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Item Bioinformatics and Pharmacogenomics in Drug Discovery and DevelopmentAnyanwu, Chukwuma Eustace; Jones, JosetteObjective: Literature review to evaluate the extent to which Bioinformatics has facilitated the drug discovery and development process from an economic perspective Problem: A plethora of genomic and proteomic information was uncovered by the U.S Human Genome Project (HGP). Despite the projected impact that Bioinformatics and Pharmacogenomics were projected to have in the drug discovery and development process, the challenges facing the pharmaceutical companies – in this regard, still persist. Design: An extensive integrated literature review of library resources such as MEDLINE, ERIC, PsychInfo, EconLit, Social Services Abstracts, ABI/INFORM and LISA (all 1990 – Present). These electronic databases were researched because of their focuses on the healthcare sector, medical and scientific innovations, economic modeling and analysis, bioinformatics and computational biology, applied social research and technology applications. Semi-structured interviews of Bioinformatics professionals were also conducted to complement the literature review. Also, Internet-based databases from reliable resources were also researched resulting in serendipitous discoveries. Sample: Published English language reports of studies and research carried out worldwide from 1990 to 2004, relating to drug discovery and development. Selection criteria: Primary focus was on research publications and journals that identify and discuss the practice of Bioinformatics, especially in the area of drug discovery and development. Premium was placed on articles and publications that discussed the economic impacts of Bioinformatics in the drug discovery process. Results: Though the goals of Bioinformatics have been clearly defined, and the discipline is widely practiced in the pharmaceutical industry, this study has not found any definite attempts to evaluate its economic and regulatory impact specifically in facilitating the drug discovery and development process, and the delivery of personalized drugs. Discussion: Bioinformatics and Pharmacogenomics are the new facets of the ever-evolving drug discovery and development process. It may still be a while before their full impact and potential is attained.Item Bioinformatics and Pharmacogenomics in Drug Discovery and Development- a Socio-economic Perspective(2006-07-26T14:37:43Z) Anyanwu, Chukwuma Eustace; Jones, JosetteA 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.Item A Call for Clear and Consistent Communications Regarding the Role of Pharmacogenetics in Antidepressant Pharmacotherapy(Wiley, 2020-01) Hicks, J. Kevin; Bishop, Jeffrey R.; Gammal, Roseann S.; Sangkuhl, Katrin; Bousman, Chad; Leeder, J. Steven; Llerena, Adrián; Mueller, Daniel J.; Ramsey, Laura B.; Scott, Stuart A.; Skaar, Todd C.; Caudle, Kelly E.; Klein, Teri E.; Gaedigk, Andrea; Medicine, School of MedicineItem Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2B6 and Efavirenz-Containing Antiretroviral Therapy(Wiley, 2019-04-21) Desta, Zeruesenay; Gammal, Roseann S.; Gong, Li; Whirl-Carrillo, Michelle; Gaur, Aditya H.; Sukasem, Chonlaphat; Hockings, Jennifer; Myers, Alan; Swart, Marelize; Tyndale, Rachel F.; Masimirembwa, Collen; Iwuchukwu, Otito F.; Chirwa, Sanika; Lennox, Jeffrey; Gaedigk, Andrea; Klein, Teri E.; Haas, David W.; Medicine, School of MedicineThe human immunodeficiency virus (HIV) type-1 non-nucleoside reverse transcriptase inhibitor, efavirenz, is widely used to treat HIV-1 infection. Efavirenz is predominantly metabolized into inactive metabolites by CYP2B6, and patients with certain CYP2B6 genetic variants may be at increased risk for adverse effects, particularly central nervous system toxicity and treatment discontinuation. We summarize the evidence from the literature and provide therapeutic recommendations for efavirenz prescribing based on CYP2B6 genotypes.Item Effects of SLCO1B1 polymorphisms on plasma estrogen concentrations in women with breast cancer receiving aromatase inhibitors exemestane and letrozole(Future Medicine, 2019-06-13) Dempsey, Jacqueline M.; Kidwell, Kelley M.; Gersch, Christina L; Pesch, Andrea M; Desta, Zeruesenay; Storniolo, Anna Maria; Stearns, Vered; Skaar, Todd C.; Hayes, Daniel F; Henry, N Lynn; Rae, James M; Hertz, Daniel L; Medicine, School of MedicineAim: This study tested for associations between SLCO1B1 polymorphisms and circulating estrogen levels in women with breast cancer treated with letrozole or exemestane. Patients & methods: Postmenopausal women with hormone-receptor positive breast cancer were genotyped for SLCO1B1*5 (rs4149056) and rs10841753. Pretreatment and on-treatment plasma estrogens and aromatase inhibitor (AI) concentrations were measured. Regression analyses were performed to test for pharmacogenetic associations with estrogens and drug concentrations. Results: SLCO1B1*5 was associated with elevated pretreatment estrone sulfate and an increased risk of detectable estrone concentrations after 3 months of AI treatment. Conclusion: These findings suggest SLCO1B1 polymorphisms may have an effect on estrogenic response to AI treatment, and therefore may adversely impact the anticancer effectiveness of these agents.Item The Impact of SBF2 on Taxane-Induced Peripheral Neuropathy(2021-05) Cunningham, Geneva Mari; Schneider, Bryan P.; Radovich, Milan; Liu, Yunlong; Skaar, Todd; Meyer, Jason; Ivan, MirceaThe 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.Item Lessons Learned When Introducing Pharmacogenomic Panel Testing into Clinical Practice(Elsevier, 2017-01-01) Rosenman, Marc B.; Decker, Brian; Levy, Kenneth D.; Holmes, Ann M.; Pratt, Victoria M.; Eadon, Michael T.; Medicine, School of MedicineObjectives: Implementing new programs to support precision medicine in clinical settings is a complex endeavor. We describe challenges and potential solutions based on the Indiana GENomics Implementation: an Opportunity for the Underserved (INGenious) program at Eskenazi Health-one of six sites supported by the Implementing GeNomics In pracTicE network grant of the National Institutes of Health/National Human Genome Research Institute. INGenious is an implementation of a panel of genomic tests. Methods: We conducted a descriptive case study of the implementation of this pharmacogenomics program, which has a wide scope (14 genes, 27 medications) and a diverse population (patients who often have multiple chronic illnesses, in a large urban safety-net hospital and its outpatient clinics). Challenges: We placed the clinical pharmacogenomics implementation challenges into six categories: patient education and engagement in care decision making; clinician education and changes in standards of care; integration of technology into electronic health record systems; translational and implementation sciences in real-world clinical environments; regulatory and reimbursement considerations, and challenges in measuring outcomes. A cross-cutting theme was the need for careful attention to workflow. Our clinical setting, a safety-net health care system, presented some distinctive challenges. Patients often had multiple chronic illnesses and sometimes were taking more than one pharmacogenomics-relevant medication. Reaching patients for recruitment or follow-up was another challenge. Conclusions: New, large-scale endeavors in health care are challenging. A description of the challenges that we encountered and the approaches that we adopted to address them may provide insights for those who implement and study innovations in other health care systems.Item Multi-site investigation of strategies for the implementation of CYP2C19 genotype-guided antiplatelet therapy(Wiley, 2018) Empey, Philip E.; Stevenson, James M.; Tuteja, Sony; Weitzel, Kristin W.; Angiolillo, Dominick J.; Beitelshees, Amber L.; Coons, James C.; Duarte, Julio D.; Franchi, Francesco; Jeng, Linda J. B.; Johnson, Julie A.; Kreutz, Rolf P.; Limdi, Nita A.; Maloney, Kristin A.; Obeng, Aniwaa Owusu; Peterson, Josh F.; Petry, Natasha; Pratt, Victoria M.; Rollini, Fabiana; Scott, Stuart A.; Skaar, Todd C.; Vesely, Mark R.; Stouffer, George A.; Wilke, Russell A.; Cavallari, Larisa H.; Lee, Craig R.; Medicine, School of MedicineCYP2C19 genotype-guided antiplatelet therapy following percutaneous coronary intervention is increasingly implemented in clinical practice. However, challenges such as selecting a testing platform, communicating test results, building clinical decision support processes, providing patient and provider education, and integrating methods to support the translation of emerging evidence to clinical practice are barriers to broad adoption. In this report, we compare and contrast implementation strategies of 12 early adopters, describing solutions to common problems and initial performance metrics for each program. Key differences between programs included the test result turnaround time and timing of therapy changes which are both related to CYP2C19 testing model and platform used. Sites reported the need for new informatics infrastructure, expert clinicians such as pharmacists to interpret results, physician champions, and ongoing education. Consensus lessons learned are presented to provide a path forward for those seeking to implement similar clinical pharmacogenomics programs within their institutions. This article is protected by copyright.Item Pharmacogenomically actionable medications in a safety net health care system(2016) Carpenter, Janet S.; Rosenman, Marc B.; Knisely, Mitchell R.; Decker, Brian S.; Levy, Kenneth D.; Flockhart, David A.; IU School of NursingOBJECTIVE: Prior to implementing a trial to evaluate the economic costs and clinical outcomes of pharmacogenetic testing in a large safety net health care system, we determined the number of patients taking targeted medications and their clinical care encounter sites. METHODS: Using 1-year electronic medical record data, we evaluated the number of patients who had started one or more of 30 known pharmacogenomically actionable medications and the number of care encounter sites the patients had visited. RESULTS: Results showed 7039 unique patients who started one or more of the target medications within a 12-month period with visits to 73 care sites within the system. CONCLUSION: Findings suggest that the type of large-scale, multi-drug, multi-gene approach to pharmacogenetic testing we are planning is widely relevant, and successful implementation will require wide-scale education of prescribers and other personnel involved in medication dispensing and handling.Item A Physiologic approach to the pharmacogenomics of hypertension(Elsevier, 2016-03) Eadon, Michael T.; Chapman, Arlene B.; Department of Medicine, IU School of MedicineHypertension is a multifactorial condition with diverse physiological systems contributing to its pathogenesis. Individuals exhibit significant variation in their response to antihypertensive agents. Traditional markers, such as age, gender, diet, plasma renin level, and ethnicity, aid in drug selection. However, this review explores the contribution of genetics to facilitate antihypertensive agent selection and predict treatment efficacy. The findings, reproducibility, and limitations of published studies are examined, with emphasis placed on candidate genetic variants affecting drug metabolism, the renin-angiotensin system, adrenergic signalling, and renal sodium reabsorption. Single-nucleotide polymorphisms identified and replicated in unbiased genome-wide association studies of hypertension treatment are reviewed to illustrate the evolving understanding of the disease's complex and polygenic pathophysiology. Implementation efforts at academic centers seek to overcome barriers to the broad adoption of pharmacogenomics in the treatment of hypertension. The level of evidence required to support the implementation of pharmacogenomics in clinical practice is considered.