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Statistical Methods for Analyzing Single-Cell Sequencing and Microbiome Data
No full textThe recent development of single-cell sequencing and microbiome sequencing technology has substantially advanced our understanding of complex biological processes and disease mechanisms. In this thesis, we developed statistical and computational methods to decipher the intrinsic relationship between biological features and sample phenotypes in large-scale single-cell sequencing and microbiome studies. First, we developed SampleClock, a computational framework for sample-level pseudotemporal trajectory construction, which reveals dynamic transcriptomic programs along the pseudotime. Second, we provided a kernel regression framework for integrative analysis of multiple microbiome studies, via incorporating study design and sequencing protocols information. Third, we proposed a zero-inflated quantile regression model to analyze longitudinal microbiome data. Our methods have been applied to several multi-sample single-cell sequencing datasets, including a pilot study of COVID-19 scRNA-seq data and a single-cell mouse embryonic developmental time course data. In addition, we also investigated the shift of diversity, membership, and compositions of microbial communities in an integrated analysis of multiple HIV studies and a longitudinal kidney transplant cohort
IMPACT OF INCLUDING ELECTRONIC NICOTINE DELIVERY SYSTEMS (ENDS) IN A STATE INSPECTION PROTOCOL ON STATE RETAIL VIOLATION RATE IN THE SYNAR YOUTH TOBACCO PREVENTION PROGRAM
Get PDFIntroduction and Background: The Synar regulation (45 C.F.R. § 96.130) is a Federal regulation and program administered by the States that requires enforcement to prevent the sale of tobacco products to those under the legal age of sale. Penalties are given to States that exceed a federally mandated retail violation rate (RVR). Tobacco use is changing with youth use of cigarette smoking decreasing and use of Electronic Nicotine Delivery Systems (ENDS) is increasing. There is a high economic and personal cost of ENDS use, although the full range of long-term negative outcomes of ENDS use are yet to be quantified. States are beginning to include ENDS in their Synar inspections and may worry that inclusion of ENDS may reduce their RVR compliance.
Methods: RVRs were collected and listed from each of the 50 States and District of Columbia through manually reviewing each State’s 2020 RVR. Retail Violation Rate was used to compare with inspection of ENDS, presence of a high prevalence of ENDS use in the environment, and presence of regulations of ENDS.
Data was collected for State RVR, Retail Availability of ENDS, ENDS Use in State, Use of Under 21 Year Old Inspectors, ENDS Included in Inspections, Inspectors Carry ID, Any Change in Law Regarding Inspections, and Other Changes in State Law. RVRs were dichotomized into categories of high RVR and low RVR and analysis was conducted.
Results: Inclusion of ENDS in Synar inspections was not found to have significant impact on RVR. High retail availability and youth inspectors carrying identification had a low association with a State having a high RVR. High ENDS use in a State, changes in state law around inspections, other state law changes, and use of inspectors over the age of 18 were not found to be related to high RVR. Discussion: A State should not be concerned that including ENDS in its Synar inspection protocol will have impact on State compliance with the requirements of the Federal Synar Regulation. These results can allow States to best target prevention resources based on the findings of which variables influence RVR. Best practices to account for these variables can be identified and targeted policies and regulations can be implemented
The Pericardium and Pericardial Inflammation During Cardiovascular Disease
No full textAn effort to marry chemical engineering and cardiac immunology led to the development of two projects: the role of GATA6+ pericardial macrophages in cardiovascular disease and the influence of genipin-crosslinked chitosan on inflammation during myocardial infarction (MI).
The pericardium is the serous cavity surrounding the heart. GATA6+ pericardial macrophages are a unique population of resident macrophages within serous cavities such as the pericardium. The role of these cells during myocardial infarction (MI) has recently become controversial. We clarify their role in cardiovascular disease by investigating MI, viral myocarditis and pericarditis. LysCreGATA6fl/fl lacking GATA6+ pericardial macrophages or LysCre WT-like controls were used for all experiments. MI was induced via permanent ligation of the left anterior descending artery. CVB3 myocarditis and IL-33 pericarditis were induced by intraperitoneal injections of CVB3 virus and IL-33 and IL-5 respectively. Results were analyzed by flow cytometry, histology, PCR, EKG and echocardiography. We found that the absence of GATA6+ pericardial macrophages only influenced pericarditis, not myocarditis or MI. In vitro experiments revealed that GATA6+ macrophages were less transcriptionally active following stimulation compared to bone marrow derived macrophages and did alter fibroblast phenotype. We therefore conclude that GATA6+ pericardial macrophages are critical in modulating pericardial inflammation through competition with other macrophages preventing the accumulation of inflammatory factors.
We also sought to investigate the role of genipin-crosslinked chitosan on cardiac inflammation. Hydrogels have been proposed as a therapeutic for MI but have failed to find clinical success. We propose that influence on the immune system may be the reason. We synthesized a hydrogel by dissolving chitosan in 2% acetic acid, crosslinking with genipin and neutralizing the pH. This gel led to a foreign body response characterized by neutrophil influx but no monocyte migration. We found during MI that the hydrogel induced B cell migration to the heart while maintaining the anti-monocyte properties. However, mice receiving the gel had greater bodyweight loss, indicative of worsened recovery. We found that there was systemic elevation of neutrophils and eosinophils in the spleen. Therefore, genipin-crosslinked chitosan induces an anti-inflammatory response locally during MI but leads to systemic neutrophilia and eosinophilia causing impaired recovery
SELECTION IN WRITTEN LANGUAGE PRODUCTION: EVIDENCE FROM APHASIA
No full textMost models of word production assume that in the process of producing a target word, multiple distractors also get activated, both other words (at the lexical level) and other phonemes/letters (at the segmental level). Thus, a selection mechanism is needed to select the targets at each level. While selection is one of the mechanisms that has received a considerable amount of attention in the spoken production literature, minimal amount of research has been dedicated to understanding this mechanism in written production. In fact, although written language is an integral part of our everyday life, written language production is the most under-researched language domain.
The work presented in this dissertation enhances our understanding of the selection mechanisms involved in written word production. Specifically, we investigated whether the selection mechanism(s) are: (1) shared across cognitive domains (language vs non-language), (2) shared across levels of processing (lexical vs segmental), and (3) internal or external to the network that supports the mapping of representations across levels of processing. To this end, we collected behavioral data from a group of individuals with post-stroke aphasia and a group of aged-matched healthy control individuals, using two experimental tasks: the written Blocked Cyclic Naming task and the Simon visual-spatial compatibility task. Structural (gray matter) neuroimaging data were also collected for the post-stroke aphasia group.
The results of the data analyses undertaken provide no evidence of a shared mechanism between the language and non-language domains investigated. With respect to levels of processing, the findings reveal that selection at the lexical and segmental levels is supported by distinct mechanisms. Finally, the evidence indicates that selection processes involved in written word production are supported by a mechanism that is external to the representational mapping system, and that this external mechanism relies on left-hemisphere inferior frontal and orbitofrontal regions of the brain. These findings significantly advance our understanding of the selection mechanisms involved in written language production, which has important theoretical implications for understanding the writing system and for theories of word production more generally, as well as having translational implications related to naming therapies in aphasia and beyond
Detection of ultrashort-chain and other per- and polyfluoroalkyl substances (PFAS) in U.S. bottled water
Get PDFPer- and polyfluoroalkyl substances (PFAS) are compounds of emerging concern due to their persistence in the global water cycle and detection in drinking water sources. However, PFAS have been poorly studied in bottled water, especially in the United States. This study investigated the occurrence of PFAS and related factors in 101 uniquely labelled bottled water products for sale in the U.S. Products were screened for 32 target PFAS by solid phase extraction-liquid chromatography-tandem mass spectrometry (SPE-LC-MS/MS). Fifteen of 32 measured analytes were detected, consisting primarily of C3-C10 perfluorocarboxylic acids (PFCA) and C3-C6 and C8 perfluorosulfonic acids (PFSA). PFAS were detected above method detection limits in 39/101 tested products. The Σ32PFAS concentrations detected were 0.17–18.87 ng/L with a median of 0.98 ng/L; 97% of samples were below 5 ng/L. PFCA (83%) and short-chain perfluoroalkyl acids (PFAA) containing 5 or less CF2 groups (67%) were more prevalent on a mass basis than PFSA and longer-chain PFAA, respectively. Ultrashort-chain PFPrA, measured for the first time in bottled water, accounted for the greatest individual fraction of detected PFAS mass (42%) and was found almost exclusively in products labeled as Spring water. Purified water products contained significantly less PFAS than Spring water products, which was attributed to the use of reverse osmosis (RO) treatment in the majority of Purified waters (25/35) compared to Spring waters (1/45). RO-treated products contained significantly lower Σ32PFAS, long-chain, short-chain, and PFPrA concentrations than products without RO. Although no enforceable PFAS regulations exist for bottled water in the U.S., the finding that some products approach levels of concern justify a framework for monitoring PFAS in bottled water production
INVESTIGATIONS ON CHROMATIN REMODELING MECHANISMS USING SINGLE-MOLECULE FRET
No full textIn eukaryotic organisms, DNA is packaged into chromatin to enable regulation of DNA processes including DNA replication, transcription and genome maintenance. During my doctoral study at the Johns Hopkins University, I investigated the molecular mechanisms underlying how the eukaryotic genome is dynamically packaged and unwrapped to regulate gene expression. The main technique I used is called single-molecule Fluorescence Resonance Energy Transfer, or smFRET. Under the co-mentorship of Prof. Taekjip Ha and Prof. Carl Wu, I used smFRET to study chromatin remodeling at the level of single nucleosomes. Nucleosomes are the fundamental units of chromatin, where around 147 bp of DNA wraps around an octameric core of histone proteins. In the first part of my thesis, I studied the H2A.Z histone exchange reaction catalyzed by the ATP-dependent chromatin remodeling complex SWR1. I found that SWR1 replaces histone H2A in canonical nucleosomes with histone variant H2A.Z through a highly coordinated process that requires the unwrapping of the nucleosomal DNA and the exchange of histone dimers. The second part of my thesis focuses on a pioneer transcription factor, which can target specific DNA motifs on DNA and closed chromatin, and recruit chromatin remodeling proteins to create more accessible chromatin. Despite an increasing number of pioneer factors identified in the past decade, how pioneer factors search for their cognate motifs on DNA and chromatin remained poorly understood. By using three-color smFRET, I found that pioneer factor GAF uses both one-dimensional DNA sliding and three-dimensional diffusion to efficiently locate its target motif on DNA and nucleosomes. Although my two thesis projects are distinct in their subject, one theme shared between them is that chromatin remodeling is a complex, dynamic, stochastic and tightly regulated process that ultimately occurs via interactions with the fundamental chromatin units of DNA and nucleosomes
GOAT KNUCKLE BONES: THE FIRST THREE CHAPTERS
No full textTimothy Phillips, a seventy-five-year-old retired cop, intends to fulfill a promise to his dead wife. He works as an armed guard to save money for a trip to Japan, where he plans to spread her ashes across Yugawara beach. After he drops off a passenger in Coney Island, Brooklyn, his plans go awry when he meets a mysterious girl who gives him an extraordinary gift in a brown paper bag, the Goat Knuckle Bones. Futuristic visions haunt Timmy, corrupt detectives hunt him, and alien entities attack him for the Goat Knuckle Bones. This story is about Timmy unraveling the secret of the Goat Knuckle Bones before uncanny forces stop him from fulfilling his promise to his wife
Randomized-Control Efficacy Study of IXL Math in Holland Public Schools
Get PDFThis study examined perceptions and effectiveness of IXL Math by using a cluster randomized-control trial (RCT) in Grades 3-5 in the four elementary schools in HPS during the spring of 2023. The RCT design randomly assigned teachers (classes) within these grades in individual schools to implement IXL Math or continue with business as usual within their classrooms. Accordingly, teachers represented the units of analyses. Eleven Grade 3-5 classrooms across four schools were randomly selected to use IXL Math, while the remaining (control) classrooms across the same four schools conducted business-as-usual instruction. Outcome measures for this study included the end-of-year (EOY) Renaissance Star Math and spring 2023 M-STEP Mathematics scores. A survey was also made available for voluntary completion to IXL Math teachers in Grades 3-5. The response rate was high, with nine of the 11 teachers who used IXL Math responding to the survey. Survey participants completed Likert-scale items relating to their perceptions of professional development, satisfaction, curriculum alignment, and program usage, along with open-ended items relating to program strengths and weaknesses and suggestions for future IXL Math implementation in HPS.
A significant positive impact of IXL Math on student mathematics achievement was observed for Grades 3-5 students in HPS. Treatment students made approximately 10-point larger gains on the Renaissance Star Math assessment than did control students. The effect size of this impact was 0.13 SDs, indicating a small to moderate practical impact of IXL Math on student mathematics achievement. Subgroup analyses showed that IXL Math had additional significant positive impacts on Hispanic, special education, ELL, and free and reduced meal (FARMS) students, with the magnitudes of these impacts ranging from 13 to 17 points.
Descriptive analyses of student program usage showed that Grade 3 students averaged the most time spent using the program, at about 10 hours total. This was followed by Grade 5 and Grade 4 students, at approximately eight and seven hours of average usage, respectively. Pearson correlations showed significant positive associations between counts of skills practiced/proficient/mastered and EOY Star Math and M-STEP Mathematics scores across all grade levels, with correlations ranging between .30-.57 in magnitude. Regression models similar to the main impact analyses showed that measures of student program time (measures of minutes and active weeks) were all significantly positively associated with Renaissance Star Math and M-STEP Mathematics achievement gains.IXL Learnin
Novel Bayesian Methods for Precision Medicine in HIV
No full textNumerous adverse effects (e.g., mental health disorders, chronic kidney failure, and cardiovascular diseases) have been reported for combination antiretroviral therapy (cART) despite its remarkable success in viral suppression in people with HIV. To improve long-term health outcomes and quality of life for people with HIV, there is an urgent need to design personalized optimal cART assignments with the lowest risk of comorbidity in the emerging field of precision medicine for HIV. Large-scale HIV databases offer researchers unprecedented opportunities to optimize personalized cART in a data-driven manner. However, the large number of possible drug combinations for cART makes the estimation a high-dimensional combinatorial problem, imposing challenges in both statistical inference and decision-making. In this dissertation, we focus on developing novel Bayesian methodologies that have clinical utility in guiding clinicians to prescribe informed and effective personalized HIV treatment based on individuals' treatment histories and clinical characteristics.
First, we develop a Bayesian nonparametric approach to learn drug combination effects on mental health in people with HIV adjusting for sociodemographic, behavioral, and clinical factors. The proposed method is built upon the subset-tree kernel that represents drug combinations in a way that synthesizes known regimen structure into a single mathematical representation. The subset-tree kernel reduces the dimension of the drug combination space to a manageable size and encourages similar effects for similar cARTs. The proposed method also utilizes a distance-dependent Chinese restaurant process to cluster heterogeneous populations while considering individuals' treatment histories.
The second main contribution of this dissertation is the development of a Bayesian regression tree model that studies the heterogeneous longitudinal drug effects of cART regimens and their interaction with genetic variants on depressive symptoms for people with HIV. The proposed method utilizes a Gaussian process to capture the longitudinal drug effects by incorporating individuals' treatment histories in its covariance function.
Lastly, we develop a two-step Bayesian decision framework for optimizing personalized sequential cART assignments with proper uncertainty propagation. In the first step, we propose a probabilistic dynamic model for individuals' longitudinal observations using a multivariate Gaussian process. In the second step, we build a probabilistic generative model for cART assignments and design an uncertainty-penalized policy optimization using the uncertainty quantification from the first step. Through both simulation and real data studies, we demonstrate the clinical utility of the proposed methods in assisting HIV physicians to make effective treatment decisions, serving the purpose of both viral suppression and comorbidity risk reduction
An Evaluation of Dent Education’s Bet on Baltimore Summer Program – Year 5
Get PDFBet on Baltimore is an intensive summer youth development program whose goals are to engage Baltimore City high school students in meaningful work, leadership, and personal development activities aimed at preparing youth for future careers and providing an experience where they realize their ability to shape the world around them. An important focus of the summer program is utilizing a combination of direct instruction and hands-on learning experiences to help students develop certain key mindsets and leadership skills oriented toward the 21st century workplace. Dent Education aims for this summer program to alter students’ self-perceptions, as well as their perceptions of the world around them. The program goals include teaching students key design thinking mindsets, such as how to see problems as opportunities, embrace failure as part of the learning journey, and feel confident in their ability to make an impact on the world. Students identify community issues and business challenges, meet with community and business leaders, learn new skills, and work to create their own social or business enterprise. During the summer of 2022, 10 groups of students (n = 108) participated in Bet on Baltimore through a six-week paid summer job opportunity funded by YouthWorks. Students were placed in one of 10 “tracks” created from a combination of youth feedback and successful programs from the past—designed to meet the needs of 21st century economic skills—focused on the following areas: graphic design, music production, physical fabrication using tools like 3D printers, social innovation, business start-ups, internships at value-aligned organizations, and a youth co-owned social enterprise, Made@Dent (madeatdent.com). The six-week session concluded with an in-person showcase, where students presented their ideas and shared lessons learned for an audience of approximately 200 people. During the summer program of 2022, 25 coaches led students through the program with the support of four site supporters and four Fellows