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Search Results: 1 - 10 of 402889 matches for " Janina M. Jeff "
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Characterization of Genome-Wide Association-Identified Variants for Atrial Fibrillation in African Americans
Jessica T. Delaney, Janina M. Jeff, Nancy J. Brown, Mias Pretorius, Henry E. Okafor, Dawood Darbar, Dan M. Roden, Dana C. Crawford
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0032338
Abstract: Background Despite a greater burden of risk factors, atrial fibrillation (AF) is less common among African Americans than European-descent populations. Genome-wide association studies (GWAS) for AF in European-descent populations have identified three predominant genomic regions associated with increased risk (1q21, 4q25, and 16q22). The contribution of these loci to AF risk in African American is unknown. Methodology/Principal Findings We studied 73 African Americans with AF from the Vanderbilt-Meharry AF registry and 71 African American controls, with no history of AF including after cardiac surgery. Tests of association were performed for 148 SNPs across the three regions associated with AF, and 22 SNPs were significantly associated with AF (P<0.05). The SNPs with the strongest associations in African Americans were both different from the index SNPs identified in European-descent populations and independent from the index European-descent population SNPs (r2<0.40 in HapMap CEU): 1q21 rs4845396 (odds ratio [OR] 0.30, 95% confidence interval [CI] 0.13–0.67, P = 0.003), 4q25 rs4631108 (OR 3.43, 95% CI 1.59–7.42, P = 0.002), and 16q22 rs16971547 (OR 8.1, 95% CI 1.46–45.4, P = 0.016). Estimates of European ancestry were similar among cases (23.6%) and controls (23.8%). Accordingly, the probability of having two copies of the European derived chromosomes at each region did not differ between cases and controls. Conclusions/Significance Variable European admixture at known AF loci does not explain decreased AF susceptibility in African Americans. These data support the role of 1q21, 4q25, and 16q22 variants in AF risk for African Americans, although the index SNPs differ from those identified in European-descent populations.
Admixture Mapping and Subsequent Fine-Mapping Suggests a Biologically Relevant and Novel Association on Chromosome 11 for Type 2 Diabetes in African Americans
Janina M. Jeff, Loren L. Armstrong, Marylyn D. Ritchie, Joshua C. Denny, Abel N. Kho, Melissa A. Basford, Wendy A. Wolf, Jennifer A. Pacheco, Rongling Li, Rex L. Chisholm, Dan M. Roden, M. Geoffrey Hayes, Dana C. Crawford
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0086931
Abstract: Type 2 diabetes (T2D) is a complex metabolic disease that disproportionately affects African Americans. Genome-wide association studies (GWAS) have identified several loci that contribute to T2D in European Americans, but few studies have been performed in admixed populations. We first performed a GWAS of 1,563 African Americans from the Vanderbilt Genome-Electronic Records Project and Northwestern University NUgene Project as part of the electronic Medical Records and Genomics (eMERGE) network. We successfully replicate an association in TCF7L2, previously identified by GWAS in this African American dataset. We were unable to identify novel associations at p<5.0×10?8 by GWAS. Using admixture mapping as an alternative method for discovery, we performed a genome-wide admixture scan that suggests multiple candidate genes associated with T2D. One finding, TCIRG1, is a T-cell immune regulator expressed in the pancreas and liver that has not been previously implicated for T2D. We performed subsequent fine-mapping to further assess the association between TCIRG1 and T2D in >5,000 African Americans. We identified 13 independent associations between TCIRG1, CHKA, and ALDH3B1 genes on chromosome 11 and T2D. Our results suggest a novel region on chromosome 11 identified by admixture mapping is associated with T2D in African Americans.
Fine-Mapping and Initial Characterization of QT Interval Loci in African Americans
Christy L. Avery ,Praveen Sethupathy,Steven Buyske,Qianchuan He,Dan-Yu Lin,Dan E. Arking,Cara L. Carty,David Duggan,Megan D. Fesinmeyer,Lucia A. Hindorff,Janina M. Jeff,Liviu Klein,Kristen K. Patton,Ulrike Peters,Ralph V. Shohet,Nona Sotoodehnia,Alicia M. Young,Charles Kooperberg,Christopher A. Haiman,Karen L. Mohlke,Eric A. Whitsel,Kari E. North
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002870
Abstract: The QT interval (QT) is heritable and its prolongation is a risk factor for ventricular tachyarrhythmias and sudden death. Most genetic studies of QT have examined European ancestral populations; however, the increased genetic diversity in African Americans provides opportunities to narrow association signals and identify population-specific variants. We therefore evaluated 6,670 SNPs spanning eleven previously identified QT loci in 8,644 African American participants from two Population Architecture using Genomics and Epidemiology (PAGE) studies: the Atherosclerosis Risk in Communities study and Women's Health Initiative Clinical Trial. Of the fifteen known independent QT variants at the eleven previously identified loci, six were significantly associated with QT in African American populations (P≤1.20×10?4): ATP1B1, PLN1, KCNQ1, NDRG4, and two NOS1AP independent signals. We also identified three population-specific signals significantly associated with QT in African Americans (P≤1.37×10?5): one at NOS1AP and two at ATP1B1. Linkage disequilibrium (LD) patterns in African Americans assisted in narrowing the region likely to contain the functional variants for several loci. For example, African American LD patterns showed that 0 SNPs were in LD with NOS1AP signal rs12143842, compared with European LD patterns that indicated 87 SNPs, which spanned 114.2 Kb, were in LD with rs12143842. Finally, bioinformatic-based characterization of the nine African American signals pointed to functional candidates located exclusively within non-coding regions, including predicted binding sites for transcription factors such as TBX5, which has been implicated in cardiac structure and conductance. In this detailed evaluation of QT loci, we identified several African Americans SNPs that better define the association with QT and successfully narrowed intervals surrounding established loci. These results demonstrate that the same loci influence variation in QT across multiple populations, that novel signals exist in African Americans, and that the SNPs identified as strong candidates for functional evaluation implicate gene regulatory dysfunction in QT prolongation.
Renal Involvement in Preeclampsia: Similarities to VEGF Ablation Therapy
Janina Müller-Deile,Mario Schiffer
Journal of Pregnancy , 2011, DOI: 10.1155/2011/176973
Abstract: Glomerular VEGF expression is critical for the maintenance and function of an intact filtration barrier. Alterations in glomerular VEGF bioavailability result in endothelial as well as in podocyte damage. Renal involvement in preeclampsia includes proteinuria, podocyturia, elevated blood pressure, edema, glomerular capillary endotheliosis, and thrombotic microangiopathy. At least the renal signs, symptoms, and other evidence can sufficiently be explained by reduced VEGF levels. The aim of this paper was to summarize our pathophysiological understanding of the renal involvement of preeclampsia and point out similarities to the renal side effects of VEGF-ablation therapy. 1. Introduction The renal involvement in preeclampsia is characterized by hypertension and proteinuria that have to present after the twentieth week of gestation to fulfil the clinical diagnosis. It is also associated with edema and hyperuricemia [1]. Glomerular capillary endotheliosis and thrombotic microangiopathy (TMA) are more severe findings. The pathophysiology of these phenomena is explained by excess placental soluble fms like tyrosin kinase-1 (sFlt-1) that binds circulating vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF) and prevents their interaction with endothelial cell-surface receptors. sFlt-1 is also known as soluble VEGF receptor-1 (sVEGFR-1). Other abbreviations for PlGF are PGF and PLGF. VEGF is a potent promoter of angiogenesis; it regulates endothelial cell function by induction of nitric oxide and vasodilatation and decreases vascular tone and blood pressure [2]. The major source of glomerular VEGF under normal conditions is the podocyte [3]. During pregnancy the placenta is the main source of sFlt-1 and PIGF. In 2003, Maynard et al. observed that the serum levels of both VEGF and PlGF were decreased in women with preeclampsia. However, the magnitude of decrease was less pronounced for VEGF since its serum level was not as high as PlGF, even in normal pregnancy [4]. De Vivo et al. showed that Endoglin, PlGF, and sFlt-1 might be used as markers for predicting preeclampsia and that sFlt-1?:?PlGF-ratio is even more accurate [5]. Eventually measurement of antiangiogenic factors might become a surrogate for renal biopsy to establish the diagnosis. Under pathological conditions VEGF is produced by various cancers to induce angiogenesis and supply the tumour with new blood vessels. In the last years anti-VEGF therapies that either block the extracellular binding of VEGF to its receptor (anti-VEGF antibodies) or inhibit intracellular signalling
Challenges in Endocrinology: Moving from the Post-Genomic Era, into the Nano-World and Beyond
Jeff M. P. Holly
Frontiers in Endocrinology , 2011, DOI: 10.3389/fendo.2010.00011
epsilon-Samples of Kernels
Jeff M. Phillips
Computer Science , 2011,
Abstract: We study the worst case error of kernel density estimates via subset approximation. A kernel density estimate of a distribution is the convolution of that distribution with a fixed kernel (e.g. Gaussian kernel). Given a subset (i.e. a point set) of the input distribution, we can compare the kernel density estimates of the input distribution with that of the subset and bound the worst case error. If the maximum error is eps, then this subset can be thought of as an eps-sample (aka an eps-approximation) of the range space defined with the input distribution as the ground set and the fixed kernel representing the family of ranges. Interestingly, in this case the ranges are not binary, but have a continuous range (for simplicity we focus on kernels with range of [0,1]); these allow for smoother notions of range spaces. It turns out, the use of this smoother family of range spaces has an added benefit of greatly decreasing the size required for eps-samples. For instance, in the plane the size is O((1/eps^{4/3}) log^{2/3}(1/eps)) for disks (based on VC-dimension arguments) but is only O((1/eps) sqrt{log (1/eps)}) for Gaussian kernels and for kernels with bounded slope that only affect a bounded domain. These bounds are accomplished by studying the discrepancy of these "kernel" range spaces, and here the improvement in bounds are even more pronounced. In the plane, we show the discrepancy is O(sqrt{log n}) for these kernels, whereas for balls there is a lower bound of Omega(n^{1/4}).
Chernoff-Hoeffding Inequality and Applications
Jeff M. Phillips
Computer Science , 2012,
Abstract: When dealing with modern big data sets, a very common theme is reducing the set through a random process. These generally work by making "many simple estimates" of the full data set, and then judging them as a whole. Perhaps magically, these "many simple estimates" can provide a very accurate and small representation of the large data set. The key tool in showing how many of these simple estimates are needed for a fixed accuracy trade-off is the Chernoff-Hoeffding inequality[Che52,Hoe63]. This document provides a simple form of this bound, and two examples of its use.
Algorithms for eps-approximations of Terrains
Jeff M. Phillips
Computer Science , 2008,
Abstract: Consider a point set D with a measure function w : D -> R. Let A be the set of subsets of D induced by containment in a shape from some geometric family (e.g. axis-aligned rectangles, half planes, balls, k-oriented polygons). We say a range space (D, A) has an eps-approximation P if max {R \in A} | w(R \cap P)/w(P) - w(R \cap D)/w(D) | <= eps. We describe algorithms for deterministically constructing discrete eps-approximations for continuous point sets such as distributions or terrains. Furthermore, for certain families of subsets A, such as those described by axis-aligned rectangles, we reduce the size of the eps-approximations by almost a square root from O(1/eps^2 log 1/eps) to O(1/eps polylog 1/eps). This is often the first step in transforming a continuous problem into a discrete one for which combinatorial techniques can be applied. We describe applications of this result in geo-spatial analysis, biosurveillance, and sensor networks.
Risk Assessment Using Two Different Diagnostic Tools: Metabolic Syndrome and Cardiovascular Risk Score (SCORE)—Data from a Weight Reduction Intervention Study  [PDF]
Janina Willers, Andreas Hahn
Food and Nutrition Sciences (FNS) , 2013, DOI: 10.4236/fns.2013.410134
Abstract: Objective: Risk score models and the diagnosis of a metabolic syndrome are useful for cardiovascular (CV) risk prediction. The identification of individuals with high CV and metabolic risk is essential to provide appropriate prevention and therapy. The present study aims at clarifying whether these indicators are altered by a weight reduction programme. Additionally, which diagnostic tool has a better predictive value is examined. Method: One hundred and twenty overweight and obese subjects aged 30 60 years were included in a 12-week weight reduction programme. The CV risk was assessed by means of German multiple-used risk charts (SCORE) at baseline and at the end of the trial. Furthermore, the prevalence of the metabolic syndrome (three out of five risk factors) was quantified. Results: The initial prevalence of the metabolic syndrome was 63.3% (n = 76) and decreased to 41.7% (n = 50) by the end of the intervention. The SCORE also decreased significantly after twelve weeks (p < 0.001). The percentage of subjects at high risk (SCORE > 5%) was comparatively low (t0: 7.4%, n = 7; t12: 5.3%, n = 5). Conclusion: The weight reduction concept was applicable to improve the CV risk SCORE and decrease the prevalence of the metabolic syndrome. The CV 10-year risk calculated using German risk charts (SCORE) probably underestimated the risk of CV diseases in this collective. In this case, the diagnosis of a metabolic syndrome is more meaningful than risk SCORE calculations.
An exploration of impaired walking dynamics and fatigue in Multiple Sclerosis
Burschka Janina M,Keune Philipp M,Menge Uwe,Oy Ulrich
BMC Neurology , 2012, DOI: 10.1186/1471-2377-12-161
Abstract: Background Physical disability in multiple sclerosis (MS) is frequently characterized by impaired ambulation. Although walking tests have been successfully employed to assess walking ability in MS patients, data analytic procedures have predominantly relied on result-oriented parameters (e.g. total distance covered during a given amount of time), whereas process-oriented, dynamic walking patterns have mostly been ignored. This is striking, since healthy individuals have been observed to display a stereotypical U-shaped pattern of walking speed during timed walking, characterized by relatively high speed during the initial phase, subsequent slowing and final acceleration. Objective of the current study was to test the utility of the 6 min Walk (6MW) and the 12 min Walk (12MW) for revealing putatively abnormal temporal dynamic features of walking in MS. Methods A group of 37 MS patients was divided into subgroups with regard to their level of disability analyzed with the Expanded Disability Status Scale (EDSS; Mild MS Group, n = 20, EDSS 0 – 3.5; Moderate MS Group, n = 17, EDSS 4 – 5). Subsequently, both groups were compared to age-matched healthy controls (n = 25) on both tests with regard to result-oriented characteristics (mean walking speed), as well as dynamic features (mean decline in walking speed, degree of observed U-shape). Results Both MS groups showed a significantly lower mean walking speed than healthy controls, independent of test duration. Compared to controls, the Moderate MS Group also slowed down more rapidly throughout both tests. The same pronounced decline in walking speed was observed for the Mild MS Group in case of the 12MW. Additionally, for both MS groups an attenuated U-shaped velocity pattern was observed relative to controls in the 6MW. Patients' subjective fatigue scores were more strongly correlated with the decline in walking speed than with the common parameter of mean walking speed in the 6MW. Conclusions MS patients display abnormal dynamics in their walking patterns. A pronounced linear decline in walking speed can be identified with the 12MW even in MS patients with seemingly mild disability. Similarly, the 6MW can be used to assess an abnormal walking profile. Particularly the linear decline in walking speed on this test shows a more robust association with subjective fatigue than mean walking speed. Dynamic walking parameters may hence represent valuable clinical features, serving as surrogate measures of motor fatigue. Future studies are needed to verify their prognostic value.
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