Browsing by Subject "Principal Component Analysis"
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Item Open Access A genome-wide association study of variants associated with acquisition of Staphylococcus aureus bacteremia in a healthcare setting.(BMC Infect Dis, 2014-02-13) Nelson, Charlotte L; Pelak, Kimberly; Podgoreanu, Mihai V; Ahn, Sun Hee; Scott, William K; Allen, Andrew S; Cowell, Lindsay G; Rude, Thomas H; Zhang, Yurong; Tong, Amy; Ruffin, Felicia; Sharma-Kuinkel, Batu K; Fowler, Vance GBACKGROUND: Humans vary in their susceptibility to acquiring Staphylococcus aureus infection, and research suggests that there is a genetic basis for this variability. Several recent genome-wide association studies (GWAS) have identified variants that may affect susceptibility to infectious diseases, demonstrating the potential value of GWAS in this arena. METHODS: We conducted a GWAS to identify common variants associated with acquisition of S. aureus bacteremia (SAB) resulting from healthcare contact. We performed a logistic regression analysis to compare patients with healthcare contact who developed SAB (361 cases) to patients with healthcare contact in the same hospital who did not develop SAB (699 controls), testing 542,410 SNPs and adjusting for age (by decade), sex, and 6 significant principal components from our EIGENSTRAT analysis. Additionally, we evaluated the joint effect of the host and pathogen genomes in association with severity of SAB infection via logistic regression, including an interaction of host SNP with bacterial genotype, and adjusting for age (by decade), sex, the 6 significant principal components, and dialysis status. Bonferroni corrections were applied in both analyses to control for multiple comparisons. RESULTS: Ours is the first study that has attempted to evaluate the entire human genome for variants potentially involved in the acquisition or severity of SAB. Although this study identified no common variant of large effect size to have genome-wide significance for association with either the risk of acquiring SAB or severity of SAB, the variant (rs2043436) most significantly associated with severity of infection is located in a biologically plausible candidate gene (CDON, a member of the immunoglobulin family) and may warrant further study. CONCLUSIONS: The genetic architecture underlying SAB is likely to be complex. Future investigations using larger samples, narrowed phenotypes, and advances in both genotyping and analytical methodologies will be important tools for identifying causative variants for this common and serious cause of healthcare-associated infection.Item Open Access A new fully automated approach for aligning and comparing shapes.(Anatomical record (Hoboken, N.J. : 2007), 2015-01) Boyer, Doug M; Puente, Jesus; Gladman, Justin T; Glynn, Chris; Mukherjee, Sayan; Yapuncich, Gabriel S; Daubechies, IngridThree-dimensional geometric morphometric (3DGM) methods for placing landmarks on digitized bones have become increasingly sophisticated in the last 20 years, including greater degrees of automation. One aspect shared by all 3DGM methods is that the researcher must designate initial landmarks. Thus, researcher interpretations of homology and correspondence are required for and influence representations of shape. We present an algorithm allowing fully automatic placement of correspondence points on samples of 3D digital models representing bones of different individuals/species, which can then be input into standard 3DGM software and analyzed with dimension reduction techniques. We test this algorithm against several samples, primarily a dataset of 106 primate calcanei represented by 1,024 correspondence points per bone. Results of our automated analysis of these samples are compared to a published study using a traditional 3DGM approach with 27 landmarks on each bone. Data were analyzed with morphologika(2.5) and PAST. Our analyses returned strong correlations between principal component scores, similar variance partitioning among components, and similarities between the shape spaces generated by the automatic and traditional methods. While cluster analyses of both automatically generated and traditional datasets produced broadly similar patterns, there were also differences. Overall these results suggest to us that automatic quantifications can lead to shape spaces that are as meaningful as those based on observer landmarks, thereby presenting potential to save time in data collection, increase completeness of morphological quantification, eliminate observer error, and allow comparisons of shape diversity between different types of bones. We provide an R package for implementing this analysis.Item Open Access Association of a peripheral blood metabolic profile with coronary artery disease and risk of subsequent cardiovascular events.(Circ Cardiovasc Genet, 2010-04) Shah, Svati H; Bain, James R; Muehlbauer, Michael J; Stevens, Robert D; Crosslin, David R; Haynes, Carol; Dungan, Jennifer; Newby, L Kristin; Hauser, Elizabeth R; Ginsburg, Geoffrey S; Newgard, Christopher B; Kraus, William EBACKGROUND: Molecular tools may provide insight into cardiovascular risk. We assessed whether metabolites discriminate coronary artery disease (CAD) and predict risk of cardiovascular events. METHODS AND RESULTS: We performed mass-spectrometry-based profiling of 69 metabolites in subjects from the CATHGEN biorepository. To evaluate discriminative capabilities of metabolites for CAD, 2 groups were profiled: 174 CAD cases and 174 sex/race-matched controls ("initial"), and 140 CAD cases and 140 controls ("replication"). To evaluate the capability of metabolites to predict cardiovascular events, cases were combined ("event" group); of these, 74 experienced death/myocardial infarction during follow-up. A third independent group was profiled ("event-replication" group; n=63 cases with cardiovascular events, 66 controls). Analysis included principal-components analysis, linear regression, and Cox proportional hazards. Two principal components analysis-derived factors were associated with CAD: 1 comprising branched-chain amino acid metabolites (factor 4, initial P=0.002, replication P=0.01), and 1 comprising urea cycle metabolites (factor 9, initial P=0.0004, replication P=0.01). In multivariable regression, these factors were independently associated with CAD in initial (factor 4, odds ratio [OR], 1.36; 95% CI, 1.06 to 1.74; P=0.02; factor 9, OR, 0.67; 95% CI, 0.52 to 0.87; P=0.003) and replication (factor 4, OR, 1.43; 95% CI, 1.07 to 1.91; P=0.02; factor 9, OR, 0.66; 95% CI, 0.48 to 0.91; P=0.01) groups. A factor composed of dicarboxylacylcarnitines predicted death/myocardial infarction (event group hazard ratio 2.17; 95% CI, 1.23 to 3.84; P=0.007) and was associated with cardiovascular events in the event-replication group (OR, 1.52; 95% CI, 1.08 to 2.14; P=0.01). CONCLUSIONS: Metabolite profiles are associated with CAD and subsequent cardiovascular events.Item Open Access Caloric restriction alters the metabolic response to a mixed-meal: results from a randomized, controlled trial.(PLoS One, 2012) Huffman, Kim M; Redman, Leanne M; Landerman, Lawrence R; Pieper, Carl F; Stevens, Robert D; Muehlbauer, Michael J; Wenner, Brett R; Bain, James R; Kraus, Virginia B; Newgard, Christopher B; Ravussin, Eric; Kraus, William EOBJECTIVES: To determine if caloric restriction (CR) would cause changes in plasma metabolic intermediates in response to a mixed meal, suggestive of changes in the capacity to adapt fuel oxidation to fuel availability or metabolic flexibility, and to determine how any such changes relate to insulin sensitivity (S(I)). METHODS: Forty-six volunteers were randomized to a weight maintenance diet (Control), 25% CR, or 12.5% CR plus 12.5% energy deficit from structured aerobic exercise (CR+EX), or a liquid calorie diet (890 kcal/d until 15% reduction in body weight)for six months. Fasting and postprandial plasma samples were obtained at baseline, three, and six months. A targeted mass spectrometry-based platform was used to measure concentrations of individual free fatty acids (FFA), amino acids (AA), and acylcarnitines (AC). S(I) was measured with an intravenous glucose tolerance test. RESULTS: Over three and six months, there were significantly larger differences in fasting-to-postprandial (FPP) concentrations of medium and long chain AC (byproducts of FA oxidation) in the CR relative to Control and a tendency for the same in CR+EX (CR-3 month P = 0.02; CR-6 month P = 0.002; CR+EX-3 month P = 0.09; CR+EX-6 month P = 0.08). After three months of CR, there was a trend towards a larger difference in FPP FFA concentrations (P = 0.07; CR-3 month P = 0.08). Time-varying differences in FPP concentrations of AC and AA were independently related to time-varying S(I) (P<0.05 for both). CONCLUSIONS: Based on changes in intermediates of FA oxidation following a food challenge, CR imparted improvements in metabolic flexibility that correlated with improvements in S(I). TRIAL REGISTRATION: ClinicalTrials.gov NCT00099151.Item Open Access Correlations between physical and chemical defences in plants: tradeoffs, syndromes, or just many different ways to skin a herbivorous cat?(The New phytologist, 2013-04) Moles, Angela T; Peco, Begoña; Wallis, Ian R; Foley, William J; Poore, Alistair GB; Seabloom, Eric W; Vesk, Peter A; Bisigato, Alejandro J; Cella-Pizarro, Lucrecia; Clark, Connie J; Cohen, Philippe S; Cornwell, William K; Edwards, Will; Ejrnaes, Rasmus; Gonzales-Ojeda, Therany; Graae, Bente J; Hay, Gregory; Lumbwe, Fainess C; Magaña-Rodríguez, Benjamín; Moore, Ben D; Peri, Pablo L; Poulsen, John R; Stegen, James C; Veldtman, Ruan; von Zeipel, Hugo; Andrew, Nigel R; Boulter, Sarah L; Borer, Elizabeth T; Cornelissen, Johannes HC; Farji-Brener, Alejandro G; DeGabriel, Jane L; Jurado, Enrique; Kyhn, Line A; Low, Bill; Mulder, Christa PH; Reardon-Smith, Kathryn; Rodríguez-Velázquez, Jorge; De Fortier, An; Zheng, Zheng; Blendinger, Pedro G; Enquist, Brian J; Facelli, Jose M; Knight, Tiffany; Majer, Jonathan D; Martínez-Ramos, Miguel; McQuillan, Peter; Hui, Francis KCMost plant species have a range of traits that deter herbivores. However, understanding of how different defences are related to one another is surprisingly weak. Many authors argue that defence traits trade off against one another, while others argue that they form coordinated defence syndromes. We collected a dataset of unprecedented taxonomic and geographic scope (261 species spanning 80 families, from 75 sites across the globe) to investigate relationships among four chemical and six physical defences. Five of the 45 pairwise correlations between defence traits were significant and three of these were tradeoffs. The relationship between species' overall chemical and physical defence levels was marginally nonsignificant (P = 0.08), and remained nonsignificant after accounting for phylogeny, growth form and abundance. Neither categorical principal component analysis (PCA) nor hierarchical cluster analysis supported the idea that species displayed defence syndromes. Our results do not support arguments for tradeoffs or for coordinated defence syndromes. Rather, plants display a range of combinations of defence traits. We suggest this lack of consistent defence syndromes may be adaptive, resulting from selective pressure to deploy a different combination of defences to coexisting species.Item Open Access Entrepreneurial Attractiveness: Amazon, Google, and the Search for Innovative Hot Spots(2018-04-18) Kropf, AnnaRecent economic literature suggests that entrepreneurship in technological fields can spur economic growth, making it a popular topic for city development officials. Yet, this increasingly popular phenomenon is met by many economic questions. One of those questions is which characteristics of metropolitan areas are attractive to entrepreneurs. To answer the question of attractiveness on both the small business and corporate levels, I compare across two case studies: Amazon’s search for a second headquarters and Google’s tech hub network. Using principal component analysis, I statistically deduce seven components of attractiveness from an original 34 variables. These components are then weighted using three methods—a case study, a survey, and an empirical method—to produce comparable indices of attractiveness. Generally, I find that sizeable population and healthy economy are the strongest components. However, the statistically insignificant components that can change an urban area’s ranking considerably are talent and geographic network effects. Ultimately, creating policy to maximize these aspects can change a city’s innovative trajectory.Item Open Access Exercise-induced changes in metabolic intermediates, hormones, and inflammatory markers associated with improvements in insulin sensitivity.(Diabetes Care, 2011-01) Huffman, Kim M; Slentz, Cris A; Bateman, Lori A; Thompson, Dana; Muehlbauer, Michael J; Bain, James R; Stevens, Robert D; Wenner, Brett R; Kraus, Virginia Byers; Newgard, Christopher B; Kraus, William EOBJECTIVE: To understand relationships between exercise training-mediated improvements in insulin sensitivity (S(I)) and changes in circulating concentrations of metabolic intermediates, hormones, and inflammatory mediators. RESEARCH DESIGN AND METHODS: Targeted mass spectrometry and enzyme-linked immunosorbent assays were used to quantify metabolic intermediates, hormones, and inflammatory markers at baseline, after 6 months of exercise training, and 2 weeks after exercise training cessation (n = 53). A principal components analysis (PCA) strategy was used to relate changes in these intermediates to changes in S(I). RESULTS: PCA reduced the number of intermediates from 90 to 24 factors composed of biologically related components. With exercise training, improvements in S(I) were associated with reductions in by-products of fatty acid oxidation and increases in glycine and proline (P < 0.05, R² = 0.59); these relationships were retained 15 days after cessation of exercise training (P < 0.05, R² = 0.34). CONCLUSIONS: These observations support prior observations in animal models that exercise training promotes more efficient mitochondrial β-oxidation and challenges current hypotheses regarding exercise training and glycine metabolism.Item Open Access Hands of early primates.(American journal of physical anthropology, 2013-12) Boyer, Doug M; Yapuncich, Gabriel S; Chester, Stephen GB; Bloch, Jonathan I; Godinot, MarcQuestions surrounding the origin and early evolution of primates continue to be the subject of debate. Though anatomy of the skull and inferred dietary shifts are often the focus, detailed studies of postcrania and inferred locomotor capabilities can also provide crucial data that advance understanding of transitions in early primate evolution. In particular, the hand skeleton includes characteristics thought to reflect foraging, locomotion, and posture. Here we review what is known about the early evolution of primate hands from a comparative perspective that incorporates data from the fossil record. Additionally, we provide new comparative data and documentation of skeletal morphology for Paleogene plesiadapiforms, notharctines, cercamoniines, adapines, and omomyiforms. Finally, we discuss implications of these data for understanding locomotor transitions during the origin and early evolutionary history of primates. Known plesiadapiform species cannot be differentiated from extant primates based on either intrinsic hand proportions or hand-to-body size proportions. Nonetheless, the presence of claws and a different metacarpophalangeal [corrected] joint form in plesiadapiforms indicate different grasping mechanics. Notharctines and cercamoniines have intrinsic hand proportions with extremely elongated proximal phalanges and digit rays relative to metacarpals, resembling tarsiers and galagos. But their hand-to-body size proportions are typical of many extant primates (unlike those of tarsiers, and possibly Teilhardina, which have extremely large hands). Non-adapine adapiforms and omomyids exhibit additional carpal features suggesting more limited dorsiflexion, greater ulnar deviation, and a more habitually divergent pollex than observed plesiadapiforms. Together, features differentiating adapiforms and omomyiforms from plesiadapiforms indicate increased reliance on vertical prehensile-clinging and grasp-leaping, possibly in combination with predatory behaviors in ancestral euprimates.Item Open Access Heritability estimates of endophenotypes of long and health life: the Long Life Family Study.(J Gerontol A Biol Sci Med Sci, 2010-12) Matteini, Amy M; Fallin, M Daniele; Kammerer, Candace M; Schupf, Nicole; Yashin, Anatoli I; Christensen, Kaare; Arbeev, Konstantin G; Barr, Graham; Mayeux, Richard; Newman, Anne B; Walston, Jeremy DBACKGROUND: Identification of gene variants that contribute to exceptional survival may provide critical biologic information that informs optimal health across the life span. METHODS: As part of phenotype development efforts for the Long Life Family Study, endophenotypes that represent exceptional survival were identified and heritability estimates were calculated. Principal components (PCs) analysis was carried out using 28 physiologic measurements from five trait domains (cardiovascular, cognition, physical function, pulmonary, and metabolic). RESULTS: The five most dominant PCs accounted for 50% of underlying trait variance. The first PC (PC1), which consisted primarily of poor pulmonary and physical function, represented 14.3% of the total variance and had an estimated heritability of 39%. PC2 consisted of measures of good metabolic and cardiovascular function with an estimated heritability of 27%. PC3 was made up of cognitive measures (h(2) = 36%). PC4 and PC5 contained measures of blood pressure and cholesterol, respectively (h(2) = 25% and 16%). CONCLUSIONS: These PCs analysis-derived endophenotypes may be used in genetic association studies to help identify underlying genetic mechanisms that drive exceptional survival in this and other populations.Item Open Access Identification of Chiari Type I Malformation subtypes using whole genome expression profiles and cranial base morphometrics.(BMC medical genomics, 2014-06) Markunas, Christina A; Lock, Eric; Soldano, Karen; Cope, Heidi; Ding, Chien-Kuang C; Enterline, David S; Grant, Gerald; Fuchs, Herbert; Ashley-Koch, Allison E; Gregory, Simon GBackground
Chiari Type I Malformation (CMI) is characterized by herniation of the cerebellar tonsils through the foramen magnum at the base of the skull, resulting in significant neurologic morbidity. As CMI patients display a high degree of clinical variability and multiple mechanisms have been proposed for tonsillar herniation, it is hypothesized that this heterogeneous disorder is due to multiple genetic and environmental factors. The purpose of the present study was to gain a better understanding of what factors contribute to this heterogeneity by using an unsupervised statistical approach to define disease subtypes within a case-only pediatric population.Methods
A collection of forty-four pediatric CMI patients were ascertained to identify disease subtypes using whole genome expression profiles generated from patient blood and dura mater tissue samples, and radiological data consisting of posterior fossa (PF) morphometrics. Sparse k-means clustering and an extension to accommodate multiple data sources were used to cluster patients into more homogeneous groups using biological and radiological data both individually and collectively.Results
All clustering analyses resulted in the significant identification of patient classes, with the pure biological classes derived from patient blood and dura mater samples demonstrating the strongest evidence. Those patient classes were further characterized by identifying enriched biological pathways, as well as correlated cranial base morphological and clinical traits.Conclusions
Our results implicate several strong biological candidates warranting further investigation from the dura expression analysis and also identified a blood gene expression profile corresponding to a global down-regulation in protein synthesis.Item Open Access Long range dynamic effects of point-mutations trap a response regulator in an active conformation.(FEBS letters, 2010-10) Bobay, Benjamin G; Thompson, Richele J; Hoch, James A; Cavanagh, JohnWhen a point-mutation in a protein elicits a functional change, it is most common to assign this change to local structural perturbations. Here we show that point-mutations, distant from an essential highly dynamic kinase recognition loop in the response regulator Spo0F, lock this loop in an active conformation. This 'conformational trapping' results in functionally hyperactive Spo0F. Consequently, point-mutations are seen to affect functionally critical motions both close to and far from the mutational site.Item Open Access Novel loci and pathways significantly associated with longevity.(Sci Rep, 2016-02-25) Zeng, Yi; Nie, Chao; Min, Junxia; Liu, Xiaomin; Li, Mengmeng; Chen, Huashuai; Xu, Hanshi; Wang, Mingbang; Ni, Ting; Li, Yang; Yan, Han; Zhang, Jin-Pei; Song, Chun; Chi, Li-Qing; Wang, Han-Ming; Dong, Jie; Zheng, Gu-Yan; Lin, Li; Qian, Feng; Qi, Yanwei; Liu, Xiao; Cao, Hongzhi; Wang, Yinghao; Zhang, Lijuan; Li, Zhaochun; Zhou, Yufeng; Wang, Yan; Lu, Jiehua; Li, Jianxin; Qi, Ming; Bolund, Lars; Yashin, Anatoliy; Land, Kenneth C; Gregory, Simon; Yang, Ze; Gottschalk, William; Tao, Wei; Wang, Jian; Wang, Jun; Xu, Xun; Bae, Harold; Nygaard, Marianne; Christiansen, Lene; Christensen, Kaare; Franceschi, Claudio; Lutz, Michael W; Gu, Jun; Tan, Qihua; Perls, Thomas; Sebastiani, Paola; Deelen, Joris; Slagboom, Eline; Hauser, Elizabeth; Xu, Huji; Tian, Xiao-Li; Yang, Huanming; Vaupel, James WOnly two genome-wide significant loci associated with longevity have been identified so far, probably because of insufficient sample sizes of centenarians, whose genomes may harbor genetic variants associated with health and longevity. Here we report a genome-wide association study (GWAS) of Han Chinese with a sample size 2.7 times the largest previously published GWAS on centenarians. We identified 11 independent loci associated with longevity replicated in Southern-Northern regions of China, including two novel loci (rs2069837-IL6; rs2440012-ANKRD20A9P) with genome-wide significance and the rest with suggestive significance (P < 3.65 × 10(-5)). Eight independent SNPs overlapped across Han Chinese, European and U.S. populations, and APOE and 5q33.3 were replicated as longevity loci. Integrated analysis indicates four pathways (starch, sucrose and xenobiotic metabolism; immune response and inflammation; MAPK; calcium signaling) highly associated with longevity (P ≤ 0.006) in Han Chinese. The association with longevity of three of these four pathways (MAPK; immunity; calcium signaling) is supported by findings in other human cohorts. Our novel finding on the association of starch, sucrose and xenobiotic metabolism pathway with longevity is consistent with the previous results from Drosophilia. This study suggests protective mechanisms including immunity and nutrient metabolism and their interactions with environmental stress play key roles in human longevity.Item Open Access Predicting health outcomes with intensive longitudinal data collected by mobile health devices: a functional principal component regression approach.(BMC medical research methodology, 2024-03) Yang, Qing; Jiang, Meilin; Li, Cai; Luo, Sheng; Crowley, Matthew J; Shaw, Ryan JBackground
Intensive longitudinal data (ILD) collected in near real time by mobile health devices provide a new opportunity for monitoring chronic diseases, early disease risk prediction, and disease prevention in health research. Functional data analysis, specifically functional principal component analysis, has great potential to abstract trends in ILD but has not been used extensively in mobile health research.Objective
To introduce functional principal component analysis (fPCA) and demonstrate its potential applicability in estimating trends in ILD collected by mobile heath devices, assessing longitudinal association between ILD and health outcomes, and predicting health outcomes.Methods
fPCA and scalar-to-function regression models were reviewed. A case study was used to illustrate the process of abstracting trends in intensively self-measured blood glucose using functional principal component analysis and then predicting future HbA1c values in patients with type 2 diabetes using a scalar-to-function regression model.Results
Based on the scalar-to-function regression model results, there was a slightly increasing trend between daily blood glucose measures and HbA1c. 61% of variation in HbA1c could be predicted by the three preceding months' blood glucose values measured before breakfast (P < 0.0001, [Formula: see text]).Conclusions
Functional data analysis, specifically fPCA, offers a unique tool to capture patterns in ILD collected by mobile health devices. It is particularly useful in assessing longitudinal dynamic association between repeated measures and outcomes, and can be easily integrated in prediction models to improve prediction precision.Item Open Access Radiomics analysis using stability selection supervised component analysis for right-censored survival data.(Computers in biology and medicine, 2020-09) Yan, Kang K; Wang, Xiaofei; Lam, Wendy WT; Vardhanabhuti, Varut; Lee, Anne WM; Pang, Herbert HRadiomics is a newly emerging field that involves the extraction of massive quantitative features from biomedical images by using data-characterization algorithms. Distinctive imaging features identified from biomedical images can be used for prognosis and therapeutic response prediction, and they can provide a noninvasive approach for personalized therapy. So far, many of the published radiomics studies utilize existing out of the box algorithms to identify the prognostic markers from biomedical images that are not specific to radiomics data. To better utilize biomedical images, we propose a novel machine learning approach, stability selection supervised principal component analysis (SSSuperPCA) that identifies stable features from radiomics big data coupled with dimension reduction for right-censored survival outcomes. The proposed approach allows us to identify a set of stable features that are highly associated with the survival outcomes in a simple yet meaningful manner, while controlling the per-family error rate. We evaluate the performance of SSSuperPCA using simulations and real data sets for non-small cell lung cancer and head and neck cancer, and compare it with other machine learning algorithms. The results demonstrate that our method has a competitive edge over other existing methods in identifying the prognostic markers from biomedical imaging data for the prediction of right-censored survival outcomes.Item Open Access Seasonal variations in air pollution particle-induced inflammatory mediator release and oxidative stress.(Environmental health perspectives, 2005-08) Becker, Susanne; Dailey, Lisa A; Soukup, Joleen M; Grambow, Steven C; Devlin, Robert B; Huang, Yuh-Chin THealth effects associated with particulate matter (PM) show seasonal variations. We hypothesized that these heterogeneous effects may be attributed partly to the differences in the elemental composition of PM. Normal human bronchial epithelial (NHBE) cells and alveolar macrophages (AMs) were exposed to equal mass of coarse [PM with aerodynamic diameter of 2.5-10 microm (PM(2.5-10)], fine (PM(2.5)), and ultrafine (PM(<0.1)) ambient PM from Chapel Hill, North Carolina, during October 2001 (fall) and January (winter), April (spring), and July (summer) 2002. Production of interleukin (IL)-8, IL-6, and reactive oxygen species (ROS) was measured. Coarse PM was more potent in inducing cytokines, but not ROSs, than was fine or ultrafine PM. In AMs, the October coarse PM was the most potent stimulator for IL-6 release, whereas the July PM consistently stimulated the highest ROS production measured by dichlorofluorescein acetate and dihydrorhodamine 123 (DHR). In NHBE cells, the January and the October PM were consistently the strongest stimulators for IL-8 and ROS, respectively. The July PM increased only ROS measured by DHR. PM had minimal effects on chemiluminescence. Principal-component analysis on elemental constituents of PM of all size fractions identified two factors, Cr/Al/Si/Ti/Fe/Cu and Zn/As/V/Ni/Pb/Se, with only the first factor correlating with IL-6/IL-8 release. Among the elements in the first factor, Fe and Si correlated with IL-6 release, whereas Cr correlated with IL-8 release. These positive correlations were confirmed in additional experiments with PM from all 12 months. These results indicate that elemental constituents of PM may in part account for the seasonal variations in PM-induced adverse health effects related to lung inflammation.Item Open Access Sex, temperament, and family context: how the interaction of early factors differentially predict adolescent alcohol use and are mediated by proximal adolescent factors.(Psychol Addict Behav, 2011-03) Burk, Linnea R; Armstrong, Jeffrey M; Goldsmith, H Hill; Klein, Marjorie H; Strauman, Timothy J; Costanzo, Phillip; Essex, Marilyn JAdolescent alcohol use is common and has serious immediate and long-term ramifications. While concurrent individual and context factors are robustly associated with adolescent alcohol use, the influence of early childhood factors, particularly in interaction with child sex, are less clear. Using a prospective community sample of 362 (190 girls), this study investigated sex differences in the joint influence of distal childhood and proximal adolescent factors on Grade 10 alcohol use. All risk factors and two-way early individual-by-context interactions, and interactions of each of these with child sex, were entered into the initial regression. Significant sex interactions prompted the use of separate models for girls and boys. In addition to the identification of early (family socioeconomic status, authoritative parenting style) and proximal adolescent (mental health symptoms, deviant friends) risk factors for both girls and boys, results highlighted important sex differences. In particular, girls with higher alcohol consumption at Grade 10 were distinguished by the interaction of early temperamental disinhibition and exposure to parental stress; boys with higher alcohol consumption at Grade 10 were distinguished primarily by early temperamental negative affect. Results have implications for the timing and type of interventions offered to adolescents.Item Open Access Strong Selection at MHC in Mexicans since Admixture.(PLoS genetics, 2016-02-10) Zhou, Quan; Zhao, Liang; Guan, YongtaoMexicans are a recent admixture of Amerindians, Europeans, and Africans. We performed local ancestry analysis of Mexican samples from two genome-wide association studies obtained from dbGaP, and discovered that at the MHC region Mexicans have excessive African ancestral alleles compared to the rest of the genome, which is the hallmark of recent selection for admixed samples. The estimated selection coefficients are 0.05 and 0.07 for two datasets, which put our finding among the strongest known selections observed in humans, namely, lactase selection in northern Europeans and sickle-cell trait in Africans. Using inaccurate Amerindian training samples was a major concern for the credibility of previously reported selection signals in Latinos. Taking advantage of the flexibility of our statistical model, we devised a model fitting technique that can learn Amerindian ancestral haplotype from the admixed samples, which allows us to infer local ancestries for Mexicans using only European and African training samples. The strong selection signal at the MHC remains without Amerindian training samples. Finally, we note that medical history studies suggest such a strong selection at MHC is plausible in Mexicans.Item Open Access Testosterone secretion varies in a sex- and stage-specific manner: Insights on the regulation of competitive traits from a sex-role reversed species.(General and comparative endocrinology, 2020-06) Lipshutz, Sara E; Rosvall, Kimberly ATestosterone (T) mediates a variety of traits that function in competition for mates, including territorial aggression, ornaments, armaments, and gametogenesis. The link between T and mating competition has been studied mainly in males, but females also face selection pressures to compete for mates. Sex-role reversed species, in which females are the more competitive sex, provide a unique perspective on the role of T in promoting competitive traits. Here, we examine patterns of T secretion in sex-role reversed northern jacanas (Jacana spinosa) during breeding, when females are fertile and males are either seeking copulations or conducting parental care. We measured baseline levels of T in circulation along with a suite of behavioral and morphological traits putatively involved in mating competition. We evaluated hypotheses that levels of T track gonadal sex and parental role, and we begin to investigate whether T and competitive traits co-vary in a sex- and stage- specific manner. Although females had higher expression of competitive traits than males at either breeding stage, we found that females and incubating males had similar levels of T secretion, which were lower than those observed in copulating males. T was correlated with wing spur length in females and testes mass in copulating males, but was otherwise uncorrelated with other competitive traits. These findings suggest that levels of T in circulation alone do not predict variation in competitive traits across levels of analysis, including gonadal sex and parental role. Instead, our findings coupled with prior research indicate that selection for female mating competition and male care may generate different physiological regulation of competitive traits.Item Open Access Tissue-specific genetic control of splicing: implications for the study of complex traits.(PLoS Biol, 2008-12-23) Heinzen, Erin L; Ge, Dongliang; Cronin, Kenneth D; Maia, Jessica M; Shianna, Kevin V; Gabriel, Willow N; Welsh-Bohmer, Kathleen A; Hulette, Christine M; Denny, Thomas N; Goldstein, David BNumerous genome-wide screens for polymorphisms that influence gene expression have provided key insights into the genetic control of transcription. Despite this work, the relevance of specific polymorphisms to in vivo expression and splicing remains unclear. We carried out the first genome-wide screen, to our knowledge, for SNPs that associate with alternative splicing and gene expression in human primary cells, evaluating 93 autopsy-collected cortical brain tissue samples with no defined neuropsychiatric condition and 80 peripheral blood mononucleated cell samples collected from living healthy donors. We identified 23 high confidence associations with total expression and 80 with alternative splicing as reflected by expression levels of specific exons. Fewer than 50% of the implicated SNPs however show effects in both tissue types, reflecting strong evidence for distinct genetic control of splicing and expression in the two tissue types. The data generated here also suggest the possibility that splicing effects may be responsible for up to 13 out of 84 reported genome-wide significant associations with human traits. These results emphasize the importance of establishing a database of polymorphisms affecting splicing and expression in primary tissue types and suggest that splicing effects may be of more phenotypic significance than overall gene expression changes.Item Open Access Use of 16S ribosomal RNA gene analyses to characterize the bacterial signature associated with poor oral health in West Virginia.(BMC Oral Health, 2011-03-01) Olson, Joan C; Cuff, Christopher F; Lukomski, Slawomir; Lukomska, Ewa; Canizales, Yeremi; Wu, Bei; Crout, Richard J; Thomas, John G; McNeil, Daniel W; Weyant, Robert J; Marazita, Mary L; Paster, Bruce J; Elliott, ThomasBACKGROUND: West Virginia has the worst oral health in the United States, but the reasons for this are unclear. This pilot study explored the etiology of this disparity using culture-independent analyses to identify bacterial species associated with oral disease. METHODS: Bacteria in subgingival plaque samples from twelve participants in two independent West Virginia dental-related studies were characterized using 16S rRNA gene sequencing and Human Oral Microbe Identification Microarray (HOMIM) analysis. Unifrac analysis was used to characterize phylogenetic differences between bacterial communities obtained from plaque of participants with low or high oral disease, which was further evaluated using clustering and Principal Coordinate Analysis. RESULTS: Statistically different bacterial signatures (P<0.001) were identified in subgingival plaque of individuals with low or high oral disease in West Virginia based on 16S rRNA gene sequencing. Low disease contained a high frequency of Veillonella and Streptococcus, with a moderate number of Capnocytophaga. High disease exhibited substantially increased bacterial diversity and included a large proportion of Clostridiales cluster bacteria (Selenomonas, Eubacterium, Dialister). Phylogenetic trees constructed using 16S rRNA gene sequencing revealed that Clostridiales were repeated colonizers in plaque associated with high oral disease, providing evidence that the oral environment is somehow influencing the bacterial signature linked to disease. CONCLUSIONS: Culture-independent analyses identified an atypical bacterial signature associated with high oral disease in West Virginians and provided evidence that the oral environment influenced this signature. Both findings provide insight into the etiology of the oral disparity in West Virginia.