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Observational studies analyzed like randomized experiments: an application to postmenopausal hormone therapy and coronary heart disease.

ABSTRACT: The Women's Health Initiative randomized trial found greater coronary heart disease (CHD) risk in women assigned to estrogen/progestin therapy than in those assigned to placebo. Observational studies had previously suggested reduced CHD risk in hormone users.Using data from the observational Nurses' Health Study, we emulated the design and intention-to-treat (ITT) analysis of the randomized trial. The observational study was conceptualized as a sequence of "trials," in which eligible women were classified as initiators or noninitiators of estrogen/progestin therapy.The ITT hazard ratios (HRs) (95% confidence intervals) of CHD for initiators versus noninitiators were 1.42 (0.92-2.20) for the first 2 years, and 0.96 (0.78-1.18) for the entire follow-up. The ITT HRs were 0.84 (0.61-1.14) in women within 10 years of menopause, and 1.12 (0.84-1.48) in the others (P value for interaction = 0.08). These ITT estimates are similar to those from the Women's Health Initiative. Because the ITT approach causes severe treatment misclassification, we also estimated adherence-adjusted effects by inverse probability weighting. The HRs were 1.61 (0.97-2.66) for the first 2 years, and 0.98 (0.66-1.49) for the entire follow-up. The HRs were 0.54 (0.19-1.51) in women within 10 years after menopause, and 1.20 (0.78-1.84) in others (P value for interaction = 0.01). We also present comparisons between these estimates and previously reported Nurses' Health Study estimates.Our findings suggest that the discrepancies between the Women's Health Initiative and Nurses' Health Study ITT estimates could be largely explained by differences in the distribution of time since menopause and length of follow-up.

SUBMITTER: Hernan MA

PROVIDER: S-EPMC3731075 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Observational studies analyzed like randomized experiments: an application to postmenopausal hormone therapy and coronary heart disease.

Hernán Miguel A MA Alonso Alvaro A Logan Roger R Grodstein Francine F Michels Karin B KB Willett Walter C WC Manson Joann E JE Robins James M JM

Epidemiology (Cambridge, Mass.) 20081101 6

<h4>Background</h4>The Women's Health Initiative randomized trial found greater coronary heart disease (CHD) risk in women assigned to estrogen/progestin therapy than in those assigned to placebo. Observational studies had previously suggested reduced CHD risk in hormone users.<h4>Methods</h4>Using data from the observational Nurses' Health Study, we emulated the design and intention-to-treat (ITT) analysis of the randomized trial. The observational study was conceptualized as a sequence of "tri ...[more]

PMID: 18854702

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Project description:BackgroundIn the WHI-HT trials (Women's Health Initiative Hormone Therapy), treatment with oral conjugated equine estrogens and medroxyprogesterone acetate (CEE+MPA) resulted in increased risk of coronary heart disease (CHD), whereas oral conjugated equine estrogens (CEE) did not.MethodsFour hundred eighty-one metabolites were measured at baseline and at 1-year in 503 and 431 participants in the WHI CEE and CEE+MPA trials, respectively. The effects of randomized HT on the metabolite profiles at 1-year was evaluated in linear models adjusting for baseline metabolite levels, age, body mass index, race, incident CHD, prevalent hypertension, and diabetes. Metabolites with discordant effects by HT type were evaluated for association with incident CHD in 944 participants (472 CHD cases) in the WHI-OS (Women's Health Initiative Observational Study), with replication in an independent cohort of 980 men and women at high risk for cardiovascular disease.ResultsHT effects on the metabolome were profound; 62% of metabolites significantly changed with randomized CEE and 52% with CEE+MPA (false discovery rate-adjusted P value<0.05) in multivariable models. Concerted increases in abundance were seen within various metabolite classes including triacylglycerols, phosphatidylethanolamines, and phosphatidylcholines; decreases in abundance was observed for acylcarnitines, lysophosphatidylcholines, quaternary amines, and cholesteryl/cholesteryl esters. Twelve metabolites had discordant effects by HT type and were associated with incident CHD in the WHI-OS; a metabolite score estimated in a Least Absolute Shrinkage and Selection Operator regression was associated with CHD risk with an odds ratio of 1.47 per SD increase (95% CI, 1.27-1.70, P<10-6). All twelve metabolites were altered in the CHD protective direction by CEE treatment. One metabolite (lysine) was significantly altered in the direction of increased CHD risk by CEE+MPA; the remaining 11 metabolites were not significantly changed by CEE+MPA. The CHD associations of a subset of 4 metabolites including C58:11 triacylglycerol, C54:9 triacylglycerol, C36:1 phosphatidylcholine and sucrose replicated in an independent dataset of 980 participants in the PREDIMED trial (Prevención con Dieta Mediterránea).ConclusionsRandomized treatment with oral HT resulted in large metabolome shifts that generally favored CEE alone over CEE+MPA in term of CHD risk. Discordant metabolite effects between HT regimens may partially mediate the differences in CHD risk between the 2 WHI-HT trials.

Project description:Consider a statistical analysis that draws causal inferences from an observational dataset, inferences that are presented as being valid in the standard frequentist senses; i.e. the analysis produces: (1) consistent point estimates, (2) valid p-values, valid in the sense of rejecting true null hypotheses at the nominal level or less often, and/or (3) confidence intervals, which are presented as having at least their nominal coverage for their estimands. For the hypothetical validity of these statements, the analysis must embed the observational study in a hypothetical randomized experiment that created the observed data, or a subset of that hypothetical randomized data set. This multistage effort with thought-provoking tasks involves: (1) a purely conceptual stage that precisely formulate the causal question in terms of a hypothetical randomized experiment where the exposure is assigned to units; (2) a design stage that approximates a randomized experiment before any outcome data are observed, (3) a statistical analysis stage comparing the outcomes of interest in the exposed and non-exposed units of the hypothetical randomized experiment, and (4) a summary stage providing conclusions about statistical evidence for the sizes of possible causal effects. Stages 2 and 3 may rely on modern computing to implement the effort, whereas Stage 1 demands careful scientific argumentation to make the embedding plausible to scientific readers of the proffered statistical analysis. Otherwise, the resulting analysis is vulnerable to criticism for being simply a presentation of scientifically meaningless arithmetic calculations. The conceptually most demanding tasks are often the most scientifically interesting to the dedicated researcher and readers of the resulting statistical analyses. This perspective is rarely implemented with any rigor, for example, completely eschewing the first stage. We illustrate our approach using an example examining the effect of parental smoking on children's lung function collected in families living in East Boston in the 1970s.

Project description:Title: Transcriptome analysis of human endometrial tissues from healthy post-menoupausal women reflecting the endometrial response to 3-weeks treatment with tibolone, E2 and E2+MPA. In an observational, open, non-randomized, controlled study uterine tissues were collected in order to generate endometrial gene expression profiles. healthy postmenopausal women were enrolled into the following treatment groups: Control-group; Tibolone-group, 2,5 mg of tibolone (administered orally) every day, starting 21 days prior to surgery; Estradiol-group, 2 mg of estradiol (administered orally) every day, starting 21 days prior to surgery; Estradiol+progestagen-group, 2 mg of estradiol (administered orally) and 5 mg of MPA (Medroxy Progesteroneacetate, administered orally) every day, starting 21 days prior to surgery. Pure (100%) endometrium was isolated from the snap-frozen uterine tissues and used for RNA isolation. RNA was labeled and hybridized to whole genome Affymetrix U133plus2 GeneChips containing 54,614 probe sets, representing approximately 47,000 transcripts. Relative to the control group, 940 genes are regulated in the endometrium of E2 treated patients, whereas only 198 genes are significantly regulated in endometria from tibolone or E2+MPA treated patients. Furthermore, only 9% of E2 regulated genes are also regulated by tibolone (85 out of 940), only 5% are also regulated by E2+MPA treatment and the overlap between tibolone and E2+MPA treatment is about 10%. This indicated that tibolone-treatment results in a weak endometrial profile similarity to E2 treatment and no profile similarity to E2+MPA treatment. A more detailed analysis showed that down stream processes, such as regulation of the cell cycle, angiogenesis and cell proliferation are almost not affected by tibolone treatment but, in contrast, are significantly affected by E2. For example, upon staining with Ki67, a marker for mitotic activity, significantly increased stromal as well as glandular cell proliferation was observed in the endometria from the E2-only treated group, while tibolone treatment resulted only in a slight increase in stromal cell proliferation (and no increase in glandular cell proliferation). These results indicate that in contrast to long-term tibolone use, short-term (21-days) use results in some estrogenic stimulation of the endometrium, which is clearly far less and rather different from what is observed during E2 treatment. References: Klaassens et al., 2006 Hanifi-Moghaddam et al., 2007 Verheul et al., 2007

Project description:IntroductionParadoxically, 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.MethodsSerum 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.ResultsFollowing 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.ConclusionsBreast 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 registrationclinicaltrials.gov identifier: NCT00000611.

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Observational studies analyzed like randomized experiments: an application to postmenopausal hormone therapy and coronary heart disease.

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Observational studies analyzed like randomized experiments: an application to postmenopausal hormone therapy and coronary heart disease.

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