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Search Results: 1 - 10 of 200495 matches for " Jonathan D. Mosley "
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Intrinsic bias in breast cancer gene expression data sets
Jonathan D Mosley, Ruth A Keri
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-214
Abstract: We ascertained how effectively unsupervised clustering employing randomly generated sets of genes could segregate tumors into prognostic groups using four well-characterized breast cancer data sets.Using a common set of 5,000 randomly generated lists (70 genes/list), the percentages of clusters with significant differences in metastasis latencies (HR p-value < 0.01) was 62%, 15%, 21% and 0% in the NKI2 (Netherlands Cancer Institute), Wang, TRANSBIG and KJX64/KJ125 data sets, respectively. Among ER positive tumors, the percentages were 38%, 11%, 4% and 0%, respectively. Few random lists were predictive among ER negative tumors in any data set. Clustering was associated with ER status and, after globally adjusting for the effects of ER-α gene expression, the percentages were 25%, 33%, 1% and 0%, respectively. The impact of adjusting for ER status depended on the extent of confounding between ER-α gene expression and markers of proliferation.It is highly probable to identify a statistically significant association between a given gene list and prognosis in the NKI2 dataset due to its large sample size and the interrelationship between ER-α expression and markers of proliferation. In most respects, the TRANSBIG data set generated similar outcomes as the NKI2 data set, although its smaller sample size led to fewer statistically significant results.Over the past decade, a large number of global gene expression data sets of human breast cancers have become publicly available [1-6]. These data sets have provided a wealth of information for the generation and testing of biological and clinical hypotheses [7]. Clinical and pathological factors with relevance to breast cancer are extensively characterized, and the prognostic significance of these factors is reflected in these publicly available data sets. These factors include tumor grade, Her2 and estrogen receptor (ER) expression [8]. Whether gene expression data contributes additional prognostic information beyond what is o
Cell cycle correlated genes dictate the prognostic power of breast cancer gene lists
Jonathan D Mosley, Ruth A Keri
BMC Medical Genomics , 2008, DOI: 10.1186/1755-8794-1-11
Abstract: We tested this hypothesis directly using a novel iterative-subtractive approach. We evaluated five gene expression data sets that sample a broad range of breast cancer subtypes. In all data sets, the dominant cluster capable of predicting metastasis was heavily populated by genes that fluctuate in concert with the cell cycle. When six well-characterized classifiers were examined, all contained a higher than expected proportion of genes that correlate with this cluster. Furthermore, when the data sets were globally adjusted for the cell cycle cluster, each classifier lost its ability to assign tumors to appropriate high and low risk groups. In contrast, adjusting for other predictive gene clusters did not impact their performance.These data indicate that the discriminative ability of breast cancer classifiers is dependent upon genes that correlate with cell cycle progression.Global gene expression profiling of breast tumors has provided considerable insight into the biological processes underlying this disease [1-3]. One application of gene expression data has been the development of prognostic "molecular signatures" or classifiers – short lists of genes that can be used to assign tumors to good or poor prognostic groups [4-11]. Some classifiers have now become commercially available diagnostic tools for breast cancer, making it imperative to understand how they function as well as how they differ from one another. A notable feature of published prognostic gene lists is that they have relatively little overlap in terms of composition. This lack of commonality has led to the proposition that prognostic lists use different genes to measure the same underlying biological process(es) [12,13]. Evidence supporting this notion includes a study evaluating the predictive abilities of five prognostic gene lists using a common gene expression data set, which showed that four of the five classifiers examined performed comparably in predicting future metastases despite having alm
Integrating EMR-Linked and In Vivo Functional Genetic Data to Identify New Genotype-Phenotype Associations
Jonathan D. Mosley, Sara L. Van Driest, Peter E. Weeke, Jessica T. Delaney, Quinn S. Wells, Lisa Bastarache, Dan M. Roden, Josh C. Denny
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0100322
Abstract: The coupling of electronic medical records (EMR) with genetic data has created the potential for implementing reverse genetic approaches in humans, whereby the function of a gene is inferred from the shared pattern of morbidity among homozygotes of a genetic variant. We explored the feasibility of this approach to identify phenotypes associated with low frequency variants using Vanderbilt's EMR-based BioVU resource. We analyzed 1,658 low frequency non-synonymous SNPs (nsSNPs) with a minor allele frequency (MAF)<10% collected on 8,546 subjects. For each nsSNP, we identified diagnoses shared by at least 2 minor allele homozygotes and with an association p<0.05. The diagnoses were reviewed by a clinician to ascertain whether they may share a common mechanistic basis. While a number of biologically compelling clinical patterns of association were observed, the frequency of these associations was identical to that observed using genotype-permuted data sets, indicating that the associations were likely due to chance. To refine our analysis associations, we then restricted the analysis to 711 nsSNPs in genes with phenotypes in the On-line Mendelian Inheritance in Man (OMIM) or knock-out mouse phenotype databases. An initial comparison of the EMR diagnoses to the known in vivo functions of the gene identified 25 candidate nsSNPs, 19 of which had significant genotype-phenotype associations when tested using matched controls. Twleve of the 19 nsSNPs associations were confirmed by a detailed record review. Four of 12 nsSNP-phenotype associations were successfully replicated in an independent data set: thrombosis (F5,rs6031), seizures/convulsions (GPR98,rs13157270), macular degeneration (CNGB3,rs3735972), and GI bleeding (HGFAC,rs16844401). These analyses demonstrate the feasibility and challenges of using reverse genetics approaches to identify novel gene-phenotype associations in human subjects using low frequency variants. As increasing amounts of rare variant data are generated from modern genotyping and sequence platforms, model organism data may be an important tool to enable discovery.
A Case Series and Review of Takotsubo Cardiomyopathy: Does Stress Really Cause the Stress Cardiomyopathy?  [PDF]
Erin N. Quattromani, Amer Z. Aldeen, William J. Mosley II, D. Mark Courtney
International Journal of Clinical Medicine (IJCM) , 2011, DOI: 10.4236/ijcm.2011.21007
Abstract: Objective: We sought to describe clinical characteristics of emergency department patients ultimately diagnosed with Takotsubo Cardiomyopathy (TCM) and to explore the causal role that stress may play in its pathogenesis. Methods: We performed a retrospective chart review analyzing all myocardial infarction patients with non-obstructive coronary artery disease on cardiac catheterization to assess for the presence of TCM. Various clinical data, including the pres-ence of stressors, from emergency department records were reported. We also analyzed factors from several studies (including ours) to assess the true causality of stress in the development of TCM. Results: Twelve ED patients out of 2,179 charts reviewed were identified as having TCM. Most were female, post-menopausal, and had chest pain, but only half had a specific stressful event identified in the ED. One-third of patients had no stressful event identified during their hospital stay. Several other studies suggest that stressful events are associated with increased diagnoses of TCM, but we found that causality of stress cannot be substantiated. Conclusion: Stressful events are often not identified in emergency department patients ultimately diagnosed with TCM. The causative nature of stress in the development of TCM cannot be firmly established from any existing data.
Consumption of Dairy and Metabolic Syndrome Risk in a Convenient Sample of Mexican College Applicants  [PDF]
Michelle A. Mosley, Flavia C. D. Andrade, Celia Aradillas-Garcia, Margarita Teran-Garcia
Food and Nutrition Sciences (FNS) , 2013, DOI: 10.4236/fns.2013.41009
Abstract:

The rise in metabolic syndrome (MetS) is accompanied by a decrease in milk and dairy consumption and an increase in sugar-sweetened beverage (SSB) consumption, with SSB possibly displacing dairy products in the diet. Our main objective was to determine whether young individuals not meeting the dairy recommendations of 3 servings per day were at greater risk for MetS. In a cross-sectional design, a food frequency questionnaire was answered by Mexican college applicants (n = 339). Medical examination at a primary health care center and evaluation for presence of MetS risk factors was completed as part of an ongoing collaborative project. Relative risk analyses were used to assess the impact of meeting or not the dairy recommendations for the presence of MetS. The MetS prevalence was 10. Three-fourths (76%) of participants were not meeting the daily recommendations. Individuals who failed to meet dairy recommendations were at 2.9 times greater risk for MetS when controlling for age, sex, family history of cardiovascular disease and type 2 diabetes, and physical activity. We did not found that SSB were displacing dairy products in the diet. Still, our data support the importance of meeting daily dairy recommendations for the prevention of MetS in young adults.

The Summation of One Class of Infinite Series  [PDF]
Jonathan D. Weiss
Applied Mathematics (AM) , 2014, DOI: 10.4236/am.2014.517269
Abstract: This paper presents closed-form expressions for the series, \"\", where the sum is from n = 1 to n = ∞. These expressions were obtained by recasting the series in a different form, followed by the use of certain relationships involving the elliptical nome. Among the values of x for which these expressions can be obtained are of the form: \"\" and \"\", where l is an integer between ∞ and ∞. The values of λ include 1,\"\",\"\"and 3. Examples of closed-form expressions obtained in this manner are first presented for \"\", \"\", \"\", and \"\". Additional examples are then presented for \"\", \"\", \"\", and \"\". This undertaking was prompted by the author’s work on an electrostatics boundary-value problem related to the van der Pauw measurement technique of electrical resistivity. The presence of this series for x = \"\" in the solution of that problem and its absence from any compendium of infinite series that he consulted led to this work.
The Gravitational Attraction between Hemispherical Masses  [PDF]
Jonathan D. Weiss
Applied Mathematics (AM) , 2017, DOI: 10.4236/am.2017.86064
Abstract: This paper is a study of the gravitational attraction between two uniform hemispherical masses aligned such that the pair is cylindrically symmetric. Three variations are considered: flat side to flat side, curved side to curved side, and flat side to curved side. Expressions for the second and third variation are derived from the first, with the use of superposition and the well-known gravitational behavior of a spherical mass as equivalent to a point mass at its center. The study covers two masses of equal diameter and of different diameters, such that one is four times that of the other. Calculations are done for separations from zero to fifty times the radius of the larger of the two, which is effectively the asymptotic limit. It is demonstrated that at any separation, the force can be expressed as if the two hemispheres were point masses separated by a certain distance. Expressions for that distance and the location of the (fictitious) point masses within each hemisphere are presented. Unlike the case of two spherical masses, the location within their respective hemisphere is not necessarily the same for each point and both are dependent upon the separation between the two hemispheres. The calculation for the first variation is done in two ways. The first is a “brute force” multi-dimensional integral with the help of Wolfram Mathematica. The second is an axial expansion for the potential modified for off-axis locations by Legendre polynomials. With only a few terms in the expansion, the results of the second method are in extremely good agreement with those of the first. Finally, an interesting application to a split earth is presented.
Certain Aspects of the Gravitational Field of a Disk  [PDF]
Jonathan D. Weiss
Applied Mathematics (AM) , 2018, DOI: 10.4236/am.2018.912089
Abstract:
There are at least two reasons why one would study the gravitational field of a disk. The first is that many astronomical objects, such as spiral galaxies like the Milky Way, are disk-like. The second is that the field of a disk is interesting, particularly when compared to that of a spherical, or near-spherical, object, which is much easier to analyze because of its high degree of symmetry. It is hoped that this study will augment previous work on this subject. The aspects presented in this paper are as follows: 1) both the radial and vertical gravitational fields of a thin disk within the plane of the disk and above it; 2) a comparison of some of the field results obtained by Lass and Blitzer (1983) involving elliptic integrals to those obtained by a standard numerical integration, now available online, and separately through the use of Legendre polynomials; 3) the logarithmic divergence of the radial field at the edge of a thin disk; 4) the fields in the plane of a disk containing a central hole, particularly within the hole, such as the rings of Saturn; 5) circular orbits within the plane of a single disk and half way between two disks, and their stability; 6) the escape velocity at a point within the Milky Way, particularly at the position of the solar system and without any added, or subtracted, orbital effects around the galactic center; and 7) the radial field at the circular edge of a disk of finite thickness.
Mechanistic Phenotypes: An Aggregative Phenotyping Strategy to Identify Disease Mechanisms Using GWAS Data
Jonathan D. Mosley, Sara L. Van Driest, Emma K. Larkin, Peter E. Weeke, John S. Witte, Quinn S. Wells, Jason H. Karnes, Yan Guo, Lisa Bastarache, Lana M. Olson, Catherine A. McCarty, Jennifer A. Pacheco, Gail P. Jarvik, David S. Carrell, Eric B. Larson, David R. Crosslin, Iftikhar J. Kullo, Gerard Tromp, Helena Kuivaniemi, David J. Carey, Marylyn D. Ritchie, Josh C. Denny, Dan M. Roden
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0081503
Abstract: A single mutation can alter cellular and global homeostatic mechanisms and give rise to multiple clinical diseases. We hypothesized that these disease mechanisms could be identified using low minor allele frequency (MAF<0.1) non-synonymous SNPs (nsSNPs) associated with “mechanistic phenotypes”, comprised of collections of related diagnoses. We studied two mechanistic phenotypes: (1) thrombosis, evaluated in a population of 1,655 African Americans; and (2) four groupings of cancer diagnoses, evaluated in 3,009 white European Americans. We tested associations between nsSNPs represented on GWAS platforms and mechanistic phenotypes ascertained from electronic medical records (EMRs), and sought enrichment in functional ontologies across the top-ranked associations. We used a two-step analytic approach whereby nsSNPs were first sorted by the strength of their association with a phenotype. We tested associations using two reverse genetic models and standard additive and recessive models. In the second step, we employed a hypothesis-free ontological enrichment analysis using the sorted nsSNPs to identify functional mechanisms underlying the diagnoses comprising the mechanistic phenotypes. The thrombosis phenotype was solely associated with ontologies related to blood coagulation (Fisher's p = 0.0001, FDR p = 0.03), driven by the F5, P2RY12 and F2RL2 genes. For the cancer phenotypes, the reverse genetics models were enriched in DNA repair functions (p = 2×10?5, FDR p = 0.03) (POLG/FANCI, SLX4/FANCP, XRCC1, BRCA1, FANCA, CHD1L) while the additive model showed enrichment related to chromatid segregation (p = 4×10?6, FDR p = 0.005) (KIF25, PINX1). We were able to replicate nsSNP associations for POLG/FANCI, BRCA1, FANCA and CHD1L in independent data sets. Mechanism-oriented phenotyping using collections of EMR-derived diagnoses can elucidate fundamental disease mechanisms.
FTO genotype is associated with body mass index and waist circumference in Mexican young adults  [PDF]
Margarita Teran-Garcia, Itzel Vazquez-Vidal, Flavia C. D. Andrade, Michelle Mosley, Eduardo Medina-Cerda, Celia Aradillas-Garcia
Open Journal of Genetics (OJGen) , 2013, DOI: 10.4236/ojgen.2013.31005
Abstract:

Individual variations in the fat mass and obesity-associated (FTO) gene have been associated with obesity and BMI in diverse populations, but there are no reports in young Mexicans. We explored the association of a common FTO single-nucleotide polymorphism (SNP, rs805704) with obesity-related phenotypes in Mexican young adults. The FTO-SNP was genotyped using the fluorescent polarization method in college-age, apparently healthy subjects from the “UP AMIGOS” cohort (n = 251, 18 - 25 yrs). Homozygotes for the A allele (15%, n = 38) were heavier (1.6 kg/m2 and6.2 kg) and had a larger waist circumference (WC,4.8 cm) than G allele carriers. The FTO genotype was associated with BMI, weight and WC independently of age and sex and explained 2.7 to 3.1% of the variance in obesity-related phenotypes. The FTO genotype was also associated with fasting glucose (P = 0.0283). No other associations were found in the additive model. Despite our small sample size, we found that the FTO-rs805704 genotype influences obesity-related phenotypes young Mexicans. Previously observed FTO associations with fasting glucose were replicated. Previously reported associations with other metabolic traits likely represent the long-term consequences of obesity.

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