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OBJECTIVE: Personalized genomic medicine (PGM) has been lauded as the future of medicine, as new human genomic research findings are applied towards the development of screenings, diagnostic tools and treatments that are tailored to the genomic profiles of individuals. However, the development of PGM is still in its nascent stages, therefore, some have supported the development of clinical tools and treatments based on population-level characteristics, such as race or ethnicity. Race-based medicine (RBM), has been, and continues to be, promoted as an interim form of PGM, and although an academic debate has flourished over medical, social and ethical concerns related to RBM, to date, there have only been a few small studies that have examined lay beliefs and attitudes regarding RBM. The extent to which the greater American public would believe in the effectiveness of RBM and indicate an intention to use RBM is unclear. Furthermore, it is possible that racial and ethnic groups would differ in their beliefs and attitudes regarding RBM, considering RBM implies the controversial and contested conceptualization of race as having some genetic basis. Therefore, the purpose of this dissertation study was to use, for the first time, a nationally representative sample of adult Americans and examine the importance of race with respect to the following: beliefs and attitudes regarding RBM; the extent to which these beliefs and attitudes can be influenced by mass media messages about the relationship between race and genetics; and how beliefs and attitudes regarding RBM compare with those regarding PGM. METHODS: In order to answer these questions, this dissertation study used a nationally representative sample of self-identified non-Hispanic white, non-Hispanic black and Hispanic U.S. residents who participated in an online survey examining beliefs and attitudes regarding RBM and PGM, and the effect of a vignette experiment using mock news articles that varied in their messages about the relationship between race and genes on these beliefs and attitudes. The survey assessed the following constructs using new measures designed for this dissertation study: RBM's effectiveness at the individual, clinical level; PGM's effectiveness at the individual, clinical level; preferences for using RBM; preferences for using PGM; and RBM's ability to address health inequalities in the U.S. Means, frequencies, mean-difference tests and multiple regression were used to examine the effect of race and/or the vignette experiment on beliefs and attitudes regarding RBM and PGM. RESULTS: The results of this dissertation study show that the majority of white, black and Hispanic Americans equally agreed that RBM would not be clinically effective at the individual level, but the majority of all groups also equally agreed that they would prefer to use RBM if it was available. More than forty percent of all respondents who did not believe RBM would be effective at the individual level, still preferred to use a race-specific treatment if it was available. The three racial/ethnic groups examined in this study did diverge in belief in RBM's ability to reduce health inequalities. Greater portions of the black and Hispanic respondents believed RBM would be effective at reducing health inequalities than white respondents. Racial differences were also seen in the effect of the vignette experiment on RBM beliefs and attitudes. While the vignette experiment had no effect on whites' beliefs and attitudes regarding RBM, vignettes that stated or implied a genetic basis to racial difference were associated with lower endorsement of RBM beliefs and attitudes among the black respondents. Finally, the results indicated that both white and black Americans endorsed PGM's effectiveness at the individual level at greater levels than RBM's effectiveness, and both groups indicated greater preferences for using PGM than RBM. However, while most white respondents indicated that they believed PGM would be effective at the individual level and that they would prefer to use PGM if it was available, nearly half of the black respondents did not believe PGM would be clinically effective, and 1 out of 4 black respondents did not prefer to use PGM. CONCLUSIONS: The results suggest that white, black and Hispanic Americans do not significantly differ in their beliefs and attitudes regarding the effectiveness of or preferences for using RBM. This finding diverges from prior studies that showed racial differences in beliefs and attitudes regarding RBM. The lack of racial difference may be due to a lack of familiarity with this concept, for the results also suggested that once respondents were exposed to varying mock news article messages about the relationship between race and genes, racial differences began to emerge. The results also showed discordance between belief in RBM's effectiveness and preferences for using RBM. This finding suggests that there is still an incentive for the pharmaceutical and diagnostic testing industries to develop and market RBM even if there is generally low public opinion regarding RBM's effectiveness. PGM has been promoted by the biomedical industry as a potential solution to racial and ethnic health disparities both in the U.S. and globally, and RBM has been promoted as an interim form of PGM until it is further developed. Despite noted clinical, social and ethical concerns regarding RBM specifically, proponents of RBM have focused on promoting the message of its potential to mitigate racial and ethnic health disparities. The results from this study indicate that on the surface at least, this argument may in fact resonate with black and Hispanic Americans. In addition to being the first nationally representative study to examine potential racial differences in RBM beliefs and attitudes, this dissertation was also the first nationally representative study to examine potential racial differences in beliefs and attitudes regarding PGM. Although the results clearly showed that all Americans endorsed the effectiveness of and preferences for using PGM at greater levels than RBM, whites were significantly more likely than blacks to believe PGM would be clinically effective and to indicate a preference for using PGM. Thus, while the merits of PGM may seem apparent to the clinical and academic communities, the results of this study indicate that there is not universal support for PGM among the public. Cautious support for PGM from black respondents may reflect more general mistrust towards the medical community and new forms of health technologies. Even though racial and ethnic minority populations seem open to RBM and PGM as potential strategies to address health inequalities, support for both could change as the public becomes more familiar with both concepts, whether through exposure to mass media messages, mass marketing of treatments and genetic testing, or through their clinical providers. The findings from this dissertation study significantly advance our knowledge of the American public's beliefs and attitudes regarding RBM and PGM, particularly with respect to racial differences, and should be considered by stakeholders in current and future debates surrounding efforts to develop and promote both.

Cognitive decline is increasingly recognized as a side effect of chemotherapy. However, cognitive decline doesn't occur in all patients receiving chemotherapy, and there is variability in the cognitive domains affected (Ahles; JCO,Oct 20, 2012:3675-3686). Safety pharmacogenomics, i.e. using genetic variations to predict response/toxicity, offers an exciting approach to identify the subset of patients most likely to suffer from cognitive decline post chemotherapy. Consequently specific therapeutic interventions can be developed to target this group of patients, and/or alternate chemotherapeutic regimens can be used to limit toxicity, thereby offering a way to individualize therapy while minimizing toxicity. In our research we studied the effect of 16 SNPs in 6 genes on cognition in a sample of healthy older adults. We found that SNPs that affect serotonin, dopamine and glutamate levels in the brain influence cognition in a healthy sample of older adults, possibly in a domain specific manner. This allowed us to identify a group of healthy adults who inherently have lower cognitive functioning in some domains but that is still within the normal range. In addition individuals with SNPs that previously were associated with lower levels of myeloperoxidase performed better on the executive functions, verbal memory, verbal IQ and IQ. SNPs associated with lower levels were also associated with improvement in self reported verbal and visual memory post chemotherapy. APOE E2 allele was associated with higher cognitive performance compared to other alleles. However we didn't see an effect of APOE post chemotherapy. In chapter five, the effects of 31 SNPs in 15 genes on cognition post chemotherapy were evaluated in community dwelling lymphoma patients. Changes in the domains of verbal memory, visual perceptual memory, and attention of the Multiple Ability Self Report Questionnaire were observed following chemotherapy, but only when groups were stratified by genotype. Contrary to what we might expect, patients showed improvements in function after chemotherapy. However, using patient stratification based on genotype, specific groups of patients had a measurable decline in cognitive function post chemotherapy. Interestingly a SNP in the DNA replication enzyme and the target of doxorubicin topoisomerase II was associated with varying degree of self reported attention; specifically the AA genotype of rs471692 was associated with statistically significant decline in attention post chemotherapy. This indicates that cognitive changes following chemotherapy can be subtle, and stratification by genotype helps us in identifying susceptible individuals and provides some insights on the inconsistencies that are frequently reported in the literature. These results allow for identifying genetic risk factors associated with chemotherapy-induced cognitive changes, which will ultimately help in developing therapeutic approaches for the management of those deficits. Strategies to avoid chemotherapy-induced cognitive changes will be prospectively evaluated in future studies and include alternative chemotherapy and less toxic regimens, intervention strategies to improve cognitive abilities, and drug therapy to improve cognition in patients who develop chemotherapy-induced cognitive changes. The overarching goals of our studies are to help improve cancer patients' quality of life while maintaining or improving cancer cure rates.

Title from title page of PDF (University of Missouri--St. Louis, viewed March 3, 2010). Includes bibliographical references (p. 26).

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Submitted to the faculty of the Informatics Graduate Program in partial fulfillment of the requirements for the degree Master of Science in Bioinformatics in the School of Informatics Indiana University May 2006 / A plethora of genomic and proteomic information was uncovered by the U.S Human Genome Project (HGP) – mostly by means of bioinformatics tools and techniques. Despite the impact that bioinformatics and pharmacogenomics were projected to have in the drug discovery and development process, the challenges facing the pharmaceutical industry, such as the high cost and the slow pace of drug development, appear to persist. Socio-economic barriers exist that mitigate the full integration of bioinformatics and pharmacogenomics into the drug discovery and development process, hence limiting the desired and expected effects.

Indiana University-Purdue University Indianapolis (IUPUI) / The main focus of this study is to determine the impact of Set-Binding Factor 2 (SBF2) on human-derived neurons in the context of taxane-induced peripheral neuropathy. Taxane-induced peripheral neuropathy (TIPN) is a devastating survivorship issue for many cancer patients; SBF2 has been previously identified as a potential germline predictor that has been found to be significantly associated with severe TIPN in African American (AA) patients. The work described here provides ex vivo support for the use of SBF2 as a genotypic biomarker to identify a priori which patients are at a higher risk of manifesting severe TIPN. This study demonstrates that diminished expression of SBF2 exacerbated the effect of paclitaxel on viability and morphology and altered the functional response of a neuronal model exposed to paclitaxel treatment. Furthermore, transcriptomic work showed that reduced expression of SBF2 in a neuronal model treated with paclitaxel impacted the expression of genes that modulate stress-induced cell death and pain threshold. Altogether, these findings suggest that SBF2 plays a role in the development of TIPN. This work sheds light on the pathways potentially involving SBF2 that can be studied to further evaluate the function of this gene in neurons and its contribution to severe TIPN. Further functional approaches investigating these pathways will be pivotal in elucidating the underlying biological mechanism for this toxicity and identifying novel targeted therapeutic strategies to prevent or treat TIPN. / 2021-05-17

Yes / Patients' pharmacogenetic data could be used to improve adherence to antipsychotic medication by increasing the likelihood of therapeutic response and reducing the prevalence of adverse drug reactions.

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Indiana University-Purdue University Indianapolis (IUPUI) / Pharmacogenetic testing has the potential to improve pain management through addressing wide interindividual variations in responses to pharmacogenetically actionable opioids, ultimately decreasing costly adverse drug effects and improving responses to these medications. A recent review of pharmacogenomics in the nursing literature highlighted the need for nurses to more fully embrace the burgeoning field of pharmacogenomics in nursing research, clinical practice, and education. Despite the promise of pharmacogenetic testing, significant challenges exist for evaluating outcomes related to its implementation, including oversimplification of medication exposure, the complexity of patients' clinical profiles, and the characteristics of healthcare contexts in which medications are prescribed. A better understanding of these challenges could enhance the assessment and documentation of the benefits of pharmacogenetic testing in guiding opioid therapies. This dissertation is intended to address the challenges of evaluating outcomes of pharmacogenetic testing implementation and the need for nurses to lead pharmacogenomic-related research. The dissertation purpose was to advance the sciences of nursing, pain management, and pharmacogenomics through the development of a typology of common patterns of medication exposure to known pharmacogenetically actionable opioids (codeine & tramadol). A qualitative, person-oriented approach was used to retrospectively analyze six months of electronic health record and pharmacogenotype data in 30 underserved adult patients. An overarching typology with eight groups of patients that had one of five opioid prescription patterns (singular, episodic, switching, sustained, or multiplex) and one of three types of medical emphasis of care (pain, comorbidities, or both) were identified. This typology consisted of a description of multiple common patterns that compare and contrast salient factors of exposure and the emphasis of why individuals were seeking care. Furthermore, in an aggregate descriptive analysis evaluating key clinical profile factors, these patients had complex medical histories, extensive healthcare utilization, and experienced significant polypharmacy. These findings can aid in addressing challenges related to the implementation of pharmacogenetic testing in clinical practice and point to ways in which nurses can take the lead in pharmacogenomics research. Findings also provide a foundation for future studies aimed at developing medication exposure measures to capture its dynamic nature and identifying and tailoring interventions in this population.