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Improving Molecular Diagnosis Of Suspected Mendelian Disorders With Rna Splicing Analysis
Get PDFExome sequencing is the most advanced standard-of-care genetic test for people with suspected Mendelian disorders. Yet, the diagnostic rate of exome sequencing is only 31%. RNA sequencing (RNA-seq) is a promising molecular test for detecting potentially pathogenic changes in RNA splicing as part of obtaining a molecular diagnosis. In this dissertation, I develop new computational tools and perform analyses towards improving how we detect these potentially pathogenic changes in RNA splicing with the goal of improving the molecular diagnostic rate. First, in Chapter 1, I review background on how we diagnose patients and how RNA splicing and RNA-seq could be used to improve this process. Then, in Chapter 2, I describe my contributions to MAJIQ v2 as methodology to study RNA splicing from large and heterogeneous RNA-seq datasets. Afterwards, I use MAJIQ v2 in Chapter 3 to evaluate how tissue-specific expression and splicing affects what clinically-relevant splicing changes we can identify from clinically-accessible tissues. Then, in Chapter 4, I describe the limitations of MAJIQ v2 for our approach to detect splicing aberrations and the development and evaluation of MAJIQ v3 to address these challenges. With MAJIQ v3, I develop MAJIQ-CLIN in Chapter 5 to identify and prioritize splicing aberrations in patient RNA-seq data and compare our method to previous approaches. Finally, in Chapter 6, I discuss overall conclusions for the work and exciting areas for future work. Together, the work in this dissertation pushes forward how we can study and use RNA-seq to improve the diagnostic rate of patients with suspected Mendelian disorders
Design, Synthesis And Reactivity Of 2,5-Bis(-Pyridyl)pyrrolate-Ligated Platinum And Palladium Complexes
No full textSelective functionalization of hydrocarbons into higher-value products would reduce the environmental impacts currently associated with the petrochemical industry. Using a green oxidant, such as dioxygen, to effect these oxidation/oxygenation reactions would also be environmentally beneficial. This dissertation reports results aimed at furthering the understanding of key fundamental reaction steps in proposed catalytic cycles of aerobic alkane activation using Pt and Pd complexes. To this end, a series of tridentate nitrogenous ligands have been synthesized and ligated to Pt and Pd. New binding modes have been observed and the general advantages and limitations of these ligands are discussed. In Chapter 2, studies into the metallation of ortho-substituted 1,3-bis(2-pyridylimino)isoindolate (BPI) ligands and a series of new ortho-functionalized 2,5-bis(-pyridyl)-pyrrolate (PDP) ligands are discussed. In Chapter 3, the metallation of PDP to Pt/Pd to form a series of monomer and dimer complexes is described. A rationale for monomer versus dimer formation is presented, as well as experiments into monomer/dimer interconversion. In Chapter 4, fundamental reactivity of the PDP-ligated Pt/Pd complexes toward individual steps of selective alkane functionalization is explored
Synthetic Studies Toward The Total Synthesis Of Nahuoic Acids Cii And Dii
No full textAs part of the continued synthetic campaign targeting the bioactive natural products in the Smith Laboratory, the dissertation herein describes the studies toward the total synthesis of nahuoic acids Cii and Dii, two polyol polyketide congeners that were isolated in culture from a tropical marine microorganism Streptomyces sp.. Their architecture features a densely functionalized cis-decalin core affixed to a polyol polyketide side chain which holds considerate promise to showcase Anion Relay Chemistry (ARC) - a focal point of research in the Smith group over the years. Our diversity-oriented approach entails an asymmetric Diels-Alder reaction to provide access to the common decalin intermediate, Type I and Type II ARC to rapidly assemble two alkyne side chains of different lengths and a strategic Micalizio alkene-alkyne reductive coupling tactic to unite the two fragments. Accordingly, the convergent blueprint proved to be a proof of concept in construction of the backbone of the two natural products. However, the inherent reluctance of the vinyl group to engage in a critical late-stage functionalization prevented us from putting the two nahuoic acids within reach. The above unfortunate outcome, despite considerable experimentation in the cross metathesis-based endgame, led us to reevaluate the synthetic route. Current synthetic efforts hinge upon the late-stage functionalization of an alkynyl moiety to the unsaturated carboxylic acid
Applications Of Advanced Statistical Modeling Techniques For Understanding Depression
Get PDFWe conducted three investigations into different facets of major depressive disorder. Chapter One describes the application of hierarchical modeling techniques in combination with the Linguistic Inquiry Word Count to characterize associations between depressed individuals’ emotion regulation strategies and their discrete state emotion. State emotion was associated with emotion regulation strategy selection, independent of the adaptiveness of the coping response. In Chapter Two we investigated the relationship between urban living and depression, using meta-analytic and meta-regression techniques to characterize how this relationship has changed over time across both developed and developing countries. In developed countries, depression prevalence was higher in urban areas than rural areas. In developing countries, no overall effect of urbanicity was found, although a relationship between urbanicity and depression appears to be emerging over time. Chapter Three describes an investigation comparing the accuracy of traditional and machine learning model building algorithms for predicting patient outcomes in response to antidepressant treatment. Traditional model building techniques designed for inferential analysis were found to be poorly suited for the purposes of prediction. Machine learning techniques designed for prediction can make accurate predictions; however, their utility is limited by how they are applied and to their access to informative predictors
Hygiene And Daily Life In Republican China, 1911—1945
Get PDFThis dissertation reveals how acceptable, clean, responsible behaviours were defined through overlapping, transnational networks of both medical professionals and laypeople, and how the proliferation of these developments featured in the everyday lives of Chinese in the early twentieth century. Responding to previous studies of public health in Republican China on the central government’s institutions, the project instead explores aspects of daily life and public opinion from grassroots actors, highlighting myriad nuanced lived experiences and the inherent value that ordinary Chinese placed on health and social responsibility. Chinese society in the early twentieth century was cosmopolitan in its outlook and influenced by internationally-circulating ideas of health, wellness, and innovative progress; even small, rural communities exercised local autonomy to institute hygiene education campaigns, leading to innovative collaborations between international organizations and local leaders.
The first chapter is an extended case study of the province of Shanxi between 1918 and 1928, and an intervention into previous scholarship which assumes that effective public health was impossible before the establishment of national infrastructure in 1928. Beginning with plague control in early 1918, Shanxi leveraged global-local partnerships into opportunities for the development of localized public health campaigns. Hygiene initiatives gained popularity precisely because reformists carefully addressed local concerns, and because the public recognized the tangible benefits to their daily lives. The themes apparent in the first chapter are then explored at length. Each following chapter focuses on a specific communal space in which new expectations of hygienic behaviour were formed. The chapters are focused on the “School”, “Kitchen”, “Home”, and “Public Streets”. At each site, the maturation of hygiene teaching and practice was driven by, and indeed made possible by, individuals at the local level, even when they mirrored national developments.
Together, the chapters are a comprehensive exploration of idiosyncratic hygiene improvement developments and their participants, elevating lived experience and local agency along the way. Moreover, the dissertation asserts China’s establishment as an important, proven participant in the global organizations for the advancement of public health
Essays In Climate Finance
Get PDFIn the first chapter, Climate Finance in Financial Markets , I propose a model that determinesthe discount rate on large-scale climate change mitigation projects. In the model, climate change is present through disasters that destroy capital. Disaster probability is endogenous and grows with emissions that evolve with new investments in carbon-intensive capital. I show that large-scale projects or policies aimed at abating climate change should be discounted with a rate significantly lower than the market rate. I also show the additional losses the economy will incur if the policy awaits several years to start. Finally, I show that only the transition risks rather than the physical risks can explain the green premium and reconcile the theoretical predictions with historical observations. The second chapter, Climate Change Adaptation in Financial Markets , proposes a model that determines the appropriate discount rate on projects that adapt to climate change. In addition, it helps determine the best time to start implementing climate policy. The model is production-based and features endogenous climate-related disasters. It suggests that the discount rate on climate change adaptation projects is lower than that on the risk-free rate and that it is optimal to start investing in them as soon as possible. The third chapter, Adapting to Climate Change: A Disaster-Based Asset Pricing Model , co-authored with Jessica A. Wachter, answers a similar question but with a different approach. In the model, disaster probability increases in the temperature anomaly as soon as the latter surpasses a tipping point. The model suggests that the discount rate on climate change adaptation projects reaches zero as soon as the tipping point is reached while the climate beta becomes negative at that time
Organizational Change, Payment Reform, And The Value Of Hospital Care
No full textThis dissertation applies economic, program evaluation, and machine learning tools to study productivity in the hospital sector. The market for hospital care has been transformed by two broad developments over the previous decade. First, traditionally independent physicians and hospitals have increasingly opted to form integrated organizations, consolidating control over both in a single firm. Second, provider payments have increasingly become linked to quality or value, generating new incentives to reduce spending and improve value. The first half of this dissertation describes new data on physician-hospital vertical integration (VI), changes in quality and spending due to VI, and whether VI promotes savings under value-based payment. The second half of this dissertation documents causal effects, selection bias, and treatment effect heterogeneity under voluntary and mandatory payment programs. The following four chapters contribute to an important literature on hospital productivity and its relationship to organizational form and the payment system.
(i) Vertical Mergers & Firm Performance. I estimate the effects of VI on quality of care and spending during and after acute hospitalization. To ameliorate concerns about patient sorting, I use an instrumental variables strategy leveraging persistent referral patterns. On average, I find no evidence that financial integration changed quality of care or spending for hospitalized patients. However, I find that average effects of VI mask substantial heterogeneity by patient illness severity. For patients in the top decile of severity, VI reduced mortality by 2 percentage points without increases in spending. However, spending increased by 4% for patients in the bottom 40% of the severity distribution without mortality benefit.
(ii) Vertical Integration & Savings in Bundled Payments. This study examines the association between VI and treatment effects of bundled payments estimated from a randomized control trial of mandatory bundled payments using a difference-in-differences framework. Institutional spending per joint replacement fell more for treated hospitals on average. These changes in spending were not associated with VI. The lack of association suggests that any advantage integrated hospitals have in coordinating care may not be necessary for success in bundled payments.
(iii) Selection & Causal Effects in Voluntary Programs. Most payment reform programs allow participants to opt in; this can improve productivity due to selection on treatment gains but may limit validity of estimated effects due to confounding. We study both in the setting of a large voluntary bundled payment reform in Medicare. We use variation in costs from idiosyncratic program rules to estimate marginal treatment effects. Our results suggest there was minimal sorting on unobserved treatment gains but meaningful selection bias due to confounding. Observable factors cannot explain more than 30% of this bias, illustrating the challenge of assessing voluntary programs.
(iv) Personalized Payment Reform? I analyze the extent to which observable characteristics predict the returns to participation in value-based payment. I leverage a field experiment of bundled payments and machine learning tools to model variation in effects across participants. Spending reductions due to bundles vary significantly – cases predicted to have the largest reductions saved $2,700 more than those that saved least. While I find no effect on average quality, complications were reduced by 2 percentage points for the group most affected by the program. Evidence suggests that vulnerable patients receive the most benefit, a finding which holds for both spending and complications
Blimp1 And Nr4a3 Transcription Factors Reciprocally Regulate Antitumor Car T-Cell Stemness And Exhaustion
Get PDFChimeric antigen receptor (CAR) T-cells have not induced meaningful clinical responses in solid tumor indications. Loss of T-cell stemness, poor expansion capacity and exhaustion during prolonged tumor antigen exposure are major causes of CAR T-cell therapeutic resistance. scRNA-sequencing analysis of CAR T-cells from a first-in-human trial in metastatic prostate cancer identified two distinct and independently validated cell states associated with antitumor potency or lack of efficacy. Low levels of the PRDM1 gene encoding the BLIMP1 transcription factor defined highly potent TCF7+CD8+ CAR T-cells, while enrichment of TIM3+CD8+ T-cells with elevated PRDM1 expression predicted poor outcome. PRDM1 single knockout promoted TCF7-dependent CAR T-cell stemness and proliferation resulting in marginally enhanced leukemia control. However, in the setting of PRDM1 deficiency, a negative epigenetic feedback program of NFAT-driven T-cell dysfunction characterized by compensatory upregulation of NR4A3 and multiple other genes encoding exhaustion-related transcription factors hampered effector function in solid tumors. PRDM1 and NR4A3 combined ablation skewed CAR T-cell phenotypes away from TIM3+CD8+ and toward TCF7+CD8+ to counter exhaustion of tumor-infiltrating CAR T-cells and improve in vivo antitumor responses, effects that were not achieved with BLIMP1 or NR4A3 single disruption alone. These data reveal a novel molecular targeting strategy to enrich stem-like CAR T-cells resistant to exhaustion and underscore dual inhibition of PRDM1/NR4A3 expression or activity as a promising approach to advance adoptive cell immuno-oncotherapy
Women Prepare More than Men in Competitive and Non-competitive Environments, Which Aligns with Gender Stereotypes
No full textGender gaps in economic outcomes persist, despite women\u27s gains in education. Various explanations have been proposed for these persistent gaps, including gender differences in competitiveness. In both lab and field studies, women tend to compete less than men, despite performing just as well. Across three studies in Chapter 1 involving over 3000 participants recruited from Amazon Mechanical Turk, we experimentally test whether variations of preparation (i.e., knowledge of an opportunity to prepare, limited opportunity to prepare, and unlimited opportunity to prepare) before performance reduce gender differences in willingness to compete. We also measure participants\u27 choice to prepare and elicit their beliefs about whether men or women will prepare more. First, we show that the preparation intervention does not increase women\u27s competitiveness across studies. Instead, we discover a novel gender difference in the choice to prepare before performance regardless of one\u27s competitiveness, risk aversion, and confidence. This finding aligns with participants\u27 incentivized beliefs—the majority of participants correctly predicted that women would practice more than men. Given this novel finding, Chapter 2 experimentally tests whether the gender difference in preparation may be exacerbated in competitive environments relative to non-competitive environments (N = 3980). Although we replicate the gender difference in preparation, we find no evidence that competitions increase preparation in men or women. This means that women prepare more than men regardless of whether they were assigned to compete. Again, this aligns with participants\u27 incentivized beliefs about gender differences in preparation. This dissertation discusses the downstream and potentially negative consequences of interventions designed to get women to compete, such as the one introduced here. It also discusses both the causes and implications of this newly discovered gender difference in preparation. Future research should explore the boundary conditions, moderators, and mediators of the newly discovered gender difference in preparation. Finally, rather than designing interventions that encourage women to compete more, we implore future research to focus on exploring interventions that change the system to be more gender-inclusive
Collation Model for Ms. Oversize 33: [Choir psalter gatherings] [manuscript].
Get PDFA section (5 gatherings) from the middle of a choir psalter containing a number of psalms (part of 67 and all of 71, 74-75, 80, 83-86, 88, 90-91, 94-98, and 102-103) in order for liturgical use, followed by the first half of the hymn Te Deum with square notation in black on 5-line staves in red. Some water damage at the top of most leaves and some repairs, with replaced text in another hand, at the bottom of leaves.https://repository.upenn.edu/sims_models/1048/thumbnail.jp