Adiposity as a cause of cardiovascular disease: a Mendelian randomization study

Background: Adiposity, as indicated by body mass index (BMI), has been associated with risk of cardiovascular diseases in epidemiological studies. We aimed to investigate if these associations are causal, using Mendelian randomization (MR) methods.

Methods: The associations of BMI with cardiovascular outcomes [coronary heart disease (CHD), heart failure and ischaemic stroke], and associations of a genetic score (32 BMI single nucleotide polymorphisms) with BMI and cardiovascular outcomes were examined in up to 22 193 individuals with 3062 incident cardiovascular events from nine prospective follow-up studies within the ENGAGE consortium. We used random-effects meta-analysis in an MR framework to provide causal estimates of the effect of adiposity on cardiovascular outcomes.

Results: There was a strong association between BMI and incident CHD (HR = 1.20 per SD-increase of BMI, 95% CI, 1.12–1.28, P = 1.9·10−7), heart failure (HR = 1.47, 95% CI, 1.35–1.60, P = 9·10−19) and ischaemic stroke (HR = 1.15, 95% CI, 1.06–1.24, P = 0.0008) in observational analyses. The genetic score was robustly associated with BMI (β = 0.030 SD-increase of BMI per additional allele, 95% CI, 0.028–0.033, P = 3·10−107). Analyses indicated a causal effect of adiposity on development of heart failure (HR = 1.93 per SD-increase of BMI, 95% CI, 1.12–3.30, P = 0.017) and ischaemic stroke (HR = 1.83, 95% CI, 1.05–3.20, P = 0.034). Additional cross-sectional analyses using both ENGAGE and CARDIoGRAMplusC4D data showed a causal effect of adiposity on CHD.

Conclusions: Using MR methods, we provide support for the hypothesis that adiposity causes CHD, heart failure and, previously not demonstrated, ischaemic stroke.

A HuGE Review and Meta-Analyses of Genetic Associations in New Onset Diabetes after Kidney Transplantation

PURPOSE: New onset diabetes after transplantation (NODAT) is a serious complication following solid organ transplantation. There is a genetic contribution to NODAT and we have conducted comprehensive meta-analysis of available genetic data in kidney transplant populations.

METHODS: Relevant articles investigating the association between genetic markers and NODAT were identified by searching PubMed, Web of Science and Google Scholar. SNPs described in a minimum of three studies were included for analysis using a random effects model. The association between identified variants and NODAT was calculated at the per-study level to generate overall significance values and effect sizes.

RESULTS: Searching the literature returned 4,147 citations. Within the 36 eligible articles identified, 18 genetic variants from 12 genes were considered for analysis. Of these, three were significantly associated with NODAT by meta-analysis at the 5% level of significance; CDKAL1 rs10946398 p = 0.006 OR = 1.43, 95% CI = 1.11-1.85 (n = 696 individuals), KCNQ1 rs2237892 p = 0.007 OR = 1.43, 95% CI = 1.10-1.86 (n = 1,270 individuals), and TCF7L2 rs7903146 p = 0.01 OR = 1.41, 95% CI = 1.07-1.85 (n = 2,967 individuals).

CONCLUSION: Evaluating cumulative evidence for SNPs associated with NODAT in kidney transplant recipients has revealed three SNPs associated with NODAT. An adequately powered, dense genome-wide association study will provide more information using a carefully defined NODAT phenotype.

Illness perceptions and coping in physical health conditions: A meta-analysis

Objective: There is a considerable body of research linking elements of Leventhal’s Common Sense Model (CSM) to emotional well-being/distress outcomes among people with physical illness. The present study aims to consolidate this literature and examine the evidence for the role of coping strategies within this literature.
Methods: A systematic review was conducted where the outcomes of interest were: depression, anxiety and quality of life. A total of 1050 articles were identified and 31 articles were considered eligible to be included in the review.
Results: Across a range of illnesses, perceptions of consequences of the illness and emotional representations were consistently the illness perceptions with the strongest relationship with the outcomes. Coping variables tend to be stronger predictors of outcomes than the illness perception variables. The evidence for the mediating effect of coping was inconsistent.
Conclusions: Illness perceptions and coping have an important role to play in the explanation of distress outcomes across a range of physical health conditions. However, some clarity about the theoretical position of coping in relation to illness perceptions, and further longitudinal work is needed if we are to apply this information to the design of interventions for the improvement of psychological health among people with physical health conditions.

Abdominal Aortic Aneurysm Genetic Associations: Mostly False? A Systematic Review and Meta-analysis

OBJECTIVE/BACKGROUND: Many associations between abdominal aortic aneurysm (AAA) and genetic polymorphisms have been reported. It is unclear which are genuine and which may be caused by type 1 errors, biases, and flexible study design. The objectives of the study were to identify associations supported by current evidence and to investigate the effect of study design on reporting associations.

METHODS: Data sources were MEDLINE, Embase, and Web of Science. Reports were dual-reviewed for relevance and inclusion against predefined criteria (studies of genetic polymorphisms and AAA risk). Study characteristics and data were extracted using an agreed tool and reports assessed for quality. Heterogeneity was assessed using I(2) and fixed- and random-effects meta-analyses were conducted for variants that were reported at least twice, if any had reported an association. Strength of evidence was assessed using a standard guideline.

RESULTS: Searches identified 467 unique articles, of which 97 were included. Of 97 studies, 63 reported at least one association. Of 92 studies that conducted multiple tests, only 27% corrected their analyses. In total, 263 genes were investigated, and associations were reported in polymorphisms in 87 genes. Associations in CDKN2BAS, SORT1, LRP1, IL6R, MMP3, AGTR1, ACE, and APOA1 were supported by meta-analyses.

CONCLUSION: Uncorrected multiple testing and flexible study design (particularly testing many inheritance models and subgroups, and failure to check for Hardy-Weinberg equilibrium) contributed to apparently false associations being reported. Heterogeneity, possibly due to the case mix, geographical, temporal, and environmental variation between different studies, was evident. Polymorphisms in nine genes had strong or moderate support on the basis of the literature at this time. Suggestions are made for improving AAA genetics study design and conduct.

Markers of vitamin D exposure and oesophageal cancer risk: a systematic review and meta-analysis.

Vitamin D has been associated with reduced risk of many cancers, but evidence for oesophageal cancer is mixed. To clarify the role of Vitamin D, we performed a systematic review and meta-analysis to evaluate the association of Vitamin D exposures and oesophageal neoplasia, including adenocarcinoma, squamous cell carcinoma (SCC), Barrett's oesophagus and squamous dysplasia. Ovid MEDLINE, EMBASE and Web of Science were searched from inception to September 2015. Fifteen publications in relation to circulating 25-hydroxyvitamin D (n=3), Vitamin D intake (n=4), UVB exposure (n=1), and genetic factors (n=7) were retrieved. Higher 25-OHD was associated with increased risk of cancer (adenocarcinoma or SCC, OR=1.39;95%CI:1.04-1.74), with the majority of participants coming from China. No association was observed between Vitamin D intake and risk of cancer overall (OR=1.03;0.65-1.42); however, a non-significantly increased risk for adenocarcinoma (OR=1.45;0.65-2.24) and non-significantly decreased risk for SCC (OR=0.80;0.48-1.12) were observed. One study reported a decreased risk of adenocarcinoma with higher UVB exposure. A decreased risk was found for VDR haplotype rs2238135(G)/rs1989969(T) carriers, OR=0.45;0.00-0.91, and a suggestive association was observed for rs2107301. No consistent associations were observed between Vitamin D exposures and occurrence of oesophageal lesions. Further adequately powered, well-designed studies are needed before conclusions can be made.

The effect of statins on intraocular pressure and on the incidence and progression of glaucoma: A Systematic Review and Meta-analysis

Purpose: We conducted a systematic review and meta-analysis of observational studies to evaluate the effect of oral statins on intraocular pressure (IOP) and the incidence and progression of glaucoma. Methods: This was a systematic review of the literature and meta-analysis. Searches of PubMed/Medline and Embase were conducted to include all types of studies. Gray literature abstracts were also considered for inclusion. Last search date was February 2016. Risk of bias was assessed using the Newcastle-Ottawa scale independently by two reviewers. Odds ratios (OR) or hazard ratios (HR) and 95% confidence intervals (CI) were extracted from each study. Pooled ORs for incidence of glaucoma were calculated using a random-effects model. Results: We identified seven cohort studies, three case–control studies, and one cross-sectional study with a total number of 583,615 participants. No randomized controlled trials were retrieved. Pooled ORs demonstrated a statistically significant association between short-term statin use (≤2 years) and reduced incidence of glaucoma (OR 0.96, 95%CI 0.94, 0.99). Pooled ORs of long-term statin use (>2 years) did not demonstrate statistically significant reduction in incidence of glaucoma (OR 0.70, 95%CI 0.46, 1.06). There was inconsistent evidence for the protective effect of statins against the progression of glaucoma, although there was no standard definition for progression across studies. There was no significant difference in IOP associated with statin use. Conclusions: Short-term statin use is associated with a reduced incidence of glaucoma. The effect of statins on glaucoma progression and IOP is uncertain.

Increased physical activity and fitness above the 50th percentile prevents the institutionalization of elderly people: a cross-sectional pilot study.

Introduction Institutionalization in a nursing home restricts autonomy, most notably free will, free choice, and free action. Decreased physical activity and fitness are predictive of disability and dependence (Rikli & Jones, 2013; Tak, Kuiper, Chorus, & Hopman-Rock, 2014); however little is known about the impact of these factors on institutionalization. Thus, this study aimed to analyze the impact of physical activity and fitness and on the risk of elderly people without cognitive impairment become institutionalized. Methods This cross-sectional study involved 195 non-institutionalized (80.14.4yrs) and 186 institutionalized (83.85.2yrs) participants. Cognitive impairment was assessed using Mini-Mental State Examination, physical activity was assessed using the International Physical Activity Questionnaire, and measures of physical fitness were determined by the Senior Fitness Test. Results: Multivariate binary logistic analysis selected 4 main predictors of institutionalization in both genders. The likelihood of becoming institutionalized increased by +18.6% for each additional year of age, while it decreased by -24.8% by each fewer kg/m2 in BMI, by -0.9% for each additional meter performed in the aerobic endurance test and by -2.0% for each additional 100MET-min/wk of physical activity expenditure (p<0.05). Values ≤50th percentile (age ≥81yrs, BMI≥26.7kg/m2, aerobic endurance ≤367.6m, and physical activity ≤693MET-min/wk) were computed using Receiver Operating Characteristics analysis as cut-offs discriminating institutionalized from non-institutionalized elderly people. Conclusion The performance of physical activity, allied to an improvement in physical fitness (mainly BMI and aerobic endurance) may prevent the institutionalization of elderly people without cognitive impairment only if they are above the 50th percentile; the following is highly recommend: expending ≥693MET-min/wk on physical activity, being ≤26.7kg/m2 on BMI, and being able to walk ≥367.6m in the aerobic endurance test, especially above the age of 80 years. The discovery of this trigger justifies the development of physical activity programs targeting the pointed cut-offs in old, and very old people. References Rikli, R., & Jones, C. (2013). Development and validation of criterion-referenced clinically relevant fitness standards for maintaining physical independence in later years. Gerontologist, 53, 255-267. Tak, E., Kuiper, R., Chorus, A., & Hopman-Rock, M. (2014). Prevention of onset and progression of basic ADL disability by physical activity in community dwelling older adults: a meta-analysis. Ageing Res Rev, 12, 329-338.

Genome-wide Association Study Identifies SESTD1 as a Novel Risk Gene for Lithium Responsive Bipolar Disorder

Lithium is the mainstay prophylactic treatment for bipolar disorder (BD), but treatment response varies considerably across individuals. Patients who respond well to lithium treatment might represent a relatively homogeneous subtype of this genetically and phenotypically diverse disorder. Here, we performed genome-wide association studies (GWAS) to identify (i) specific genetic variations influencing lithium response and (ii) genetic variants associated with risk for lithium-responsive BD. Patients with BD and controls were recruited from Sweden and the United Kingdom. GWAS were performed on 2698 patients with subjectively defined (self-reported) lithium response and 1176 patients with objectively defined (clinically documented) lithium response. We next conducted GWAS comparing lithium responders with healthy controls (1639 subjective responders and 8899 controls; 323 objective responders and 6684 controls). Meta-analyses of Swedish and UK results revealed no significant associations with lithium response within the bipolar subjects. However, when comparing lithium-responsive patients with controls, two imputed markers attained genome-wide significant associations, among which one was validated in confirmatory genotyping (rs116323614, P=2.74 × 10-8). It is an intronic single-nucleotide polymorphism (SNP) on chromosome 2q31.2 in the gene SEC14 and spectrin domains 1 (SESTD1), which encodes a protein involved in regulation of phospholipids. Phospholipids have been strongly implicated as lithium treatment targets. Furthermore, we estimated the proportion of variance for lithium-responsive BD explained by common variants ('SNP heritability') as 0.25 and 0.29 using two definitions of lithium response. Our results revealed a genetic variant in SESTD1 associated with risk for lithium-responsive BD, suggesting that the understanding of BD etiology could be furthered by focusing on this subtype of BD.

New methods for meta-analysis under a fixed effects framework, with frequentist and Bayesian estimation.

Thesis (Ph.D.)--University of Washington, 2015

Multi-apprentice learning for meta-heuristics parameter tuning in a multi agent scheduling system

The scheduling problem is considered in complexity theory as a NP-hard combinatorial optimization problem. Meta-heuristics proved to be very useful in the resolution of this class of problems. However, these techniques require parameter tuning which is a very hard task to perform. A Case-based Reasoning module is proposed in order to solve the parameter tuning problem in a Multi-Agent Scheduling System. A computational study is performed in order to evaluate the proposed CBR module performance.

Is mental practice an effective adjunct therapeutic strategy for upper limb motor restoration after stroke? A systematic review and meta- analysis

Stroke is one of the most common conditions requiring rehabilitation, and its motor impairments are a major cause of permanent disability. Hemiparesis is observed by 80% of the patients after acute stroke. Neuroimaging studies showed that real and imagined movements have similarities regarding brain activation, supplying evidence that those similarities are based on the same process. Within this context, the combination of mental practice (MP) with physical and occupational therapy appears to be a natural complement based on neurorehabilitation concepts. Our study seeks to investigate if MP for stroke rehabilitation of upper limbs is an effective adjunct therapy. PubMed (Medline), ISI knowledge (Institute for Scientific Information) and SciELO (Scientific Electronic Library) were terminated on 20 February 2015. Data were collected on variables as follows: sample size, type of supervision, configuration of mental practice, setting the physical practice (intensity, number of sets and repetitions, duration of contractions, rest interval between sets, weekly and total duration), measures of sensorimotor deficits used in the main studies and significant results. Random effects models were used that take into account the variance within and between studies. Seven articles were selected. As there was no statistically significant difference between the two groups (MP vs control), showed a - 0.6 (95% CI: -1.27 to 0.04), for upper limb motor restoration after stroke. The present meta-analysis concluded that MP is not effective as adjunct therapeutic strategy for upper limb motor restoration after stroke.

From Mind to Body: Is Mental Practice Effective on Strength Gains? A Meta-Analysis

Mental practice is an internal reproduction of a motor act (whose intention is to promote learning and improving motor skills). Some studies have shown that other cognitive strategies also increase the strength and muscular resistance in healthy people by the enhancement of the performance during dynamic tasks. Mental training sessions may be primordial to improving muscle strength in different subjects. The aim of this study was to systematically review and meta-analiyze studies that assessed whether mental practice is effective in improving muscular strength. We conducted an electronic-computed search in Pub-Med/Medline and ISI Web of Knowledge, Scielo and manual searchs, searching papers written in English between 1991 and 2014. There were 44 studies in Pub-Med/Medline, 631 in ISI Web of Knowledge, 11 in Scielo and 3 in manual searchs databases. After exclusion of studies for duplicate, unrelated to the topic by title and summary, different samples and methodologies, a meta-analysis of 4 studies was carried out to identify the dose-response relationship. We did not find evidence that mental practice is effective in increasing strength in healthy individuals. There is no evidence that mental practice alone can be effective to induce strength gains or to optimize the training effects.

Quality control and conduct of genome-wide association meta-analyses.

Rigorous organization and quality control (QC) are necessary to facilitate successful genome-wide association meta-analyses (GWAMAs) of statistics aggregated across multiple genome-wide association studies. This protocol provides guidelines for (i) organizational aspects of GWAMAs, and for (ii) QC at the study file level, the meta-level across studies and the meta-analysis output level. Real-world examples highlight issues experienced and solutions developed by the GIANT Consortium that has conducted meta-analyses including data from 125 studies comprising more than 330,000 individuals. We provide a general protocol for conducting GWAMAs and carrying out QC to minimize errors and to guarantee maximum use of the data. We also include details for the use of a powerful and flexible software package called EasyQC. Precise timings will be greatly influenced by consortium size. For consortia of comparable size to the GIANT Consortium, this protocol takes a minimum of about 10 months to complete.

PFO closure vs. medical therapy in cryptogenic stroke or transient ischemic attack: A systematic review and meta-analysis.

BACKGROUND/OBJECTIVES: This study aims to assess whether patent foramen ovale (PFO) closure is superior to medical therapy in preventing recurrence of cryptogenic ischemic stroke or transient ischemic attack (TIA). METHODS: We searched PubMed for randomized trials which compared PFO closure with medical therapy in cryptogenic stroke/TIA using the items: "stroke or cerebrovascular accident or TIA" and "patent foramen ovale or paradoxical embolism" and "trial or study". RESULTS: Among 650 potentially eligible articles, 3 were included including 2303 patients. There was no statistically significant difference between PFO-closure and medical therapy in ischemic stroke recurrence (1.91% vs. 2.94% respectively, OR: 0.64, 95%CI: 0.37-1.10), TIA (2.08% vs. 2.42% respectively, OR: 0.87, 95%CI: 0.50-1.51) and death (0.60% vs. 0.86% respectively, OR: 0.71, 95%CI: 0.28-1.82). In subgroup analysis, there was significant reduction of ischemic strokes in the AMPLATZER PFO Occluder arm vs. medical therapy (1.4% vs. 3.04% respectively, OR: 0.46, 95%CI: 0.21-0.98, relative-risk-reduction: 53.2%, absolute-risk-reduction: 1.6%, number-needed-to-treat: 61.8) but not in the STARFlex device (2.7% vs. 2.8% with medical therapy, OR: 0.93, 95%CI: 0.45-2.11). Compared to medical therapy, the number of patients with new-onset atrial fibrillation (AF) was similar in the AMPLATZER PFO Occluder arm (0.72% vs. 1.28% respectively, OR: 1.81, 95%CI: 0.60-5.42) but higher in the STARFlex device (0.64% vs. 5.14% respectively, OR: 8.30, 95%CI: 2.47-27.84). CONCLUSIONS: This meta-analysis does not support PFO closure for secondary prevention with unselected devices in cryptogenic stroke/TIA. In subgroup analysis, selected closure devices may be superior to medical therapy without increasing the risk of new-onset AF, however. This observation should be confirmed in further trials using inclusion criteria for patients with high likelihood of PFO-related stroke recurrence.

Congenital heart disease in pregnancies complicated by maternal diabetes mellitus. An international clinical collaboration, literature review, and meta-analysis.

PURPOSE: Investigation of the incidence and distribution of congenital structural cardiac malformations among the offspring of mothers with diabetes type 1 and of the influence of periconceptional glycemic control. METHODS: Multicenter retrospective clinical study, literature review, and meta-analysis. The incidence and pattern of congenital heart disease in the own study population and in the literature on the offspring of type 1 diabetic mothers were compared with the incidence and spectrum of the various cardiovascular defects in the offspring of nondiabetic mothers as registered by EUROCAT Northern Netherlands. Medical records were, in addition, reviewed for HbA(1c) during the 1st trimester. RESULTS: The distribution of congenital heart anomalies in the own diabetic study population was in accordance with the distribution encountered in the literature. This distribution differed considerably from that in the nondiabetic population. Approximately half the cardiovascular defects were conotruncal anomalies. The authors' study demonstrated a remarkable increase in the likelihood of visceral heterotaxia and variants of single ventricle among these patients. As expected, elevated HbA(1c) values during the 1st trimester were associated with offspring fetal cardiovascular defects. CONCLUSION: This study shows an increased likelihood of specific heart anomalies, namely transposition of the great arteries, persistent truncus arteriosus, visceral heterotaxia and single ventricle, among offspring of diabetic mothers. This suggests a profound teratogenic effect at a very early stage in cardiogenesis. The study emphasizes the frequency with which the offspring of diabetes-complicated pregnancies suffer from complex forms of congenital heart disease. Pregnancies with poor 1st-trimester glycemic control are more prone to the presence of fetal heart disease.