EQUITABLE PHARMACOGENETIC TESTING IMPLEMENTATION FOR RURAL AND UNDERSERVED POPULATIONS

Pharmacogenetic testing has potential to transform healthcare, yet implementation strategies have been limited to major academic medical centers serving metropolitan communities and large health systems. In contrast, rural, community-based health systems are slow to implement these advances, threatening to exacerbate existing healthcare disparities for rural populations. A majority of Montanans live in rural areas, with unique challenges in providing access to pharmacogenetics. We have established partnerships with three clinical sites who serve rural, underserved populations including American Indian, pediatric, and low socioeconomic status patients. We conducted a needs assessment for pharmacogenetic testing implementation by interviewing 48 key stakeholders. Interview questions were centered around participants opinions regarding pharmacogenetics and their perceived barriers and facilitators for implementation of testing. A codebook was created by analysis and organization of common themes. Positive opinions on using pharmacogenetics to guide therapy were common. Perceived benefits included reduced time to symptom management, fewer adverse events, and improved adherence. Concerns expressed in similar studies based in larger medical centers were also present, including conflicts with reimbursement and test turnaround time. Unique concerns for vulnerable, underserved populations included equitable access based on socioeconomic status and sensitivity to culture and historical injustices, particularly for tribal people. Participants were enthusiastic about using telehealth to implement pharmacogenetics in these communities. This will provide an innovative strategy for pharmacogenetic testing and consultations. Participants were eager to implement testing in their facilities. Many concerns can be mitigated with a strategic implementation plan targeted for underserved patients. Our model will implement pharmacogenetics using a telehealth delivery model centered at the University of Montana with outreach to rural health systems and providers. This has the potential to expand as new health innovations are translated into practice. Future work in this area will involve assisting partner sites with implementation efforts and measuring clinical outcomes related to testing services. Our study will help overcome the unique challenges in delivering pharmacogenetics to rural and underserved communities and we aim to provide a model for states with similar patient populations. Our goal is to pave the way for equitable access to pharmacogenetics for all

The pharmacogenomic landscape of an Indigenous Australian population

Background: Population genomic studies of individuals of Indigenous ancestry have been extremely limited comprising <0.5% of participants in international genetic databases and genome-wide association studies, contributing to a "genomic gap" that limits their access to personalised medicine. While Indigenous Australians face a high burden of chronic disease and associated medication exposure, corresponding genomic and drug safety datasets are sorely lacking.Methods: To address this, we conducted a pharmacogenomic study of almost 500 individuals from a founder Indigenous Tiwi population. Whole genome sequencing was performed using short-read Illumina Novaseq6000 technology. We characterised the pharmacogenomics (PGx) landscape of this population by analysing sequencing results and associated pharmacological treatment data.Results: We observed that every individual in the cohort carry at least one actionable genotype and 77% of them carry at least three clinically actionable genotypes across 19 pharmacogenes. Overall, 41% of the Tiwi cohort were predicted to exhibit impaired CYP2D6 metabolism, with this frequency being much higher than that for other global populations. Over half of the population predicted an impaired CYP2C9, CYP2C19, and CYP2B6 metabolism with implications for the processing of commonly used analgesics, statins, anticoagulants, antiretrovirals, antidepressants, and antipsychotics. Moreover, we identified 31 potentially actionable novel variants within Very Important Pharmacogenes (VIPs), five of which were common among the Tiwi. We further detected important clinical implications for the drugs involved with cancer pharmacogenomics such as thiopurines and tamoxifen, immunosuppressants like tacrolimus and certain antivirals used in the hepatitis C treatment due to potential differences in their metabolic processing.Conclusion: The pharmacogenomic profiles generated in our study demonstrate the utility of pre-emptive PGx testing and have the potential to help guide the development and application of precision therapeutic strategies tailored to Tiwi Indigenous patients. Our research provides valuable insights on pre-emptive PGx testing and the feasibility of its use in ancestrally diverse populations, emphasizing the need for increased diversity and inclusivity in PGx investigations.Personalised Therapeutic

The Pharmacoepigenomics Informatics Pipeline and H-GREEN Hi-C Compiler: Discovering Pharmacogenomic Variants and Pathways with the Epigenome and Spatial Genome

Over the last decade, biomedical science has been transformed by the epigenome and spatial genome, but the discipline of pharmacogenomics, the study of the genetic underpinnings of pharmacological phenotypes like drug response and adverse events, has not. Scientists have begun to use omics atlases of increasing depth, and inferences relating to the bidirectional causal relationship between the spatial epigenome and gene expression, as a foundational underpinning for genetics research. The epigenome and spatial genome are increasingly used to discover causative regulatory variants in the significance regions of genome-wide association studies, for the discovery of the biological mechanisms underlying these phenotypes and the design of genetic tests to predict them. Such variants often have more predictive power than coding variants, but in the area of pharmacogenomics, such advances have been radically underapplied. The majority of pharmacogenomics tests are designed manually on the basis of mechanistic work with coding variants in candidate genes, and where genome wide approaches are used, they are typically not interpreted with the epigenome. This work describes a series of analyses of pharmacogenomics association studies with the tools and datasets of the epigenome and spatial genome, undertaken with the intent of discovering causative regulatory variants to enable new genetic tests. It describes the potent regulatory variants discovered thereby to have a putative causative and predictive role in a number of medically important phenotypes, including analgesia and the treatment of depression, bipolar disorder, and traumatic brain injury with opiates, anxiolytics, antidepressants, lithium, and valproate, and in particular the tendency for such variants to cluster into spatially interacting, conceptually unified pathways which offer mechanistic insight into these phenotypes. It describes the Pharmacoepigenomics Informatics Pipeline (PIP), an integrative multiple omics variant discovery pipeline designed to make this kind of analysis easier and cheaper to perform, more reproducible, and amenable to the addition of advanced features. It described the successes of the PIP in rediscovering manually discovered gene networks for lithium response, as well as discovering a previously unknown genetic basis for warfarin response in anticoagulation therapy. It describes the H-GREEN Hi-C compiler, which was designed to analyze spatial genome data and discover the distant target genes of such regulatory variants, and its success in discovering spatial contacts not detectable by preceding methods and using them to build spatial contact networks that unite disparate TADs with phenotypic relationships. It describes a potential featureset of a future pipeline, using the latest epigenome research and the lessons of the previous pipeline. It describes my thinking about how to use the output of a multiple omics variant pipeline to design genetic tests that also incorporate clinical data. And it concludes by describing a long term vision for a comprehensive pharmacophenomic atlas, to be constructed by applying a variant pipeline and machine learning test design system, such as is described, to thousands of phenotypes in parallel. Scientists struggled to assay genotypes for the better part of a century, and in the last twenty years, succeeded. The struggle to predict phenotypes on the basis of the genotypes we assay remains ongoing. The use of multiple omics variant pipelines and machine learning models with omics atlases, genetic association, and medical records data will be an increasingly significant part of that struggle for the foreseeable future.PHDBioinformaticsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/145835/1/ariallyn_1.pd

Pharmacogenomics

This Special Issue focuses on the current state of pharmacogenomics (PGx) and the extensive translational process, including the identification of functionally important PGx variation; the characterization of PGx haplotypes and metabolizer statuses, their clinical interpretation, clinical decision support, and the incorporation of PGx into clinical care

Configuring an implementation model for multi-drug pharmacogenomic testing in the NHS

Backgrounds Pharmacogenomic testing can improve patient outcomes through safer and more efficient dose and drug selection. Implementation of multi-drug pharmacogenomic testing in clinical care has been fragmented internationally and is largely absent within the NHS. The aim of this thesis was to develop and refine a programme theory using behaviour science for the implementation of multi-drug pharmacogenomic testing within an NHS context. Methods Underpinned by behavioural science, the research programme comprised three empirical studies. The first study modelled the impact of multi-drug pharmacogenomic testing in UK primary care, by estimating the occurrence of actionable drug gene interactions in daily practice, using first prescription volumes for 56 PGx drugs and phenotype frequency data. The second study involved a systematic review and narrative synthesis of the barriers and enablers to implementing multi-drug pharmacogenomic testing, using the TDF to map factors affecting prescriber, pharmacist, and patient behaviours. Finally, the third study was a qualitative exploration of the real-world implementation of multi-drug pharmacogenomic testing in the NHS, conducted using a case study methodology. Results Over 20% of all new prescriptions annually issued for 56 medicines in UK primary care had an actionable drug-gene interaction according to guidelines from the Dutch Pharmacogenetic Working Group and/or the Clinical Pharmacogenetics Implementation Consortium. A multi-drug pharmacogenomic testing programme which constitutes testing genetic variants in four genes (CYP2C19, CYP2D6, SLCO1B1, HLA-B) would cover more than 95% of the potential drug-gene interactions occurring in UK primary care. The systematic review found barriers to the implementation of multi-drug pharmacogenomic testing can be organised around four themes influencing behaviours of prescribers, pharmacists and patients. These are: IT infrastructure, Effort, Rewards and Unknown Territory. Barriers were most consistently mapped to TDF domains: memory, attention and decision-making processes, environmental context and resources, and belief about consequences. Pharmacists played a vital role in PGx testing implementation model and enabled prescribers to order and deliver PGx testing for patients. Empirical data using a case study methodology of real-world implementation of multi-drug pharmacogenomic testing, found pharmacists were key drivers for PGx testing implementation model within an NHS context. Training to prepare health professionals to deliver and utilise PGx testing in clinical decision making, should focus on skills development and managing expectations of both patients and health professionals of what PGx testing can provide. Conclusions These three studies advance the understanding of implementing multi-drug pharmacogenomic testing by converging implementation science and genomic medicine. The modelling study provides researchers and policy makers with new knowledge to design a minimum drug-gene panel for a PGx testing panel relevant to the UK population. The multi-drug PGx testing implementation configuration informed by the systematic review and case study requires further modelling and feasibility testing to optimise before implementation across NHS settings. Keywords: pharmacogenomics, personalised medicine, implementatio

Population genomics and ancestral origins for health disparities research

Ameliorating health disparities – avoidable differences in health outcomes between population groups – is both a social imperative and a pressing scientific challenge. The relative importance of genetic versus environmental effects for health disparities, i.e. the enduring question of nature versus nurture, particularly for complex common diseases that have multifactorial etiologies, has long been debated. The importance of social and environmental determinants of health disparities is well established, whereas the role of genetics is more controversial. Nevertheless, these two classes of effects are not mutually exclusive; genes are expressed and function in the context of specific environmental conditions. Thus, it is reasonable to consider the influence of genetic and environmental factors on health disparities together. Indeed, the importance of interactions between genetic and environmental factors for shaping health outcomes has recently been recognized as a promising avenue for health disparities research. The major aim of this thesis was to investigate both genetic and environmental contributions to health disparities by leveraging population biobanks and large genomic datasets. Biobank datasets, which include collections of genetic data together with rich clinical, phenotypic, and environmental data for thousands of individuals, are ideally suited for this purpose. The thesis consists of two main parts: (1) population pharmacogenomics, and (2) complex common health disparities. The first part of the thesis investigates the partitioning of pharmacogenomic variation between populations in different geographic and socioeconomic locales (in Colombia and the US) to study differences in predicted therapeutic response among populations, and the second part of the thesis illustrates the use of a large population biobank to understand health disparities and their complex relationship to genetic, environmental, and social factors. Results from the first part of the thesis highlight how population genomics can be a powerful tool for clinical decision-making especially in settings where resources are limited (e.g. Colombia) or where resources are unequally distributed between population groups (e.g. US). These findings support the precision public health paradigm, which shifts the focus of genomic characterization efforts from individuals to populations to identify interventions that work best at the population level. This allows for uniform priors for treatment to be adjusted based on population membership. Results from the second part of the thesis demonstrate the massive potential of employing biobanks to investigate health disparities and to decompose their effects into genetic and environmental components. Interactions discovered between genetic and environmental risk factors underscore how environmental effects on disease can differ among ancestry groups, suggesting the need for group-specific interventions. Beyond these specific research advances, this thesis also takes a step towards addressing the lack of diversity in genomics research. Genomics research is currently biased towards European ancestry cohorts, and results from these studies may not transfer to more diverse ancestry groups. This genomics research gap has the potential to exacerbate existing health disparities. The focus on ancestrally diverse populations, both in developing countries and for underrepresented minority groups in the US and the UK, has the potential to support health equity through ancestrally-guided insights and interventions.Ph.D

African researchers' perceptions and expectations of the benefits of genomics research in Africa : a qualitative study

Introduction: Genomics research raises a number of ethical, legal and social issues (ELSI), one of which is the concept of benefit sharing. While benefits and benefit sharing are difficult to discuss because of questions on what needs to be shared, with whom and by whom, it cannot be pushed to the side-lines especially as it is a way of promoting justice in health research and of ensuring that research is of social value to study communities. In this study, we explored the perceptions and expectations of African genomics scientists on the benefits of genomics research to Africa. Method: This was a qualitative study and we adopted a grounded theory approach. I conducted 17 in-depth interviews with genomics researchers in Africa to explore their perceptions of benefits and benefit sharing in genomics research in Africa. Transcripts of interviews were imported into QSR-NVivo 10 for thematic analysis. A thematic analysis of informed consent documents used in 13 genomics studies in Africa was also done to explore how research benefits are documented. Results: Research collaboration, research capacity building and access to genomics medicine were perceived to be the main benefits of African genomics science (AGS). In terms of research collaboration, there were perceived fears of exploitation of African researchers and research participants, and the non-sustainability of AGS. To address the problem of exploitation, African researchers expressed the need for fairness in AGS through transparency and equity in research collaborations, enhancing research oversight, African ownership and leadership of AGS, community engagement and research capacity building. In terms of genomics medicine, African genomics researchers perceived that AGS would have an impact on healthcare in Africa in the area of diagnosis, pharmacogenomics and public health. However, there were concerns around access to genomics medicine by African populations, lack of capacity for genomics medicine in Africa and the need for AGS to focus on Africa's healthcare priorities. There was however limited awareness of the concept of benefit sharing among African genomics researchers though they perceived it is as an important concept for AGS. Interviewees suggested that benefit sharing could be in the form of research capacity building, feedback of study findings, science education, community projects and the sharing of profits

Pharmacogenetic Investigations Using Community-Based Participatory Research to Address Health Disparities in Minnesota Hmong

University of Minnesota Ph.D. dissertation. August 2017. Major: Experimental & Clinical Pharmacology. Advisor: Robert Straka. 1 computer file (PDF); xii, 237 pages.Introduction: Pharmacogenomics is an approach to personalizing therapy to help patients achieve their therapeutic goals with the least possible adverse events. This approach relies on the knowledge derived from large genetic studies that involve diverse populations to guide the development of treatment algorithms. The underrepresentation of select populations or unique sub-populations in genetic-based research presents as a gap in knowledge to create comprehensive genetic-based treatment algorithms and a missed opportunity to address health disparities within those unique populations. A prime example is the Minnesota Hmong. The Hmong is an Asian sub-population minimally represented in clinical or genetic-based research with a high prevalence of gout and gout-related comorbidities than non-Hmong. Methods: Using the principles of community-based participatory research and the establishment of the Hmong advisory board, assessment of the community’s perception of genetics and preparedness for engagement in research were conducted. Capitalizing on the findings from the first informational study, two Hmong genetic-based studies were conducted. The first study was to ascertain the frequency of select pharmacogenes and disease-risk genes in the Hmong, relative to non-Hmong. The second study was to quantify the effect of genetic variations within uric acid transportome and purine metabolizing genes on the pharmacokinetics and pharmacodynamics of allopurinol in Hmong adults with gout or hyperuricemia. Results: The informational study results indicated that most Hmong are willing to participate in research to help themselves and the Hmong community. Some of the genetic perceptions in the Hmong were not scientifically grounded and some concerns about privacy were reported while the return of genetic results to participants had mixed responses. The first genetic-based study indicated that more than 80% of Hmong participants were willing to store their DNA for future analyses and share their DNA with other scientists. Pharmacogenes risk allele frequencies of CYP2C19, CYP2C9, VKORC1, and CYP4F2 were higher in the Hmong relative to Caucasian. Disease risk allele frequencies of hyperuricemia and gout associated genes such as SLC2A9, SLC17A1, SLC22A11, SLC22A12, ABCG2, PDZK1, were also higher in the Hmong than Caucasian and Han-Chinese. The second genetic-based study indicated that the genetic variation within SLC22A12 (rs505803T>C) significantly affects the exposure to and the renal clearance of the active metabolite of allopurinol, oxipurinol. Additionally, the rs505802 was also significantly associated with the overall response to allopurinol. Conclusions: Engaging the Hmong in genetic-based research is a step forward to advance precision medicine while addressing health disparities within the Hmong community. The prevalence of pharmacogenes within the Hmong suggest that the Hmong will require a lower starting dose of warfarin and unlikely to benefit from clopidogrel. The prevalence of hyperuricemia and gout associated risk alleles in the Hmong are consistent with the higher prevalence of gout in the Hmong. Finally, the rs505802 T>C within SLC22A12 gene could predict the overall response to allopurinol

Factors influencing the efficacy of praziquantel in a schistosome-exposed population

Urogenital schistosomiasis, caused by the Schistosoma haematobium parasite, is a global cause of morbidity and mortality and affects millions of people each year. The mass drug administration (MDA) of praziquantel (PZQ) is a vital intervention to treat schistosome infections and eliminate schistosomiasis as a public health problem. After decades of use, variable PZQ efficacy and persistent schistosome infections have been reported across multiple schistosome-endemic African countries. However, there is a paucity of information on the factors that influence the efficacy of a PZQ treatment and contribute to the persistence of infection, particularly in schistosome-exposed populations where the drug is commonly used. To address this, I examined the factors that influence individual responses to PZQ and how these contribute to variable PZQ efficacy. This focused on alterations to PZQ metabolism, which regulates the concentration of the schistosome-killing PZQ, and thus can be a crucial determinant of PZQ efficacy and adverse drug reactions (ADRs). During a review of published studies, I identified several drug and host-related factors, such as drug-drug interactions (DDIs) and the liver’s capacity to metabolise PZQ, that influenced the systemic concentrations of PZQ via altered PZQ metabolism, and discussed the resultant impact on PZQ efficacy. This review also highlighted gaps in the research regarding pharmacogenetic (PGx) and metabolomic studies. Consequently, I characterised PGx variations in PZQ- metabolising cytochrome P450 (CYP) enzymes and determined associations between each detected variant and the efficacy of PZQ treatment in S. haematobium-infected Zimbabweans. Four single nucleotide polymorphisms (SNPs) across the CYP1A2, CYP2D6 and CYP3A5 enzymes were significantly associated with PZQ treatment outcome, including genotypes that increased the odds of an individual clearing or not clearing schistosome infection. A further study using in vivo analyte concentrations detected no associations with PZQ efficacy. Yet, there were significant associations between variants in the CYP1A2 and CYP2C9 enzymes and in vivo analyte concentrations indicative of increased metabolism and decreased PZQ exposure. Both PGx studies provided insight into the drug-gene interactions in schistosome-infected patients during a PZQ treatment and suggested that the PGx impact on PZQ exposure and efficacy may be underestimated in the diverse African populations where PZQ is utilised. To determine if variable PZQ efficacy and persistent schistosome infections occurred during MDAs in Zimbabwe, I identified persistent hotspots of S. haematobium infection prevalence (PPHS) and hotspots of decreasing efficacy of PZQ (EPHS). Further, the risk factors of hotspot emergence were evaluated, and EPHS were not identified as a primary cause for PPHS based on these analyses. Initial infection intensity was significantly higher in PPHS than in responder districts, providing valuable information on the possibility of early identification of persistent schistosome infections to improve on current control strategies. However, there was no clear predictor of EPHS occurrence. Overall, this thesis highlighted key factors that influence an individual’s response to a PZQ treatment, including multiple PGx determinants which were previously underreported. Together, this thesis produced significant novel data towards the characterisation of the host factors that contribute towards variable PZQ efficacy, and in the identification of hotspots of persistent infections. Together, these findings will inform policymakers on the factors that influence PZQ efficacy to improve schistosomiasis control and eliminate this disease

From Isolation to Inclusion: Embracing Local Perspectives in Examining the Treatment Model of Care for Aboriginal Persons Affected by Tuberculosis or Leprosy in the Kimberley Region, North Western Australia

In the remote Kimberley region of North Western Australia, tuberculosis (TB) and leprosy continue to affect a small number of Aboriginal people, despite historical efforts to eliminate either disease. Treatment, predominantly antibiotic therapy, is a principal therapeutic intervention used to cure TB and leprosy and halt infection transmission. Decisions made around treatment therefore impact not only the individual person affected, but also their families and communities. The well-worn models of Directly Observed Therapy (DOT) and case management are used nationally to assist treatment continuity and completion. Neither model has been substantiated for cultural appropriateness nor for meeting the specific needs of Aboriginal people. Given the important role of treatment, this thesis uses decolonial theory to critically examine how culturally secure and person-centred care practice could be better incorporated into the current treatment model of care used in the Kimberley region for Aboriginal persons affected by TB or leprosy. To achieve this, qualitative methods were employed to explore the lived experience of Aboriginal persons affected by either disease, as well as community members and Health Care Workers involved in care. In addition, archival research of historical documents relating to treatment was conducted. The findings of this research revealed deeper narratives about medication safety concerns, the importance of family history knowledge for early treatment intervention, and challenges relating to integrating TB and leprosy management into primary health care due to competing priorities of more prevalent chronic diseases. Health care relationships were found to play a key role in optimising treatment. However, gaps and inconsistences were identified within these relationships in the areas of two-way trust, communicating importance and consequences of treatment, providing feedback, shared treatment decision-making, and the provision of culturally respectful support. Family relationships and connection to culture were also significant for psychosocial support. Understanding the history of TB and leprosy treatment specific to the region was found to be an integral part of understanding contemporary treatment models and in identifying ongoing colonising within the way health care services for the treatment of TB and leprosy are delivered. Using these findings, a novel treatment model of care is presented. This offers theoretical and practical strategies to re-think and apply culturally responsive approaches to optimising treatment for Aboriginal persons affected by TB or leprosy. This has the potential benefit of improved wellbeing and elimination of disease for current and future generations