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Item Open Access Amino Acid-Level Signal-to-Noise Analysis Aids in Pathogenicity Prediction of Incidentally Identified TTN-Encoded Titin Truncating Variants.(Circulation. Genomic and precision medicine, 2021-02) Connell, Patrick S; Berkman, Amy M; Souder, BriAnna M; Pirozzi, Elisa J; Lovin, Julia J; Rosenfeld, Jill A; Liu, Pengfei; Tunuguntla, Hari; Allen, Hugh D; Denfield, Susan W; Kim, Jeffrey J; Landstrom, Andrew PBackground
TTN, the largest gene in the human body, encodes TTN (titin), a protein that plays key structural, developmental, and regulatory roles in skeletal and cardiac muscle. Variants in TTN, particularly truncating variants (TTNtvs), have been implicated in the pathogenicity of cardiomyopathy. Despite this link, there is also a high burden of TTNtvs in the ostensibly healthy general population. This complicates the diagnostic interpretation of incidentally identified TTNtvs, which are of increasing abundance given expanding clinical exome sequencing.Methods
Incidentally identified TTNtvs were obtained from a large referral database of clinical exome sequencing (Baylor Genetics) and compared with rare population variants from genome aggregation database and cardiomyopathy-associated variants from cohort studies in the literature. A subset of TTNtv-positive children evaluated for cardiomyopathy at Texas Children's Hospital was retrospectively reviewed for clinical features of cardiomyopathy. Amino acid-level signal-to-noise analysis was performed.Results
Pathological hotspots were identified within the A-band and N-terminal I-band that closely correlated with regions of high percent-spliced in of exons. Incidental TTNtvs and population TTNtvs did not localize to these regions. Variants were reclassified based on current American College of Medical Genetics and Genomics criteria with incorporation of signal-to-noise analysis among Texas Children's Hospital cases. Those reclassified as likely pathogenic or pathogenic were more likely to have evidence of cardiomyopathy on echocardiography than those reclassified as variants of unknown significance.Conclusions
Incidentally found TTNtvs are common among clinical exome sequencing referrals. Pathological hotspots within the A-band of TTN may be informative in determining variant pathogenicity when incorporated into current American College of Medical Genetics and Genomics guidelines.Item Open Access Essays on Population, Environment and Development(2018) Burrows, Michael AndrewEcological factors and the policy environment are central constraints on population well-being. This dissertation emphasizes the role of shocks to help understand the nature of such constraints, and explores the relationship between population, environment, and development in greater detail than is typically possible.
Chapter 1 opens by contributing to a growing body of evidence around the impacts of old-age pensions on the well-being of pension recipients and their families. I draw from the unique disbursement structure of a popular, widely utilized benefits program in rural Brazil, and data from two nationally representative surveys conducted in 2013 by the Brazilian Institute of Geography and Statistics. I first employ regression discontinuity design to measure the direct effect of the program’s age threshold on pension take-up. Second, I compare differences in reports of health and well-being among age-eligible and age-ineligible adults in rural areas to the same differences among populations that generally do not qualify for the benefit (i.e., urban populations). This difference-in-differences shows robust evidence of a beneficial pension effect, though along somewhat different dimensions by gender. I then show evidence of two credible mechanisms for improved health and well-being: first, improved food security within households that have eligible pension recipients; second, the cohabitation of younger family members, potentially providing support to aging family members. Taken together, this chapter demonstrates that the rural benefits program in Brazil leads to tangible health benefits for its recipients, through channels that are likely to complement rather than crowd out other public services.
Chapter 2 moves on to explore how a massive natural disaster affected smoking behavior, a common coping mechanism. External stressors are commonly hypothesized to play a role in the adoption of certain health behaviors, but understanding the role of exposure is frequently hampered by research designs and data that are inadequate for tracing causality. I use this study to evaluate the relationship between unanticipated exposure to a natural disaster and smoking behaviors using longitudinal data collected from families in Aceh, Indonesia before and after the 2004 Indian Ocean tsunami. Exposure to the tsunami is measured as a community indicator of physical proximity to damage, and as individual indicators of personal experiences at the time of the tsunami. My analysis indicates that the effect of exposure on smoking uptake varies considerably by age, and that most forms of exposure increase smoking volume. These effects appear to be temporary, but even in the context of Indonesia’s extraordinarily high smoking rates an impact is perceptible even ten years after the tsunami.
Chapter 3 delves further into the effects of the tsunami, exploring the distribution of resources after the broad destruction of infrastructure and subsequent, fast-paced reconstruction. I evaluate multiple aspects of water access for roughly 6,000 families through 2014. Logit regression analysis show increasing disparities in access to basic amounts of water, and multinomial logit regression analysis indicates that shifts are driven by a massive increase in the market for privately distributed bottled water. This study disentangles key distributional processes to show how reconstruction influenced a central social determinant of health among an already vulnerable population.
The chapters to follow aim to relate the well-being of individuals to the influences that arise from interconnected policy choices and ecological factors. The first chapter emphasizes a policy shock, the second an ecological shock, and the second seeks to identify a combined effect of the two. This original research is intended to help illuminate the role that institutions might play in improving population well-being.
Item Open Access GWAS Identifies New Loci for Painful Temporomandibular Disorder.(J Dent Res, 2017-01-01) Sanders, AE; Jain, D; Sofer, T; Kerr, KF; Laurie, CC; Shaffer, JR; Marazita, ML; Kaste, LM; Slade, GD; Fillingim, RB; Ohrbach, R; Maixner, W; Kocher, T; Bernhardt, O; Teumer, A; Schwahn, C; Sipilä, K; Lähdesmäki, R; Männikkö, M; Pesonen, P; Järvelin, M; Rizzatti-Barbosa, CM; Meloto, CB; Ribeiro-Dasilva, M; Diatchenko, L; Serrano, P; Smith, SBTemporomandibular disorder (TMD) is a musculoskeletal condition characterized by pain and reduced function in the temporomandibular joint and/or associated masticatory musculature. Prevalence in the United States is 5% and twice as high among women as men. We conducted a discovery genome-wide association study (GWAS) of TMD in 10,153 participants (769 cases, 9,384 controls) of the US Hispanic Community Health Study/Study of Latinos (HCHS/SOL). The most promising single-nucleotide polymorphisms (SNPs) were tested in meta-analysis of 4 independent cohorts. One replication cohort was from the United States, and the others were from Germany, Finland, and Brazil, totaling 1,911 TMD cases and 6,903 controls. A locus near the sarcoglycan alpha ( SGCA), rs4794106, was suggestive in the discovery analysis ( P = 2.6 × 10(6)) and replicated (i.e., 1-tailed P = 0.016) in the Brazilian cohort. In the discovery cohort, sex-stratified analysis identified 2 additional genome-wide significant loci in females. One lying upstream of the relaxin/insulin-like family peptide receptor 2 ( RXP2) (chromosome 13, rs60249166, odds ratio [OR] = 0.65, P = 3.6 × 10(-8)) was replicated among females in the meta-analysis (1-tailed P = 0.052). The other (chromosome 17, rs1531554, OR = 0.68, P = 2.9 × 10(-8)) was replicated among females (1-tailed P = 0.002), as well as replicated in meta-analysis of both sexes (1-tailed P = 0.021). A novel locus at genome-wide level of significance (rs73460075, OR = 0.56, P = 3.8 × 10(-8)) in the intron of the dystrophin gene DMD (X chromosome), and a suggestive locus on chromosome 7 (rs73271865, P = 2.9 × 10(-7)) upstream of the Sp4 Transcription Factor ( SP4) gene were identified in the discovery cohort, but neither of these was replicated. The SGCA gene encodes SGCA, which is involved in the cellular structure of muscle fibers and, along with DMD, forms part of the dystrophin-glycoprotein complex. Functional annotation suggested that several of these variants reside in loci that regulate processes relevant to TMD pathobiologic processes.Item Embargo “Make Me Live Long Enough to See Such Things”: Citizenship, Labor, and Population Politics in the Nineteenth-Century French Caribbean(2023) Allain, JacquelineThis dissertation centers on Antillean women’s brushes with the French colonial state in nineteenth-century Martinique and Guadeloupe. It argues that while nineteenth-century French Caribbean of African descent women were, by and large, ignored by colonial authorities—unsurprisingly, considered less-than-citizens and, more surprisingly, seldom targeted for or involved in interventions aimed at ‘moral uplift’—they found myriad ways to enact citizenship and forms of belonging. Close analysis of women’s encounters with colonial power in the French Antilles reveals the ways in which gender shaped the contours of women’s political subjectivities. Anchored and intervening in the broad, overlapping fields of Caribbean history, French imperial history, women’s and gender history, and labor history, this dissertation examines subaltern women’s political praxis as they engaged in the realm of reproduction writ large in the midst of their work in both plantation labor and non-plantation waged labor. I argue that, through these engagements, women often offered visions of home and citizenship that transcended the commodifying logics of slavery, racial capitalism, and colonialism.
Item Open Access Practice-Level Variation in Outpatient Cardiac Care and Association With Outcomes.(J Am Heart Assoc, 2016-02-23) Clough, Jeffrey D; Rajkumar, Rahul; Crim, Matthew T; Ott, Lesli S; Desai, Nihar R; Conway, Patrick H; Maresh, Sha; Kahvecioglu, Daver C; Krumholz, Harlan MBACKGROUND: Utilization of cardiac services varies across regions and hospitals, yet little is known regarding variation in the intensity of outpatient cardiac care across cardiology physician practices or the association with clinical endpoints, an area of potential importance to promote efficient care. METHODS AND RESULTS: We included 7 160 732 Medicare beneficiaries who received services from 5635 cardiology practices in 2012. Beneficiaries were assigned to practices providing the plurality of office visits, and practices were ranked and assigned to quartiles using the ratio of observed to predicted annual payments per beneficiary for common cardiac services (outpatient intensity index). The median (interquartile range) outpatient intensity index was 1.00 (0.81-1.24). Mean payments for beneficiaries attributed to practices in the highest (Q4) and lowest (Q1) quartile of outpatient intensity were: all cardiac payments (Q4 $1272 vs Q1 $581; ratio, 2.2); cardiac catheterization (Q4 $215 vs Q1 $64; ratio, 3.4); myocardial perfusion imaging (Q4 $253 vs Q1 $83; ratio, 3.0); and electrophysiology device procedures (Q4 $353 vs Q1 $142; ratio, 2.5). The adjusted odds ratios (95% CI) for 1 incremental quartile of outpatient intensity for each outcome was: cardiac surgical/procedural hospitalization (1.09 [1.09, 1.10]); cardiac medical hospitalization (1.00 [0.99, 1.00]); noncardiac hospitalization (0.99 [0.99, 0.99]); and death at 1 year (1.00 [0.99, 1.00]). CONCLUSION: Substantial variation in the intensity of outpatient care exists at the cardiology practice level, and higher intensity is not associated with reduced mortality or hospitalizations. Outpatient cardiac care is a potentially important target for efforts to improve efficiency in the Medicare population.Item Open Access Seed Dispersal, Gene Flow, and Hybridization in Red Oak(2010) Moran, Emily VictoriaUnderstanding the ecological and evolutionary responses of plant species to shifts in climate (and other rapid environmental perturbations) will require an improved knowledge of interactions between ecological and evolutionary processes as mediated by reproduction and gene flow. This dissertation research examines the processes of seed dispersal, intra- and inter-specific gene flow, and reproductive success in two red oak populations in North Carolina; the variation in these processes from site to site; and their influence on genetic structure, population dynamics, and migration potential.
Using genetic and ecological data collected from two large long-term study sites, I develop a hierarchical Bayesian model to identify the parents of sampled seedlings and characterize the scale of effective seed and pollen dispersal. I examine differences in scale of dispersal between the Appalachian and Piedmont sites in light of the spatial genetic structure and ecological differences of the two sites. I then use the pedigree and dispersal estimates derived from these analyses to examine variation in reproductive success and to test hypotheses about the causes and consequences of such variation. Using parentage estimates and measures of genetic differentiation between species, I study the likely extent of hybridization in these mixed-species secondary forests. Finally, using the SLIP stand simulator, I explore the implications of new genetic dispersal estimates for migration potential in oaks.
I find that effective seed dispersal distances are longer than estimated using seed trap data. While at the Piedmont site the large number of seedling found >100 m from their mother trees suggests that animal dispersers play a vital role, at the Appalachian site seedling distributions conform more closely to the original gravity-created pattern of seed density. Individual trees vary widely in their reproductive success. Seedling production was found to be positively associated with annual seed production, but exhibited hump-shaped or reversing relationships with age (suggesting the effect of senescence) and growth rate (suggesting tradeoffs in allocation). Germination fraction was negatively associated with fecundity, suggesting that density-dependent mortality may be acting on the high concentrations of seeds near highly fecund adults. Due to overlapping generations and variation in individual reproductive success, effective population size is estimated to be less than half the size that numbers of "adult" individuals would suggest, with consequences for the relative strength of drift and selection. Hybridization may boost effective population size somewhat; my analyses suggest that inter-specific gene flow is common at both study sites. Finally, simulations show that dispersal has a relatively stronger effect on migration rate and population growth than fecundity or size at maturity, and that genetic estimates of seed dispersal can yield significantly higher rates of migration and/or population persistence than seed-trap based estimates under both competitive and non-competitive conditions.
Item Open Access Separable codes for read-out of mouse primary visual cortex across attentional states(2019) Wilson, Ashley MarieAttentional modulation of neuronal activity in sensory cortex could alter perception by enhancing the local representation of attended stimuli or its behavioral read-out downstream. We tested these hypotheses using a task in which mice are cued on interleaved trials to attend visual or auditory targets. Neurons in primary visual cortex (V1) that encode task stimuli have larger visually-evoked responses when attention is directed toward vision. To determine whether the attention-dependent changes in V1 reflect changes in representation or read-out, we decoded task stimuli and choices from population activity. Surprisingly, both visual and auditory choices can be decoded from V1, but decoding takes advantage of unique activity patterns across modalities. Furthermore, decoding of choices, but not stimuli, is impaired when attention is directed toward the opposite modality. The specific effect on choice suggests behavioral improvements with attention are largely due to targeted read-out of the most informative V1 neurons.
Item Open Access The Ends of the World-System: Resource Scarcity and Population Panics from Chesney to London(2022) Ren, JosephThis dissertation seeks to understand the conditions of hegemonic transfer, in the case of world-historical cycles of accumulation, through investigating the cultural production of the period. I examine turn of the century British and American science fiction to more fully comprehend the historical situation of imperial decline, and find that a concern with the possibility of resource depletion and imminent future “overpopulation” of racialized people, specifically Chinese people, lie at the heart of cultural understandings of the turmoil which the British-led world economic, social, and political system had entered. I thus study its science fictional imaginations of the future, mainly constellated around the threat of social collapse occasioned by future war, invasion, or resource scarcity, then emergent in order to elucidate how cultural production narrates the historical tendencies of intensifying industrialization, the formation of the military-industrial complex, economic stagnation, and increasing imperial instability. Given that the US-led world-system has itself has seemingly entered protracted decline, and as “overpopulation” once more emerges as a prominent social problem, especially as imbricated within global climate collapse, this dissertation contributes to a more thorough understanding of the present through comparison with a historically analogous cultural instance.
Item Open Access Trends in clinical, demographic, and biochemical characteristics of patients with acute myocardial infarction from 2003 to 2008: a report from the american heart association get with the guidelines coronary artery disease program.(J Am Heart Assoc, 2012-08) Boyer, Nathan M; Laskey, Warren K; Cox, Margueritte; Hernandez, Adrian F; Peterson, Eric D; Bhatt, Deepak L; Cannon, Christopher P; Fonarow, Gregg CBACKGROUND: An analysis of the changes in the clinical and demographic characteristics of patients with acute myocardial infarction could identify successes and failures of risk factor identification and treatment of patients at increased risk for cardiovascular events. METHODS AND RESULTS: We reviewed data collected from 138 122 patients with acute myocardial infarction admitted from 2003 to 2008 to hospitals participating in the American Heart Association Get With The Guidelines Coronary Artery Disease program. Clinical, demographic, and laboratory characteristics were analyzed for each year stratified on the electrocardiogram at presentation. Patients with non-ST-segment-elevation myocardial infarction were older, more likely to be women, and more likely to have hypertension, diabetes mellitus, and a history of past cardiovascular disease than were patients with ST-elevation myocardial infarction. In the overall patient sample, significant trends were observed of an increase over time in the proportions of non-ST-segment-elevation myocardial infarction, patient age of 45 to 65 years, obesity, and female sex. The prevalence of diabetes mellitus decreased over time, whereas the prevalences of hypertension and smoking were substantial and unchanging. The prevalence of "low" high-density lipoprotein increased over time, whereas that of "high" low-density lipoprotein decreased. Stratum-specific univariate analysis revealed quantitative and qualitative differences between strata in time trends for numerous demographic, clinical, and biochemical measures. On multivariable analysis, there was concordance between strata with regard to the increase in prevalence of patients 45 to 65 years of age, obesity, and "low" high-density lipoprotein and the decrease in prevalence of "high" low-density lipoprotein. However, changes in trends in age distribution, sex ratio, and prevalence of smokers and the magnitude of change in diabetes mellitus prevalence differed between strata. CONCLUSIONS: There were notable differences in risk factors and patient characteristics among patients with ST-elevation myocardial infarction and those with non-ST-segment-elevation myocardial infarction. The increasing prevalence of dysmetabolic markers in a growing proportion of patients with acute myocardial infarction suggests further opportunities for risk factor modification. (J Am Heart Assoc. 2012;1:e001206 doi: 10.1161/JAHA.112.001206.).