Search

The Cardiometabolic Disorders in African-Ancestry Populations (CARDINAL) study site is a well-powered, first-of-its-kind resource for developing, refining and validating methods for research into polygenic risk scores that accounts for local ancestry, to improve risk prediction in diverse populations.

Background Poor access to care and physician shortage are major barriers to hypertension control in sub-Saharan Africa. Implementation of evidence-based systems-level strategies targeted at these barriers are lacking. We conducted a study to evaluate the comparative effectiveness of provision of health insurance coverage (HIC) alone versus a nurse-led task shifting strategy for hypertension control (TASSH) plus HIC on systolic blood pressure (SBP) reduction among patients with uncontrolled hypertension in Ghana. Methods and findings Using a pragmatic cluster randomized trial, 32 community health centers within Ghana’s public healthcare system were randomly assigned to either HIC alone or TASSH + HIC. A total of 757 patients with uncontrolled hypertension were recruited between November 28, 2012, and June 11, 2014, and followed up to October 7, 2016. Both intervention groups received health insurance coverage plus scheduled nurse visits, while TASSH + HIC comprised cardiovascular risk assessment, lifestyle counseling, and initiation/titration of antihypertensive medications for 12 months, delivered by trained nurses within the healthcare system. The primary outcome was change in SBP from baseline to 12 months. Secondary outcomes included lifestyle behaviors and blood pressure control at 12 months and sustainability of SBP reduction at 24 months. Of the 757 patients (389 in the HIC group and 368 in the TASSH + HIC group), 85% had 12-month data available (60% women, mean BP 155.9/89.6 mm Hg). In intention-to-treat analyses adjusted for clustering, the TASSH + HIC group had a greater SBP reduction (−20.4 mm Hg; 95% CI −25.2 to −15.6) than the HIC group (−16.8 mm Hg; 95% CI −19.2 to −15.6), with a statistically significant between-group difference of −3.6 mm Hg (95% CI −6.1 to −0.5; p = 0.021). Blood pressure control improved significantly in both groups (55.2%, 95% CI 50.0% to 60.3%, for the TASSH + HIC group versus 49.9%, 95% CI 44.9% to 54.9%, for the HIC group), with a non-significant between-group difference of 5.2% (95% CI −1.8% to 12.4%; p = 0.29). Lifestyle behaviors did not change appreciably in either group. Twenty-one adverse events were reported (9 and 12 in the TASSH + HIC and HIC groups, respectively). The main study limitation is the lack of cost-effectiveness analysis to determine the additional costs and benefits, if any, of the TASSH + HIC group. Conclusions Provision of health insurance coverage plus a nurse-led task shifting strategy was associated with a greater reduction in SBP than provision of health insurance coverage alone, among patients with uncontrolled hypertension in Ghana. Future scale-up of these systems-level strategies for hypertension control in sub-Saharan Africa requires a cost–benefit analysis. Trial registration ClinicalTrials.gov NCT01802372, In a cluster randomized trial, Gbenga Ogedegbe and colleageues examine the effectiveness of a nurse-led task shifting strategy for hypertension control in Ghana, Author summary Why was this study done? The burden of cardiovascular diseases in sub-Saharan Africa (SSA) is growing due to an increased prevalence of uncontrolled hypertension. Poor access to healthcare and physician shortage are major barriers to hypertension control in SSA. Implementation of evidence-based systems-level strategies targeted at these barriers are lacking. What did the researchers do and find? In this cluster randomized controlled trial conducted among 757 patients across 32 community health centers in Ghana, we examined whether the addition of a nurse-led intervention for hypertension control to health insurance coverage led to a greater reduction in systolic blood pressure (BP) than provision of health insurance coverage alone. We found that the addition of a nurse-led intervention to provision of health insurance coverage led to a greater reduction in systolic BP (−20.4 mm Hg) than health insurance coverage alone (−16.8 mm Hg), with a net difference in reduction of 3.6 mm Hg (p = 0.021) at 12 months. What do these findings mean? The study findings provide evidence for policy makers to recommend addition of a nurse-led task shifting strategy for hypertension control to health insurance coverage for management of hypertension in SSA. Future scale-up of this nurse-led strategy in SSA would require a cost–benefit analysis and establishment of a policy that grants nurses prescribing power to treat patients with uncomplicated hypertension, similar to current policy for treatment of HIV.

CKDGen study contributions assigned to replication set for illustration of procedures controlling type I error. (DOCX 18 kb)

The role played by epistasis between alleles at unlinked loci in shaping population fitness has been debated for many years and the existing evidence has been mainly accumulated from model organisms. In model organisms, fitness epistasis can be systematically inferred by detecting nonindependence of genotypic values between loci in a population and confirmed through examining the number of offspring produced in two-locus genotype groups. No systematic study has been conducted to detect epistasis of fitness in humans owing to experimental constraints. In this study, we developed a novel method to detect fitness epistasis by testing the correlation between local ancestries on different chromosomes in an admixed population. We inferred local ancestry across the genome in 16,252 unrelated African Americans and systematically examined the pairwise correlations between the genomic regions on different chromosomes. Our analysis revealed a pair of genomic regions on chromosomes 4 and 6 that show significant local ancestry correlation (P-value = 4.01 × 10-8 ) that can be potentially attributed to fitness epistasis. However, we also observed substantial local ancestry correlation that cannot be explained by systemic ancestry inference bias. To our knowledge, this study is the first to systematically examine evidence of fitness epistasis across the human genome.

Alcohol consumption has a complex relationship with blood pressure (BP). Whereas heavy alcohol consumption is associated with high BP, moderate alcohol consumption is associated with unchanged or modestly lower BP. We performed genome-wide meta-analysis of single SNP x alcohol drinking status interaction on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) blood pressure using 1000G imputed data. Our preliminary results comprise 23 European ancestry studies, including 87,098 individuals with known drinking status. Interaction associations were preformed using linear regression with main and interaction effects and accounting for family structure as needed. Meta-analyses were performed with METAL, for a 2 degrees of freedom joint test, after applying study- and meta-based genomic control adjustments. Results were further filtered if the meta-analysis N < 5,000 individuals or if the number of cohorts contributing to meta-analysis were < 3 for each SNP. For DBP, six novel loci (TRAF3IP1, ANKRD36, NLGN1, UBE3D, OFCC1 and C1orf167) were identified (p < 5E-08). Known BP loci were found to be significant using the same interaction model, including MTHFR, CLCN6, NPPB, MECOM, NOS3, CACNB2, SH2B3, ATXN2, ALDH2, ATP2B1, CSK, FURIN and ZNF831. The significant DBP genes are enriched for hypertension (p-FDR=8.5E-08) and cardiac arrhythmias (p-FDR=5.3E-07) disease loci. MAP analyses identified similar loci as for DBP, while for SBP, ANKRD36 SNPs yielded the most significant associations. For PP, MYPN variants were most significant. In general for the joint test, known BP gene variants showed non-significant levels of meta-heterogeneity and common allele frequency (≥5%), whereas the novel loci often presented meta-heterogeneity and low allele frequency (≈1-5%). TRAF3IP1 interacts among others with TRAF3, reported in mice involved in a new pathway TRAF3-TBK1-AKT for cardiac hypertrophy and heart failure. ANKRD36 interacts with PHLPP2, involved in rats in FKBP51-PHLPP2-AKT signaling during cerebral ischemia/reperfusion injury. NLGN1 has been reported to associate with BP in ASCOT study (N=3,802), while in our meta-analysis out of 6 contributing studies, the joint test significance originates only from the GS_SFHS (N=6,504). Another significant result was C1orf167- rs12561919, a missense SNP considered cis-eQTL for neighboring BP known genes CLCN6 and MTHFR. Employing SNP x drinking status interaction for BP traits, we identified both novel and previously known BP genes. Our findings may provide insights into mechanisms underlying BP and inform lifestyle and therapeutic BP interventions.

Motivation: Adjustment for population structure is necessary to avoid bias in genetic association studies of susceptibility variants for complex diseases. Population structure may differ from one genomic region to another due to the variability of individual ancestry associated with migration, random genetic drift or natural selection. Current association methods for correcting population stratification usually involve adjustment of global ancestry between study subjects. Results: We suggest interrogating local population structure for fine mapping to more accurately locate true casual genes by better adjusting the confounding effect due to local ancestry. By extensive simulations on genome-wide datasets, we show that adjusting global ancestry may lead to false positives when local population structure is an important confounding factor. In contrast, adjusting local ancestry can effectively prevent false positives due to local population structure and thus can improve fine mapping for disease gene localization. We applied the local and global adjustments to the analysis of datasets from three genome-wide association studies, including European Americans, African Americans and Nigerians. Both European Americans and African Americans demonstrate greater variability in local ancestry than Nigerians. Adjusting local ancestry successfully eliminated the known spurious association between SNPs in the LCT gene and height due to the population structure existed in European Americans. Contact: xiaofeng.zhu@case.edu Supplementary information: Supplementary data are available at Bioinformatics online.

Gene expression profiles obtained from samples of diabetic and normal rats with and without treatments can be used to identify genes that distinguish normal and diabetic individuals and also to evaluate the effectiveness of drug treatments. This study examines changes in global gene expression in rat muscle caused by streptozotocin-induced diabetes and vanadyl sulfate treatment. We explored model-based and algorithm-based methods with gene screening measures for microarray gene expression data to classify and predict individuals with high risk of diabetes. Results show that the mixed ANOVA model-based approach provides an efficient way to conduct an investigation of the inherent variability in gene expression data and to estimate the effects of experimental factors such as treatments and diseases and their interactions. The algorithm-based weighted voting and neural network classifiers show good classification performance for the diabetes and treatment groups. Although neural network performs better than weighted voting with higher classification rate, the interpretation of weighted voting is more straightforward. The study indicates that the choice of the gene selection procedure is at least as important as the choice of the classification procedure. We conclude that both mixed model-based and algorithm-based approaches provide the statistical evidence of the biological hypotheses that vanadyl sulfate treatment of diabetic animals restores gene expression patterns to normal. Although model-based and algorithm-based methods provide different strengths and perspective for the analysis of the same set of data, in general both can be considered and developed for analyzing factorial design experiments with multiple groups and factors. This study represents a major step towards the discovery of responsible genes related to diabetes and its treatment.

Motivation: The issue of high dimensionality in microarray data has been, and remains, a hot topic in statistical and computational analysis. Efficient gene filtering and differentiation approaches can reduce the dimensions of data, help to remove redundant genes and noises, and highlight the most relevant genes that are major players in the development of certain diseases or the effect of drug treatment. The purpose of this study is to investigate the efficiency of parametric (including Bayesian and non-Bayesian, linear and non-linear), non-parametric and semi-parametric gene filtering methods through the application of time course microarray data from multiple sclerosis patients being treated with interferon-β-1a. The analysis of variance with bootstrapping (parametric), class dispersion (semi-parametric) and Pareto (non-parametric) with permutation methods are presented and compared for filtering and finding differentially expressed genes. The Bayesian linear correlated model, the Bayesian non-linear model the and non-Bayesian mixed effects model with bootstrap were also developed to characterize the differential expression patterns. Furthermore, trajectory-clustering approaches were developed in order to investigate the dynamic patterns and inter-dependency of drug treatment effects on gene expression. Results: Results show that the presented methods performed significant differently but all were adequate in capturing a small number of the potentially relevant genes to the disease. The parametric method, such as the mixed model and two Bayesian approaches proved to be more conservative. This may because these methods are based on overall variation in expression across all time points. The semi-parametric (class dispersion) and non-parametric (Pareto) methods were appropriate in capturing variation in expression from time point to time point, thereby making them more suitable for investigating significant monotonic changes and trajectories of changes in gene expressions in time course microarray data. Also, the non-linear Bayesian model proved to be less conservative than linear Bayesian correlated growth models to filter out the redundant genes, although the linear model showed better fit than non-linear model (smaller DIC). We also report the trajectories of significant genes---since we have been able to isolate trajectories of genes whose regulations appear to be inter-dependent. Availability: SAS, R and WinBugs codes are available upon request from the authors. Contact: yliang@buffalo.edu

Energy requirements at rest account for 50% to 75% of total energy expenditure. Interindividual variation in resting energy expenditure (REE) has been studied for potential links to obesity and hypertension. REE is a modestly heritable trait, and yet virtually nothing is known about the genetic factors that might influence the familial patterns. The objectives of this study were to identify the genomic regions showing genetic linkage to REE variation in a Nigerian population. For linkage analysis across the genome, three hundred seventy-seven microsatellite markers were typed on DNA from 995 individuals in 153 families. A genome scan was performed using a multipoint variance component method. Heritability of REE was 0.30 after adjustment for body size. The strongest linkage signal was detected on chromosome 16 (16q22.3) with a likelihood of odds of 2.96 (p = 0.08). Linkage evidence (likelihood of odds > 1) was detected on another three chromosomal regions, namely 2q12.1, 8q21.2, and 15p11.2.

Background In West Africa, hypertension, once rare, has now emerged as a critical health concern and the trajectory is upward and factors are complex. The true magnitude of hypertension in some West African countries, including in-depth knowledge of underlying risk factors is not completely understood. There is also a paucity of research on adequate systems-level approaches designed to mitigate the growing burden of hypertension in the region. Aims In this review, we thematically synthesize available literature pertaining to the prevalence of hypertension in West Africa and discuss factors that influence its diagnosis, treatment and control. We aimed to address the social and structural determinants influencing hypertension in the sub-region including the effects of urbanization, health infrastructure and healthcare workforce. Findings The prevalence of hypertension in West Africa has increased over the past decade and is rising rapidly with an urban-rural gradient that places higher hypertension prevalence on urban settings compared to rural settings. Overall levels of awareness of one’s hypertension status remain consistently low in West African. Structural and economic determinants related to conditions of poverty such as insufficient finances have a direct impact on adherence to prescribed antihypertensive medications. Urbanization contributes to the increasing incidence of hypertension in the sub-region and available evidence indicates that inadequate health infrastructure may act as a barrier to optimal hypertension control in West Africa. Conclusion Given that optimal hypertension control in West Africa depends on multiple factors that go beyond simply modifying the behaviors of the individuals alone, we conclude by discussing the potential role systems-thinking approaches can play to achieve optimal control in the sub-region. In the context of recent advances in hypertension management including new therapeutic options and innovative solutions to expand health workforce so as to meet the high demand for healthcare, the success of these strategies will rely on a new understanding of the complexity of human behaviors and interactions most aptly framed from a systems-thinking perspective.

Background Using the dataset provided for Genetic Analysis Workshop 14 by the Collaborative Study on the Genetics of Alcoholism, we performed genome-wide linkage analysis of age at onset of alcoholism to compare the utility of microsatellites and single-nucleotide polymorphisms (SNPs) in genetic linkage study. Methods A multipoint nonparametric variance component linkage analysis method was applied to the survival distribution function obtained from semiparametric proportional hazards model of the age at onset phenotype of alcoholism. Three separate linkage analyses were carried out using 315 microsatellites, 2,467 and 9,467 SNPs, spanning the 22 autosomal chromosomes. Results Heritability of age at onset was estimated to be approximately 12% (p < 0.001). We observed weak correlation, both in trend and strength, of genome-wide linkage signals between microsatellites and SNPs. Results from SNPs revealed more and stronger linkage signals across the genome compared with those from microsatellites. The only suggestive evidence of linkage from microsatellites was on chromosome 1 (LOD of 1.43). Differences in map densities between the two sets of SNPs used in this study did not appear to confer an advantage in terms of strength of linkage signals. Conclusion Our study provided support for better performance of dense SNP maps compared with the sparse mirosatellite maps currently available for linkage analysis of quantitative traits. This better performance could be attributable to precise definition and high map resolutions achievable with dense SNP maps, thus resulting in increased power to detect possible loci affecting given trait or disease.

Objective: Interest in mapping genetic variants that are associated with obesity remains high because of the increasing prevalence of obesity and its complications worldwide. Data on genetic determinants of obesity in African populations are rare. Research Methods and Procedures: We have undertaken a genome-wide scan for body mass index (BMI) in 182 Nigerian families that included 769 individuals. Results: The prevalence of obesity was only 5%, yet polygenic heritability for BMI was in the expected range (0.46 ± 0.07). Tandem repeat markers (402) were typed across the genome with an average map density of 9 cM. Pedigree-based analysis using a variance components linkage model demonstrated evidence for linkage on chromosome 7 (near marker D7S817 at 7p14) with a logarithm of odds (LOD) score of 3.8 and on chromosome 11 (marker D11S2000 at 11q22) with an LOD score of 3.3. Weaker evidence for linkage was found on chromosomes 1 (1q21, LOD = 2.2) and 8 (8p22, LOD = 2.3). Several candidate genes, including neuropeptide Y, DRD2, APOA4, lamin A/C, and lipoprotein lipase, lie in or close to the chromosomal regions where strong linkage signals were found. Discussion: The findings of this study suggest that, as in other populations with higher prevalences of obesity, positive linkage signals can be found on genome scans for obesity-related traits. Follow-up studies may be warranted to investigate these linkages, especially the one on chromosome 11, which has been reported in a population at the opposite end of the BMI distribution.

Background Nurses in Ghana play a vital role in the delivery of primary health care at both the household and community level. However, there is lack of information on task shifting the management and control of hypertension to community health nurses in low- and middle-income countries including Ghana. The purpose of this study was to assess nurses’ knowledge and practice of hypertension management and control pre- and post-training utilizing task-shifting strategies for hypertension control in Ghana (TASSH). Methods A pre- and post- test survey was administered to 64 community health nurses (CHNs) and enrolled nurses (ENs) employed in community health centers and district hospitals before and after the TASSH training, followed by semi-structured qualitative interviews that assessed nurses’ satisfaction with the training, resultant changes in practice and barriers and facilitators to optimal hypertension management. Results A total of 64 CHNs and ENs participated in the TASSH training. The findings of the pre- and post-training assessments showed a marked improvement in nurses’ knowledge and practice related to hypertension detection and treatment. At pre-assessment 26.9% of the nurses scored 80% or more on the hypertension knowledge test, whereas this improved significantly to 95.7% post-training. Improvement of interpersonal skills and patient education were also mentioned by the nurses as positive outcomes of participation in the intervention. Conclusions Findings suggest that if all nurses receive even brief training in the management and control of hypertension, major public health benefits are likely to be achieved in low-income countries like Ghana. However, more research is needed to ascertain implementation fidelity and sustainability of interventions such as TASSH that highlight the potential role of nurses in mitigating barriers to optimal hypertension control in Ghana. Trial registration Trial registration for parent TASSH study: NCT01802372. Registered February 27, 2013.