ObjectiveBecause of the pressure for timely, informed decisions in public health
and clinical practice and the explosion of information in the scientific literature,
research results must be synthesized. Meta-analyses are increasingly used
to address this problem, and they often evaluate observational studies. A
workshop was held in Atlanta, Ga, in April 1997, to examine the reporting
of meta-analyses of observational studies and to make recommendations to aid
authors, reviewers, editors, and readers.ParticipantsTwenty-seven participants were selected by a steering committee, based
on expertise in clinical practice, trials, statistics, epidemiology, social
sciences, and biomedical editing. Deliberations of the workshop were open
to other interested scientists. Funding for this activity was provided by
the Centers for Disease Control and Prevention.EvidenceWe conducted a systematic review of the published literature on the
conduct and reporting of meta-analyses in observational studies using MEDLINE,
Educational Research Information Center (ERIC), PsycLIT, and the Current Index
to Statistics. We also examined reference lists of the 32 studies retrieved
and contacted experts in the field. Participants were assigned to small-group
discussions on the subjects of bias, searching and abstracting, heterogeneity,
study categorization, and statistical methods.Consensus ProcessFrom the material presented at the workshop, the authors developed a
checklist summarizing recommendations for reporting meta-analyses of observational
studies. The checklist and supporting evidence were circulated to all conference
attendees and additional experts. All suggestions for revisions were addressed.ConclusionsThe proposed checklist contains specifications for reporting of meta-analyses
of observational studies in epidemiology, including background, search strategy,
methods, results, discussion, and conclusion. Use of the checklist should
improve the usefulness of meta-analyses for authors, reviewers, editors, readers,
and decision makers. An evaluation plan is suggested and research areas are
explored.

https://jamanetwork.com/journals/jama/articlepdf/192614/JST00003.pdf

Meta-analysis of observational studies in epidemiology - A proposal for reporting

Context Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain Objective To assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States Design Estrogen plus progestin component of the Women's Health Initiative, a randomized controlled primary prevention trial (planned duration, 85 years) in which 16608 postmenopausal women aged 50-79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993-1998 Interventions Participants received conjugated equine estrogens, 0625 mg/d, plus medroxyprogesterone acetate, 25 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102) Main outcomes measures The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes Results On May 31, 2002, after a mean of 52 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits This report includes data on the major clinical outcomes through April 30, 2002 Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 129 (102-163) with 286 cases; breast cancer, 126 (100-159) with 290 cases; stroke, 141 (107-185) with 212 cases; PE, 213 (139-325) with 101 cases; colorectal cancer, 063 (043-092) with 112 cases; endometrial cancer, 083 (047-147) with 47 cases; hip fracture, 066 (045-098) with 106 cases; and death due to other causes, 092 (074-114) with 331 cases Corresponding HRs (nominal 95% CIs) for composite outcomes were 122 (109-136) for total cardiovascular disease (arterial and venous disease), 103 (090-117) for total cancer, 076 (069-085) for combined fractures, 098 (082-118) for total mortality, and 115 (103-128) for the global index Absolute excess risks per 10 000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10 000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures The absolute excess risk of events included in the global index was 19 per 10 000 person-years Conclusions Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 52-year follow-up among healthy postmenopausal US women All-cause mortality was not affected during the trial The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD

/pdf/risks-and-benefits-of-estrogen-plus-progestin-in-healthy-4glim99n2t.pdf

Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial

Detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III)

Author(s): Anderson, Garnet L; Limacher, Marian; Assaf, Annlouise R; Bassford, Tamsen; Beresford, Shirley AA; Black, Henry; Bonds, Denise; Brunner, Robert; Brzyski, Robert; Caan, Bette; Chlebowski, Rowan; Curb, David; Gass, Margery; Hays, Jennifer; Heiss, Gerardo; Hendrix, Susan; Howard, Barbara V; Hsia, Judith; Hubbell, Allan; Jackson, Rebecca; Johnson, Karen C; Judd, Howard; Kotchen, Jane Morley; Kuller, Lewis; LaCroix, Andrea Z; Lane, Dorothy; Langer, Robert D; Lasser, Norman; Lewis, Cora E; Manson, JoAnn; Margolis, Karen; Ockene, Judith; O'Sullivan, Mary Jo; Phillips, Lawrence; Prentice, Ross L; Ritenbaugh, Cheryl; Robbins, John; Rossouw, Jacques E; Sarto, Gloria; Stefanick, Marcia L; Van Horn, Linda; Wactawski-Wende, Jean; Wallace, Robert; Wassertheil-Smoller, Sylvia; Women's Health Initiative Steering Committee | Abstract: Despite decades of use and considerable research, the role of estrogen alone in preventing chronic diseases in postmenopausal women remains uncertain.To assess the effects on major disease incidence rates of the most commonly used postmenopausal hormone therapy in the United States.A randomized, double-blind, placebo-controlled disease prevention trial (the estrogen-alone component of the Women's Health Initiative [WHI]) conducted in 40 US clinical centers beginning in 1993. Enrolled were 10 739 postmenopausal women, aged 50-79 years, with prior hysterectomy, including 23% of minority race/ethnicity.Women were randomly assigned to receive either 0.625 mg/d of conjugated equine estrogen (CEE) or placebo.The primary outcome was coronary heart disease (CHD) incidence (nonfatal myocardial infarction or CHD death). Invasive breast cancer incidence was the primary safety outcome. A global index of risks and benefits, including these primary outcomes plus stroke, pulmonary embolism (PE), colorectal cancer, hip fracture, and deaths from other causes, was used for summarizing overall effects.In February 2004, after reviewing data through November 30, 2003, the National Institutes of Health (NIH) decided to end the intervention phase of the trial early. Estimated hazard ratios (HRs) (95% confidence intervals [CIs]) for CEE vs placebo for the major clinical outcomes available through February 29, 2004 (average follow-up 6.8 years), were: CHD, 0.91 (0.75-1.12) with 376 cases; breast cancer, 0.77 (0.59-1.01) with 218 cases; stroke, 1.39 (1.10-1.77) with 276 cases; PE, 1.34 (0.87-2.06) with 85 cases; colorectal cancer, 1.08 (0.75-1.55) with 119 cases; and hip fracture, 0.61 (0.41-0.91) with 102 cases. Corresponding results for composite outcomes were: total cardiovascular disease, 1.12 (1.01-1.24); total cancer, 0.93 (0.81-1.07); total fractures, 0.70 (0.63-0.79); total mortality, 1.04 (0.88-1.22), and the global index, 1.01 (0.91-1.12). For the outcomes significantly affected by CEE, there was an absolute excess risk of 12 additional strokes per 10 000 person-years and an absolute risk reduction of 6 fewer hip fractures per 10 000 person-years. The estimated excess risk for all monitored events in the global index was a nonsignificant 2 events per 10 000 person-years.The use of CEE increases the risk of stroke, decreases the risk of hip fracture, and does not affect CHD incidence in postmenopausal women with prior hysterectomy over an average of 6.8 years. A possible reduction in breast cancer risk requires further investigation. The burden of incident disease events was equivalent in the CEE and placebo groups, indicating no overall benefit. Thus, CEE should not be recommended for chronic disease prevention in postmenopausal women.

/pdf/effects-of-conjugated-equine-estrogen-in-postmenopausal-56019yuhvy.pdf

Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial

Associations between modifiable exposures and disease seen in observational epidemiology are sometimes confounded and thus misleading, despite our best efforts to improve the design and analysis of studies. Mendelian randomization-the random assortment of genes from parents to offspring that occurs during gamete formation and conception-provides one method for assessing the causal nature of some environmental exposures. The association between a disease and a polymorphism that mimics the biological link between a proposed exposure and disease is not generally susceptible to the reverse causation or confounding that may distort interpretations of conventional observational studies. Several examples where the phenotypic effects of polymorphisms are well documented provide encouraging evidence of the explanatory power of Mendelian randomization and are described. The limitations of the approach include confounding by polymorphisms in linkage disequilibrium with the polymorphism under study, that polymorphisms may have several phenotypic effects associated with disease, the lack of suitable polymorphisms for studying modifiable exposures of interest, and canalization-the buffering of the effects of genetic variation during development. Nevertheless, Mendelian randomization provides new opportunities to test causality and demonstrates how investment in the human genome project may contribute to understanding and preventing the adverse effects on human health of modifiable exposures.

/pdf/mendelian-randomization-can-genetic-epidemiology-contribute-vb0zjyrtxf.pdf

‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease?

To quantify the effect of estrogen replacement therapy on breast cancer risk, we combined dose-response slopes of the relative risk of breast cancer against the duration of estrogen use across 16 studies. Using this summary dose-response slope, we calculated the proportional increase in risk of breast cancer for each year of estrogen use. For women who experienced any type of menopause, risk did not appear to increase until after at least 5 years of estrogen use. After 15 years of estrogen use, we found a 30% increase in the risk of breast cancer (relative risk, 1.3; 95% confidence interval [CI], 1.2 to 1.6). The increase in risk was largely due to results of studies that included premenopausal women or women using estradiol (with or without progestin), studies for which the estimated relative risk was 2.2 (CI, 1.4 to 3.4) after 15 years. Among women with a family history of breast cancer, those who had ever used estrogen replacement had a significantly higher risk (3.4; CI, 2.0 to 6.0) than those who had not (1.5; CI, 1.2 to 1.7). (JAMA. 1991;265:1985-1990)

A Meta-analysis of the Effect of Estrogen Replacement Therapy on the Risk of Breast Cancer

Objective. —To develop recommendations for obtaining adequate informed consent in the future when gathering tissue samples that may be used for genetic studies and defining the circumstances under which it is necessary to obtain further consent if tissue samples already in hand are to be used for such research. Participants. —Scientists, ethicists, lawyers, and consumers selected by the National Center for Human Genome Research and the Centers for Disease Control and Prevention to represent a wide array of opinions. Evidence. —Statutes, regulations, and cases and articles on law and ethics. Consensus Process. —Initial workshop, followed by circulation of several drafts of this document with opportunities for comment by workshop participants and others as well as smaller meetings involving participants with widely differing views. Conclusions. —Genetic research using stored tissue samples poses an array of benefits and risks to individuals, researchers, and society. As a result, the workshop participants conclude that (1) informed consent is required for all genetic research using linkable samples unless conditions for limitation or waiver are met; (2) informed consent is not required for genetic research using anonymous samples but may be considered if identifiers are to be removed from currently linkable samples; (3) institutional review boards could usefully review all protocols that propose to use samples for genetic research; and (4) further work regarding these issues is warranted. ( JAMA . 1995;274:1786-1792)

https://jamanetwork.com/journals/jama/articlepdf/392627/jama_274_22_033.pdf

Informed Consent for Genetic Research on Stored Tissue Samples

Background Elevated concentrations of homocyst(e)ine are thought to increase the risk of vascular diseases including coronary heart disease and cerebrovascular disease. Methods We searched MEDLINE (1966-1999), EMBASE (1974-1999), SciSearch (1974- 1999), and Dissertation Abstracts (1999) for articles and theses about homocyst(e)ine concentration and coronary heart disease and cerebrovascular disease. Results We included 57 publications (3 cohort studies, 12 nested case-control studies, 42 case-control studies) that reported results on 5518 people with coronary heart disease (11,068 control subjects) and 1817 people with cerebrovascular disease (4787 control subjects) in our analysis. For coronary heart disease, the summary odds ratios (OR) for a 5-micromol/l increase in homocyst(e)ine concentration were 1.06 (95% CI : 0.99-1.13) for 2 publications of cohort studies, 1.23 (95% CI : 1.07-1.41) for 10 publications of nested case-control studies, and 1.70 (95% CI : 1.50-1.93) for 26 publications of case-control studies. For cerebrovascular disease, the summary OR for a 5-micromol/l increase in homocyst(e)ine concentration were 1.10 (95% CI : 0.94-1.28) for 2 publications of cohort studies, 1.58 (95% CI : 1.35-1.85) for 5 publications of nested case-control studies, and 2.16 (95% CI : 1.65-2.82) for 17 publications of case-control studies. Conclusions Prospective studies offer weaker support than case-control studies for an association between homocyst(e)ine concentration and cardiovascular disease. Although other lines of evidence support a role for homocyst(e)ine in the pathogenesis of cardiovascular disease, more information from prospective epidemiological studies or clinical trials is needed to clarify this role.

/pdf/homocyst-e-ine-and-cardiovascular-disease-a-systematic-1vl28wjbog.pdf

Homocyst(e)ine and cardiovascular disease: a systematic review of the evidence with special emphasis on case-control studies and nested case-control studies

Results The prevalence of C282Y homozygosity is estimated to be 0.26% (95% confidence interval [CI], 0.12%-0.49%); 1.89% (95% CI, 1.48%-2.43%) for H63D homozygosity; and 1.97% (95% CI, 1.54%-2.49%) for compound heterozygosity. The prevalence estimates for C282Y heterozygosity (C282Y/wild type) are 9.54% among non-Hispanic whites, 2.33% among non-Hispanic blacks, and 2.75% among MexicanAmericans. The prevalence estimates of the C282Y mutation in the US population are 5.4% (95% CI, 4.7%-6.2%) and 13.5% (95% CI, 12.5%-14.8%) for the H63D mutation. Conclusions Estimates of prevalence of HFE mutations are within the expected range for non-Hispanic whites and blacks but the estimated prevalence of the C282Y mutation among Mexican-Americans is less than expected. Mutation data now need to be linked to clinically relevant indices, such as transferrin saturation level.

https://jamanetwork.com/journals/jama/articlepdf/193800/JOC02264.pdf

Prevalence of C282Y and H63D mutations in the hemochromatosis (HFE) gene in the United States.

Bone density begins to decline in women before menopause, and the degree of bone loss is variable. We performed a cross-sectional analysis on the entry data of a 5-yr prospective study of risk factors for osteoporosis to determine the correlation of bone density with serum sex steroid concentrations and body weight. We studied 292 healthy white women, aged 35-50 yr, who were menstruating regularly or had had menses in the past 12 months. Blood samples were drawn in the early follicular phase for estradiol (E2), testosterone (T), dehydroepiandrosterone sulfate, and sex hormone-binding globulin (SHBG). Free levels of E2 (FE2) and T (FT) were calculated based on total T and E2, SHBG, and albumin levels. Women were classified as premenopausal (FSH, <12 U/L) and perimenopausal (FSH ≥12 U/L; n = 46; 16%). Bone density was measured by dual photon absorptiometry of the lumbar spine (L2-L4) and hip and by single photon absorptiometry of the wrist. Perimenopausal women were older than premenopausal women (45.5+−3.5...

Karen K. Steinberg

Papers

A Meta-analysis of the Effect of Estrogen Replacement Therapy on the Risk of Breast Cancer

Informed Consent for Genetic Research on Stored Tissue Samples

Homocyst(e)ine and cardiovascular disease: a systematic review of the evidence with special emphasis on case-control studies and nested case-control studies

Prevalence of C282Y and H63D mutations in the hemochromatosis (HFE) gene in the United States.

Sex Steroids and Bone Density in Premenopausal and Perimenopausal Women