Alan R. Kristal

Design of the Women's Health Initiative clinical trial and observational study

The Womens Health Initiative (WHI) is a large and complex clinical investigation of strategies for the prevention and control of some of the most common causes of morbidity and mortality among postmenopausal women, including cancer, cardiovascular disease, and osteoporotic fractures. The WHI was initiated in 1992, with a planned completion date of 2007. Postmenopausal women ranging in age from 50 to 79 are enrolled at one of 40 WHI clinical centers nationwide into either a clinical trial (CT) that will include about 64,500 women or an observational study (OS) that will include about 100,000 women. The CT is designed to allow randomized controlled evaluation of three distinct interventions: a low-fat eating pattern, hypothesized to prevent breast cancer and colorectal cancer and, secondarily, coronary heart disease; hormone replacement therapy, hypothesized to reduce the risk of coronary heart disease and other cardiovascular diseases and, secondarily, to reduce the risk of hip and other fractures, with increased breast cancer risk as a possible adverse outcome; and calcium and vitamin D supplementation, hypothesized to prevent hip fractures and, secondarily, other fractures and colorectal cancer. Overall benefit-versus-risk assessment is a central focus in each of the three CT components. Women are screened for participation in one or both of the components--dietary modification (DM) or hormone replacement therapy (HRT)--of the CT, which will randomize 48,000 and 27,500 women, respectively. Women who prove to be ineligible for, or who are unwilling to enroll in, these CT components are invited to enroll in the OS. At their 1-year anniversary of randomization, CT women are invited to be further randomized into the calcium and vitamin D (CaD) trial component, which is projected to include 45,000 women. The average follow-up for women in either CT or OS is approximately 9 years. Concerted efforts are made to enroll women of racial and ethnic minority groups, with a target of 20% of overall enrollment in both the CT and OS. This article gives a brief description of the rationale for the interventions being studied in each of the CT components and for the inclusion of the OS component. Some detail is provided on specific study design choices, including eligibility criteria, recruitment strategy, and sample size, with attention to the partial factorial design of the CT. Some aspects of the CT monitoring approach are also outlined. The scientific and logistic complexity of the WHI implies particular leadership and management challenges. The WHI organization and committee structure employed to respond to these challenges is also briefly described.

Effect of Selenium and Vitamin E on Risk of Prostate Cancer and Other Cancers: The Selenium and Vitamin E Cancer Prevention Trial (SELECT)

CONTEXT Secondary analyses of 2 randomized controlled trials and supportive epidemiologic and preclinical data indicated the potential of selenium and vitamin E for preventing prostate cancer. OBJECTIVE To determine whether selenium, vitamin E, or both could prevent prostate cancer and other diseases with little or no toxicity in relatively healthy men. DESIGN, SETTING, AND PARTICIPANTS A randomized, placebo-controlled trial (Selenium and Vitamin E Cancer Prevention Trial [SELECT]) of 35,533 men from 427 participating sites in the United States, Canada, and Puerto Rico randomly assigned to 4 groups (selenium, vitamin E, selenium + vitamin E, and placebo) in a double-blind fashion between August 22, 2001, and June 24, 2004. Baseline eligibility included age 50 years or older (African American men) or 55 years or older (all other men), a serum prostate-specific antigen level of 4 ng/mL or less, and a digital rectal examination not suspicious for prostate cancer. INTERVENTIONS Oral selenium (200 microg/d from L-selenomethionine) and matched vitamin E placebo, vitamin E (400 IU/d of all rac-alpha-tocopheryl acetate) and matched selenium placebo, selenium + vitamin E, or placebo + placebo for a planned follow-up of minimum of 7 years and a maximum of 12 years. MAIN OUTCOME MEASURES Prostate cancer and prespecified secondary outcomes, including lung, colorectal, and overall primary cancer. RESULTS As of October 23, 2008, median overall follow-up was 5.46 years (range, 4.17-7.33 years). Hazard ratios (99% confidence intervals [CIs]) for prostate cancer were 1.13 (99% CI, 0.95-1.35; n = 473) for vitamin E, 1.04 (99% CI, 0.87-1.24; n = 432) for selenium, and 1.05 (99% CI, 0.88-1.25; n = 437) for selenium + vitamin E vs 1.00 (n = 416) for placebo. There were no significant differences (all P>.15) in any other prespecified cancer end points. There were statistically nonsignificant increased risks of prostate cancer in the vitamin E group (P = .06) and type 2 diabetes mellitus in the selenium group (relative risk, 1.07; 99% CI, 0.94-1.22; P = .16) but not in the selenium + vitamin E group. CONCLUSION Selenium or vitamin E, alone or in combination at the doses and formulations used, did not prevent prostate cancer in this population of relatively healthy men. TRIAL REGISTRATION clinicaltrials.gov identifier: NCT00006392.

Measurement Characteristics of the Women’s Health Initiative Food Frequency Questionnaire

PURPOSE The Womens Health Initiative (WHI) is the largest research program ever initiated in the United States with a focus on diet and health. Therefore, it is important to understand and document the measurement characteristics of the key dietary assessment instrument: the WHI food frequency questionnaire (FFQ). METHODS Data are from 113 women screened for participation in the WHI in 1995. We assessed bias and precision of the FFQ by comparing the intake of 30 nutrients estimated from the FFQ with means from four 24-hour dietary recalls and a 4-day food record. RESULTS For most nutrients, means estimated by the FFQ were within 10% of the records or recalls. Precision, defined as the correlation between the FFQ and the records and recalls, was similar to other FFQs. Energy adjusted correlation coefficients ranged from 0.2 (vitamin B12) to 0.7 (magnesium) with a mean of 0.5. The correlation for percentage energy from fat (a key measure in WHI) was 0.6. Vitamin supplement use was common. For example, almost half of total vitamin E intake was obtained from supplements. Including supplemental vitamins and minerals increased micronutrient correlation coefficients, which ranged from 0.2 (thiamin) to 0.8 (vitamin E) with a mean of 0.6. CONCLUSIONS The WHI FFQ produced nutrient estimate, that were similar to those obtained from short-term dietary recall and recording methods. Comparison of WHI FFQ nutrient intake measures to independent and unbiased measures, such as doubly labeled water estimates of energy expenditure, are needed to help address the validity of the FFQ in this population.

Is It Time to Abandon the Food Frequency Questionnaire

Although painful to admit, it is possible that epidemiologists have been deluded in their acceptance of food frequency questionnaires (FFQ) as the standard tool for dietary assessment in large studies of diet and cancer. The substantial limitations of FFQs have been known for some time ([1][1]) and

Community-level comparisons between the grocery store environment and individual dietary practices

BACKGROUND This article examines the relationship at the community level between individual dietary practice and the grocery store environment. METHODS Individual dietary practice was measured in 12 communities using a telephone survey to obtain self-reported diet. A protocol was developed to measure two aspects of the grocery store environment in these same 12 communities: the relative availability of healthful (low-fat and high-fiber) products, and the amount of health-education information provided. Comparisons were made between individual and store-level measures at two levels of geographic aggregation: community (typically a county) and zip code within community (n = 34). RESULTS We found positive and statistically significant correlations at both the community and the zip code level between the availability of healthful products in stores and the reported healthfulness of individual diets. Positive correlations were also found between measures of the amount of health-education material provided by stores and the healthfulness of individual diets, but these correlations did not reach statistical significance. CONCLUSIONS The results provide support for including measures of the grocery store environment as part of a community-level assessment of dietary behavior.

Use Of Food Nutrition Labels is Associated with Lower Fat Intake

OBJECTIVE The Nutrition Labeling and Education Act of 1990 mandated that standardized nutrition information appear on almost all packaged foods manufactured after May 1994. This study describes the demographic and diet-related psychosocial correlates of nutrition label use, and examines the relationship between label use and diet. DESIGN/SUBJECTS Data are from a random-digit-dial telephone survey of 1,450 adult residents of Washington State. The questionnaire assessed nutrition label use, fat-related diet habits, fruit and vegetable consumption, diet-related psychosocial factors, health behavior, and demographic characteristics. STATISTICAL ANALYSES Analyses examined associations of demographic characteristics with nutrition label use; diet-related psychosocial factors and health behavior with nutrition label use, controlled for demographic characteristics; and nutrition label use with fat and fruit and vegetable intake, controlled for demographic characteristics and psychosocial factors. RESULTS Nutrition label use was significantly higher among women, residents younger than 35 years, and residents with more than a high school education. When controlled for demographic characteristics, the strongest predictors of label use were believing in the importance of eating a low-fat diet, believing in an association between diet and cancer, and being in the maintenance stage of change for adopting a low-fat diet. Label use was significantly associated with lower fat intake and, after controlling for all demographic, psychosocial, and behavioral variables, explained 6% of the variance in fat intake (P < .001). Label use was not associated with fruit and vegetable consumption. APPLICATIONS/CONCLUSION Persons successfully limiting their fat intake use nutrition labels, suggesting that the new nutrition labels are helpful. Dietetics professionals can use the results of this study to emphasize to their clients the importance of reading nutrition labels in maintaining a low-fat diet.

Obesity, diabetes, and risk of prostate cancer: Results from the prostate cancer prevention trial

Studies on the relationship between obesity and prostate cancer incidence are inconsistent. In part, this inconsistency may be due to a differential effect of obesity on low-grade and high-grade cancer or confounding of the association of obesity with prostate cancer risk by diabetes. We investigated the associations of obesity and diabetes with low-grade and high-grade prostate cancer risk. Data were from 10,258 participants (1,936 prostate cancers) in the Prostate Cancer Prevention Trial who all had cancer presence or absence determined by prostate biopsy. Multiple logistic regression was used to model the risk of total prostate cancer, and polytomous logistic regression was used to model the risk of low-grade and high-grade prostate cancer. Compared with men with body mass index < 25, obese men (body mass index ≥30) had an 18% [odds ratio (OR), 0.82; 95% confidence interval (95% CI), 0.69-0.98] decreased risk of low-grade prostate cancer (Gleason <7) and a 29% (OR, 1.29; 95% CI, 1.01-1.67) increased risk of high-grade prostate cancer (Gleason ≥7) or, alternatively, a 78% (OR, 1.78; 95% CI, 1.10-2.87) increased risk defining high-grade cancer as Gleason sum 8 to 10. Diabetes was associated with a 47% (OR, 0.53; 95% CI, 0.34-0.83) reduced risk of low-grade prostate cancer and a 28% (OR, 0.72; 95% CI, 0.55-0.94) reduced risk of high-grade prostate cancer. Associations of obesity or diabetes with cancer risk were not substantially changed by mutually statistical controlling for each other. Obesity increases the risk of high-grade but decreases the risk of low-grade prostate cancer, and this relationship is independent of the lower risk for prostate cancer among men with diabetes. (Cancer Epidemiol Biomarkers Prev 2006;15(10):1977–83)

Stages of Change in Adopting Healthy Diets: Fat, Fiber, and Correlates of Nutrient Intake

The stages of change construct, which addresses the readiness to change, has only recently been applied to dietary behavior, such as fat consumption. This article describes the application of the stages of change construct to dietary fat and fiber consumption and examines the association of dietary stages to eating practices and related demographic and psychosocial factors in a large, geographically diverse population of workers. We present results from the baseline survey of 17,121 employees in the Working Well Trial. We assessed stage from an algorithm based on seven items and measured dietary intake with an 88-item food frequency questionnaire. Findings indicated that a greater proportion of the population has actively tried to reduce fat intake than to consume more fiber. Stage of change was associated with fat, fiber, and fruit and vegetable intake in a stepwise manner, as predicted. In multivariate analyses that controlled for demographic characteristics, stage of change predicted between 8 and 13% of the variance in dietary intake, and more than demographic variables. These findings have implications for the design of nutrition interventions and for the evaluation of intermediate outcomes.

Brassica Vegetables and Prostate Cancer Risk: A Review of the Epidemiological Evidence

Epidemiological studies have yielded conflicting results on the associations of diet with prostate cancer. We review evidence that Brassica vegetables are associated with reduced prostate cancer risk. Brassica vegetables, which include broccoli, cabbage, mustard and collard greens, and bok choy, contain glucosinolates, the metabolic breakdown products of which are potent modulators of xenobiotic-metabolizing enzymes that protect DNA from damage. Twelve published studies give some information about Brassica vegetables and prostate cancer risk; six of these studies can be clearly interpreted. Of these, three reported statistically significant reduced risks (P < 0.05) and one reported a borderline significant reduced risk (P = 0.06) with high Brassica vegetable consumption. The epidemiological literature provides modest support for the hypothesis that high intakes of Brassica vegetables reduce prostate cancer risk.

The association of body mass index and prostate-specific antigen in a population-based study

Recent studies of men with prostate carcinoma suggest that obesity may be associated with more advanced‐stage disease and lower overall survival rates. One possible link between body mass index (BMI) and prostate carcinoma prognosis may be disease ascertainment. Prostate‐specific antigen (PSA) is widely used to screen for prostate carcinoma.