Combined analysis of Women's Health Initiative observational and clinical trial data on postmenopausal hormone treatment and cardiovascular disease

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.     

Relevance of triple CGG repeats in the FMR1 gene to ovarian reserve

Most individuals demonstrate 29–30 CGG triple repeats on the FMR1 gene. This may functionally represent a normal range in regard to ovarian reserve. Higher counts reflect risk towards premature ovarian senescence, but lower counts have not been investigated before and, therefore, were the principal subject of this investigation. Amongst 316 consecutive infertility patients, 94 demonstrated <28 repeats (group A), 163 28–33 repeats (group B, considered normal repeat numbers) and 59 ≥34 repeats (group C). The three groups did not differ in age, FSH or anti-Müllerian hormone (AMH) concentrations. Neither FSH nor AMH correlated in linear regression with <28 CGG repeats. In logistic regression, AMH of ≤0.8 ng/ml (indicative of diminished ovarian reserve at all ages) was, however, significantly associated with number of repeats (P < 0.001). Every decrease by five CGG repeats in group A increased the likelihood of diminished ovarian reserve by 40%, while every increase by five CGG repeats in group C increased risk by 50% (both P <0.002). AMH of ≤0.8 ng/ml statistically correlated overall with decreasing triple CGG repeats throughout all ranges (P < 0.001). Approximately 29–30 CGG repeats appear reflective of normal ovarian reserve, with higher and lower counts denoting similar risks towards premature ovarian senescence.     

Misplaced obsession with prospectively randomized studies

Medical care should be based on best available evidence. While randomized controlled trials (RCT) are currently considered a gold standard of study design, they are not always available and do not represent the only study format that can lead to best available evidence. This communication argues that overvaluation of RCT and undervaluation of other study formats in establishing best available evidence hurts progress in reproductive medicine and in medicine in general.     

Competition for priority in processing increases prefrontal cortex's involvement in top-down control: an event-related fMRI study of the stroop task

Prior work indicates that various aspects of task-irrelevant information (e.g. its salience, task-relatedness, emotionality) can increase the involvement of prefrontal cortex (PFC) in top-down attentional control. In light of these findings, we hypothesize that PFC's involvement increases when task-irrelevant information competes for priority in processing. In an event-related fMRI study using an oddball variant of the Stroop task, we examine the generality of this hypothesis using three manipulations designed to increase the ability of task-irrelevant information to compete for priority in processing. First, we investigated how the frequency of occurrence of task-irrelevant information affects PFC activity. Second, we examined whether conflicting color information (i.e. incongruent trials) increases activity in regions of PFC that are similar to or distinct from those sensitive to infrequently occurring task-irrelevant information. Finally, we examined the impact of the number of levels at which conflict could occur (e.g. non-response only, non-response and response). Activity in posterior-dorsolateral and posterior-inferior PFC increased for infrequently occurring task-irrelevant information, being largest when the task-irrelevant information contained conflicting color-information. In contrast, increases in mid-dorsolateral prefrontal cortex's activity were only noted when conflicting color information was present, being largest when conflict occurred at multiple levels. The anterior cingulate was primarily sensitive to the occurrence of conflict at the response level with only a small sub-region exhibiting sensitivity to non-response conflict as well. From these findings we suggest that posterior DLPFC and PIPFC are involved in biasing processing in posterior processing systems, mid-DLPFC is involved in biasing the processing of the contents of working memory, and ACC is primarily involved in response-related processes.