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Interpretable Machine Learning And Causal Inference In Medicine And Public Health, Colleen Elise Chan

Yale Graduate School of Arts and Sciences Dissertations

Machine learning (ML) methods have seen rapidly increasing prevalence and adoption across many industries due to their ability to learn complex patterns from large amounts of data with high accuracy. However, these models often lack transparency, operating as opaque ``black boxes’’, which is especially concerning in high-stakes domains. Two key avenues to improve transparency and user trust are 1) developing interpretable ML models that explain their reasoning to users and 2) developing causal methods to estimate the effects of interventions from observational data when randomized controlled trials are infeasible. This dissertation addresses challenges and advances methods in interpretable ML and …

Business Groups And Misallocation: Theory And Evidence From Chaebols, Jihoon Sung

Yale Graduate School of Arts and Sciences Dissertations

I study the role of business groups - collections of firms owned by a single family - in determining factor misallocation and aggregate productivity. One might expect that business groups improve allocative efficiency because profit-maximizing owners can allocate resources efficiently across their firms. Surprisingly, using evidence from Korea, an economy wherelarge business groups (chaebols) are prominent, I find the contrary: business groups appear to worsen misallocation. In the first chapter, I describe the history and institutional details of chaebols. In the second chapter, I present the empirical findings. I show, using firm-level data with business group ownership information, that factor …

Engineering Polymeric Nanoparticles For Intra-Amniotic And Intravenous In Utero Delivery, Anna Lynn

Yale Graduate School of Arts and Sciences Dissertations

Fetal therapy is a rapidly expanding field that provides opportunities to treat or prevent congenital diseases early in the process of fetal development. Prior studies suggest that polymeric nanoparticles (NPs) are a safe, tunable, and effective vehicle for in utero delivery of therapeutic agents via administration into the amniotic fluid space. Previous work has focused on the feasibility of using poly(lactic-co-glycolic acid) (PLGA) NPs, as well as viral vectors and lipid NPs, for in utero delivery. Modifications to the core polymer and surface chemistry of NPs are known to be key in modulating the performance of NPs in various biological …

From Efficacy To Implementation: Translating Lifestyle Behavior Interventions Into Routine Breast Oncology Care, Leah Silverman Puklin

Yale Graduate School of Arts and Sciences Dissertations

Background: Obesity, poor diet quality, and low levels of physical activity (PA) are increasingly prevalent public health challenges with important implications for breast cancer treatment adherence and survival. The field of energy balance and breast cancer survivorship has made significant advancements in recognizing the importance of integrating programs that promote positive lifestyle behavior change in oncology care. However, there remain significant gaps in translating research findings into routine clinical practice. These gaps include conflicting evidence surrounding who experiences weight change post breast cancer diagnosis and how post-diagnosis weight patterns impact survival; what aspects need to be addressed when designing and …

Maternal And Paternal Migration And Children’S Human Capital, Siuyuat Wong

Yale Graduate School of Arts and Sciences Dissertations

International migration opportunities improve earnings capacity, but can also create parental separation from children. The net effect of migration on children depends on the relative importance of money and parental presence in determining a child's human capital development, which parent migrates, and at what age they separate from the child. These considerations in turn affect whether, when, and who migrates. I estimate a dynamic model of migrant households with an embedded age-specific child education production function by conducting a panel survey of Filipino migrants and combining it with newly assembled administrative data from the Philippines Department of Education and the …

Mechanisms And Functions Of Lipodystrophy In Dermal Fibrosis, Elizabeth Ann Caves

Yale Graduate School of Arts and Sciences Dissertations

The skin is the largest organ in the human body and acts as a barrier between the inside and outside environments. A significant function of the skin is to maintain its structural integrity through extracellular matrix protein (ECM) homeostasis. Tissue fibrosis is characterized by a failure of ECM homeostasis, resulting in the accumulation of ECM proteins in healthy tissue. Systemic sclerosis is an autoimmune disease in which fibrosis develops throughout the body in organs such as the heart, lungs, and skin. Interestingly, during skin fibrosis, resident lipid-filled, mature adipocytes are depleted in humans and mice concomitant with ECM expansion. However, …

Uncovering A Critical Role For Calmodulin In Calcium-Dependent Regulation Of The Nociceptor Trpa1, Justin Sanders

Yale Graduate School of Arts and Sciences Dissertations

Transient receptor potential (TRP) channels are sensory receptors expressed throughout the peripheral nervous system that help shape how we respond to our environment. TRPA1 has been identified as a key component in the transition from acute to chronic pain and inflammation making it a prime target for development of novel analgesics. Calcium has been shown to regulate TRPA1 by rapidly potentiating channel activity followed by rapid desensitization. While the effects of calcium on TRPA1 activity have been well-described, the mechanisms governing these calcium effects have been difficult to elucidate. Work described within this thesis details the discovery of a novel …

An Epigenetic Timer Regulates The Transition From Cell Division To Cell Expansion During Arabidopsis Petal Organogenesis, Ruirui Huang

Yale Graduate School of Arts and Sciences Dissertations

Epigenetic changes, such as histone modifications or DNA methylation, can modify gene expression without affecting the genetic code. Such alterations can persist for many cell generations, and often are induced by various environmental inputs in both plants and animals. A number of studies have demonstrated that epigenetic factors regulate plant developmental timing in response to environmental changes. However, we still have an incomplete view of how epigenetic factors can regulate developmental events such as organogenesis, and the transition from cell division to cell expansion, in plants. The small number of cell types and the relatively simple developmental progression required to …

Investor Relations And Esg, Tendai Masaya

Yale Graduate School of Arts and Sciences Dissertations

I investigate the relation between increased investor relations (IR) activities and four ESG outcomes: coverage by ESG rating agencies, ESG rating levels, the stock market response to bad ESG news, and the use of ESG-related terms in earnings conference calls. Firms with more IR activities—indicated by an IR Officer’s (IRO) presence on conference calls—could improve communication about ESG efforts with investors and ESG rating agencies, and feedback received might even increase the level of ESG efforts. I find that firms with IR prominence (1) are more likely to be covered by ESG raters; (2) experience an increase in overall, E, …

Diverse Models Of Immunoediting: Exploring Tumor-T Cell Interactions In Developing Cancers, Julie F. Cheung

Yale Graduate School of Arts and Sciences Dissertations

Cancer's complexity is characterized by its genetic diversity, adaptability to environmental changes, and the extent of immunoediting that results from interactions with the immune system. T cells, tasked with eliminating mutated cells, have entered the cancer research spotlight due to their therapeutic potential to restore the natural host immune response against established tumors. However, their effectiveness is limited to a subset of cancers, and their inability to eradicate all tumors from the outset has perplexed researchers. Consequently, immunoediting, which encapsulates the interplay between T cells and developing tumor cells within their specific microenvironment, is a linchpin in determining cancer fate. …

Developing Metabolism-Targeting Adjuvants To Immunotherapy In Murine Melanoma, Xinyi Zhang

Yale Graduate School of Arts and Sciences Dissertations

Melanoma is the deadliest skin cancer type, causing 8000 deaths per year in the United States. The development of immunotherapy significantly prolongs the survival of cancer patients, including patients with melanoma. By impairing the inhibitory signaling pathway, immunotherapy, for example anti-PD-1 monoclonal antibody, reinforces the anti-tumor effector function of T cells that recognize cancer cells and therefore suppresses tumor progression. However, the problem of low responsiveness and development of resistance significantly prevents a large proportion of patients from benefiting from immunotherapy. Therefore, it is of great importance to develop adjuvants to increase the efficacy of immunotherapy. Metabolic alterations have long …

Insights On The Functional Importance Of Molecular Motions In Phosphatases, Erik Zavala

Yale Graduate School of Arts and Sciences Dissertations

Enzymes are biomolecules that catalyze biological reactions, and as such, demand thorough investigation so that manipulation of their associated biological processes can be achieved. Biological processes are made up of complex pathways where enzymes play a key role in regulating pathway flux. Enzymes are a diverse subset of biomolecules and different classes of enzymes regulate pathway activity in different ways. For example, phosphatases and kinases are the enzymes responsible for regulating the phosphorylation levels of proteins. Phosphatases remove phosphates by catalyzing the hydrolysis of phosphate groups and kinases attach phosphate groups by catalyzing the transfer of phosphates from adenosine triphosphate …

Deep Learning For Multi-Modal Tomography Imaging: Radiation Dose, Image Artifacts, And Acquisition Time Reductions, Bo Zhou

Yale Graduate School of Arts and Sciences Dissertations

PET-CT/MRI is the most used multi-modal tomography imaging exam which can provide both functional and anatomical information from a single exam and aid clinical decision-making. The CT/MRI component focuses on visualizing the anatomical structures, and the PET component focuses on visualizing molecular-level functional activities in tissues. Millions of PET-CT/MRI scans were performed each year worldwide with wide applications in oncology, cardiology, neurology, and biomedical research. While being an indispensable multi-modal tomography imaging tool in medicine, PET-CT/MRI has several key issues limiting its broader impacts on patients, including 1) the potential hazard caused by radiation dose from the PET and CT, …

Decoding Novel Metabolic Functions And Binding Products Of Human Aldo-Keto Reductase 1c3, Natavan Dudkina

Yale Graduate School of Arts and Sciences Dissertations

The increased incidents of many chronic diseases such as asthma, allergies, diabetes, heart disease, and mental disorders cannot be fully explained by genetic factors. The exposure to environment, diet, and behavioral changes is equally or sometimes even more greatly associated with disease progression. Such non-genetic factors could be reflected in chemical fingerprints that cellular processes leave behind. Metabolite profiling provides biochemical information that is not available at the gene or protein level. The emerging technological advances such as sensitive metabolomic approaches have allowed to assess these metabolic changes in a way that was not possible before. As a consequence, in …

Coding Sequence Dependent Mrna Decay Regulation, Damir Musaev

Yale Graduate School of Arts and Sciences Dissertations

Post-transcriptional mRNA regulation shapes gene expression, yet the full extent of cis-regulatory sequences and how translation shapes the regulation of these elements is poorly understood. To identify conserved cis-regulatory elements shaping mRNA stability, I analyzed the features associated with differential mRNA decay in two vertebrate systems: steady-state HEK293 cells and developing zebrafish embryos. I found that strength of translation initiation (Kozak score), uORF content, codon optimality, AU-rich elements, microRNA binding sites, and ORF length function combinatorially to regulate mRNA stability. Surprisingly, machine learning analysis identified ORF length as the most important conserved feature regulating mRNA decay. I found that mRNAs …

Advances In Multi-Agent Learning And Private Statistical Estimation, John Lazarsfeld

Yale Graduate School of Arts and Sciences Dissertations

Modern machine learning systems and other data science settings are increasingly subject to various reliability constraints: these systems may be decentralized and involve multiple agents acting without coordination, may be limited in memory and other computational resources, or may be subject to societal constraints like differential privacy. This dissertation presents algorithmic advances for several learning and data analysis tasks under such constraints. In the first chapter, we present new families of algorithms for the multi-agent cooperative bandit problem in the randomized gossip communication model. Our algorithms are fully decentralized and require only constant local memory per agent, and we highlight …

Transcriptional Regulation Of Fate Specification In Human Megakaryocytic-Erythroid Progenitors, Nayoung Kwon

Yale Graduate School of Arts and Sciences Dissertations

Megakaryocytic-erythroid progenitors (MEP) are a population of bipotent hematopoietic progenitors that give rise to the megakaryocytic (Mk) or erythroid (E) lineages. The Mk lineage produces platelets, and the E lineage produces RBCs, that govern coagulation and oxygen transport, respectively. Both are critical components of the blood system, and maintaining an adequate and balanced pool of platelets and red blood cells is essential for life. As MEP stand as a final branchpoint before committing to Mk or E lineages, understanding the fate specification mechanism of MEP may provide insight into treating conditions that involve platelets and/or red blood cells.This thesis focuses …

Rare And Undiagnosed Liver Diseases: New Insights From Genomic And Single Cell Transcriptomic Analyses, Chigoziri Konkwo

Yale Medicine Thesis Digital Library

Chronic liver disease (CLD) is a major global health problem, leading to an estimatedtwo million annual deaths worldwide. Advances in next generation sequencing (NGS) technologies have revolutionized our ability to diagnose and investigate disease pathogenesis. Our research group has previously shown that genomic analysis is useful in the diagnosis of patients with unexplained CLD, providing a diagnostic yield of up to 30%. Moreover, this approach has revealed a newly described cause of non-cirrhotic portal hypertension and nodular regenerative hyperplasia due to GIMAP5 deficiency, which is recapitulated in a mouse model. Additionally, the growing use of single cell RNA sequencing (scRNA-seq) …

A Hero's Journey: Experiences Using A Therapeutic Comicbook In A Children’S Psychiatric Inpatient Unit, Idil Yazgan

Yale Medicine Thesis Digital Library

Children’s mental health care has been on the decline since the start of the century. The COVID-19 pandemic further unearthed this significant worsening of mental health in children with heightened levels of anxiety, depression, loneliness, anger, and fatigue leading to an increase in the number of emergency room visits and inpatient hospitalizations. Art and narrative-based interventions are known to improve patient outcomes and are a crucial component of pediatric inpatient psychiatric care. We discuss the process of adoption of a novel therapeutic comic book that was developed for children admitted to the hospital in a psychiatric inpatient unit at Yale-New …

The Choroid Plexus Links Innate Immunity To Dysregulation Of Csf Homeostasis In Diverse Forms Of Hydrocephalus, Emre Kiziltug

Yale Medicine Thesis Digital Library

The choroid plexus (ChP) secretes a half-liter/day of cerebrospinal fluid (CSF) and is the blood-CSF barrier with critical immune functions. Hydrocephalus, commonly caused by infection or hemorrhage, lacks non-surgical treatments due to obscure pathobiology. We hypothesize that in acquired hydrocephalus, the dual ChP functions of CSF secretion and blood-CSF barrier maintenance become pathologically entangled in a maladaptive disease state. To test this hypothesis, we created novel rat models of post-infectious (PIH) and posthemorrhagic hydrocephalus (PHH) and conducted a multi-omics investigation of these animals to dissect the cellular, molecular, and physiological pathology underlying PIH and PHH . Our systems approach combined …

Meningioma Relational Database Curation Using A Pacs-Integrated Tool For Collection Of Clinical And Imaging Features, Ryan Mclean

Yale Medicine Thesis Digital Library

Meningiomas are the most common primary intracranial neoplasm seen in adults, and despite the largely benign nature of these tumors, they are associated with significant morbidity and mortality1. Physicians specialized in CNS pathologies, such as neurosurgeons, neuroradiologists, and neuro-oncologists rely on multiparametric MRI (mpMRI) for diagnosis, guidance of management, and response to therapy of CNS lesions. Today, in the era of artificial intelligence, with high-throughput computing and accessibility to massive amounts of data, we see the emergence of new fields in translational science. Proteomics, genomics, metabolomics, and more recently, radiomics are quantitative and analytical fields that are driven by the …

Permanent Pacemaker Implantation After Tricuspid Valve Repair Surgery, Alyssa Morrison

Yale Medicine Thesis Digital Library

Recent studies suggest that permanent pacemaker implantation after tricuspid valve repair may be more common than previously thought. Our primary aim was to assess the rates of early (within 30 days of surgery) and late (more than 30 days after surgery) permanent pacemaker implantation (PPI) after tricuspid valve repair (TVr) surgery. Our secondary aims included exploring risk factors for PPI after TVr and assessing outcomes.

We performed a retrospective analysis of 231 isolated and concomitant tricuspid valve repairs for primary and secondary tricuspid valve regurgitation at a single quaternary academic center performed from 2014–2022.

Early pacemaker implantation was performed in …

Maternal And Donor Human Milk Support Robust Intestinal Epithelial Growth And Differentiation In A Fetal Intestinal Organoid Model, Lauren Smith

Yale Medicine Thesis Digital Library

Necrotizing enterocolitis (NEC) is a severe gastrointestinal complication of prematurity. Using small intestinal organoids derived from fetal tissue of a gestational age similar to an extremely preterm infant, this study aims to assess the effect of diet on intestinal epithelial growth and differentiation to elucidate the role nutrition type plays in intestinal development and modifies the risk for NEC.

Organoids were cultured for 5 days in organoid growth media and 5 days in organoid differentiation media supplemented 1:40 with four different diet conditions: maternal milk (MM), donor human milk (DHM), standard formula (SF), or extensively hydrolyzed formula (HF). 4x images …

Gestational Weight Gain And Epilepsy In The Offspring: A Population-Based Retrospective Cohort Study, Jiawen Chen

Public Health Theses

AbstractBackground and aims: Epilepsy is one of the most common neurologic disorders in childhood, but the etiology for the majority of the cases remains unknown. As a modifiable trait in pregnancy, gestational weight gain (GWG) has been shown to be a risk factor for multiple adverse birth outcomes. This study aims to investigate whether non-optimal GWG is associated with the risk of epilepsy in the offspring using a linked database in California. Methods: A population-based cohort study was conducted using the linked database from the Birth Certificate Record in California (2007-2015) for GWG, and the diagnostic records of epilepsy from …

Development And Optimization Of A Novel Eeev Microsphere Immunoassay: Using Xeno-Surveillance Methodology To Characterize Avian Herd Immunity, Kaitlyn Gabriele Maurais

Public Health Theses

Introduction: Eastern equine encephalitis virus (EEEV), a mosquito-borne alphavirus, is detected throughout the eastern United States. The primary enzootic vector, Culiseta melanura (Blacktailed mosquito), allows transmission among 50+ avian host species resulting in complex disease patterns. Spillover to dead-end host mammals, such as equines and humans, rarely occurs, however, human cases can cause severe neurological deficits and have a 30% mortality rate. Eco-epidemiology and avian host immunity patterns are not well characterized for EEEV and require ongoing surveillance to develop more targeted interventions. Methods: Xeno-surveillance is an approach to survey EEEV through hematophagous arthropods, instead of collecting samples from a …

Total Synthesis Of Novel Core Modified Pleuromutilin Analogs And Studies Towards The Total Synthesis Of (€“)-Lomaiviticin A, Mikaela Mary Dibello

Yale Graduate School of Arts and Sciences Dissertations

In the first chapter, I describe the development of a modular synthetic route that allows for the de novo synthesis of novel pleuromutilin analogs, including analogs with modified cores. (+)-Pleuromutilin (11) is a diterpene fungal metabolite that displays moderate antimicrobial activity against Gram-positive pathogens. Semisynthetic modifications of 11 resulted in derivatives with improved activity and pharmacological properties. However, the majority of derivatization studies have focused on modifying the periphery of the molecule. Studies on the impact of structural modifications to the tricyclic core have been limited as this type of diversification is inaccessible via semisynthesis. Herein, I outline our development …

Stakeholder Perspectives On Therapeutic Value Assessment, Victor M. Amana

Public Health Theses

No abstract provided.

Ivermectin Mda For Malaria Control And Plasmodium Species Diversity In Burkina Faso, Julia Ellman

Public Health Theses

Malaria is a major cause of mortality globally, but particularly in Africa and among children. As the growth of drug resistance threatens current malaria control and treatment strategies, novel interventions are needed to combat the recent increase in cases. Ivermectin is an endectocide that has been historically used to treat neglected tropical parasitic diseases through mass drug administration (MDA). Recently, it has been demonstrated to have a lethal effect on mosquitos, suggesting its potential as a valuable vector control strategy. RIMDAMAL II is a cluster randomized control trial that was conducted in southwestern Burkina Faso in 2019-2020 to evaluate the …

Constructing The Birthing Body Across The 20th Century: A Thematic Analysis Of Infertility Disorders In The New England Journal Of Medicine, Nicola Davis

Public Health Theses

Obstetrics and Gynecology (OB/GYN) is a medical subspecialty primarily concerned with birth care, reproduction, and gynecological health. OB/GYN practice plays a historically significant role in the treatment of infertility and reproductive disorders as cultural ideologies of fertility and motherhood have been co-constructed alongside the development of OB/GYN medical practice and knowledge. These constructs inform obstetric practice and serve as a framework for contemporary reproductive care. Modern birth care in the medical setting often reinforces a myriad of issues including stigmatization of birthing people’s bodies, over-medicalization of birth, obstetric racism, and obstetric violence. This paper focuses on the evolution of particular …

Comparative Effectiveness Of First-Line Treatments For Advanced Non-Small Cell Lung Cancer Patients With Pd-L1 Expression 1-49%, Peiru Pan

Public Health Theses

Introduction: Lung cancer, particularly non-small cell lung cancer (NSCLC), remains a leading cause of cancer-related mortality worldwide. While immunotherapy has revolutionized the treatment landscape for advanced NSCLC, optimal first-line therapy for patients with programmed death-ligand 1 (PD-L1) expression levels between 1-49% remains uncertain.

Objective: To investigate the comparative effectiveness of different first-line treatment options for advanced NSCLC patients with PD-L1 expression levels between 1-49%.

Methods: We conducted a retrospective analysis using patient data from the Flatiron Health database. Our patient sample includes adult patients diagnosed with advanced NSCLC between 2016 and 2021, with PD-L1 expression levels ranging from 1-49%. Treatment …