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1.  Regression Calibration in Nutritional Epidemiology: Example of Fat Density and Total Energy in Relationship to Postmenopausal Breast Cancer 
American Journal of Epidemiology  2013;178(11):1663-1672.
Regression calibration using biomarkers provides an attractive approach to strengthening nutritional epidemiology. We consider this approach to assessing the relationship of fat and total energy consumption with postmenopausal breast cancer. In analyses that included fat density data, biomarker-calibrated total energy was positively associated with postmenopausal breast cancer incidence in cohorts of the US Women's Health Initiative from 1994–2010. The estimated hazard ratio for a 20% increment in calibrated food frequency questionnaire (FFQ) energy was 1.22 (95% confidence interval (CI): 1.15, 1.30). This association was not evident without biomarker calibration, and it ceased to be apparent following control for body mass index (weight (kg)/height (m)2), suggesting that the association is mediated by body fat deposition over time. The hazard ratio for a corresponding 40% increment in FFQ fat density was 1.05 (95% CI: 1.00, 1.09). A stronger fat density association, with a hazard ratio of 1.19 (95% CI: 1.00, 1.41), emerged from analyses that used 4-day food records for dietary assessment. FFQ-based analyses were also carried out by using a second dietary assessment in place of the biomarker for calibration. This type of calibration did not correct for systematic bias in energy assessment, but may be able to accommodate the “noise” component of dietary measurement error. Implications for epidemiologic applications more generally are described.
PMCID: PMC3842904  PMID: 24064741
bias; biological markers; breast cancer; dietary assessment; dietary energy; dietary fat; postmenopausal women
The respiratory quotient (RQ), defined as the ratio of carbon dioxide exhaled to oxygen uptake, reflects substrate utilization when energy is expended. Fat and alcohol have RQ values of about 0.7, compared to 1.0 for carbohydrate, and about 0.8 for protein. Here, the association between RQ and postmenopausal breast cancer risk is studied.
Paired RQ measurements were obtained, separated by about 6 months, for women in the reliability subset of a Women’s Health Initiative (WHI) Nutrition and Physical Activity Assessment Study. Linear regression of the average of the paired log RQ assessments on a corresponding log food quotient (FQ) average and other study subject characteristics, including age, body mass index, race, and education, yielded calibration equations for predicting RQ.
Calibration equations, using any of food frequency, food record, or dietary recall data, explained an appreciable fraction of measured log RQ variation, and these were used to compute calibrated RQ estimates throughout WHI cohorts. Calibrated RQ estimates using four-day food record data related inversely (P=0.004) to (invasive) breast cancer risk in the WHI Dietary Modification trial comparison group, and corresponding RQ estimates using food frequency data related inversely (P=0.002) to breast cancer incidence in this cohort combined with the larger WHI Observational Study.
Though preliminary, these analyses suggest a substantially higher postmenopausal breast cancer risk among women having relatively low RQ.
RQ elevation could provide a novel target for breast cancer risk reduction.
PMCID: PMC3864792  PMID: 24108790
breast cancer; dietary assessment; food quotient; indirect calorimetry; postmenopausal women; respiratory quotient; substrate utilization
3.  The Role of Epidemiology in the Era of Molecular Epidemiology and Genomics: Summary of the 2013 AJE-sponsored Society of Epidemiologic Research Symposium 
American Journal of Epidemiology  2013;178(9):1350-1354.
On June 20, 2013, the American Journal of Epidemiology sponsored a symposium at the Society for Epidemiologic Research's 46th Annual Meeting in Boston, Massachusetts, entitled, “What Is the Role of Epidemiology in the Era of Molecular Biology and Genomics?” The future of epidemiology depends on innovation in generating interesting and important testable hypotheses that are relevant to population health. These new strategies will depend on new technology, both in measurement of agents and environment and in the fields of pathophysiology and outcomes, such as cellular epidemiology and molecular pathology. The populations to be studied, sample sizes, and study designs should be selected based on the hypotheses to be tested and include case-control, cohort, and clinical trials. Developing large mega cohorts without attention to specific hypotheses is inefficient, will fail to address many associations with high-quality data, and may well produce spurious results.
PMCID: PMC3988450  PMID: 24105654
immunology; pathology; study design
4.  Postmenopausal Hormone Therapy and the Risks of Coronary Heart Disease, Breast Cancer, and Stroke 
Seminars in reproductive medicine  2014;32(6):419-425.
The principal findings are briefly reviewed from the Women's Health Initiative (WHI) trials of the most commonly used postmenopausal hormone regimens in the US, conjugated equine estrogens and these same estrogens plus medroxyprogesterone acetate. A more detailed review is presented for three major clinical outcomes: coronary heart disease, the primary trial outcome for which a major benefit was hypothesized; invasive breast cancer, the primary safety outcome for which some adverse effect was expected; and stroke which surfaced as an important adverse effect with both regimens, and one that is influential in decisions concerning the continued use of postmenopausal estrogens alone. The review for these outcomes includes an update on interactions of treatment effects with study subject characteristics and exposures and with pre-randomization biomarker levels. It also includes a focus on timing issues that are important to the understanding of treatment effects. Specifically, with combined estrogen plus progestin coronary heart disease risk was elevated early with the elevation dissipating after a few years of treatment, whereas breast cancer elevations increased during the treatment period, and climbed to about a 3-fold increase following 5 years of adherence. Importantly, breast cancer risk elevations appear to be higher among women who initiate treatment at the menopause, or soon thereafter, compared to women having a longer gap time. Stroke effects, on the other hand didn't seem to vary appreciably with these timing issues. The adverse effect was evidently localized to ischemic strokes, for which there was an approximate 50% increase with either regimen. The rather limited knowledge concerning the biomarkers and biological pathways that mediate the hormone therapy effects on these diseases is also briefly reviewed.
PMCID: PMC4212810  PMID: 25321418
breast cancer; coronary heart disease; postmenopausal hormone therapy; randomized controlled trial; stroke
5.  Calibration Of Self-Reported Dietary Measures Using Biomarkers: An Approach To Enhancing Nutritional Epidemiology Reliability 
Current atherosclerosis reports  2013;15(9):10.1007/s11883-013-0353-5.
Reports from nutritional epidemiology studies lack reliability if based solely on self-reported dietary consumption estimates. Consumption biomarkers are available for some components of diet. These can be collected in subsets of study cohorts, along with corresponding self-report assessments. Linear regression of (log-transformed) biomarker values on corresponding self-report values and other pertinent study subject characteristics yields calibration equations for dietary consumption, from which calibrated consumption estimates can be calculated throughout study cohorts. Nutritional epidemiology disease association studies of enhanced reliability can be expected from analyses that relate disease risk to calibrated consumption estimates. Applications to the study of energy and protein consumption in relation to cardiovascular diseases, type 2 diabetes, and cancer in the Women’s Health Initiative will be briefly summarized. Also, challenges related to variables that may either mediate or confound associations of interest will be described, along with the need for longitudinal biomarker and self-report data, and the need for additional nutritional biomarkers development.
PMCID: PMC3832356  PMID: 23881548
biomarker; calibration; cardiovascular disease; epidemiology; nutrition; measurement error
6.  Estrogen Plus Progestin and Colorectal Cancer Incidence and Mortality 
Journal of Clinical Oncology  2012;30(32):3983-3990.
During the intervention phase in the Women's Health Initiative (WHI) clinical trial, use of estrogen plus progestin reduced the colorectal cancer diagnosis rate, but the cancers were found at a substantially higher stage. To assess the clinical relevance of the findings, analyses of the influence of combined hormone therapy on colorectal cancer incidence and colorectal cancer mortality were conducted after extended follow-up.
Patients and Methods
The WHI study was a randomized, double-blind, placebo-controlled clinical trial involving 16,608 postmenopausal women with an intact uterus who were randomly assigned to daily 0.625 mg conjugated equine estrogen plus 2.5 mg medroxyprogesterone acetate (n = 8,506) or matching placebo (n = 8,102). Colorectal cancer diagnosis rates and colorectal cancer mortality were assessed.
After a mean of 5.6 years (standard deviation [SD], 1.03 years) of intervention and 11.6 years (SD, 3.1 years) of total follow-up, fewer colorectal cancers were diagnosed in the combined hormone therapy group compared with the placebo group (diagnoses/year, 0.12% v 0.16%; hazard ratio [HR], 0.72; 95% CI, 0.56 to 0.94; P = .014). Bowel screening examinations were comparable between groups throughout. Cancers in the combined hormone therapy group more commonly had positive lymph nodes (50.5% v 28.6%; P < .001) and were at higher stage (regional or distant, 68.8% v 51.4%; P = .003). Although not statistically significant, there was a higher number of colorectal cancer deaths in the combined hormone therapy group (37 v 27 deaths; 0.04% v 0.03%; HR, 1.29; 95% CI, 0.78 to 2.11; P = .320).
The findings, suggestive of diagnostic delay, do not support a clinically meaningful benefit for combined hormone therapy on colorectal cancer.
PMCID: PMC3488271  PMID: 23008295
7.  Biomarker-Calibrated Protein Intake and Physical Function in the Women’s Health Initiative 
Preserving physical function with aging may be partially met through modification in dietary protein intake.
Women’s Health Initiative Clinical Trials (CT) and Observational Study (OS).
Women age 50–79 y (n=134,961) with dietary data and ≥ 1 physical function measure.
Physical function was assessed by short form RAND-36 at baseline and annually beginning in 2005 for all WHI participants, and at closeout for CT participants (average ~7 y after baseline). In a subset of 5346 participants, physical performance measures (grip strength, number of chair stands in 15 seconds, and timed 6-meter walk) were assessed at baseline and years 1, 3, and 6. Calibrated energy and protein intake were derived from regression equations using baseline food frequency questionnaire data collected on the entire cohort and doubly labeled water and 24-hour urinary nitrogen collected from a representative sample as reference measures. Associations between calibrated protein intake and each of the physical function measures were assessed using generalized estimating equations.
Calibrated protein intake ranged from 6.6 to 22.3% energy. Higher calibrated protein intake at baseline was associated with higher self-reported physical function [quintile (Q) 5 vs. Q1: 85.6 (95% CI, 81.9 to 87.5) vs. 75.4 (73.2 to 78.5), Ptrend=0.002] and a slower rate of functional decline [Q5 vs. Q1 annualized change: −0.47 (−0.63 to −0.39) vs. −0.98 (−1.18 to −0.75), Ptrend=0.022]. Women with higher calibrated protein intake also had higher grip strength at baseline [Q5 vs. Q1: 24.7 (24.3 to 25.2) vs. 24.1 (23.6 to 24.5), Ptrend=0.036] and showed slower declines in grip strength [Q5 vs. Q1 annualized change: −0.45 kg (−0.39 to −0.63) vs. −0.59 kg (−0.50 to −0.66), Ptrend=0.028]. Additionally, women with higher calibrated protein intake completed more chair stands at baseline [Q5 vs. Q1: 7.11 (6.91 to 7.26) vs. 6.61 (6.46 to 6.76), Ptrend=0.002].
Higher calibrated protein intake is associated with greater physical function and performance and slower rates of decline in postmenopausal women.
PMCID: PMC3928025  PMID: 24219187
dietary protein intake; physical performance; physical function; grip strength
8.  A regularized Hotelling’s T2 test for pathway analysis in proteomic studies 
Recent proteomic studies have identified proteins related to specific phenotypes. In addition to marginal association analysis for individual proteins, analyzing pathways (functionally related sets of proteins) may yield additional valuable insights. Identifying pathways that differ between phenotypes can be conceptualized as a multivariate hypothesis testing problem: whether the mean vector μ of a p-dimensional random vector X is μ0. Proteins within the same biological pathway may correlate with one another in a complicated way, and type I error rates can be inflated if such correlations are incorrectly assumed to be absent. The inflation tends to be more pronounced when the sample size is very small or there is a large amount of missingness in the data, as is frequently the case in proteomic discovery studies. To tackle these challenges, we propose a regularized Hotelling’s T2 (RHT) statistic together with a non-parametric testing procedure, which effectively controls the type I error rate and maintains good power in the presence of complex correlation structures and missing data patterns. We investigate asymptotic properties of the RHT statistic under pertinent assumptions and compare the test performance with four existing methods through simulation examples. We apply the RHT test to a hormone therapy proteomics data set, and identify several interesting biological pathways for which blood serum concentrations changed following hormone therapy initiation.
PMCID: PMC3755504  PMID: 23997374
proteomics; pathway analysis; regularization; Hotelling’s T2
9.  The Women’s Health Initiative Hormone Therapy Trials: Update and Overview of Health Outcomes During the Intervention and Post-Stopping Phases 
Menopausal hormone therapy continues in clinical use but questions remain regarding its risks and benefits for chronic disease prevention.
To provide a comprehensive, integrated overview of findings from the two Women’s Health Initiative (WHI) hormone therapy (HT) trials with extended post-intervention follow up.
27,347 postmenopausal women, age 50–79 years, were enrolled at 40 US centers. Interventions were conjugated equine estrogens (CEE, 0.625 mg/day) with medroxyprogesterone acetate (MPA, 2.5 mg/day) for women with an intact uterus (N = 16,608) and CEE alone for women with hysterectomy (N= 10,739), or their placebos. Intervention continued for 5.6 and 7.2 years (median), respectively, with cumulative follow-up of 13 years through September 30, 2010.
The primary efficacy and safety outcomes were coronary heart disease (CHD) and invasive breast cancer, respectively. A global index also included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and deaths. Secondary and quality-of-life outcomes were also assessed.
During the intervention phase for CEE+MPA, the hazard ratio (HR) for CHD was 1.18 (95% confidence interval [CI] 0.95–1.45) and overall risks outweighed benefits, with increases in invasive breast cancer, stroke, pulmonary embolism, and the global index. Other risks included increased dementia (in women >65 years), gallbladder disease, and urinary incontinence, while benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Post-intervention, most risks and benefits dissipated, although some elevation in breast cancer risk persisted (cumulative hazard ratio [HR] =1.28; 95% confidence interval, 1.11–1.48). During intervention for CEE alone, risks and benefits were more balanced, with a HR for CHD of 0.94 (0.78–1.14), increased stroke and venous thrombosis, decreased hip fractures and diabetes, and over cumulative follow-up, decreased breast cancer (HR=0.79 [0.65–0.97]). Neither regimen affected all-cause mortality. With CEE, younger women (50–59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index (nominal P values for trend by age <0.05), but not for stroke and venous thrombosis. Absolute risks of adverse events (measured by the global index) per 10,000 women per year on CEE+MPA ranged from 12 excess cases for age 50–59 to 38 for age 70–79 and, for CEE, from 19 fewer cases for age 50–59 to 51 excess cases for age 70–79. Results for quality of life outcomes in both trials were mixed.
Menopausal hormone therapy has a complex pattern of risks and benefits. While appropriate for symptom management in some women, its use for chronic disease prevention is not supported by the WHI randomized trials.
clinical Identifier: NCT00000611
PMCID: PMC3963523  PMID: 24084921
10.  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.
PMCID: PMC3202154  PMID: 21765003
bias (epidemiology); biological markers; diet; energy intake; epidemiologic methods; measurement error; nutrition assessment
12.  Concordant release of glycolysis proteins into the plasma preceding a diagnosis of ER+ breast cancer 
Cancer research  2012;72(8):1935-1942.
Although the identification of peripheral blood biomarkers would enhance early detection strategies for breast cancer, the discovery of protein markers has been challenging. In this study, we sought to identify coordinated changes in plasma proteins associated with breast cancer based on large scale quantitative mass spectrometry. We analyzed plasma samples collected up to 74 weeks prior to diagnosis from 420 ER+ cases and matched controls enrolled in the Women's Health Initiative cohort. A gene set enrichment analysis was applied to 467 quantified proteins linking their corresponding genes to particular biological pathways. Based upon differences in the concentration of individual proteins, glycolysis pathway proteins exhibited a statistically significant difference between cases and controls. In particular, the enrichment was observed among cases in which blood was drawn closer to diagnosis (effect size for the 0–38 weeks pre-diagnostic group: 1.91; p-value: 8.3E-05). Analysis of plasmas collected at the time of diagnosis from an independent set of cases and controls confirmed upregulated levels of glycolysis proteins among cases relative to controls. Together, our findings indicate that the concomitant release of glycolysis proteins into the plasma is a pathophysiological event that precedes a diagnosis of ER+ breast cancer.
PMCID: PMC4066614  PMID: 22367215
13.  A penalized EM algorithm incorporating missing data mechanism for Gaussian parameter estimation 
Biometrics  2014;70(2):312-322.
Missing data rates could depend on the targeted values in many settings, including mass spectrometry-based proteomic profiling studies. Here we consider mean and covariance estimation under a multivariate Gaussian distribution with non-ignorable missingness, including scenarios in which the dimension (p) of the response vector is equal to or greater than the number (n) of independent observations. A parameter estimation procedure is developed by maximizing a class of penalized likelihood functions that entails explicit modeling of missing data probabilities. The performance of the resulting ‘penalized EM algorithm incorporating missing data mechanism (PEMM)’ estimation procedure is evaluated in simulation studies and in a proteomic data illustration.
PMCID: PMC4061266  PMID: 24471933
Expectation-maximization (EM) algorithm; maximum penalized likelihood estimate; not-missing-at-random (NMAR)
14.  Biomarker-Calibrated Energy and Protein Consumption and Cardiovascular Disease Risk Among Postmenopausal Women 
Epidemiology (Cambridge, Mass.)  2011;22(2):170-179.
Nutritional epidemiology cohort studies primarily use food frequency questionnaires (FFQs). In part because FFQs are more reliable for nutrient densities than for absolute nutrient consumption, reports from association studies typically present only nutrient density measures in relation to disease risk.
We used objective biomarkers to correct FFQ assessments for measurement error, and examined absolute energy and protein consumption in relation to cardiovascular disease incidence. FFQs and subsequent physician-adjudicated cardiovascular disease incidence were assessed for 80,370 postmenopausal women in the age range 50–79 years at enrollment in the comparison group of the Dietary Modification Trial or the prospective Observational Study in the Women’s Health Initiative. Urinary recovery biomarkers of energy and protein were obtained from a subsample of 544 women, with concurrent FFQ information.
Following biomarker correction, energy consumption was positively associated with coronary heart disease incidence (hazard ratio = 1.18 [95% confidence interval = 1.04–1.33], for 20% consumption increment) and protein density was inversely associated (0.85 [0.75–0.97]). The positive energy association appeared to be mediated by body fat accumulation. Ischemic stroke incidence was inversely associated with energy and protein consumption, but not with protein density.
A positive association between energy and coronary heart disease risk can be attributed to body mass accumulation. Ischemic stroke risk is inversely associated with energy and protein consumption, possibly due to correlations between consumption and physical activity.
PMCID: PMC3033986  PMID: 21206366
15.  The Influence of Obesity-Related Single Nucleotide Polymorphisms on BMI Across the Life Course 
Diabetes  2013;62(5):1763-1767.
Evidence is limited as to whether heritable risk of obesity varies throughout adulthood. Among >34,000 European Americans, aged 18–100 years, from multiple U.S. studies in the Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we examined evidence for heterogeneity in the associations of five established obesity risk variants (near FTO, GNPDA2, MTCH2, TMEM18, and NEGR1) with BMI across four distinct epochs of adulthood: 1) young adulthood (ages 18–25 years), adulthood (ages 26–49 years), middle-age adulthood (ages 50–69 years), and older adulthood (ages ≥70 years); or 2) by menopausal status in women and stratification by age 50 years in men. Summary-effect estimates from each meta-analysis were compared for heterogeneity across the life epochs. We found heterogeneity in the association of the FTO (rs8050136) variant with BMI across the four adulthood epochs (P = 0.0006), with larger effects in young adults relative to older adults (β [SE] = 1.17 [0.45] vs. 0.09 [0.09] kg/m2, respectively, per A allele) and smaller intermediate effects. We found no evidence for heterogeneity in the association of GNPDA2, MTCH2, TMEM18, and NEGR1 with BMI across adulthood. Genetic predisposition to obesity may have greater effects on body weight in young compared with older adulthood for FTO, suggesting changes by age, generation, or secular trends. Future research should compare and contrast our findings with results using longitudinal data.
PMCID: PMC3636619  PMID: 23300277
16.  Estrogen Plus Progestin and Breast Cancer Incidence and Mortality in the Women’s Health Initiative Observational Study 
In the Women’s Health Initiative (WHI) randomized trial, estrogen plus progestin increased both breast cancer incidence and mortality. In contrast, most observational studies associate estrogen plus progestin with favorable prognosis breast cancers. To address differences, a cohort of WHI observational study participants with characteristics similar to the WHI clinical trial was studied.
We identified 41 449 postmenopausal women with no prior hysterectomy and mammogram negative within 2 years who were either not hormone users (n = 25 328) or estrogen and progestin users (n = 16 121). Multivariable-adjusted Cox proportional hazard regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CI). All statistical tests were two-sided.
After a mean of 11.3 (SD = 3.1) years, with 2236 breast cancers, incidence was higher in estrogen plus progestin users than in nonusers (0.60% vs 0.42%, annualized rate, respectively; HR = 1.55, 95% CI = 1.41 to 1.70, P < .001). Women initiating hormone therapy closer to menopause had higher breast cancer risk with linear diminishing influence as time from menopause increased (P < .001). Survival after breast cancer, measured from diagnosis, was similar in combined hormone therapy users and nonusers (HR = 1.03, 95% CI = 0.79 to 1.35). On a population basis, there were somewhat more deaths from breast cancer, measured from cohort entry (HR = 1.32, 95% CI = 0.90 to 1.93, P = .15), and more all-cause deaths after breast cancer (HR = 1.65, 95% CI = 1.29 to 2.12, P < .001) in estrogen plus progestin users than in nonusers.
Consistent with WHI randomized trial findings, estrogen plus progestin use is associated with increased breast cancer incidence. Because prognosis after diagnosis on combined hormone therapy is similar to that of nonusers, increased breast cancer mortality can be expected.
PMCID: PMC3691942  PMID: 23543779
17.  Identification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-wide Meta-analysis 
Peters, Ulrike | Jiao, Shuo | Schumacher, Fredrick R. | Hutter, Carolyn M. | Aragaki, Aaron K. | Baron, John A. | Berndt, Sonja I. | Bézieau, Stéphane | Brenner, Hermann | Butterbach, Katja | Caan, Bette J. | Campbell, Peter T. | Carlson, Christopher S. | Casey, Graham | Chan, Andrew T. | Chang-Claude, Jenny | Chanock, Stephen J. | Chen, Lin S. | Coetzee, Gerhard A. | Coetzee, Simon G. | Conti, David V. | Curtis, Keith R. | Duggan, David | Edwards, Todd | Fuchs, Charles S. | Gallinger, Steven | Giovannucci, Edward L. | Gogarten, Stephanie M. | Gruber, Stephen B. | Haile, Robert W. | Harrison, Tabitha A. | Hayes, Richard B. | Henderson, Brian E. | Hoffmeister, Michael | Hopper, John L. | Hudson, Thomas J. | Hunter, David J. | Jackson, Rebecca D. | Jee, Sun Ha | Jenkins, Mark A. | Jia, Wei-Hua | Kolonel, Laurence N. | Kooperberg, Charles | Küry, Sébastien | Lacroix, Andrea Z. | Laurie, Cathy C. | Laurie, Cecelia A. | Le Marchand, Loic | Lemire, Mathieu | Levine, David | Lindor, Noralane M. | Liu, Yan | Ma, Jing | Makar, Karen W. | Matsuo, Keitaro | Newcomb, Polly A. | Potter, John D. | Prentice, Ross L. | Qu, Conghui | Rohan, Thomas | Rosse, Stephanie A. | Schoen, Robert E. | Seminara, Daniela | Shrubsole, Martha | Shu, Xiao-Ou | Slattery, Martha L. | Taverna, Darin | Thibodeau, Stephen N. | Ulrich, Cornelia M. | White, Emily | Xiang, Yongbing | Zanke, Brent W. | Zeng, Yi-Xin | Zhang, Ben | Zheng, Wei | Hsu, Li
Gastroenterology  2012;144(4):799-807.e24.
Heritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis.
We conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent.
Based on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 × 10−8: an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 × 10−8). We also found evidence for 3 additional loci with P values less than 5.0 × 10−7: a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 × 10−8), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 × 10−8), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 × 10−7).
In a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to β-catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation.
PMCID: PMC3636812  PMID: 23266556
Colon Cancer; Genetics; Risk Factors; SNP
18.  Sex hormone associations with breast cancer risk and the mediation of randomized trial postmenopausal hormone therapy effects 
Paradoxically, a breast cancer risk reduction with conjugated equine estrogens (CEE) and a risk elevation with CEE plus medroxyprogesterone acetate (CEE + MPA) were observed in the Women’s Health Initiative (WHI) randomized controlled trials. The effects of hormone therapy on serum sex hormone levels, and on the association between baseline sex hormones and disease risk, may help explain these divergent breast cancer findings.
Serum sex hormone concentrations were measured for 348 breast cancer cases in the CEE + MPA trial and for 235 cases in the CEE trial along with corresponding pair-matched controls, nested within the WHI trials of healthy postmenopausal women. Association and mediation analyses, to examine the extent to which sex hormone levels and changes can explain the breast cancer findings, were conducted using logistic regression.
Following CEE treatment, breast cancer risk was associated with higher concentrations of baseline serum estrogens, and with lower concentrations of sex hormone binding globulin. However, following CEE + MPA, there was no association of breast cancer risk with baseline sex hormone levels. The sex hormone changes from baseline to year 1 provided an explanation for much of the reduced breast cancer risk with CEE. Specifically, the treatment odds ratio (95% confidence interval) increased from 0.71 (0.43, 1.15) to 0.92 (0.41, 2.09) when the year 1 measures were included in the logistic regression analysis. In comparison, the CEE + MPA odds ratio was essentially unchanged when these year 1 measures were included.
Breast cancer risk remains low following CEE use among women having favorable baseline sex hormone profiles, but CEE + MPA evidently produces a breast cancer risk for all women similar to that for women having an unfavorable baseline sex hormone profile. These patterns could reflect breast ductal epithelial cell stimulation by CEE + MPA that is substantially avoided with CEE, in conjunction with relatively more favorable effects of either regimen following a sustained period of estrogen deprivation. These findings may have implications for other hormone therapy formulations and routes of delivery.
Trial registration identifier: NCT00000611.
PMCID: PMC4053241  PMID: 24670297
19.  Breast Cancer after Use of Estrogen plus Progestin in Postmenopausal Women 
The New England journal of medicine  2009;360(6):573-587.
Following the release of the 2002 report of the Women’s Health Initiative (WHI) trial of estrogen plus progestin, the use of menopausal hormone therapy in the United States decreased substantially. Subsequently, the incidence of breast cancer also dropped, suggesting a cause-and-effect relation between hormone treatment and breast cancer. However, the cause of this decrease remains controversial.
We analyzed the results of the WHI randomized clinical trial — in which one study group received 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxy-progesterone acetate daily and another group received placebo — and examined temporal trends in breast-cancer diagnoses in the WHI observational-study cohort. Risk factors for breast cancer, frequency of mammography, and time-specific incidence of breast cancer were assessed in relation to combined hormone use.
In the clinical trial, there were fewer breast-cancer diagnoses in the group receiving estrogen plus progestin than in the placebo group in the initial 2 years of the study, but the number of diagnoses increased over the course of the 5.6-year intervention period. The elevated risk decreased rapidly after both groups stopped taking the study pills, despite a similar frequency of mammography. In the observational study, the incidence of breast cancer was initially about two times as high in the group receiving menopausal hormones as in the placebo group, but this difference in incidence decreased rapidly in about 2 years, coinciding with year-to-year reductions in combined hormone use. During this period, differences in the frequency of mammography between the two groups were unchanged.
The increased risk of breast cancer associated with the use of estrogen plus progestin declined markedly soon after discontinuation of combined hormone therapy and was unrelated to changes in frequency of mammography.
PMCID: PMC3963492  PMID: 19196674
20.  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.
PMCID: PMC3626043  PMID: 23436896
biomakers; measurement error; physical activity; postmenopausal women
22.  Variation in the FGFR2 Gene and the Effect of a Low-Fat Dietary Pattern on Invasive Breast Cancer 
The Women’s Health Initiative (WHI) dietary modification (DM) trial provided suggestive evidence of a benefit of a low-fat dietary pattern on breast cancer risk, with stronger evidence among women whose baseline diet was high in fat. Single nucleotide polymorphisms (SNPs) in the FGFR2 gene relate strongly to breast cancer risk, and could influence intervention effects.
Participants and Methods
All 48,835 trial participants were postmenopausal and aged 50–79 at enrollment (1993–98). We interrogated eight SNPs in intron 2 of the FGFR2 gene for 1676 women who developed breast cancer during trial follow-up (1993–2005). Case-only analyses were used to estimate odds ratios for the DM intervention in relation to SNP genotype.
Odds ratios for the DM intervention did not vary significantly with the genotype for any of the eight FGFR2 SNPs (p≥0.18). However, odds ratios varied (p<0.05) with the genotype of six of these SNPs, among women having baseline percent of energy from fat in the upper quartile (≥36.8%). This variation is most evident for SNP rs3750817, with odds ratios (95% confidence intervals) for the DM intervention at 0, 1, and 2 minor SNP alleles of 1.06 (0.80, 1.41), 0.53 (0.38, 0.74), and 0.62 (0.33, 1.15). The nominal significance level for this interaction is p=0.005, and is p=0.03 following multiple testing adjustment, with most evidence deriving from hormone receptor-positive tumors.
Invasive breast cancer odds ratios for a low-fat dietary pattern, among women whose usual diets are high in fat, appear to vary with SNP rs3750817 in the FGFR2 gene.
PMCID: PMC2806599  PMID: 20056625
breast cancer; genotype; gene-intervention interaction; low fat dietary pattern; randomized controlled trial
23.  Variation in the FGFR2 Gene and the Effects of Postmenopausal Hormone Therapy on Invasive Breast Cancer 
Breast cancer concern is a major reason for the recent marked reduction in use of postmenopausal hormone therapy, though equally effective means of controlling menopausal symptoms are lacking. Single nucleotide polymorphisms (SNPs) in the fibroblast growth factor receptor two (FGFR2) gene are substantially associated with postmenopausal breast cancer risk, and could influence hormone therapy effects.
Participants and Methods
We interrogated eight SNPs in intron 2 of the FGFR2 gene for 2166 invasive breast cancer cases from the Women's Health Initiative clinical trial and one-to-one matched controls, to confirm an association with breast cancer risk. We used case-only analyses to examine the dependence of estrogen plus progestin and estrogen-alone odds ratios on SNP genotype.
Seven FGFR2 SNPs, including six in a single linkage disequilibrium region, were found to associate strongly (p<10−7) with breast cancer risk. SNP rs3750817 (minor allele T with frequency 0.37) had an estimated `per minor allele' odds ratio of 0.78, and was not in such strong linkage disequilibrium with the other SNPs. The genotype of this SNP related significantly (p<0.05) to hormone therapy odds ratios. For estrogen plus progestin, the odds ratios (95% confidence intervals) at 0, 1, and 2 minor SNP alleles were 1.52 (1.14, 2.02), 1.33 (1.01, 1.75), and 0.69 (0.41, 1.17), while corresponding values for estrogen-alone were 0.74 (0.51, 1.09), 0.99 (0.68, 1.44), and 0.34 (0.15, 0.76).
Postmenopausal women having TT genotype for SNP rs3750817 have a reduced breast cancer risk, and appear to experience comparatively favorable effects of postmenopausal hormone therapy.
PMCID: PMC2783392  PMID: 19861516
breast cancer; genotype; gene-treatment interaction; randomized controlled trial; postmenopausal hormone therapy
24.  Benefits and Risks of Postmenopausal Hormone Therapy When It Is Initiated Soon After Menopause 
American Journal of Epidemiology  2009;170(1):12-23.
The authors further analyzed results from the Women's Health Initiative randomized trials (1993–2004) of conjugated equine estrogens, with or without medroxyprogesterone acetate, focusing on health benefits versus risks among women who initiated hormone therapy soon after menopause. Data from the Women's Health Initiative observational study (1993–2004) were included in some analyses for additional precision. Results are presented here for incident coronary heart disease, stroke, venous thromboembolism, breast cancer, colorectal cancer, endometrial cancer, or hip fracture; death from other causes; a summary global index; total cancer; and total mortality. Hazard ratios for breast cancer and total cancer were comparatively higher (P < 0.05) among women who initiated hormone therapy soon after menopause, for both regimens. Among these women, use of conjugated equine estrogens appeared to produce elevations in venous thromboembolism and stroke and a reduction in hip fracture. Estrogen plus progestin results among women who initiated use soon after menopause were similar for venous thromboembolism, stroke, and hip fracture but also included evidence of longer-term elevations in breast cancer, total cancer, and the global index. These analyses provide little support for the hypothesis of favorable effects among women who initiate postmenopausal estrogen use soon after menopause, either for coronary heart disease or for health benefits versus risk indices considered.
PMCID: PMC2733042  PMID: 19468079
clinical trial; cohort studies; estrogens; estrogen replacement therapy; hormone replacement therapy; medroxyprogesterone 17-acetate; postmenopause; progestins
Colorectal cancer incidence was reduced among women assigned to active treatment in the Women's Health Initiative (WHI) estrogen plus progestin randomized trial, but the interpretation was obscured by an associated later stage of diagnosis. In contrast the estrogen-alone trial showed no incidence reduction or differential stage at diagnosis. Here, data from the WHI observational study are considered, in conjunction with colorectal cancer mortality data from the hormone therapy trials, in an attempt to clarify postmenopausal hormone therapy effects.
Participants and Methods
Postmenopausal women aged 50−79 at WHI enrollment. Estrogen-alone analyses include 21,552 and 10,739 women who were post-hysterectomy from the observational study and clinical trial respectively. Estrogen plus progestin analyses include 32,084 and 16,608 observational study and clinical trial women with uterus. Colorectal cancers were verified by central medical and pathology report review.
Hazard ratios (95% confidence intervals) from the WHI observational study were 0.80 (0.53 to 1.20) for estrogen and 1.15 (0.74 to 1.79) for estrogen plus progestin, with respectively 168 and 175 women diagnosed with colorectal cancer. Delayed diagnosis with estrogen plus progestin is not evident in the observational study. No protective effect on colorectal cancer mortality in the estrogen plus progestin trial is seen over an 8-year intervention and follow-up period.
Hazard ratio patterns in the WHI clinical trial and observational study do not provide strong evidence of a clinically important colorectal cancer benefit with either estrogen-alone or estrogen plus progestin over 7−8 years of treatment and follow-up.
PMCID: PMC2689377  PMID: 19423530
cohort study; colorectal cancer; randomized controlled trial; postmenopausal hormone therapy

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