Showing papers by "Ross L. Prentice published in 2006"

Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus

Abstract: Background: Postmenopausal hormone therapy has been associated with a 2- to 3-fold increased risk of venous thromboembolism (VT) (including deep vein thrombosis and pulmonary embolism) in observational studies and secondary prevention clinical trials. Clinical trial data on the effects of estrogen alone on VT are limited. Methods: The Women’s Health Initiative estrogen trial enrolled 10 739 women aged 50 to 79 years without a uterus. Participants were randomly assigned to receive conjugated equine estrogen (0.625 mg/d) or placebo. Results: During a mean of 7.1 years, VT occurred in 111 women randomly assigned to receive estrogen (3.0 per 1000 person-years) and 86 randomly assigned to receive placebo (2.2 per 1000 person-years; hazard ratio, 1.32; 95% confidence interval, 0.99-1.75). Deep venous thrombosis was reported in 85 women randomly assigned to receive estrogen (2.3 per 1000 person-years) and 59 randomly assigned to receive placebo (1.5 per 1000 person-years; hazard ratio, 1.47; 95% confidence interval, 1.06-2.06). The VT risk was highest in the first 2 years. There were no significant interactions between estrogen use and age, body mass index, or most other VT risk factors. Comparison of Women’s Health Initiative VT findings for estrogen and previous Women’s Health Initiative findings for estrogen plus progestin showed that the hazard ratios for estrogen plus progestin were significantly higher than those for estrogen alone (P=.03), even after adjusting for VT risk factors. Conclusion: An early increased VT risk is associated with use of estrogen, especially within the first 2 years, but this risk increase is less than that for estrogen plus progestin. Arch Intern Med. 2006;166:772-780

Statin Use and Breast Cancer: Prospective Results From the Women's Health Initiative

Abstract: Author(s): Cauley, Jane A; McTiernan, Anne; Rodabough, Rebecca J; LaCroix, Andrea; Bauer, Douglas C; Margolis, Karen L; Paskett, Electra D; Vitolins, Mara Z; Furberg, Curt D; Chlebowski, Rowan T; Women's Health Initiative Research Group | Abstract: BackgroundDespite experimental observations suggesting that 3-hydroxy-3-methylglutaryl coenzyme A inhibitors (statins) have antitumor activity, clinical studies have reached mixed conclusions about the relationship between statin use and breast cancer risk.MethodsTo investigate associations between potency, duration of use, and type of statin used and risk of invasive breast cancer, we examined data for 156,351 postmenopausal women who were enrolled in the Women's Health Initiative. Information was collected on breast cancer risk factors and on the use of statins and other lipid-lowering drugs. Cox proportional hazards regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). Statistical tests were two-sided.ResultsOver an average follow-up of 6.7 years, 4383 invasive breast cancers were confirmed by medical record and pathology report review. Statins were used by 11,710 (7.5%) of the cohort. Breast cancer incidence was 4.09 per 1000 person-years (PY) among statin users and 4.28 per 1000 PY among nonusers. In multivariable models, the hazard ratio of breast cancer among users of any statin, compared with nonusers, was 0.91 (95% CI = 0.80 to 1.05, P = .20). There was no trend in risk by duration of statin use, with HR = 0.80 (95% CI = 0.63 to 1.03) for l 1 year of use, HR = 0.99 (95% CI = 0.80 to 1.23) for 1- l 3 years of use, and HR = 0.94 (95% CI = 0.75 to 1.18) for g or = 3 years of use. Hydrophobic statins (i.e., simvastatin, lovastatin, and fluvastatin) were used by 8106 women, and their use was associated with an 18% lower breast cancer incidence (HR = 0.82, 95% CI = 0.70 to 0.97, P = .02). Use of other statins (i.e., pravastatin and atorvastatin) or nonstatin lipid-lowering agents was not associated with breast cancer incidence.ConclusionsOverall statin use was not associated with invasive breast cancer incidence. Our finding that use of hydrophobic statins may be associated with lower breast cancer incidence suggests possible within-class differences that warrant further evaluation.

Combined analysis of women's health initiative observational and clinical trial data on postmenopausal hormone treatment and cardiovascular disease

Abstract: Circumstances in which both randomized controlled trial and observational study data are available provide an important opportunity to identify biases and improve study design and analysis procedures. In addition, joint analyses of data from the two sources can extend clinical trial findings. The US Women's Health Initiative includes randomized controlled trials of use of estrogen by posthysterectomy women and of estrogen plus progestin by women with a uterus, along with corresponding observational study components. In this paper, for coronary heart disease, stroke, and venous thromboembolism, results are first presented from joint analysis of estrogen clinical trial and observational study data to show that residual bias patterns are similar to those previously reported for estrogen plus progestin. These findings support certain combined analyses of the observational data on estrogen and the estrogen plus progestin clinical trial and observational study data to give adjusted observational study estimates of estrogen treatment effects. The resulting treatment effect estimates are compared with corresponding clinical trial estimates, and parallel analyses are also presented for estrogen plus progestin. An application to postmenopausal hormone treatment effects on coronary heart disease among younger women is also provided.

A comparison of two dietary instruments for evaluating the fat–breast cancer relationship

Abstract: Methods Participants were from the non-intervention group of the dietary modification component of the Women’s Health Initiative Clinical Trial: 603 breast cancer cases and 1206 controls matched on age, clinic, and length of follow-up. Relative risks (RRs) were estimated using unconditional logistic regression, adjusted for confounders and for the selection into the trial of women with an FFQ report exceeding 32% calories from fat. Direct comparison of the statistical power of the two instruments used the standardized log RR. An alternative analysis after removing subjects with missing covariate data was also conducted. Results The RR estimate for breast cancer in the top quintile of total fat intake, adjusted for confounders and total energy, was 1.82 (P for trend 0.02) for the FR but 0.67 for the FFQ (P for trend 0.24). Following adjustment for selection, estimates were 2.09 (P for trend 0.008) for the FR (alternative: 2.54, P for trend 0.006) and 1.71 (P for trend 0.18) for the FFQ (alternative: 1.24, P for trend 0.41). Similar results were seen for fat subtypes, particularly unsaturated fats. Comparisons showed higher statistical power for the FR than the FFQ (e.g. total fat, P 5 0.08: alternative P 5 0.01). Conclusions Alternative instruments, such as FRs, may be preferable to FFQs for evaluating diet–disease relationships in cohort studies. The results support a positive association between dietary fat and breast cancer.

Aspects of the design and analysis of high-dimensional SNP studies for disease risk estimation

Abstract: SUMMARY The state of readiness for high-dimensional single nucleotide polymorphism (SNP) epidemiologic association studies is described, as background for a discussion of statistical aspects of case–control study design and analysis. Specifically, the important role that multistage designs can play in the elimination of false-positive associations and in the control of study costs will be noted. Also, the trade-offs associated with using pooled DNA at early design stages for additional important cost reductions will be discussed in some detail. An odds ratio approach to relating SNP alleles to disease risk using pooled DNA will be proposed, in conjunction with a simple empirical variance estimator, based on comparisons among logodds ratio estimators from distinct pairs of case and control pools. Simulation studies will be presented to evaluate the moderate sample size properties of such multistage designs and estimation procedures. The design of an ongoing three-stage study in the Women’s Health Initiative to relate 250 000 SNPs to the risk of coronary heart disease, stroke, and breast cancer will provide illustration, and will be used to motivate the choice of simulation configurations.

Calcium plus vitamin D supplementation and the risk of fractures: Commentary

Abstract: Randomized trials have indicated that calcium or vitamin D supplements—or both—may slow bone loss in postmenopausal women, but whether the risk of bone fracture is reduced remains uncertain. This study randomly assigned 36,282 postmenopausal women 50 to 79 years of age, who were enrolled in the Women’s Health Initiative clinical trial, to receive either 1000 mg calcium in carbonate form plus 400 IU vitamin D3 daily or placebo and followed them for an average of 7 years. Women on active treatment had levels of 25-hydroxyvitamin D 28% higher than those in placebo recipients. Bone mineral density (BMD) at the hip remained higher than in women assigned to receive placebo. The mean group difference at the ninth annual visit was 1.06%. Annualized rates of fracture per 10,000 person-years in the supplement and placebo groups were 14 and 16, respectively, for hip fracture; 44 and 44 for lower arm/wrist fractures; 14 and 15 for clinical vertebral fractures; and 164 and 170 for all fractures combined. Women assigned to supplements had a 12% lower risk of hip fracture than placebo recipients, but this was not a statistically significant effect. There were no significant group differences in rates of major diseases, including cardiovascular disease and cancer. The hazard ratio for kidney stones in women receiving supplements was 1.17 (95% confidence interval, 1.02–1.34). This finding was not related to a high baseline calcium intake. Gastrointestinal symptoms occurred in approximately 9% to 10% of both groups. In generally healthy postmenopausal women, daily supplements of calcium and vitamin D were associated with modest improvement in bone density at the hip, but did not substantially lower the risk of hip fracture in this large-scale study. Compared with placebo, supplementation did appear to increase the risk of kidney stones.

Calcium plus vitamin D supplementation and the risk of colorectal cancer: Commentary

Abstract: Some epidemiologic studies have reported a reduction in colorectal cancer in persons reporting a relatively high intake of calcium and vitamin D. The risk of recurrent polyps also may be decreased. The present randomized, double-blind, placebo-controlled trial enrolled 36,282 postmenopausal women 50 to 79 years of age from 40 centers taking part in the Women's Health Initiative. Approximately half the women received 500 mg elemental calcium as calcium carbonate plus 200 IU vitamin D 3 twice a day, whereas the others received a matching placebo. The average follow up was 7 years. At least 70% of women in the trial took half or more of their assigned medication through year 6 of the trial. Women in the supplement and placebo groups had their bowels examined at similar frequencies throughout the trial. Analysis of 322 pathologically confirmed invasive colorectal cancers showed no substantial effect of calcium/ vitamin D supplementation on the cancer risk (hazard ratio [HR], 1.08; 95% confidence interval [CI], 0.86-1.34). Similar results were obtained when omitting women in both groups who had a history of colorectal cancer. Allowing for personal use of calcium supplements, reported by just over half the women, left the findings essentially unchanged. Sites of cancer and their location, histologic features, grade, and stage were similar in the supplement and placebo groups. The HR for death from colorectal cancer in the supplement group was 0.82 (95% CI, 0.52-1.29), but there were not enough events to make the comparison meaningful. Supplementation could not be related to any significant risk or benefit with regard to major disease outcomes, including cancer and cardiovascular disease. Polyps were reported by similar numbers of women in the 2 groups. In general, supplementation was well tolerated. In this randomized trial, daily supplements of calcium carbonate and vitamin D 3 did not influence the risk of colorectal cancer over a 7-year period. Supplementation may protect to some degree against bone fracture, but the present findings do not support its use to prevent colorectal cancer.