Browsing by Subject "Pharmacogenetics"
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Item Open Access Gene Expression Profiles Link Respiratory Viral Infection, Platelet Response to Aspirin, and Acute Myocardial Infarction.(PLoS One, 2015) Rose, Jason J; Voora, Deepak; Cyr, Derek D; Lucas, Joseph E; Zaas, Aimee K; Woods, Christopher W; Newby, L Kristin; Kraus, William E; Ginsburg, Geoffrey SBACKGROUND: Influenza infection is associated with myocardial infarction (MI), suggesting that respiratory viral infection may induce biologic pathways that contribute to MI. We tested the hypotheses that 1) a validated blood gene expression signature of respiratory viral infection (viral GES) was associated with MI and 2) respiratory viral exposure changes levels of a validated platelet gene expression signature (platelet GES) of platelet function in response to aspirin that is associated with MI. METHODS: A previously defined viral GES was projected into blood RNA data from 594 patients undergoing elective cardiac catheterization and used to classify patients as having evidence of viral infection or not and tested for association with acute MI using logistic regression. A previously defined platelet GES was projected into blood RNA data from 81 healthy subjects before and after exposure to four respiratory viruses: Respiratory Syncytial Virus (RSV) (n=20), Human Rhinovirus (HRV) (n=20), Influenza A virus subtype H1N1 (H1N1) (n=24), Influenza A Virus subtype H3N2 (H3N2) (n=17). We tested for the change in platelet GES with viral exposure using linear mixed-effects regression and by symptom status. RESULTS: In the catheterization cohort, 32 patients had evidence of viral infection based upon the viral GES, of which 25% (8/32) had MI versus 12.2% (69/567) among those without evidence of viral infection (OR 2.3; CI [1.03-5.5], p=0.04). In the infection cohorts, only H1N1 exposure increased platelet GES over time (time course p-value = 1e-04). CONCLUSIONS: A viral GES of non-specific, respiratory viral infection was associated with acute MI; 18% of the top 49 genes in the viral GES are involved with hemostasis and/or platelet aggregation. Separately, H1N1 exposure, but not exposure to other respiratory viruses, increased a platelet GES previously shown to be associated with MI. Together, these results highlight specific genes and pathways that link viral infection, platelet activation, and MI especially in the case of H1N1 influenza infection.Item Open Access Integrating pharmacogenomics into clinical trials of hearing disorders.(The Journal of the Acoustical Society of America, 2022-11) Brutnell, Thomas P; Wang, Xinwen; Bao, JianxinIn 2019, the U.S. Food and Drug Administration issued guidance to increase the efficiency of drug development and support precision medicine, including tailoring treatments to those patients who will benefit based on genetic variation even in the absence of a documented mechanism of action. Although multiple advancements have been made in the field of pharmacogenetics (PGx) for other disease conditions, there are no approved PGx guidelines in the treatment of hearing disorders. In studies of noise-induced hearing loss (NIHL), some progress has been made in the last several years associating genomic loci with susceptibility to noise damage. However, the power of such studies is limited as the underlying physiological responses may vary considerably among the patient populations. Here, we have summarized previous animal studies to argue that NIHL subtyping is a promising strategy to increase the granularity of audiological assessments. By coupling this enhanced phenotyping capability with genetic association studies, we suggest that drug efficacy will be better predicted, increasing the likelihood of success in clinical trials when populations are stratified based on genetic variation or designed with multidrug combinations to reach a broader segment of individuals suffering or at risk from NIHL.Item Open Access Pharmacogenomics in early-phase clinical development.(Pharmacogenomics, 2013-07) Burt, Tal; Dhillon, SavitaPharmacogenomics (PGx) offers the promise of utilizing genetic fingerprints to predict individual responses to drugs in terms of safety, efficacy and pharmacokinetics. Early-phase clinical trial PGx applications can identify human genome variations that are meaningful to study design, selection of participants, allocation of resources and clinical research ethics. Results can inform later-phase study design and pipeline developmental decisions. Nevertheless, our review of the clinicaltrials.gov database demonstrates that PGx is rarely used by drug developers. Of the total 323 trials that included PGx as an outcome, 80% have been conducted by academic institutions after initial regulatory approval. Barriers for the application of PGx are discussed. We propose a framework for the role of PGx in early-phase drug development and recommend PGx be universally considered in study design, result interpretation and hypothesis generation for later-phase studies, but PGx results from underpowered studies should not be used by themselves to terminate drug-development programs.Item Open Access Striking a balance in communicating pharmacogenetic test results: promoting comprehension and minimizing adverse psychological and behavioral response.(Patient education and counseling, 2014-10) Haga, Susanne B; Mills, Rachel; Bosworth, HaydenObjective
Pharmacogenetic (PGx) testing can provide information about a patient's likelihood to respond to a medication or experience an adverse event, and be used to inform medication selection and/or dosing. Promoting patient comprehension of PGx test results will be important to improving engagement and understanding of treatment decisions.Methods
The discussion in this paper is based on our experiences and the literature on communication of genetic test results for disease risk and broad risk communication strategies.Results
Clinical laboratory reports often describe PGx test results using standard terminology such as 'poor metabolizer' or 'ultra-rapid metabolizer.' While this type of terminology may promote patient recall with its simple, yet descriptive nature, it may be difficult for some patients to comprehend and/or cause adverse psychological or behavioral responses.Conclusion
The language used to communicate results and their significance to patients will be important to consider in order to minimize confusion and potential psychological consequences such as increased anxiety that can adversely impact medication-taking behaviors.Practice implications
Due to patients' unfamiliarity with PGx testing and the potential for confusion, adverse psychological effects, and decreased medication adherence, health providers need to be cognizant of the language used in discussing PGx test results with patients.Item Open Access United States Emergency Department Use of Medications with Pharmacogenetic Recommendations.(The western journal of emergency medicine, 2021-09-23) Limkakeng, Alexander T; Manandhar, Pratik; Erkanli, Alaatin; Eucker, Stephanie A; Root, Adam; Voora, DeepakIntroduction
Emergency departments (ED) use many medications with a range of therapeutic efficacy and potential significant side effects, and many medications have dosage adjustment recommendations based on the patient's specific genotype. How frequently medications with such pharmaco-genetic recommendations are used in United States (US) EDs has not been studied.Methods
We conducted a cross-sectional analysis of the 2010-2015 National Hospital Ambulatory Medical Care Survey (NHAMCS). We reported the proportion of ED visits in which at least one medication with Clinical Pharmacogenetics Implementation Consortium (CPIC) recommendation of Level A or B evidence was ordered. Secondary comparisons included distributions and 95% confidence intervals of age, gender, race/ethnicity, ED disposition, geographical region, immediacy, and insurance status between all ED visits and those involving a CPIC medication.Results
From 165,155 entries representing 805,726,000 US ED visits in the 2010-2015 NHAMCS, 148,243,000 ED visits (18.4%) led to orders of CPIC medications. The most common CPIC medication was tramadol (6.3%). Visits involving CPIC medications had higher proportions of patients who were female, had private insurance and self-pay, and were discharged from the ED. They also involved lower proportions of patients with Medicare and Medicaid.Conclusion
Almost one fifth of US ED visits involve a medication with a pharmacogenetic recommendation that may impact the efficacy and toxicity for individual patients. While direct application of genotyping is still in development, it is important for emergency care providers to understand and support this technology given its potential to improve individualized, patient-centered care.Item Open Access Workforce readiness for pharmacogenomics and key elements for sustainment within the Veterans Health Administration.(Pharmacogenomics, 2024-02) Wu, Rebekah Ryanne; Benevent, Richelle; Sperber, Nina R; Bates, Jill S; Villa, Daniel; Weeraratne, Dilhan; Burrell, Timothy A; Voora, DeepakAim: Understanding barriers and facilitators to pharmacogenomics (PGx) implementation and how to structure a clinical program with the Veterans Health Administration (VA). Materials & methods: Healthcare provider (HCP) survey at 20 VA facilities assessing PGx knowledge/acceptance and qualitative interviews to understand how best to design and sustain a national program. Results: 186 (12% response rate) surveyed believed PGx informs drug efficacy (74.7%) and adverse events (71.0%). Low confidence in knowledge (43.0%) and ability to implement (35.4-43.5%). 23 (60.5% response rate) interviewees supported a nationally program to oversee VA education, consultation and IT resources. Prescribing HCPs should be directing local activities. Conclusion: HCPs recognize PGx value but are not prepared to implement. Healthcare systems should build system-wide programs for implementation education and support.