Clare Oliver-Williams

Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies

Objective To evaluate the extent to which circulating biomarker and supplements of vitamin D are associated with mortality from cardiovascular, cancer, or other conditions, under various circumstances. Design Systematic review and meta-analysis of observational studies and randomised controlled trials. Data sources Medline, Embase, Cochrane Library, and reference lists of relevant studies to August 2013; correspondance with investigators. Study selection Observational cohort studies and randomised controlled trials in adults, which reported associations between vitamin D (measured as circulating 25-hydroxyvitamin D concentration or vitamin D supplement given singly) and cause specific mortality outcomes. Data extraction Data were extracted by two independent investigators, and a consensus was reached with involvement of a third. Study specific relative risks from 73 cohort studies (849 412 participants) and 22 randomised controlled trials (vitamin D given alone versus placebo or no treatment; 30 716 participants) were meta-analysed using random effects models and were grouped by study and population characteristics. Results In the primary prevention observational studies, comparing bottom versus top thirds of baseline circulating 25-hydroxyvitamin D distribution, pooled relative risks were 1.35 (95% confidence interval 1.13 to 1.61) for death from cardiovascular disease, 1.14 (1.01 to 1.29) for death from cancer, 1.30 (1.07 to 1.59) for non-vascular, non-cancer death, and 1.35 (1.22 to 1.49) for all cause mortality. Subgroup analyses in the observational studies indicated that risk of mortality was significantly higher in studies with lower baseline use of vitamin D supplements. In randomised controlled trials, relative risks for all cause mortality were 0.89 (0.80 to 0.99) for vitamin D3 supplementation and 1.04 (0.97 to 1.11) for vitamin D2 supplementation. The effects observed for vitamin D3 supplementation remained unchanged when grouped by various characteristics. However, for vitamin D2 supplementation, increased risks of mortality were observed in studies with lower intervention doses and shorter average intervention periods. Conclusions Evidence from observational studies indicates inverse associations of circulating 25-hydroxyvitamin D with risks of death due to cardiovascular disease, cancer, and other causes. Supplementation with vitamin D3 significantly reduces overall mortality among older adults; however, before any widespread supplementation, further investigations will be required to establish the optimal dose and duration and whether vitamin D3 and D2 have different effects on mortality risk.

Association of Age at Onset of Menopause and Time Since Onset of Menopause With Cardiovascular Outcomes, Intermediate Vascular Traits, and All-Cause Mortality: A Systematic Review and Meta-analysis.

Importance As many as 10% of women experience natural menopause by the age of 45 years. If confirmed, an increased risk of cardiovascular disease (CVD) and all-cause mortality associated with premature and early-onset menopause could be an important factor affecting risk of disease and mortality among middle-aged and older women. Objective To systematically review and meta-analyze studies evaluating the effect of age at onset of menopause and duration since onset of menopause on intermediate CVD end points, CVD outcomes, and all-cause mortality. Data Sources Medical databases (ie, Medline, EMBASE, and Web of Science) until March 2015. Study Selection Studies (ie, observational cohort, case-control, or cross-sectional) that assessed age at onset of menopause and/or time since onset of menopause as exposures as well as risk of cardiovascular outcomes and intermediate CVD end points in perimenopausal, menopausal, or postmenopausal women. Data Extraction and Synthesis Studies were sought if they were observational cohort, case-control, or cross-sectional studies; reported on age at onset of menopause and/or time since onset of menopause as exposures; and assessed associations with risk of CVD-related outcomes, all-cause mortality, or intermediate CVD end points. Data were extracted by 2 independent reviewers using a predesigned data collection form. The inverse-variance weighted method was used to combine relative risks to produce a pooled relative risk using random-effects models to allow for between-study heterogeneity. Main Outcomes and Measures Cardiovascular disease outcomes (ie, composite CVD, fatal and nonfatal coronary heart disease [CHD], and overall stroke and stroke mortality), CVD mortality, all-cause mortality, and intermediate CVD end points. Results Of the initially identified references, 32 studies were selected that included 310 329 nonoverlapping women. Outcomes were compared between women who experienced menopause younger than 45 years and women 45 years or older at onset; the relative risks (95% CIs) were 1.50 (1.28-1.76) for overall CHD, 1.11 (1.03-1.20) for fatal CHD, 1.23 (0.98-1.53) for overall stroke, 0.99 (0.92-1.07) for stroke mortality, 1.19 (1.08-1.31) for CVD mortality, and 1.12 (1.03-1.21) for all-cause mortality. Outcomes were also compared between women between 50 and 54 years at onset of menopause and women younger than 50 years at onset; there was a decreased risk of fatal CHD (relative risk, 0.87; 95% CI, 0.80-0.96) and no effect on stroke. Time since onset of menopause in relation to risk of developing intermediate cardiovascular traits or CVD outcomes was reported in 4 observational studies with inconsistent results. Conclusions and Relevance The findings of this review indicate a higher risk of CHD, CVD mortality, and overall mortality in women who experience premature or early-onset menopause.

Use of Plant-Based Therapies and Menopausal Symptoms: A Systematic Review and Meta-analysis

IMPORTANCE Between 40% and 50% of women in Western countries use complementary therapies to manage menopausal symptoms. OBJECTIVE To determine the association of plant-based therapies with menopausal symptoms, including hot flashes, night sweats, and vaginal dryness. DATA SOURCES The electronic databases Ovid MEDLINE, EMBASE, and Cochrane Central were systematically searched to identify eligible studies published before March 27, 2016. Reference lists of the included studies were searched for further identification of relevant studies. STUDY SELECTION Randomized clinical trials that assessed plant-based therapies and the presence of hot flashes, night sweats, and vaginal dryness. DATA EXTRACTION Data were extracted by 2 independent reviewers using a predesigned data collection form. MAIN OUTCOMES AND MEASURES Hot flashes, night sweats, and vaginal dryness. RESULTS In total, 62 studies were identified, including 6653 individual women. Use of phytoestrogens was associated with a decrease in the number of daily hot flashes (pooled mean difference of changes, -1.31 [95% CI, -2.02 to -0.61]) and vaginal dryness score (pooled mean difference of changes, -0.31 [95% CI, -0.52 to -0.10]) between the treatment groups but not in the number of night sweats (pooled mean difference of changes, -2.14 [95% CI, -5.57 to 1.29]). Individual phytoestrogen interventions such as dietary and supplemental soy isoflavones were associated with improvement in daily hot flashes (pooled mean difference of changes, -0.79 [-1.35 to -0.23]) and vaginal dryness score (pooled mean difference of changes, -0.26 [-0.48 to -0.04]). Several herbal remedies, but not Chinese medicinal herbs, were associated with an overall decrease in the frequency of vasomotor symptoms. There was substantial heterogeneity in quality across the available studies, and 46 (74%) of the included randomized clinical trials demonstrated a high risk of bias within 3 or more areas of study quality. CONCLUSIONS AND RELEVANCE This meta-analysis of clinical trials suggests that composite and specific phytoestrogen supplementations were associated with modest reductions in the frequency of hot flashes and vaginal dryness but no significant reduction in night sweats. However, because of general suboptimal quality and the heterogeneous nature of the current evidence, further rigorous studies are needed to determine the association of plant-based and natural therapies with menopausal health.

Association of Genetic Variants Related to CETP Inhibitors and Statins With Lipoprotein Levels and Cardiovascular Risk

Importance Some cholesteryl ester transfer protein (CETP) inhibitors lower low-density lipoprotein cholesterol (LDL-C) levels without reducing cardiovascular events, suggesting that the clinical benefit of lowering LDL-C may depend on how LDL-C is lowered. Objective To estimate the association between changes in levels of LDL-C (and other lipoproteins) and the risk of cardiovascular events related to variants in the CETP gene, both alone and in combination with variants in the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) gene. Design, Setting, and Participants Mendelian randomization analyses evaluating the association between CETP and HMGCR scores, changes in lipid and lipoprotein levels, and the risk of cardiovascular events involving 102 837 participants from 14 cohort or case-control studies conducted in North America or the United Kingdom between 1948 and 2012. The associations with cardiovascular events were externally validated in 189 539 participants from 48 studies conducted between 2011 and 2015. Exposures Differences in mean high-density lipoprotein cholesterol (HDL-C), LDL-C, and apolipoprotein B (apoB) levels in participants with CETP scores at or above vs below the median. Main Outcomes and Measures Odds ratio (OR) for major cardiovascular events. Results The primary analysis included 102 837 participants (mean age, 59.9 years; 58% women) who experienced 13 821 major cardiovascular events. The validation analyses included 189 539 participants (mean age, 58.5 years; 39% women) with 62 240 cases of coronary heart disease (CHD). Considered alone, the CETP score was associated with higher levels of HDL-C, lower LDL-C, concordantly lower apoB, and a corresponding lower risk of major vascular events (OR, 0.946 [95% CI, 0.921-0.972]) that was similar in magnitude to the association between the HMGCR score and risk of major cardiovascular events per unit change in levels of LDL-C (and apoB). When combined with the HMGCR score, the CETP score was associated with the same reduction in LDL-C levels but an attenuated reduction in apoB levels and a corresponding attenuated nonsignificant risk of major cardiovascular events (OR, 0.985 [95% CI, 0.955-1.015]). In external validation analyses, a genetic score consisting of variants with naturally occurring discordance between levels of LDL-C and apoB was associated with a similar risk of CHD per unit change in apoB level (OR, 0.782 [95% CI, 0.720-0.845] vs 0.793 [95% CI, 0.774-0.812]; P = .79 for difference), but a significantly attenuated risk of CHD per unit change in LDL-C level (OR, 0.916 [95% CI, 0.890-0.943] vs 0.831 [95% CI, 0.816-0.847]; P < .001) compared with a genetic score associated with concordant changes in levels of LDL-C and apoB. Conclusions and Relevance Combined exposure to variants in the genes that encode the targets of CETP inhibitors and statins was associated with discordant reductions in LDL-C and apoB levels and a corresponding risk of cardiovascular events that was proportional to the attenuated reduction in apoB but significantly less than expected per unit change in LDL-C. The clinical benefit of lowering LDL-C levels may therefore depend on the corresponding reduction in apoB-containing lipoprotein particles.

Miscarriage and future maternal cardiovascular disease: a systematic review and meta-analysis

Context The 2011 American Heart Association guidelines identified pregnancy complications as a risk factor for cardiovascular disease in women. However, miscarriage was not mentioned within the guidelines, and there is no consensus on the association between miscarriage and future risk of cardiovascular disease. Objective To confirm or refute the association, a meta-analysis of published papers was conducted. Data sources PubMed, Web of Knowledge and Scopus were systematically searched to identify appropriate articles. Reference lists were then hand searched for additional relevant titles. Study Selection To be included, articles had to assess the association between miscarriage and subsequent cardiovascular disease in otherwise healthy women. Only women who had miscarriages were considered exposed. Pooled association measures, using random effects meta-analysis, were calculated for coronary heart disease and cerebrovascular disease. Publication bias and between-study heterogeneity were evaluated. Data Extraction Two authors individually reviewed all studies and extracted data on patient and study characteristics along with cardiovascular outcomes. Results 10 studies were identified, with 517 504 individuals included in the coronary heart disease meta-analysis and 134 461 individuals in the cerebrovascular disease analysis. A history of miscarriage was associated with a greater odds of developing coronary heart disease, OR (95% CI) =1.45 (1.18 to 1.78), but not with cerebrovascular disease, OR=1.11 (0.72 to 1.69). There was a strong association between recurrent miscarriage and coronary heart disease OR=1.99 (1.13 to 3.50). Evidence was found for moderate between-study heterogeneity and publication bias in the coronary heart disease analysis. Conclusions The meta-analysis indicates that a history of miscarriage or recurrent miscarriage is associated with a greater risk of subsequent coronary heart disease.

Previous caesarean delivery and the risk of unexplained stillbirth: retrospective cohort study and meta-analysis

To determine whether caesarean delivery in the first pregnancy is a risk factor for unexplained antepartum stillbirth in a second pregnancy.

Consequences Of Natural Perturbations In The Human Plasma Proteome

Proteins are the primary functional units of biology and the direct targets of most drugs, yet there is limited knowledge of the genetic factors determining inter-individual variation in protein levels. Here we reveal the genetic architecture of the human plasma proteome, testing 10.6 million DNA variants against levels of 2,994 proteins in 3,301 individuals. We identify 1,927 genetic associations with 1,478 proteins, a 4-fold increase on existing knowledge, including trans associations for 1,104 proteins. To understand consequences of perturbations in plasma protein levels, we introduce an approach that links naturally occurring genetic variation with biological, disease, and drug databases. We provide insights into pathogenesis by uncovering the molecular effects of disease-associated variants. We identify causal roles for protein biomarkers in disease through Mendelian randomization analysis. Our results reveal new drug targets, opportunities for matching existing drugs with new disease indications, and potential safety concerns for drugs under development.

Association of Vasomotor and Other Menopausal Symptoms with Risk of Cardiovascular Disease: A Systematic Review and Meta-Analysis

Importance Vasomotor symptoms (hot flushes and night sweats) and other symptoms, including depression, anxiety and panic attacks, are commonly experienced by menopausal women and have been associated with an unfavourable cardiovascular risk profile. Objective To investigate whether presence of menopausal symptoms is associated with the development of cardiovascular disease (CVD). Methods Five electronic databases (Medline, EMBASE and Web of Science) were search until February 17th, 2015 to identify relevant studies. Observational cohort studies or randomised intervention studies were eligible for inclusion if they followed participants prospectively (at least 1 year of follow-up), and reported relevant estimates on the association of any vasomotor symptoms, or other menopausal symptoms, with risk of CVD, coronary heart disease (CHD), or stroke in perimenopausal, menopausal, or postmenopausal women. Data were extracted by two independent reviewers using a pre-designed data collection form. Separate pooled relative risks (RRs) for age and non-established cardiovascular risk factors (e.g., education, ethnicity) adjusted data and for established cardiovascular risk factors and potential mediators-adjusted data (e.g., smoking, body mass index, and hypertension) were calculated. Results Out of 9,987 initially identified references, ten studies were selected, including 213,976 women with a total of 10,037 cardiovascular disease outcomes. The age and non-established cardiovascular risk factors adjusted RRs) [95% confidence intervals] for development of CHD, Stroke and CVD comparing women with and without any menopausal symptoms were 1.34 [1.13–1.58], 1.30 [0.99–1.70], 1.48 [1.21–1.80] respectively, and the corresponding RRs adjusted for cardiovascular risk factors and potential mediators were 1.18 [1.03–1.35], 1.08 [0.89–1.32], 1.29 [0.98–1.71]. However, these analyses were limited by potential unmeasured confounding and the small number of studies on this topic. Conclusion Presence of vasomotor symptoms and other menopausal symptoms are generally associated with an increased risk of cardiovascular disease, which is mainly explained by cardiovascular risk factors.

Previous miscarriage and the subsequent risk of preterm birth in Scotland, 1980-2008: a historical cohort study.

To determine whether the relationship between previous miscarriage and risk of preterm birth changed over the period 1980–2008, and to determine whether the pattern varied according to the cause of the preterm birth.

Mid- and Long-Term Health Risks in Living Kidney Donors: A Systematic Review and Meta-analysis.

Living kidney donation is the gold standard treatment of end-stage renal disease (ESRD); more than 8000 living-donor kidney transplantations were done in 2013 in the United States, Brazil, and Japan alone (1). Although living donation is highly beneficial to recipients, it remains a complex ethical, moral, and medical issue. It is practiced with the expectation that risk for minimal short- and long-term harm to the donor is outweighed by the psychological benefits of altruism and improved recipient health (2). A short-term reduction in glomerular filtration rate after nephrectomy is a known consequence of kidney donation (3). However, the mid- and long-term health risks remain uncertain, despite their critical role in informing clinical guidelines for follow-up and supporting the process of informed consent (4, 5). Although narrative reviews (1, 6, 7) and individual studies have reported on the longer-term health risks of living kidney donation, most have not been systematically assessed and quantified. For example, the 3 previously published meta-analyses (each involving up to 6 studies comparing donors vs. a nondonor control group) focused only on a limited number of outcomes (such as hypertension and renal function) and involved only about half of the currently available data (3, 8, 9). Interpretation of the evidence has also been complicated by diverse selection criteria for nondonor control groups (for example, general population vs. based on donation criteria), follow-up durations, and analytic approaches (for example, different matching criteria or adjustment for potential confounders) (4, 10). To help quantify the mid- and long-term risks of living kidney donation, we conducted a systematic review and meta-analysis of observational studies comparing living kidney donors with control participants (nondonors) for a broad range of health outcomes. Methods Data Sources and Searches This review was done using a predefined protocol published in PROSPERO (CRD42017072284) and in accordance with MOOSE (Meta-analysis of Observational Studies in Epidemiology) guidelines. Studies published from April 1964 to 20 July 2017 were identified, without language restriction, through electronic searches using PubMed, Embase, Scopus, and PsycINFO. We supplemented this search by scanning reference lists of relevant articles (including studies as well as reviews and meta-analyses) and by backward and forward citation searching of all included studies. The computer-based searches combined terms related to living organ donation, health related quality of life, and epidemiological studies without health outcomes restriction (Supplement). Supplement. Supplementary Online Content Study Selection Studies were eligible for inclusion if they reported associations between living kidney donation and any health outcomes, disease traits, or health-related quality of life (HRQoL) using a validated instrument; had a mean follow-up after donation of at least 1 year; and provided a comparison group of control participants who had not donated a kidney. Outcomes evaluated in only 1 study (gout and kidney stones) were not included. Data Extraction and Quality Assessment Two investigators independently extracted data on the following characteristics using standardized protocols: sample size; study design; sampling population; location; year of publication; years of baseline survey (year of kidney donation); follow-up duration; participant sex, age range, and ethnicity; number of donors and control participants; selection criteria for control participants; outcomes recorded; outcome definitions and methods of ascertainment (Supplement Table 1); reported risk estimates; and degree of statistical adjustment used or, where relevant, mean level of disease traits and HRQoL assessment scores in donors and control participants. Discrepancies were resolved by discussion and adjudication by a third reviewer. We used the most up-to-date or comprehensive information when more than 1 article reported on the same study. Study quality was evaluated with the Newcastle-Ottawa Scale (NOS) (11), which uses a star system (maximum of 9 stars) to assess quality in the following 3 domains: selection of participants, comparability of study groups, and ascertainment of outcomes of interest. Studies with 4 stars or more were rated as medium or higher quality. We classified selection of control participants as +++ if they were eligible for nephrectomy based on medical status and assessment of renal function; ++ if they were eligible for nephrectomy based on medical status but without assessment of renal function, or if renal function was assessed but limited information on medical history was available; and + if limited screening or information on controls selection was available. Furthermore, we classified matching of donors with control participants as +++ if it was done according to age, sex, sociodemographic factors, or other factors potentially influencing the outcome of interest (for example, body mass index, blood pressure, medical history, and smoking history); ++ if it was based on age, sex, and sociodemographic factors; + if it was based only on age or sex; and null if no matching was done. Data Synthesis and Analysis Primary analyses involved only within-study comparisons to limit potential biases. We restricted primary analyses to studies with an NOS score of at least 4 and baseline recruitment period ending in or after 2000 to provide more reliable and contemporary summary estimates. Supplementary analyses involved all available studies. We used reported relative risks (RRs) or unadjusted RRs or odds ratios calculated from study-specific data to quantify the association between living kidney donation and each of the binary outcomes of interest. Hazard ratios and odds ratios were assumed to approximate the same measure of RR. Incidence rates per 1000 person-years in donors were extracted from studies or calculated as the ratio of events in donors and control participants over the number of person-years at risk. This number in each group was extracted from each study or estimated by multiplying the mean (or median) years of follow-up by the number of donors and control participants. For pregnancy outcomes, incidence of adverse outcomes per 100 pregnancies was calculated by dividing the number of adverse events by the number of pregnancies. We assessed continuous outcomes (disease traits and HRQoL outcomes) by comparing mean differences in living kidney donors with those in control participants for each study. Standardized mean difference (SMD) was calculated within each study as the mean difference between cases and control participants divided by the pooled SD (12). This estimate allows comparison among disparate outcome measures reported with different units. Summary RRs, incidence rates, and SMDs comparing donors with control participants were calculated for each outcome by pooling the study-specific estimates using the random-effects profile likelihood meta-analysis method (13). Consistency of findings across individual studies for outcomes reported in 3 or more studies was assessed by the I 2 statistic. Evidence of publication bias across studies was assessed for outcomes with more than 10 studies using funnel plots and the Egger test. All analyses were 2-sided, used a significance level of P< 0.05, and were done with Stata, version 14.2 (StataCorp). Role of the Funding Source None of the funding organizations were involved in the design or conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication. Results Overall, 52 unique studies from 17 countries involving 118426 donors and 117656 control participants met the inclusion criteria (Figure 1 and Appendix Table). Twenty-three studies were based in North America, 10 in Europe, 2 in Australia, 5 in South America, and 12 in other or several regions. Donors were primarily recruited from hospital registries: 39 studies recruited donors from hospitals and 11 from national or regional donor registries (2 studies did not report this information). The average follow-up ranged from 1 to 24 years, and 14 studies reported a mean or median follow-up of 10 years or more. Selection of the control population differed between studies, with 8 studies selecting control participants from population-based studies, 11 from the general population, 14 from siblings and other volunteers, and 19 from other sources. Twenty-seven studies used several characteristics to match the control and donor populations, and 17 excluded control participants with 2 or more contraindications for nephrectomy. Of these, only 5 selected the control population on the basis of completion of living donor screening or eligibility for nephrectomy based on medical status and renal function tests (Supplement Table 2). Twenty-eight studies were judged to have an NOS score of at least 4 (Supplement Table 3) and had a baseline recruitment period ending in or after 2000. Figure 1. Evidence search and selection. Appendix Table. Summary of 52 Included Unique Prospective Studies on Outcomes of Living Kidney Donation* Association With Disease Traits Twenty-six studies reported associations with disease traits, of which 17 reported information on blood pressure, 6 on metabolic markers, and 17 on markers of renal function (Appendix Table). In the primary analysis (up to 8 studies, 1040 donors, and 1032 control participants), living kidney donors had higher mean diastolic blood pressure (SMD, 0.17 [95% CI, 0.03 to 0.34]) and lower levels of high-density lipoprotein cholesterol than control participants (SMD, 0.29 [CI, 0.52 to 0.11]). Donors also had poorer renal function than control participants, with a lower mean estimated glomerular filtration rate (SMD, 1.59 [CI, 1.86 to 0.33]) and higher mean level of serum creatinine (SMD, 1.0