Public health genetics

Permanent URI for this collectionhttps://digital.lib.washington.edu/handle/1773/4960

Browse

Now showing 1 - 20 of 121

Advancing Thinking on Evidence for Biological Event Investigations
(2026-02-05) Warmbrod, Kelsey Lane; Meschke, John S
Biological events pose serious threats to public health, national security, and global stability. Identifyingthe origins of a biological event is critical for effective response and prevention of future events. However, biological attribution remains underdeveloped, lacking a conceptual framework and trusted investigatory processes internationally. This dissertation advances thinking about evidence for biological attribution by examining how diverse stakeholders perceive, interpret, and weigh evidence in the context of biological event investigations and by developing a conceptual framework to guide future efforts. Using a mixed methods approach, this research draws on expert interviews in the scientific, public health, nonproliferation, and policy domains, as well as scenario-based exercises that tested how partici- pants evaluated and prioritized different types of evidence. The findings reveal that across disciplines there are different views on the scope, feasibility, and the role of international organizations for biological attribu- tion. Results highlight tension between scientific complexity and political realities, particularly concerning evidence collection, laboratory analysis, and communication of findings. Scenario exercises demonstrate that while genetic and laboratory data are often considered highly probative, other forms of evidence, such as epidemiological patterns or intelligence reports, are critical in shaping perceived credibility, intent, and actionability. From these insights, a conceptual framework is proposed that integrates technical capabilities, investi- gation strategies, and contextual social and political factors. This framework underscores that attribution is not only a scientific determination, but a multidisciplinary endeavor that requires the convergence of diverse evidence streams, transparent processes, and international confidence building. By systematically exploring the evidentiary, social, and policy dimensions of attribution, this dissertation contributes to filling a critical gap in global biosecurity scholarship. The work offers practical guidance for designing future attribution investigations, informs ongoing debates about deterrence and accountability, and lays the groundwork for developing international norms and frameworks that can enhance preparedness, trust, and resilience in the face of biological threats.
CD101 Immunoglobulin-like Variants and Cytokine Profiles in the Female Genital Tract: A Confirmatory and Exploratory Analysis with Vaginal Swab Samples from a large cohort of African HIV-1 serodifferent couples
(2025-10-02) Chang, Alene; Lingappa, Jairam
Variants in the Ig-like domain of CD101 are associated with an increased risk of heterosexually acquired HIV infection. The mechanism through which CD101 influences HIV susceptibility is still unclear. HIV-1 primarily gains access to the host through the genital mucosa after sexual exposure, and analysis of epidemiological and tissue-specific inflammatory factors are critical. We used existing vaginal swab samples and epidemiological data from the Partners PrEP study from HIV-seronegative women (N=89) in heterosexual couples. Genotypes for 12 CD101 SNPs and 28 soluble immune factors were assayed. Based on 4 candidate cytokines from previous work, and to conduct an exploratory analysis on the other cytokines, we ran multivariable linear regression models (frequency of condomless sex, BV, DMPA, and PrEP as covariates) to compare log10 cytokines and chemokine levels to the number of Ig-like variants (copies of alleles). We did not find any significant cytokines at the  < 0.05 for the confirmatory analysis, nor did we find any significant cytokines at the FDR  < 0.05 level in our exploratory analysis.
A pilot retrospective longitudinal case-control study of individuals diagnosed with Cystic Fibrosis after a false-negative newborn screen
(2025-10-02) Bridges, Gracia; Blue, Elizabeth
Cystic fibrosis (CF) has been universally included in newborn screening (NBS) programs across the United States for nearly two decades. In Washington State, CF NBS was introduced in 2006 and follows a two-step protocol: initial immunoreactive trypsinogen (IRT) measurement, followed by limited CFTR variant analysis for samples exceeding an IRT threshold. Studies from multiple regions and countries have shown that CF NBS is associated with improved early outcomes, including enhanced nutritional status, delayed chronic Pseudomonas aeruginosa infection, and expedited lung function growth1. However, inequities persist, with Black/African American and Asian infants experiencing false-negative screens at disproportionately higher rates than non-Hispanic White infants2. Although false-negatives are an inherent risk of biomarker-based screening, their disproportionate burden raises concerns about systemic bias within existing NBS algorithms. To explore longitudinal clinical impacts of false-negative NBS, we conducted a pilot project assessing long-term clinical outcomes among children diagnosed with CF after false-negative NBS in WA State compared to matched peers diagnosed after positive screens. We conducted a retrospective matched case-control study of individuals born between 2006 and 2024 in WA State and followed at Seattle Children's Hospital CF Center. Cases were diagnosed after a false-negative NBS; controls were matched 1:1 by birth year (±1 year) and pancreatic sufficiency status. Data collected included demographics (birth month/year, race/ethnicity, zip code), newborn screen and diagnostic characteristics (NBS IRT level and CF variant panel results, diagnosis month/year, CFTR genotype, clinical presentation, hospitalization status at diagnosis), and longitudinal clinical outcomes (height and weight percentiles, forced expiratory volume in one second (FEV1) from spirometry). Additional indicators included number and duration of hospitalizations and age at first positive Pseudomonas aeruginosa culture. Prior analyses have suggested that individuals diagnosed with CF after a false-negative NBS may experience less favorable outcomes than matched peers, including lower weight trajectories and higher hospitalization rates.1,3,4 Our results mirrored these patterns. False-negative cases were more racially and ethnically diverse (36.3% vs. 0%, p = 0.027), diagnosed later (median 19 vs. 1 month, p < 0.0001), and more often hospitalized at diagnosis (36.4% vs. 0%, p = 0.045). They also had higher annualized hospitalization rates (p = 0.018) and significantly slower growth trajectories. These findings suggest that false-negative NBS results may delay diagnosis and contribute to worse clinical outcomes, reinforcing concerns about equity in current screening algorithms.
Transcriptome and spatial analyses of tumor microenvironment in addressing colorectal cancer racial and ethnic disparities; and ethical evaluation of results communication in polygenic risk score-based prediction tool
(2025-10-02) Yin, Hang; Peters, Ulrike
Substantial and persistent racial and ethnic differences exist in colorectal cancer (CRC) incidence and mortality, while the underlying biology remains incompletely understood. To bridge this knowledge gap, I leveraged tumor RNA sequencing data from 548 CRC patients from African American, Alaska Native, Hispanic, and non-Hispanic White groups. Within each racial and ethnic group, a nested case-control design was employed to match patients who died of CRC to those who did not, on key clinical factors. I observed that Alaska Native and Hispanic patients exhibited significantly higher mean T cell-inflamed gene expression profile scores than the other two groups, which is indicative of an immunologically "hot" tumor, with active T cell infiltration, IFN-gamma pathway activation, and immune checkpoint expression. I identified 14 genes, multiple pathways, and 4 immune cell types that significantly differed between patients with and without CRC-specific death. Specifically, 6 genes reported to be associated with CRC death for the first time. I developed a gene expression-based model to predict CRC-specific death with a better predictive performance compared to existing signatures. With the inclusion of diverse patient populations, we identified novel prognostic biomarkers, which also provide potential biological explanations for observed racial and ethnic disparities in CRC outcomes. To further characterize the spatial organization within the tumor microenvironment, I investigated the spatial proteomics profile of 97 Alaska Native CRC patients using Akoya Biosciences' PhenoCycler-Fusion system. I included 35 patients who died of CRC and 62 matched patients who did not die of CRC based on key clinical factors. I classified 2.35 million cells into 16 different cell types and eight cellular neighborhoods with distinct local cell composition. I found that patients with a higher proportion of M2 macrophages were more likely to die of CRC. While no significant associations between cellular neighborhoods and CRC-specific death, I observed a higher proportion of podoplanin-expressing stromal cells and M1 macrophages within the tumor epithelial compartment among patients who died of CRC compared to patients who did not, which emphasizes the value of cell locations. I calculated the spatial proximity between different cell types and found colocalizations of stromal and immune cells (e.g., podoplanin-expressing stromal cells and CD8+ T cells) were associated with CRC-specific deaths. These results reveal the prognostic value and biological relevance of colocalized stromal and immune cell types, suggesting that spatial patterns between cells may serve as a prognostic biomarker to reduce CRC mortality. In the era of precision medicine, polygenic risk scores (PRS) demonstrate strong performance in risk prediction for multiple diseases, and are increasingly returned in direct-to-consumer genetic testing. I summarized current approaches to communicating PRS and the associated perceptual, psychological and behavioral changes observed, which provided advice for standardizing PRS communication metrics and the optimization of report design to facilitate further implementation research.
How biological essentialism limits transgender people’s autonomy in public policy
(2025-08-01) Dusic, Emerson; Starks, Helene
There is a growing population of transgender and nonbinary (trans) people in the United States (US) who face significant health and healthcare disparities due to a history of marginalization and discrimination, particularly in the realm of gender-affirming care and reproductive health. The current political climate is actively pursuing legislative restrictions to limit or eliminate access to these services. These limitations continue the long history of active eugenic practices, including forced sterilization for lesbian, gay, bisexual, transgender, and queer (LGBTQ+) people. These eugenic policies and practices are designed to reinforce social norms that determine who should and should not reproduce and are justified by biological and genetic essentialism--the idea that an individual’s phenotypic characteristics and social identity are solely determined by their biological (genetic, hormonal, anatomical, etc.) makeup. Biological essentialism often serves as the frame of reference for public policies that limit trans individuals’ access to services, public accommodations, and legal recognition. As an example, current policies in the US and abroad explicitly require that trans persons first demonstrate they are incapable of having children or have had “sex reassignment surgeries” before they may change their legal gender marker on identification documents (IDs). The purpose of this work is to understand how a history of eugenics has led to biological essentialism that is weaponized against trans people in public policy. This study uses a social-ecological approach to investigate how eugenics limits access to reproductive healthcare for trans people in modern America at both the macro and micro level using three different datasets and analytic methods: (1) a policy analysis examining how trans individuals’ capability to have children is impacted by changing legal gender marker or name on IDs; (2) multi-level analysis of survey data to identify associations between anti-trans policies and parental desire; and (3) key informant interviews with trans people about their perspectives on biological essentialism and public policy. I argue that eugenics continues to target trans people in the modern day through biological essentialism, resulting in limitations to bodily autonomy and self-determination for transgender individuals. To improve the health and well-being of trans individuals, it is first necessary to step away from medicalized and biological definitions of trans identities.
The Influence of Maternal Immune Events on the Establishment of Maternal Microchimerism
(2025-08-01) Weaver, Jacquelyn; Harrington, Whitney
Maternal microchimerism (MMc), or the transfer of maternal cells to the offspring, has been associated with immune modulation and improved health outcomes in newborns. Using data collected from a prospective cohort, we assessed how maternal immune events during pregnancy, including vaccinations and illnesses, influenced the odds of detecting MMc in cord blood. Additionally, we examined the dynamic changes that occurred in the maternal T cell repertoire across trimesters. We observed that vaccination was associated with higher odds of detectable cord blood T cell MMc (OR: 1.68, 95% CI: 0.42- 6.75) and that this effect was modified by gestational age, with the strongest effect with vaccination in first trimester (OR: 1.38, 95% CI: 0.36- 5.29). We also found that T cell repertoire varied greatly across individuals and by trimester. These findings suggest that the timing of immune exposures and the individual immune history of the mother are important factors influencing the transfer of maternal T cells to the fetus, with potential implications for offspring immune development and health.
Taiwanese primary care physicians’ experience and confidence in genetic service delivery: A pilot survey study
(2025-08-01) Chen, I-ling; Knerr, Sarah SK
BackgroundWith the rapid advancement of genetic testing technologies and their increasing application in preventive care, the role of primary care physicians (PCPs) in genetic service delivery is gaining importance. In Taiwan, where direct-to-consumer genetic testing is prohibited and the certified genetics workforce is limited and unevenly distributed, PCPs may serve as crucial entry points for patient access to genetic services. However, little is known about Taiwanese PCPs’ current experience, confidence, and attitudes toward delivering these services. Objectives This study aims to explore the experiences, perceived barriers, and training needs of Taiwanese PCPs in the context of ordering genetic tests and referring patients for genetic counseling. Findings are intended to inform policy and workforce development strategies to improve the integration of genetic services into primary care in Taiwan. Methods An anonymous online survey was conducted between November 2024 and March 2025 among Taiwanese PCPs. The 58-item survey included questions on physician characteristics, experience with genetic services, attitudes toward genetic testing, confidence in genetic knowledge, and views on genetic education and certification. Descriptive statistics and Fisher’s exact tests were used to analyze the data. Results A total of 96 PCPs completed the survey. More than half (57.3%) had ordered genetic tests, and 79% had referred patients to genetic specialists. Common barriers to ordering tests included patients’ financial concerns (69.8%) and uncertainty about test selection (64.6%), while referral barriers included unclear pathways (57.3%), uncertainty about referral options (57.3%), and patients’ financial concerns (52.0%). Only a small proportion of respondents reported confidence in interpreting genetic reports (23.9.0%) or understanding legal (14.6%) and insurance-related (11.5%) issues. Although most respondents agreed that current genetic knowledge among PCPs is insufficient and that enhanced genetic education during medical school can be beneficial, opinions were divided on the effectiveness of continuing education and the necessity of board certification. Conclusion Taiwanese PCPs encounter multiple barriers in delivering genetic services, particularly related to knowledge gaps, referral infrastructure, and policy ambiguity. Addressing these challenges through tailored education, clear service models, and health system support is essential for enabling PCPs to meet the growing demand for genetic services in Taiwan’s primary care settings.
Exploring Genetic Testing Conversations in the Context of Hematopoietic Cell Transplant Survivors: A Thematic Analysis
(2025-08-01) Raol, Viveka; Yu, Joon-Ho
Background:Hematopoietic cell transplant (HCT) survivors face complex medical decisions throughout their long-term follow up (LTFU) care, including considerations around genetic testing. While research has examined genetic testing in various oncology settings, little is known about how HCT survivors engage with genetic testing conversations in LTFU care. Methods: We conducted a mixed-methods study with 23 HCT survivors receiving LTFU care.Semi-structured interviews exploring genetic testing experiences were conducted with 23 survivors who responded to genetics-specific questions (13 with original genetics questions and 10 with updated questions). Interviews were analyzed using thematic analysis. Results: Three key usage patterns emerged in how survivors engaged with genetic testing conversations: active integration (n=8), treatment-focused use (n=10), and non-integration (n=5). Family communication emerged as a central mechanism influencing engagement with genetic information. Key barriers included limited access to genetic services and varying levels of family involvement. Age-related differences appeared in how survivors approached genetic testing conversations, with younger survivors more focused on future implications and older survivors emphasizing immediate treatment decisions. Conclusions: Findings suggest opportunities to better support HCT survivors in genetic testing conversations through systematic approaches that consider age, family communication patterns, and timing of genetic services in LTFU care.
Age-Dependent Variability in Immune Host Responses to SARS-CoV-2: Implications for Inclusive Clinical Trial Design
(2025-08-01) Johnson, Taylor; Fohner, Alison
The COVID-19 pandemic, caused by SARS-CoV-2 has disproportionately affected older adults,who account for the majority of COVID-19-related hospitalizations and deaths. Although disease severity has declined, periodic surges continue to pose significant risks to aging populations, exacerbated by age-associated immune dysfunction, or immunosenescence. This dissertation investigates the immune responses that contribute to protection against SARS-CoV-2 and how these responses become dysregulated with increasing age. Given the evidence of impaired antiviral immunity in aged models, we also evaluated the representation of older adults in COVID-19 vaccine clinical trials to assess whether key age-associated immune differences are being adequately captured in clinical research. In Chapter 1, we examined the effects of IFNβ pre-treatment on SARS-CoV-2 infection dynamics in lung epithelial cell models. We identified interferon-stimulated gene signatures associated with antiviral protection, and found that pre-activation of the IFN pathway significantly reduced viral replication and dampened inflammatory responses associated with severe disease. In Chapter 2, leveraging a cohort of young, mature, and aged mice infected with mouse-adapted SARS-CoV-2, we performed temporally resolved transcriptomic analyses of lung tissues. Aged mice exhibited impaired early cytokine and IFN signaling, dysregulated T cell activation during recovery, and elevated baseline inflammatory signatures, all of which contributed to delayed viral clearance and worsened disease outcomes. Moreover, these immune response are crucial for effective vaccine-induced protection against COVID-19. In Chapter 3, we conducted a cross-sectional analysis of COVID-19 vaccine clinical trials, quantifying the underrepresentation of older adults and identifying exclusion criteria disproportionately impacting this group. Our analysis reveals significant underrepresentation of older adults in these trials, key barriers to their enrollment, and provides recommendations for improving inclusivity of this group in clinical trials. Together, these studies provide new insights into the molecular mechanisms underlying age-associated susceptibility to SARS-CoV-2 and offer a framework for improving immune protection and clinical trial participation for older adults.
Evaluating user adaptations and perceptions of OpenELIS in sustaining its implementation in CÃ´te d'Ivoire: A Qualitative Study
(2025-08-01) AbuShweimeh, Rahmeh; Rao, Deepa
Background: Sustainability remains one of the most persistent challenges facing digital health interventions in low- and middle-income countries (LMICs). OpenELIS (OE), a laboratory information system introduced across CÃ´te d’Ivoire’s public health laboratories with donor support, offers an opportunity to examine how digital health systems evolve in resource-constrained settings and what factors may shape their long-term adoption and institutionalization. Methods:This qualitative study analyzed stakeholder perspectives on the implementation and sustainability of OE across 37 laboratories in CÃ´te d’Ivoire. In-depth interviews were conducted with laboratory personnel, information technology staff, and other stakeholders involved in OE use. A hybrid inductive-deductive thematic analysis was performed using the Consolidated Framework for Implementation Research (CFIR) and the Dynamic Sustainability Framework (DSF) to guide coding and interpretation. Analytic memoing and reflexivity practices, including a positionality statement, were used throughout the process to ensure rigor. Results:Findings were organized into four interconnected themes: (1) system readiness and infrastructure; (2) leadership and workforce capacity; (3) system adaptation and workflow alignment; and (4) perceptions of sustainability and donor dependency. Participants described how inconsistent infrastructure, informal leadership structures, staff turnover, and limited training disrupted OE implementation. However, adaptive transitions—such as the shift from OE Basic to OE Classic—improved usability and trust. Concerns about future sustainability were prevalent, especially in the absence of national transition plans and institutional ownership. These findings map onto CFIR’s Outer and Inner Setting domains and DSF’s emphasis on the dynamic interplay between intervention, setting, and broader ecological factors. Conclusions:The study highlights the complexity of sustaining donor-funded digital health tools in LMICs. Implementation success does not guarantee long-term sustainability without adequate investment in infrastructure, human capacity, and national ownership. Integrating implementation science frameworks such as CFIR and DSF can support more context-responsive digital health strategies that evolve with systems over time. Lessons from the OE experience in CÃ´te d’Ivoire can inform broader efforts to strengthen digital health sustainability in similar settings.
Metagenomic estimation of absolute bacterial biomass in the mammalian gut through host-derived read normalization
(2025-08-01) Tang, Gechlang; Fohner, Alison
Absolute bacterial biomass estimation in the human gut is crucial for understanding microbiomedynamics and host-microbe interactions. Current methods for quantifying bacterial biomass in stool, such as flow cytometry, qPCR, or spike-ins (i.e., adding cells or DNA from an organism not normally found in a sample), can be labor-intensive, costly, and confounded by factors like water content, DNA extraction efficiency, PCR inhibitors, and other technical challenges that add bias and noise. We propose a simple, cost-effective approach that circumvents some of these technical challenges: directly estimating bacterial biomass from metagenomes using bacterial-tohost (B:H) read ratios. We compare B:H ratios to the standard methods outlined above, demonstrating that B:H ratios are useful proxies for bacterial biomass in stool and possibly in other host-associated substrates. We show how B:H ratios can be used to track antibiotic treatment response and recovery in both mice and humans, which showed 403-fold and 45-fold reductions in bacterial biomass during antibiotic treatment, respectively. Our results indicate that host and bacterial metagenomic DNA fractions in human stool fluctuate longitudinally around a stable mean in healthy individuals, and the average host read fraction varies across healthy individuals by < 9 fold. B:H ratios offer a convenient alternative to other absolute biomass quantification methods, without the need for additional measurements, experimental design considerations, or machine learning algorithms, enabling retrospective absolute biomass estimates from existing stool metagenomic data.
Assessing Gene-Environment Interaction in the Association Between Smoking and Leukocyte Telomere Length
(2025-08-01) Kanavel, Kelsey Suzanne; Lindstroem, Sara
Telomere length is influenced by both genetic and environmental factors, including smoking behavior. While smoking is associated with shorter telomeres, this association may vary by genotype. In a subset of the UK Biobank cohort (N = 360,909) with genetically inferred European ancestry, we analyzed 581,069 common single nucleotide polymorphisms (SNPs) and average relative telomere length estimates derived from quantitative PCR (qPCR) to test whether the association between ever/never smoking status and telomere length differs by genotype. One SNP, rs4418881, reached genome-wide significance (P = 4.49e-8) in the 2 degrees of freedom gene-environment interaction joint test but did not reach significance in the overall genome-wide association study (P = 4.19e-7). Stratified analyses revealed that rs4418881 was genome-wide significant in ever smokers (P = 1.06e-8) but not in never smokers (P = 0.35), suggesting that this SNP may modify the effect of smoking on telomere length.
Understanding parent/caregiver support needs during genome sequencing in a pediatric research setting
(2025-05-12) Murali, Priyank; Yu, Joon-ho
Pediatric patients benefit from genome sequencing (GS) for disease diagnosis, treatment guidance, and reducing diagnostic delays. However, parents and caregivers navigating this complex system face unique challenges, including informed consent, understanding results, and managing expectations. The variability in genetic service delivery in different clinical contexts can impact the parent/caregiver experience. Existing research often examines implementation factors like clinical utility, provider perspectives, and ethical/social concerns but tends to focus on specific aspects of genetic testing or lacks a comprehensive look at parental needs during GS specifically. This dissertation aims to address this gap by examining parent/caregiver needs throughout the entire pediatric GS process, from pre-test counseling to post-test follow-up as well as in different clinical settings. It integrates findings from a scoping review of existing literature examining parental needs during both pediatric whole exome and genome sequencing and qualitative interviews conducted within the SeqFirst project, which investigates GS as a first-line diagnostic tool in children with atypical development and infants admitted to the neonatal intensive care unit (NICU). My results identify key themes: parents need clear, empathetic communication and tailored information, emotional support, and logistical guidance at every stage of GS. Findings highlight the interconnected nature of informational, emotional, and logistical needs, underscoring the importance of addressing them comprehensively. Recognizing and responding to these needs can inform patient-centered implementation practices, ultimately improving healthcare experiences and outcomes. Addressing gaps in current support strategies, especially in the NICU and developmental disorder settings, is crucial as GS becomes a mainstay in pediatric care. This study advocates for tailored interventions to support parents, ensuring effective communication, emotional well-being, and navigational assistance through complex healthcare landscapes.
Integrating Genomic and Contextual Determinants to Investigate Disparities in Alzheimer’s Disease and Dementia
(2025-01-23) Xue, Diane; Fohner, Alison E
One in three older adults dies with dementia. Alzheimer’s disease (AD), a progressive neurodegenerative disorder influenced by genetic and environmental risk factors, is the most common cause of dementia. By 2050, >12 million people in the United States will have AD, and the risk for AD is not evenly distributed across the population. To predict and prevent AD and related dementia, identify precision treatments, and reduce disparities, it is crucial to understand the influence of genetic and environmental risk factors on disease susceptibility. In the following papers, we investigated the racial/ethnic representation of participants in United States-based AD genetic studies, characterized the predictive accuracy of various polygenic risk scores for AD in a multi-ethnic cohort, and identified social, built, and physical environment determinants associated with dementia and cognition independent of and modified by genetic risk. We demonstrate that the lack of diversity in current genetic datasets results in insufficient statistical power to detect genetic variants associated with AD in non-European ancestry populations, particularly for variants with small to moderate effect sizes. Beyond the potential for the lack of diversity to exacerbate inequalities in AD outcomes, it also leads to an incomplete understanding of the genetic architecture of AD – an argument supported by our polygenic risk score comparisons. We show that while variants identified by genome-wide associated studies are meaningful for capturing genetic risk in some populations, the overall predictive accuracy of current polygenic risk score models are limited. Finally, we show that after controlling for individual-level genetic and demographic risk factors, contextual determinants actionable at the population-level are associated with cognition and dementia risk. There is evidence that neighborhood socioeconomic status is differentially associated with dementia across groups with different genetic risk. In sum, this body of work contributes toward a better understanding of the etiology of AD in diverse populations, with an emphasis on how systemic population-level solutions can help reduce disparities in AD outcomes from both genetic and environmental perspectives.
Genetic risk of type 2 diabetes and its relationship to severe Covid-19 disease
(2024-10-16) Kushleika, John Vytas; Darst, Burcu
Type 2 diabetes (T2D) is a risk factor for severe cases of Covid-19. T2D is partially heritable, though few studies have examined the role of T2D genetic risk factors in severe Covid-19. We analyzed data from 459,493 participants in the UK Biobank for association of a T2D polygenic risk score (PRS) with severe Covid-19 outcomes diagnosed between February 1, 2020 and October 31, 2022. Participants with severe Covid-19 (SC, N=8,367) were those hospitalized for Covid-19 (ICD-10 codes U07.1 or U07.2) or who died of Covid-19. Logistic regression using SC (yes/no) as the outcome was employed, adjusting for age, sex and the first ten principal components to account for potential population stratification. We found positive and statistically significant relationships between the T2D PRS and SC. Among all participants, each SD unit increase in PRS was associated with an odds ratio of 1.09 (95% CI= 1.06 – 1.11; p=1.7e-12) for risk of SC. Examined as a categorical variable, participants within the top T2D PRS quintile had 18% (95% CI= 11% – 27%; p=9.1e-7) higher risks of SC in comparison to participants in the median (40%-60%) T2D PRS quintile. To address potential issues with selection bias, we repeated our analyses using three alternative control groups including those who (i) had never been diagnosed with Covid-19 at time of data collection, (ii) had non-severe Covid-19, or (iii) had undergone Covid-19-testing (regardless of their test results), obtaining very similar results. The T2D PRS was also predictive of severe Covid-19 among participants with no diagnosis of T2D. These results imply that genetic factors associated with T2D influence susceptibility to SC outcomes, providing support for the potential use of PRS in assessing patient risks and furthering our understanding of the mechanisms underlying the increased risk of SC among individuals with T2D.
Characterizing Mutagenesis Across Developmental Time with single-cell indexing (sci) ATAC-seq
(2024-09-09) Pan, Yu-Chen; Harris, Kelley
Mutations in DNA are caused by replication errors or exposure to mutagen that damage the DNA repair mechanisms. Germline variants are mutations that occur in germ cells and can be passed onto offspring, ultimately becoming polymorphic sites; while somatic variants are mutations that arise spontaneously in the soma cells during growth and aging. Somatic mutations have been traditionally studied in cancer due to their natural clonal expansion. However, recent work has described an association of the accumulation of somatic mutations in healthy tissues with aging and age-related diseases. The current methodologies for obtaining clonal sequences from healthy and developing tissues are either costly or laborious, limiting scalability. Therefore, in this thesis, we explored the feasibility of using single-cell combinatorial indexing (sci) ATAC-seq data toidentify somatic and germline mutations and to study mutational processes across tissues during embryogenesis. Leveraging available sci-ATAC-seq datasets from fruit fly embryo and human fetal samples, we were able to identify mutations and differentiate them into germline polymorphisms and somatic mutations. In the fruit fly embryo dataset, we detected population structure based on the extracted germline polymorphisms, while in human fetal samples, we observed an increase in somatic mutation burden over developmental time. We also performed mutational signature extraction, finding that the activities of clock-like signatures, such as SBS1 and SBS5, positively correlated with developmental time. This indicates a potential association between somatic mutation accumulation and aging during embryogenesis. We also observed variations in the mutational processes across tissues. Finally, we reconstructed the main tissue layers of early development from the detected somatic mutations, suggesting these datasets may help validate transcriptionally based lineage predictions. Our analysis showed that the reanalysis of available sci-ATAC-seq datasets can be an alternative solution to study somatic mutagenesis at a more affordable cost and enhanced scalability. These findings also have provided insights into developmental processes and cell lineage tracing during embryonic development.
Stigma Among Sex Workers in Dakar, Senegal
(2024-09-09) Rater, Claire; Hawes, Stephen E
In Dakar, Senegal, the approach to sex work supervision is legalization and regulation. Sex workers can register in Senegal and can participate in sex work legally while in accordance with government policies which include regular testing and health screenings. In a study conducted in Dakar by Dr. Shanthi Manian, certification rates remained low among sex workers despite an intervention to incentivize registration. As stigma seemed to have influence in women’s decisions to register, I analyzed factors which may lead to experiences with (1) community stigma and (2) internalized stigma. I looked at exposure factors such as age, educational attainment levels and parental status (number of children) and their potential associations with community and internalized stigma. I conducted analysis on the univariate and multivariate relationships between these exposures and outcomes to varying risks for experiencing community or internalized stigma. I found that increased educational attainment levels were associated with increased internalized stigma among sex workers in Dakar, Senegal.
Feasibility of Using Patient Navigation to Improve Identification of Inherited Colorectal Cancer (CRC) Syndromes
(2024-09-09) Sears, Emma; Knerr, Sarah
Colorectal cancer (CRC) is a major health concern in the United States (US), with a significant percentage attributed to inherited syndromes like Lynch Syndrome (LS). Despite current clinical guidelines recommending genetic testing for CRC patients many eligible patients are not accessing these services. To address this gap, we aimed to describe the feasibility of implementing patient navigation for hereditary CRC syndromes across a range of health care settings. Our qualitative study involved interviews with healthcare professional across various roles and settings in the US. Participants were purposively sampled and interviewed about current genetic services about current genetic service delivery methods, perceived barriers, and facilitators to implementing a patient navigation program within their health care organization. We identified several barriers to the feasibility of the patient navigation program, including limited funding, staffing challenges, inadequate health information technology, and difficulties gaining administrative buy-in. Despite these barriers, participants suggested potential strategies for overcoming them, such as cross training staff and seeking external funding. However, patient navigation may not align with the rapidly evolving models of genetic services delivery. In conclusion, while the patient navigation program does address perceived barriers to genetic service uptake, its feasibility is limited by resource constraints and evolving services delivery models. Future efforts should prioritize creating standardized guidelines for hereditary cancer prevention to guide quality improvement initiatives.
Unraveling Pregnancy-Induced Modulation of the Innate Immune Response to Mycobacterium tuberculosis Through mRNA Sequencing of Infected Monocytes
(2024-09-09) Saha, Aparajita; Shah, Javeed A
This thesis investigates the dynamics of monocyte-derived macrophage gene expression in response to Mycobacterium tuberculosis (Mtb) infection during pregnancy, focusing specifically on the third trimester. Using mRNA sequencing, we found significant changes in gene expression related to the innate immune response, particularly in the JAK-STAT pathway associated with tuberculosis reactivation. Analysis revealed over 500 differently expressed genes in infected samples, primarily involved in cytokine signaling and inflammation. Comparing third trimester of pregnancy to pre-pregnancy highlighted differences in pathways such as calcium signaling, MAPK, TNF, MTORC, and hypoxia signaling. Downregulated genes like GBP5, TNFRSF4, and NIBAN1 suggest compromised immune response in late pregnancy, potentially worsening TB infection or reactivation of latent TB. Understanding these changes could improve TB prevention, diagnosis, and treatment in pregnant populations.
Longitudinal associations of branched-chain amino acids with type 2 diabetes and markers of insulin secretion and sensitivity in Japanese Americans
(2024-09-09) Chandra, Makena; Wander, Pandora "Luke"
Background and aims: To prospectively investigate the associations of branched-chain amino acids (BCAA) with incident diabetes and estimates of insulin secretion and sensitivity.Methods and results: We conducted a secondary analysis among participants free from diabetes in the Japanese American Community Diabetes Study (n=349). For the biomarker study, participants were assessed for diabetes at baseline and 5–6 years of follow-up and estimates of insulin sensitivity and secretion were obtained. Baseline plasma samples in adults free from diabetes were assayed for BCAA levels. We fit logistic regression models to examine associations of BCAA with incident diabetes at 5–6 years and linear regression models to examine associations with estimates of insulin secretion (oral disposition index, oDI) and insulin sensitivity (Matsuda index and HOMA2-%S) at baseline and 5–6 years. Models were adjusted for age, sex, BMI, and smoking status (Model 2); and for age, sex, BMI, smoking status, and family history of T2D (Model 3). For the oDI and Matsuda index, we fit sex-stratified models and examined whether associations depended on sex on a multiplicative scale. Results: The mean age was 56.5. 50.7% (n=177) were men. Higher valine was associated with higher odds of incident diabetes (OR for a 1SD change 1.06, 95% CI 1.03, 1.09, Model 2). After adjustment, no BCAA was associated with oDI at baseline or follow-up. Higher isoleucine was associated with lower Matsuda index at baseline (β for 1SD change -0.02, 95%CI – (0.03, -0.01, Model 2)). Higher isoleucine and valine were associated with lower HOMA2-%S at baseline (β for 1SD change -0.43, 95%CI (-0.62, -0.23), and -0.58, 95%CI (-0.82, -0.35), Model 2, respectively). No BCAA was associated with Matsuda index or HOMA2%S at follow-up. Associations were similar in models with and without adjustment for family history of T2D. In men, no BCAA was associated with oDI or Matsuda index at baseline. In women, higher isoleucine was associated with lower Matsuda index at baseline (β for 1SD change: -0.04, 95%CI (-0.06, -0.02), Model 2, p for interaction >0.05). Conclusion: Higher valine was associated with a higher risk of incident diabetes at 5–6 years. Higher isoleucine and valine were associated with lower insulin sensitivity (isoleucine with Matsuda index and HOMA2-%S, valine with HOMA2-%S only) at baseline but not at follow up. Results were similar with and without adjustment for family history of T2D. Associations may differ by sex. More research is needed to characterize the roles of sex and genetic variation in associations of circulating BCAA with diabetes risk and insulin secretion and sensitivity measures.

Browse

Recent Submissions