided information in 1995-1996 on long-term (high school through age 54 years) and recent (past 3 years) participation in moderate and strenuous recreational physical activities. The 3,539 women diagnosed with invasive breast cancer after cohort entry and through December 31, 2004, were followed through December 31, 2005. Of these, 460 women died, 221 from breast cancer. Moderate and strenuous physical activities were combined into low (≤0.50 h/wk/y of any activity), intermediate (0.51-3.0 h/wk/y of moderate or strenuous activity but no activity >3.0 h/wk/y), or high activity (>3.0 h/wk/y of either activity type). Multivariable relative risks (RR) and 95% confidence intervals (95% CI) for mortality were estimated using Cox proportional hazards methods, adjusting for race/ethnicity, estrogen receptor status, disease stage, and baseline information on comorbidities, body mass index, and caloric intake. Results: Women with high or intermediate levels of long-term physical activity had lower risk of breast cancer death (RR, 0.53; 95% CI, 0.35-0.80; and RR, 0.65; 95% CI, 0.45-0.93, respectively) than women with low activity levels. These associations were consistent across estrogen receptor status and disease stage, but were confined to overweight women. Deaths due to causes other than breast cancer were related only to recent activity. Conclusions: Consistent long-term participation in physical activity before breast cancer diagnosis may lower risk of breast cancer death, providing further justification for public health strategies to increase physical activity throughout the lifespan. (Cancer Epidemiol Biomarkers Prev 2009;18(11):2851–9)

Association Studies of Common Variants in 10 Hypogonadotropic Hypogonadism Genes with Age at Menarche

CONTEXT Although the timing of puberty is a highly heritable trait, little is known about the genes that regulate pubertal timing in the general population. Several genes have been identified that, when mutated, cause disorders of delayed or absent puberty such as hypogonadotropic hypogonadism (HH). OBJECTIVE Because severe variants in HH-related genes cause a severe puberty phenotype, we hypothesized that common subtle variation in these genes could contribute to the population variation in pubertal timing. DESIGN We assessed common genetic variation in 10 HH-related genes in 1801 women from the Hawaii and Los Angeles Multiethnic Cohort with either early (age<11 yr) or late (age>14 yr) menarche and in other replication samples. In addition to these common variants, we also studied the most frequently reported HH mutations to assess their role in the population variation in pubertal timing. SETTING AND PATIENTS/OTHER PARTICIPANTS: Within the general community, 1801 women from the Hawaii and Los Angeles Multiethnic Cohort participated. MAIN OUTCOME MEASURES We assessed the association of genetic variation with age at menarche. RESULTS We found no significant association between any of the variants tested and age at menarche, although we cannot rule out modest effects of these variants or of other variants at long distances from the coding region. In several self-reported racial/ethnic groups represented in our study, we observed an association between estimated genetic ancestry and age at menarche. CONCLUSIONS Our results suggest that common variants near 10 HH-related loci do not play a substantial role in the regulation of age at menarche in the general population.