Joseph Beyene

Prediction of Long-Term Prognosis in 12 169 Men Referred for Cardiac Rehabilitation

Background—Predicting the risk of cardiac and all-cause death in patients with established coronary heart disease is important in counseling the individual and designing risk-stratified rehabilitation and secondary prevention programs. Cox proportional hazards and Kaplan-Meier survival curves were thus completed on initial assessment data obtained from patients referred to an outpatient cardiac rehabilitation center. Methods and Results—A single-center prospective observational design took peak cardiorespiratory exercise test data for 12 169 male rehabilitation candidates aged 55.0±9.6 years (7096 myocardial infarctions [MIs], 3077 coronary artery bypass grafts [CABGs], and 1996 documented cases of ischemic heart disease [IHD]). A follow-up of 4 to 29 years (median, 7.9) yielded 107 698 man-years of experience. Entry data were tested for associations with time to cardiac and all-cause death. We recorded 1336 cardiac deaths (953 MI, 225 CABG, and 158 IHD) and 2352 all-cause deaths. A powerful predictor of cardiac and all-cause mortality was measured peak oxygen intake (&OV0312;o2peak). For the overall sample, values of <15, 15 to 22, and >22 mL/kg per minute yielded respective multivariate adjusted hazard ratios of 1.00, 0.62, and 0.39 for cardiac and 1.00, 0.66, and 0.45 for all-cause deaths. For the separate diagnostic categories, apart from &OV0312;o2peak, the only other significant predictors of cardiac death common to all 3 were smoking and digoxin, and for all-cause death, age, smoking, digoxin, and diabetes. Conclusions—Exercise capacity, as determined by direct measurement of &OV0312;o2peak, exerts a major long-term influence on prognosis in men after MI, CABG, or IHD and can play a valuable role in risk stratification and counseling.

Overweight and obesity in mothers and risk of preterm birth and low birth weight infants: systematic review and meta-analyses

Objective To determine the relation between overweight and obesity in mothers and preterm birth and low birth weight in singleton pregnancies in developed and developing countries. Design Systematic review and meta-analyses. Data sources Medline and Embase from their inceptions, and reference lists of identified articles. Study selection Studies including a reference group of women with normal body mass index that assessed the effect of overweight and obesity on two primary outcomes: preterm birth (before 37 weeks) and low birth weight (<2500 g). Data extraction Two assessors independently reviewed titles, abstracts, and full articles, extracted data using a piloted data collection form, and assessed quality. Data synthesis 84 studies (64 cohort and 20 case-control) were included, totalling 1 095 834 women. Although the overall risk of preterm birth was similar in overweight and obese women and women of normal weight, the risk of induced preterm birth was increased in overweight and obese women (relative risk 1.30, 95% confidence interval 1.23 to 1.37). Although overall the risk of having an infant of low birth weight was decreased in overweight and obese women (0.84, 0.75 to 0.95), the decrease was greater in developing countries than in developed countries (0.58, 0.47 to 0.71 v 0.90, 0.79 to 1.01). After accounting for publication bias, the apparent protective effect of overweight and obesity on low birth weight disappeared with the addition of imputed “missing” studies (0.95, 0.85 to 1.07), whereas the risk of preterm birth appeared significantly higher in overweight and obese women (1.24, 1.13 to 1.37). Conclusions Overweight and obese women have increased risks of preterm birth and induced preterm birth and, after accounting for publication bias, appeared to have increased risks of preterm birth overall. The beneficial effects of maternal overweight and obesity on low birth weight were greater in developing countries and disappeared after accounting for publication bias.

Intake of saturated and trans unsaturated fatty acids and risk of all cause mortality, cardiovascular disease, and type 2 diabetes: systematic review and meta-analysis of observational studies

Objective To systematically review associations between intake of saturated fat and trans unsaturated fat and all cause mortality, cardiovascular disease (CVD) and associated mortality, coronary heart disease (CHD) and associated mortality, ischemic stroke, and type 2 diabetes. Design Systematic review and meta-analysis. Data sources Medline, Embase, Cochrane Central Registry of Controlled Trials, Evidence-Based Medicine Reviews, and CINAHL from inception to 1 May 2015, supplemented by bibliographies of retrieved articles and previous reviews. Eligibility criteria for selecting studies Observational studies reporting associations of saturated fat and/or trans unsaturated fat (total, industrially manufactured, or from ruminant animals) with all cause mortality, CHD/CVD mortality, total CHD, ischemic stroke, or type 2 diabetes. Data extraction and synthesis Two reviewers independently extracted data and assessed study risks of bias. Multivariable relative risks were pooled. Heterogeneity was assessed and quantified. Potential publication bias was assessed and subgroup analyses were undertaken. The GRADE approach was used to evaluate quality of evidence and certainty of conclusions. Results For saturated fat, three to 12 prospective cohort studies for each association were pooled (five to 17 comparisons with 90 501-339 090 participants). Saturated fat intake was not associated with all cause mortality (relative risk 0.99, 95% confidence interval 0.91 to 1.09), CVD mortality (0.97, 0.84 to 1.12), total CHD (1.06, 0.95 to 1.17), ischemic stroke (1.02, 0.90 to 1.15), or type 2 diabetes (0.95, 0.88 to 1.03). There was no convincing lack of association between saturated fat and CHD mortality (1.15, 0.97 to 1.36; P=0.10). For trans fats, one to six prospective cohort studies for each association were pooled (two to seven comparisons with 12 942-230 135 participants). Total trans fat intake was associated with all cause mortality (1.34, 1.16 to 1.56), CHD mortality (1.28, 1.09 to 1.50), and total CHD (1.21, 1.10 to 1.33) but not ischemic stroke (1.07, 0.88 to 1.28) or type 2 diabetes (1.10, 0.95 to 1.27). Industrial, but not ruminant, trans fats were associated with CHD mortality (1.18 (1.04 to 1.33) v 1.01 (0.71 to 1.43)) and CHD (1.42 (1.05 to 1.92) v 0.93 (0.73 to 1.18)). Ruminant trans-palmitoleic acid was inversely associated with type 2 diabetes (0.58, 0.46 to 0.74). The certainty of associations between saturated fat and all outcomes was “very low.” The certainty of associations of trans fat with CHD outcomes was “moderate” and “very low” to “low” for other associations. Conclusions Saturated fats are not associated with all cause mortality, CVD, CHD, ischemic stroke, or type 2 diabetes, but the evidence is heterogeneous with methodological limitations. Trans fats are associated with all cause mortality, total CHD, and CHD mortality, probably because of higher levels of intake of industrial trans fats than ruminant trans fats. Dietary guidelines must carefully consider the health effects of recommendations for alternative macronutrients to replace trans fats and saturated fats.

Preterm birth and low birth weight among in vitro fertilization singletons: A systematic review and meta-analyses

Our objective was to determine the risks of preterm birth (PTB) and low birth weight (LBW) in singletons conceived through in vitro fertilization (IVF)+/-intracytoplasmic sperm injection (ICSI) compared to spontaneously conceived singletons after matching or controlling for at least maternal age. The MOOSE guidelines for meta-analysis of observational studies were followed. Medline and Embase were searched using comprehensive search strategies. Bibliographies of identified articles were reviewed. English language studies examining LBW or PTB in singletons conceived by IVF or IVF/intracytoplasmic sperm injection, compared with spontaneously conceived singletons, that matched or controlled for at least maternal age. Two reviewers independently assessed titles, abstracts, full articles and study quality and extracted data. Dichotomous data were meta-analyzed using relative risks (RR) as measures of effect size with a random effects model and for continuous data weighted mean difference was calculated. Seventeen studies were included with 31,032 singletons conceived through IVF (+/-ICSI) and 81,119 spontaneously conceived singletons. After matching or controlling for maternal age and often other factors, compared to spontaneously conceived singletons, IVF singletons had increased risks of our two primary outcomes, PTB (RR 1.84, 95% CI 1.54, 2.21) and LBW (<2500 g, RR 1.60, 95% CI 1.29, 1.98). Singletons conceived through IVF or IVF/ICSI were at increased risk for late PTB (32-36 weeks, RR 1.52, 95% CI 1.01, 2.30), moderate PTB <32-33 weeks (RR 2.27, 95% CI 1.73, 2.97), very LBW (<1500 g, RR 2.65, 95% CI 1.83, 3.84), and intrauterine growth restriction (RR 1.45, 95% CI 1.04, 2.00), lower birth weights (-97 g, 95% CI -161 g, -33 g) and shorter mean gestations (-0.6 weeks, 95% CI -0.9 weeks, -0.4 weeks). In conclusion, IVF singletons have significantly increased risks of PTB, LBW and other adverse perinatal outcomes compared to spontaneously conceived singletons after matching or controlling for maternal age at least.

Inclusion of zero total event trials in meta-analyses maintains analytic consistency and incorporates all available data

BackgroundMeta-analysis handles randomized trials with no outcome events in both treatment and control arms inconsistently, including them when risk difference (RD) is the effect measure but excluding them when relative risk (RR) or odds ratio (OR) are used. This study examined the influence of such trials on pooled treatment effects.MethodsAnalysis with and without zero total event trials of three illustrative published meta-analyses with a range of proportions of zero total event trials, treatment effects, and heterogeneity using inverse variance weighting and random effects that incorporates between-study heterogeneity.ResultsIncluding zero total event trials in meta-analyses moves the pooled estimate of treatment effect closer to nil, decreases its confidence interval and decreases between-study heterogeneity. For RR and OR, inclusion of such trials causes small changes, even when they comprise the large majority of included trials. For RD, the changes are more substantial, and in extreme cases can eliminate a statistically significant effect estimate.ConclusionTo include all relevant data regardless of effect measure chosen, reviewers should also include zero total event trials when calculating pooled estimates using OR and RR.

Phase 3 trials of stereotactic radiosurgery with or without whole-brain radiation therapy for 1 to 4 brain metastases: individual patient data meta-analysis.

PURPOSE To perform an individual patient data (IPD) meta-analysis of randomized controlled trials evaluating stereotactic radiosurgery (SRS) with or without whole-brain radiation therapy (WBRT) for patients presenting with 1 to 4 brain metastases. METHOD AND MATERIALS Three trials were identified through a literature search, and IPD were obtained. Outcomes of interest were survival, local failure, and distant brain failure. The treatment effect was estimated after adjustments for age, recursive partitioning analysis (RPA) score, number of brain metastases, and treatment arm. RESULTS A total of 364 of the pooled 389 patients met eligibility criteria, of whom 51% were treated with SRS alone and 49% were treated with SRS plus WBRT. For survival, age was a significant effect modifier (P=.04) favoring SRS alone in patients ≤50 years of age, and no significant differences were observed in older patients. Hazard ratios (HRs) for patients 35, 40, 45, and 50 years of age were 0.46 (95% confidence interval [CI] = 0.24-0.90), 0.52 (95% CI = 0.29-0.92), 0.58 (95% CI = 0.35-0.95), and 0.64 (95% CI = 0.42-0.99), respectively. Patients with a single metastasis had significantly better survival than those who had 2 to 4 metastases. For distant brain failure, age was a significant effect modifier (P=.043), with similar rates in the 2 arms for patients ≤50 of age; otherwise, the risk was reduced with WBRT for patients >50 years of age. Patients with a single metastasis also had a significantly lower risk of distant brain failure than patients who had 2 to 4 metastases. Local control significantly favored additional WBRT in all age groups. CONCLUSIONS For patients ≤50 years of age, SRS alone favored survival, in addition, the initial omission of WBRT did not impact distant brain relapse rates. SRS alone may be the preferred treatment for this age group.

Sparse canonical correlation analysis with application to genomic data integration.

Large scale genomic studies with multiple phenotypic or genotypic measures may require the identification of complex multivariate relationships. In multivariate analysis a common way to inspect the relationship between two sets of variables based on their correlation is canonical correlation analysis, which determines linear combinations of all variables of each type with maximal correlation between the two linear combinations. However, in high dimensional data analysis, when the number of variables under consideration exceeds tens of thousands, linear combinations of the entire sets of features may lack biological plausibility and interpretability. In addition, insufficient sample size may lead to computational problems, inaccurate estimates of parameters and non-generalizable results. These problems may be solved by selecting sparse subsets of variables, i.e. obtaining sparse loadings in the linear combinations of variables of each type. In this paper we present Sparse Canonical Correlation Analysis (SCCA) which examines the relationships between two types of variables and provides sparse solutions that include only small subsets of variables of each type by maximizing the correlation between the subsets of variables of different types while performing variable selection. We also present an extension of SCCA - adaptive SCCA. We evaluate their properties using simulated data and illustrate practical use by applying both methods to the study of natural variation in human gene expression.

Maternal underweight and the risk of preterm birth and low birth weight: a systematic review and meta-analyses

BACKGROUND Despite the current obesity epidemic, maternal underweight remains a common occurrence with potential adverse perinatal outcomes. Our objective was to determine the relationship between maternal underweight and preterm birth (PTB) and low birth weight (LBW) in singleton pregnancies in developing and developed countries. METHODS We followed the MOOSE consensus statement. We searched MEDLINE and EMBASE from their inceptions. We included studies that assessed the effect of maternal underweight compared with normal weight according to body mass index in singleton gestations on our two primary outcomes: PTB (<37 weeks) and LBW (<2500 g). Two assessors independently reviewed citations, extracted data and assessed quality. RESULTS A total of 78 studies were included involving 1 025 794 women. The overall risk of PTB was increased in the cohort studies of underweight women [adjusted relative risk (RR) 1.29, 95% confidence interval (CI) 1.15-1.46], as were the risks of spontaneous PTB (adjusted RR 1.32, 95% CI 1.10-1.57) and induced PTB (adjusted RR 1.21, 95% CI 1.07-1.36). Underweight women had an increased risk of an LBW infant (adjusted RR 1.64, 95% CI 1.38-1.94). In developed countries, underweight women had an increased risk of PTB (RR 1.22, 95% CI 1.15-1.30) but not in developing countries (RR 0.99, 95% CI 0.67-1.45). In both developed and developing countries, underweight women were at increased risk of having an LBW infant (RR 1.48, 95% CI 1.29-1.68, and RR 1.52, 95% CI 1.25-1.85, respectively). CONCLUSIONS In this systematic review and meta-analyses, we determined that singletons born to underweight women have higher risks of PTB (overall, spontaneous and induced) and LBW than those born to women with normal weight.

Intention to Become Pregnant and Low Birth Weight and Preterm Birth: A Systematic Review

Increased stress, psychosocial problems, economic disadvantages, and lack of prenatal care are proposed to explain discrepancies in the outcome of unintended pregnancies. Studies of maternal intention and pregnancy outcomes have yielded varied results. Objective is to review studies of the risk of low birth weight (LBW)/preterm births (PTB) associated with unintended pregnancies ending in a live birth. We reviewed studies reporting on maternal intentions and outcomes from Medline, Embase, CINAHL, and bibliographies of identified articles. An unintended pregnancy was further classified as mistimed (not intended at that time) or unwanted (not desired at any time). Studies reporting an association between pregnancy intention and any of the outcomes were included. Study quality was assessed for biases in selection, exposure assessment, confounder adjustment, analyses, outcomes assessment, and attrition. Unadjusted and adjusted data from included studies were extracted by two reviewers. There were significantly increased odds of LBW among unintended pregnancies [odds ratio (OR) 1.36, 95% confidence interval (CI) 1.25, 1.48] ending in a live birth. Within the unintended category, mistimed (OR 1.31, 95% CI 1.13, 1.52) and unwanted (OR 1.51, 95% CI 1.29, 1.78) pregnancies were associated with LBW. There were statistically significantly increased odds of PTB among unintended (OR 1.31, 95% CI 1.09, 1.58), and unwanted (OR 1.50, 95% CI 1.41, 1.61) but not for mistimed (OR 1.36, 95% CI 0.96, 1.93) pregnancies. Unintended, unwanted, and mistimed pregnancies ending in a live birth are associated with a significantly increased risk of LBW and PTB.

Perinatal Outcomes of Singleton Pregnancies Achieved by In Vitro Fertilization: A Systematic Review and Meta-Analysis

Abstract Objective : To determine whether the incidence of adverse obstetric outcomes is higher in singleton pregnancies achieved by in vitro fertilization (IVF) than in spontaneously conceived singletons matched for maternal age. Methods : We used comprehensive search strategies to search MEDLINE and EMBASE databases. We selected case-control and cohort studies that compared singleton pregnancies conceived by IVF or intracytoplasmic sperm injection (ICSI) with spontaneously conceived singletons (matched for maternal age [case-control studies] or controlled for maternal age [cohort studies]). Two reviewers independently assessed titles, abstracts, and study quality and extracted data. Statistical analysis was performed with Review Manager for Windows (Version 4.2, Oxford, UK). We performed meta-analysis of dichotomous data, using odds ratios (ORs) as measures of effect size, with a random effects model. We followed the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines for meta-analysis of observational studies. Results : Singleton pregnancies resulting from IVF have increased rates of poor obstetric outcome, compared with spontaneously conceived singletons matched for maternal age, with increases in perinatal mortality (OR 2.40; 95% confidence interval [CI] 1.59-3.63), preterm birth at Conclusions : IVF singleton pregnancies have increased rates of poor obstetric outcome, compared with spontaneously conceived singletons matched for maternal age.