Karin B. Michels

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

Background: The Womens 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. Methods: 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. Results: 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 Womens 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. Conclusions: Our findings suggest that the discrepancies between the Womens 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.

Reproducibility and Validity of Maternal Recall of Pregnancy-related Events

We assessed the reproducibility and validity of a questionnaire that asks mothers to recall pregnancy-related events from thirty or more years ago. Among 146 women who completed the questionnaire twice, responses were highly reproducible for pre-pregnancy height and weight (r = 0.95), pregnancy complications (r = 0.74), substance use (r = 0.80), preterm delivery (r = 0.82), birthweight (r = 0.94), and breastfeeding (r = 0.89). Among 154 women whose questionnaire responses were compared to data collected during their pregnancies, recall was highly accurate for height (r = 0.90), pre-pregnancy weight (r = 0.86), birthweight (r = 0.91), and smoking (sensitivity = 0.86, specificity = 0.94). These findings suggest that long-term maternal recall is both reproducible and accurate for many factors related to pregnancy and delivery.

Does PTCA in Acute Myocardial Infarction Affect Mortality and Reinfarction Rates? A Quantitative Overview (Meta-Analysis) of the Randomized Clinical Trials

BACKGROUND Percutaneous transluminal coronary angioplasty (PTCA) is often performed after acute myocardial infarction (AMI) either as an adjuvant to thrombolytic therapy or instead of thrombolysis. The effect of PTCA in AMI on mortality and reinfarction has remained unclear, with the available randomized trials indicating inconsistent results. METHODS AND RESULTS A systematic overview (meta-analysis) of the randomized trials was conducted to assess the effect of PTCA in AMI on mortality and reinfarction rates. Data from 7 trials in which primary PTCA was evaluated and 16 trials in which PTCA after thrombolysis was studied were included in this overview, comprising a total of 8496 patient. The trials represented different approaches to the timing of PTCA after AMI. The trials of PTCA after thrombolytic therapy were also categorized according to the different protocols with respect to the routine or elective character of PTCA in the invasive group. A reduction in short-term (6 week) mortality (odds ratio, 0.56; 95% CI, 0.33, 0.94) and in the combined outcome of short-term mortality and nonfatal reinfarction (odds ratio, 0.53; 95% CI, 0.35, 0.80) was observed in the trials comparing primary PTCA with thrombolytic therapy. In contrast, in trials in which an approach of thrombolysis and PTCA was compared with thrombolytic therapy alone, there was no important difference in early mortality, with an apparent reduction in mortality between 6 and 52 weeks. The lower mortality between 6 and 52 weeks among 6-week survivors seemed to be restricted to the subgroup of trials in which PTCA was used as a routine strategy (odds ratio, 0.58; 95% CI, 0.39, 0.87). CONCLUSIONS Although the analyses of the various categories of trials suggest that primary PTCA may be more beneficial than thrombolytic therapy in AMI, these data should be interpreted cautiously unless confirmed by larger studies. In contrast, the addition of various other strategies of PTCA to thrombolytic therapy does not convincingly indicate a clinically different outcome than if a more conservative strategy is followed, in which PTCA is used only if clinically indicated. Some specific strategies, however, such as rescue PTCA in high-risk patients with occluded arteries, may be of benefit.

Diabetes, metabolic syndrome, and breast cancer: a review of the current evidence

Incidences of breast cancer, type 2 diabetes, and metabolic syndrome have increased over the past decades with the obesity epidemic, especially in industrialized countries. Insulin resistance, hyperinsulinemia, and changes in the signaling of growth hormones and steroid hormones associated with diabetes may affect the risk of breast cancer. We reviewed epidemiologic studies of the association between type 2 diabetes and risk of breast cancer and the available evidence on the role of hormonal mediators of an association between diabetes and breast cancer. The combined evidence supports a modest association between type 2 diabetes and the risk of breast cancer, which appears to be more consistent among postmenopausal than among premenopausal women. Despite many proposed potential pathways, the mechanisms underlying an association between diabetes and breast cancer risk remain unclear, particularly because the 2 diseases share several risk factors, including obesity, a sedentary lifestyle, and possibly intake of saturated fat and refined carbohydrates, that may confound this association. Although the metabolic syndrome is closely related to diabetes and embraces additional components that might influence breast cancer risk, the role of the metabolic syndrome in breast carcinogenesis has not been studied and thus remains unknown.

Allergic diseases and atopic sensitization in children related to farming and anthroposophic lifestyle – the PARSIFAL study

Background:  The prevalence of allergic diseases has increased rapidly in recent decades, particularly in children. For adequate prevention it is important not only to identify risk factors, but also possible protective factors. The aim of this study was to compare the prevalence of allergic diseases and sensitization between farm children, children in anthroposophic families, and reference children, with the aim to identify factors that may protect against allergic disease.

Diet and breast cancer: a review of the prospective observational studies.

The role of diet for the risk of breast cancer is of great interest as a potentially modifiable risk factor. The evidence from prospective observational studies was reviewed and summarized on selected dietary factors, gene‐diet interactions, and breast cancer incidence. Dietary factors were considered that, based on their nutritional constituents, are of particular interest in the context of breast cancer: fat intake, biomarkers of fat intake, fruit and vegetable consumption, antioxidant vitamins (vitamins A, C, E, and beta‐carotene), serum antioxidants, carbohydrate intake, glycemic index and glycemic load, dairy consumption (including vitamin D), consumption of soy products and isoflavones, green tea, heterocyclic amines, and adolescent diet. The PubMed database was searched for all prospective studies that relate these dietary items to the incidence of breast cancer or consider gene‐diet interactions. Among the prospective epidemiologic studies conducted on diet and breast cancer incidence and gene‐diet interactions and breast cancer incidence, to date there is no association that is consistent, strong, and statistically significant, with the exception of alcohol intake, overweight, and weight gain. The apparent lack of association between diet and breast cancer may reflect a true absence of association between diet and breast cancer incidence or may be due to measurement error exceeding the variation in the diet studied, lack of sufficient follow‐up, and focus on an age range of low susceptibility. The risk of breast cancer can be reduced by avoidance of weight gain in adulthood and limiting the consumption of alcohol. Cancer 2007.

Urinary bisphenol A and obesity: NHANES 2003–2006

BACKGROUND Bisphenol A (BPA) is a chemical suspected of causing endocrine and metabolic disruption in animals and humans. In rodents, in utero exposure to low-dose BPA is associated with weight gain. Detectable levels of BPA are found in most Americans due to its widespread use in the manufacture of food and drink packaging. We hypothesized that urinary BPA concentrations would be positively associated with general and central obesity. METHODS Cross-sectional analysis of urinary BPA concentrations, body mass index, and waist circumference in 2747 adults (aged 18-74), using pooled data from the 2003/04 and 2005/06 National Health and Nutrition Examination Surveys. RESULTS The creatinine-adjusted geometric mean urinary BPA concentration was 2.05μg/g creatinine (25th percentile: 1.18, 75% percentile: 3.33). Relative to those in the lowest BPA quartile, participants in the upper BPA quartiles were more likely to be classified as obese (quartile 2 odds ratio (OR): 1.85, 95% confidence interval (CI): 1.22, 2.79; quartile 3 OR: 1.60, 95% CI: 1.05-2.44; quartile 4 OR: 1.76, 95% CI: 1.06-2.94). Higher BPA concentration was also associated with abdominal obesity (quartile 2 OR: 1.62, 95% CI: 1.11, 2.36; quartile 3 OR: 1.39, 95% CI: 1.02-1.90; quartile 4 OR: 1.58, 95% CI: 1.03-2.42). CONCLUSIONS Higher BPA exposure is associated with general and central obesity in the general adult population of the United States. Reverse causation is of concern due to the cross-sectional nature of this study; longitudinal studies are needed to clarify the direction of the association.

Recommendations for the design and analysis of epigenome-wide association studies

Epigenome-wide association studies (EWAS) hold promise for the detection of new regulatory mechanisms that may be susceptible to modification by environmental and lifestyle factors affecting susceptibility to disease. Epigenome-wide screening methods cover an increasing number of CpG sites, but the complexity of the data poses a challenge to separating robust signals from noise. Appropriate study design, a detailed a priori analysis plan and validation of results are essential to minimize the danger of false positive results and contribute to a unified approach. Epigenome-wide mapping studies in homogenous cell populations will inform our understanding of normal variation in the methylome that is not associated with disease or aging. Here we review concepts for conducting a stringent and powerful EWAS, including the choice of analyzed tissue, sources of variability and systematic biases, outline analytical solutions to EWAS-specific problems and highlight caveats in interpretation of data generated from samples with cellular heterogeneity.

Longitudinal study of birth weight and adult body mass index in predicting risk of coronary heart disease and stroke in women.

Abstract Objectives To determine whether birth weight and adult body size interact to predict coronary heart disease in women, as has been observed for men. To determine whether birth weight and adult body size interact to predict risk of stroke. Design Longitudinal cohort study. Setting and participants 66 111 female nurses followed since 1976 who were born of singleton, term pregnancies and reported their birth weight in 1992. Main outcome measures 1504 events of coronary heart disease (myocardial infarction or sudden cardiac death) and 1164 strokes. Results For each kilogram of higher birth weight, age adjusted hazard ratios from prospective analysis were 0.77 (95% confidence interval 0.69 to 0.87) for coronary heart disease and 0.89 (0.78 to 1.01) for total stroke. In combined prospective and retrospective analysis, hazard ratios were 0.84 (0.76 to 0.93) for total stroke, 0.83 (0.71 to 0.96) for ischaemic stroke, and 0.86 (0.66 to 1.11) for haemorrhagic stroke. Exclusion of macrosomic infants (> 4536 g) yielded stronger estimates. Risk of coronary heart disease was especially high for women who crossed from a low centile of weight at birth to a high centile of body mass index in adulthood. The association of lower birth weight with increased risk of stroke was apparent across categories of body mass index in adults and was not especially strong among heavier women. Conclusions Higher body mass index in adulthood is an especially strong risk factor for coronary heart disease among women who were small at birth. In this large cohort of women, size at birth and adiposity in adulthood interacted to predict events of coronary heart disease but not stroke events.

Inverse association of farm milk consumption with asthma and allergy in rural and suburban populations across Europe

Background Dietary interventions as a means for atopy prevention attract great interest. Some studies in rural environments claimed an inverse association between consumption of farm‐produced dairy products and the prevalence of allergic diseases, but current evidence is controversial.