Publications by authors named "Todd C Skaar"

115 Publications

The Access Technology Program of the Indiana Clinical Translational Sciences Institute (CTSI): A model to facilitate access to cutting-edge technologies across a state.

J Clin Transl Sci 2020 Aug 19;5(1):e33. Epub 2020 Aug 19.

Indiana CTSI, Indiana University School of Medicine, Indianapolis, IN, USA.

Introduction: Access to cutting-edge technologies is essential for investigators to advance translational research. The Indiana Clinical and Translational Sciences Institute (CTSI) spans three major and preeminent universities, four large academic campuses across the state of Indiana, and is mandate to provide best practices to a whole state.

Methods: To address the need to facilitate the availability of innovative technologies to its investigators, the Indiana CTSI implemented the Access Technology Program (ATP). The activities of the ATP, or any program of the Indiana CTSI, are challenged to connect technologies and investigators on the multiple Indiana CTSI campuses by the geographical distances between campuses (1-4 hr driving time).

Results: Herein, we describe the initiatives developed by the ATP to increase the availability of state-of-the-art technologies to its investigators on all Indiana CTSI campuses, and the methods developed by the ATP to bridge the distance between campuses, technologies, and investigators for the advancement of clinical translational research.

Conclusions: The methods and practices described in this publication may inform other approaches to enhance translational research, dissemination, and usage of innovative technologies by translational investigators, especially when distance or multi-campus cultural differences are factors to efficient application.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/cts.2020.525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057440PMC
August 2020

Establishing the value of genomics in medicine: the IGNITE Pragmatic Trials Network.

Genet Med 2021 Mar 29. Epub 2021 Mar 29.

Division of Genomic Medicine, National Human Genome Research Institute, NIH, Bethesda, MD, USA.

Purpose: A critical gap in the adoption of genomic medicine into medical practice is the need for the rigorous evaluation of the utility of genomic medicine interventions.

Methods: The Implementing Genomics in Practice Pragmatic Trials Network (IGNITE PTN) was formed in 2018 to measure the clinical utility and cost-effectiveness of genomic medicine interventions, to assess approaches for real-world application of genomic medicine in diverse clinical settings, and to produce generalizable knowledge on clinical trials using genomic interventions. Five clinical sites and a coordinating center evaluated trial proposals and developed working groups to enable their implementation.

Results: Two pragmatic clinical trials (PCTs) have been initiated, one evaluating genetic risk APOL1 variants in African Americans in the management of their hypertension, and the other to evaluate the use of pharmacogenetic testing for medications to manage acute and chronic pain as well as depression.

Conclusion: IGNITE PTN is a network that carries out PCTs in genomic medicine; it is focused on diversity and inclusion of underrepresented minority trial participants; it uses electronic health records and clinical decision support to deliver the interventions. IGNITE PTN will develop the evidence to support (or oppose) the adoption of genomic medicine interventions by patients, providers, and payers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-021-01118-9DOI Listing
March 2021

Ending the pharmacogenomic gag rule: the imperative to report all results.

Pharmacogenomics 2021 Mar 24;22(4):191-193. Epub 2021 Feb 24.

Center for Bioethics, Indiana University, Indianapolis, IN 46202, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/pgs-2020-0172DOI Listing
March 2021

Variability of Dosing and Number of Medications Needed to Achieve Adequate Sedation in Mechanically Ventilated Pediatric Intensive Care Patients.

Clin Transl Sci 2021 01 3;14(1):310-316. Epub 2020 Sep 3.

Department of Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana, USA.

Children admitted to the pediatric intensive care unit (PICU) often require multiple medications to achieve comfort and sedation. Although starting doses are available, these medications are typically titrated to the desired effect. Both oversedation and undersedation are associated with adverse events. The aim of this retrospective study was to evaluate cumulative medication burden necessary to achieve comfort in patients in the PICU and determine relevant predictors of medication needs. In order to account for all of the sedative medications, z-scores were used to assess the population average dose of each medication and compare each patient day to this population average. Sedation regimens for 130 patients in the PICU were evaluated. Mean overall infusion rates of fentanyl, morphine, and hydromorphone were 1.67 ± 0.81 µg/kg/hour, 0.12 ± 0.08 mg/kg/hour, and 17.84 ± 13.4 µg/kg/hour, respectively. The mean infusion rate of dexmedetomidine was 0.59 ± 0.28 µg/kg/hour, and midazolam was 0.14 ± 0.1 mg/kg/hour. Summation z-sores were used to rank the amount of sedation medication needed to achieve comfort for each individual patient for his/her PICU stay in relation to the entire sample. Patient age, weight, and length of mechanical ventilation were all significant predictors of sedation requirement. This study will provide data necessary to develop a model of cumulative medication burden needed to achieve appropriate sedation in this population. This descriptive model in appropriately ranking patients based on sedative needs is the first step in exploring potential genetic factors that may provide an insight into homing in on the appropriate sedation regimen.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cts.12870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877817PMC
January 2021

Opportunity for Genotype-Guided Prescribing Among Adult Patients in 11 US Health Systems.

Clin Pharmacol Ther 2021 Jan 11. Epub 2021 Jan 11.

Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

The value of utilizing a multigene pharmacogenetic panel to tailor pharmacotherapy is contingent on the prevalence of prescribed medications with an actionable pharmacogenetic association. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has categorized over 35 gene-drug pairs as "level A," for which there is sufficiently strong evidence to recommend that genetic information be used to guide drug prescribing. The opportunity to use genetic information to tailor pharmacotherapy among adult patients was determined by elucidating the exposure to CPIC level A drugs among 11 Implementing Genomics In Practice Network (IGNITE)-affiliated health systems across the US. Inpatient and/or outpatient electronic-prescribing data were collected between January 1, 2011 and December 31, 2016 for patients ≥ 18 years of age who had at least one medical encounter that was eligible for drug prescribing in a calendar year. A median of ~ 7.2 million adult patients was available for assessment of drug prescribing per year. From 2011 to 2016, the annual estimated prevalence of exposure to at least one CPIC level A drug prescribed to unique patients ranged between 15,719 (95% confidence interval (CI): 15,658-15,781) in 2011 to 17,335 (CI: 17,283-17,386) in 2016 per 100,000 patients. The estimated annual exposure to at least 2 drugs was above 7,200 per 100,000 patients in most years of the study, reaching an apex of 7,660 (CI: 7,632-7,687) per 100,000 patients in 2014. An estimated 4,748 per 100,000 prescribing events were potentially eligible for a genotype-guided intervention. Results from this study show that a significant portion of adults treated at medical institutions across the United States is exposed to medications for which genetic information, if available, should be used to guide prescribing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpt.2161DOI Listing
January 2021

Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6, OPRM1, and COMT Genotypes and Select Opioid Therapy.

Clin Pharmacol Ther 2021 Jan 2. Epub 2021 Jan 2.

Department of Medicine, Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana, USA.

Opioids are mainly used to treat both acute and chronic pain. Several opioids are metabolized to some extent by CYP2D6 (codeine, tramadol, hydrocodone, oxycodone, and methadone). Polymorphisms in CYP2D6 have been studied for an association with the clinical effect and safety of these drugs. Other genes that have been studied for their association with opioid clinical effect or adverse events include OPRM1 (mu receptor) and COMT (catechol-O-methyltransferase). This guideline updates and expands the 2014 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 genotype and codeine therapy and includes a summation of the evidence describing the impact of CYP2D6, OPRM1, and COMT on opioid analgesia and adverse events. We provide therapeutic recommendations for the use of CYP2D6 genotype results for prescribing codeine and tramadol and describe the limited and/or weak data for CYP2D6 and hydrocodone, oxycodone, and methadone, and for OPRM1 and COMT for clinical use.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpt.2149DOI Listing
January 2021

Prescribing Prevalence of Medications With Potential Genotype-Guided Dosing in Pediatric Patients.

JAMA Netw Open 2020 12 1;3(12):e2029411. Epub 2020 Dec 1.

Personalized Medicine Initiative, Nicklaus Children's Health System, Miami, Florida.

Importance: Genotype-guided prescribing in pediatrics could prevent adverse drug reactions and improve therapeutic response. Clinical pharmacogenetic implementation guidelines are available for many medications commonly prescribed to children. Frequencies of medication prescription and actionable genotypes (genotypes where a prescribing change may be indicated) inform the potential value of pharmacogenetic implementation.

Objective: To assess potential opportunities for genotype-guided prescribing in pediatric populations among multiple health systems by examining the prevalence of prescriptions for each drug with the highest level of evidence (Clinical Pharmacogenetics Implementation Consortium level A) and estimating the prevalence of potential actionable prescribing decisions.

Design, Setting, And Participants: This serial cross-sectional study of prescribing prevalences in 16 health systems included electronic health records data from pediatric inpatient and outpatient encounters from January 1, 2011, to December 31, 2017. The health systems included academic medical centers with free-standing children's hospitals and community hospitals that were part of an adult health care system. Participants included approximately 2.9 million patients younger than 21 years observed per year. Data were analyzed from June 5, 2018, to April 14, 2020.

Exposures: Prescription of 38 level A medications based on electronic health records.

Main Outcomes And Measures: Annual prevalence of level A medication prescribing and estimated actionable exposures, calculated by combining estimated site-year prevalences across sites with each site weighted equally.

Results: Data from approximately 2.9 million pediatric patients (median age, 8 [interquartile range, 2-16] years; 50.7% female, 62.3% White) were analyzed for a typical calendar year. The annual prescribing prevalence of at least 1 level A drug ranged from 7987 to 10 629 per 100 000 patients with increasing trends from 2011 to 2014. The most prescribed level A drug was the antiemetic ondansetron (annual prevalence of exposure, 8107 [95% CI, 8077-8137] per 100 000 children). Among commonly prescribed opioids, annual prevalence per 100 000 patients was 295 (95% CI, 273-317) for tramadol, 571 (95% CI, 557-586) for codeine, and 2116 (95% CI, 2097-2135) for oxycodone. The antidepressants citalopram, escitalopram, and amitriptyline were also commonly prescribed (annual prevalence, approximately 250 per 100 000 patients for each). Estimated prevalences of actionable exposures were highest for oxycodone and ondansetron (>300 per 100 000 patients annually). CYP2D6 and CYP2C19 substrates were more frequently prescribed than medications influenced by other genes.

Conclusions And Relevance: These findings suggest that opportunities for pharmacogenetic implementation among pediatric patients in the US are abundant. As expected, the greatest opportunity exists with implementing CYP2D6 and CYP2C19 pharmacogenetic guidance for commonly prescribed antiemetics, analgesics, and antidepressants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamanetworkopen.2020.29411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737091PMC
December 2020

Impact of the CYP2C19*17 Allele on Outcomes in Patients Receiving Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention.

Clin Pharmacol Ther 2021 Mar 2;109(3):705-715. Epub 2020 Oct 2.

Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics and Precision Medicine, University of Florida, Gainesville, Florida, USA.

Genotyping for CYP2C19 no function alleles to guide antiplatelet therapy after percutaneous coronary intervention (PCI) improves clinical outcomes. Although results for the increased function CYP2C19*17 allele are also reported, its clinical relevance in this setting remains unclear. A collaboration across nine sites examined antiplatelet therapy prescribing and clinical outcomes in 3,342 patients after implementation of CYP2C19-guided antiplatelet therapy. Risk of major atherothrombotic and bleeding events over 12 months after PCI were compared across cytochrome P450 2C19 isozyme (CYP2C19) metabolizer phenotype and antiplatelet therapy groups by proportional hazards regression. Clopidogrel was prescribed to a similar proportion of CYP2C19 normal (84.5%), rapid (82.9%), and ultrarapid metabolizers (80.6%) (P = 0.360). Clopidogrel-treated normal metabolizers (20.4 events/100 patient-years; adjusted hazard ratio (HR) 1.00, 95% confidence interval (CI), 0.75-1.33, P = 0.993) and clopidogrel-treated rapid or ultrarapid metabolizers (19.1 events/100 patient-years; adjusted HR 0.95, 95% CI, 0.69-1.30, P = 0.734) exhibited no difference in major atherothrombotic events compared with patients treated with prasugrel or ticagrelor (17.6 events/100 patient-years). In contrast, clopidogrel-treated intermediate and poor metabolizers exhibited significantly higher atherothrombotic event risk compared with prasugrel/ticagrelor-treated patients (adjusted HR 1.56, 95% CI, 1.12-2.16, P = 0.008). When comparing clopidogrel-treated rapid or ultrarapid metabolizers to normal metabolizers, no difference in atherothrombotic (adjusted HR 0.97, 95% CI, 0.73-1.29, P = 0.808) or bleeding events (adjusted HR 1.34, 95% CI, 0.83-2.17, P = 0.224) were observed. In a real-world setting of genotype-guided antiplatelet therapy, the CYP2C19*17 allele did not significantly impact post-PCI prescribing decisions or clinical outcomes. These results suggest the CYP2C19 *1/*17 and *17/*17 genotypes have limited clinical utility to guide antiplatelet therapy after PCI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpt.2039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902344PMC
March 2021

Phase I, Pharmacogenomic, Drug Interaction Study of Sorafenib and Bevacizumab in Combination with Paclitaxel in Patients with Advanced Refractory Solid Tumors.

Mol Cancer Ther 2020 10 26;19(10):2155-2162. Epub 2020 Aug 26.

Northwestern University, Chicago, Illinois.

VEGF blockade does not uniformly result in clinical benefit. We evaluated safety, dose-limiting toxicities (DLT), recommended phase II dose (RP2D), antitumor efficacy, and exploratory biomarkers including pharmacogenomics and pharmacokinetics with sorafenib, bevacizumab, and paclitaxel in patients with refractory cancers. The study had a "3 + 3" design, using paclitaxel 80 mg/m every week for 3 weeks, in every 4 week cycles, bevacizumab 5 mg/kg every 2 weeks, and sorafenib 200 or 400 mg twice a day, 5 or 7 days/week (5/7, 7/7). The MTD cohort was expanded. Twenty-seven patients enrolled in 3 cohorts: sorafenib 200 mg twice a day 5/7, 200 mg twice a day 7/7, and 400 mg twice a day 5/7. DLTs were grade 3 neutropenia >7 days (cohort 1, 1), grade 3 hypertension (cohort 2, 1), grade 3 hand-foot skin reaction (HFSR; cohort 3, 2). MTD was sorafenib 200 mg twice a day 7/7. Six DLTs occurred in cohort 2 expansion: grade 3 HFSR (2), grade 2 HFSR with sorafenib delay >7 days (2), grade 4 cerebrovascular accident (1), grade 3 neutropenia >7 days (1). RP2D was sorafenib 200 mg twice a day 5/7. Most patients (62%) dose reduced sorafenib to 200 mg daily 5/7 after a median 3 (range, 2-17) cycles. Response rates were 48% overall (27) and 64% for ovarian cancers (14). -1154AA and -7TT recessive homozygous genotypes conferred worse overall survival versus alternative genotypes (7 vs. 22 months). Intermittent, low-dose sorafenib (200 mg twice a day 5/7) combined with bevacizumab and paclitaxel was tolerable and had high antitumor efficacy in patients with refractory cancer (NCT00572078).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-20-0277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541675PMC
October 2020

Circulating miRNAs as Biomarkers for CYP2B6 Enzyme Activity.

Clin Pharmacol Ther 2021 Feb 5;109(2):485-493. Epub 2020 Oct 5.

Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana, USA.

The CYP2B6 gene is highly polymorphic and its activity shows wide interindividual variability. However, substantial variability in CYP2B6 activity remains unexplained by the known CYP2B6 genetic variations. Circulating, cell-free micro RNAs (miRNAs) may serve as biomarkers of hepatic enzyme activity. CYP2B6 activity in 72 healthy volunteers was determined using the disposition of efavirenz as a probe drug. Circulating miRNA expression was quantified from baseline plasma samples. A linear model consisting of the effects of miRNA expression, genotype-determined metabolizer status, and demographic information was developed to predict CYP2B6 activity. Expression of 2,510 miRNAs were quantified out of which 7 miRNAs, together with the CYP2B6-genotypic metabolizer status and demographics, was shown to be predictive markers for CYP2B6 activity. The reproducibility of the model was evaluated by cross-validation. The average Pearson's correlation (R) between the predicted and observed maximum plasma concentration (C ) ratios of efavirenz and its metabolite-8-OH efavirenz using the linear model with all features (7 miRNA + metabolizer status + age + sex + race) was 0.6702. Similar results were also observed using area under the curve (AUC) ratios (Pearson correlation's R = 0.6035). Thus, at least 36% (R ) of the variability of in vivo CYP2B6 activity was explained using this model. This is a significant improvement over the models using only the genotype-based metabolizer status or the demographic information, which explained only 6% or less of the variability of in vivo CYP2B6 activity. Our results, therefore, demonstrate that circulating plasma miRNAs can be valuable biomarkers for in vivo CYP2B6 activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpt.2018DOI Listing
February 2021

Correction: Evaluating the extent of reusability of CYP2C19 genotype data among patients genotyped for antiplatelet therapy selection.

Genet Med 2020 Nov;22(11):1919

University of Florida College of Pharmacy, Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, Gainesville, FL, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-020-0931-1DOI Listing
November 2020

Tracheal Aspirate as an Alternative Biologic Sample for Pharmacogenomics Testing in Mechanically Ventilated Pediatric Patients.

Clin Transl Sci 2021 Mar 25;14(2):497-501. Epub 2021 Jan 25.

Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana, USA.

Patients in the pediatric intensive care unit are exposed to multiple medications and are at high risk for adverse drug reactions. Pharmacogenomic (PGx) testing could help decrease their risk of adverse reactions. Although whole blood is preferred for PGx testing, blood volume in this population is often limited. However, for patients on mechanical ventilation, tracheal secretions are abundant, frequently suctioned, and discarded. Thus, the aim of this pilot study was to determine if tracheal aspirates could be used as a source of human genomic DNA for PGx testing. We successfully extracted DNA from tracheal secretions of all 23 patients in the study. The samples were successfully genotyped for 10 clinically actionable single nucleotide variants across 3 cytochrome P450 genes (CYP2D6, CYP2C19, and CYP3A5). Using DNA from whole blood samples in 11 of the patients, we confirmed the accuracy of the genotyping with 100% concordance. Therefore, our results support the use of tracheal aspirates from mechanically ventilated children as an adequate biospecimen for clinical genetic testing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cts.12847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993287PMC
March 2021

Evaluating the extent of reusability of CYP2C19 genotype data among patients genotyped for antiplatelet therapy selection.

Genet Med 2020 11 17;22(11):1898-1902. Epub 2020 Jul 17.

University of Florida College of Pharmacy, Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, Gainesville, FL, USA.

Purpose: Genotype-guided antiplatelet therapy is increasingly being incorporated into clinical care. The purpose of this study is to determine the extent to which patients initially genotyped for CYP2C19 to guide antiplatelet therapy were prescribed additional medications affected by CYP2C19.

Methods: We assembled a cohort of patients from eight sites performingCYP2C19 genotyping to inform antiplatelet therapy. Medication orders were evaluated from time of genotyping through one year. The primary endpoint was the proportion of patients prescribed two or more CYP2C19 substrates. Secondary endpoints were the proportion of patients with a drug-genotype interaction and time to receiving a CYP2C19 substrate.

Results: Nine thousand one hundred ninety-one genotyped patients (17% nonwhite) with a mean age of 68 ± 3 years were evaluated; 4701 (51%) of patients received two or more CYP2C19 substrates and 3835 (42%) of patients had a drug-genotype interaction. The average time between genotyping and CYP2C19 substrate other than antiplatelet therapy was 25 ± 10 days.

Conclusions: More than half of patients genotyped in the setting of CYP2C19-guided antiplatelet therapy received another medication impacted by CYP2C19 in the following year. Given that genotype is stable for a patient's lifetime, this finding has implications for cost effectiveness, patient care, and treatment outcomes beyond the indication for which it was originally performed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-020-0894-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606808PMC
November 2020

Enrollment of Diverse Populations in the INGENIOUS Pharmacogenetics Clinical Trial.

Front Genet 2020 25;11:571. Epub 2020 Jun 25.

Department of Medicine, Indiana University, Indianapolis, IN, United States.

Recruitment of diverse populations and subjects living in Medically Underserved Areas and Populations (MUA/P's) into clinical trials is a considerable challenge. Likewise, representation of African-Americans in pharmacogenetic trials is often inadequate, but critical for identifying genetic variation within and between populations. To identify enrollment patterns and variables that predict enrollment in a diverse underserved population, we analyzed data from the INGENIOUS (Indiana GENomics Implementation and Opportunity for the UnderServed), pharmacogenomics implementation clinical trial conducted at a community hospital for underserved subjects (Safety net hospital), and a statewide healthcare system (Academic hospital). We used a logistic regression model to identify patient variables that predicted successful enrollment after subjects were contacted and evaluated the reasons that clinical trial eligible subjects refused enrollment. In both healthcare systems, African-Americans were less likely to refuse the study than non-Hispanic Whites (Safety net, OR = 0.68, and < 0.002; Academic hospital, OR = 0.64, and < 0.001). At the Safety net hospital, other minorities were more likely to refuse the study than non-Hispanic Whites (OR = 1.58, < 0.04). The odds of refusing the study once contacted increased with patient age (Safety net hospital, OR = 1.02, < 0.001, Academic hospital, OR = 1.02, and < 0.001). At the Academic hospital, females were less likely to refuse the study than males (OR = 0.81, = 0.01) and those not living in MUA/P's were less likely to refuse the study than those living in MUA/P's (OR = 0.81, = 0.007). The most frequent barriers to enrollment included not being interested, being too busy, transportation, and illness. A lack of trust was reported less frequently. In conclusion, African-Americans can be readily recruited to pharmacogenetic clinical trials once contact has been successfully initiated. However, health care initiatives and increased recruitment efforts of subjects living in MUA/Ps are needed. Enrollment could be further enhanced by improving research awareness and knowledge of clinical trials, reducing time needed for participation, and compensating for travel.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fgene.2020.00571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330082PMC
June 2020

Implementation of a Renal Precision Medicine Program: Clinician Attitudes and Acceptance.

Life (Basel) 2020 Mar 26;10(4). Epub 2020 Mar 26.

Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

A precision health initiative was implemented across a multi-hospital health system, wherein a panel of genetic variants was tested and utilized in the clinical care of chronic kidney disease (CKD) patients. Pharmacogenomic predictors of antihypertensive response and genomic predictors of CKD were provided to clinicians caring for nephrology patients. To assess clinician knowledge, attitudes, and willingness to act on genetic testing results, a Likert-scale survey was sent to and self-administered by these nephrology providers (N = 76). Most respondents agreed that utilizing pharmacogenomic-guided antihypertensive prescribing is valuable (4.0 ± 0.7 on a scale of 1 to 5, where 5 indicates strong agreement). However, the respondents also expressed reluctance to use genetic testing for CKD risk stratification due to a perceived lack of supporting evidence (3.2 ± 0.9). Exploratory sub-group analyses associated this reluctance with negative responses to both knowledge and attitude discipline questions, thus suggesting reduced exposure to and comfort with genetic information. Given the evolving nature of genomic implementation in clinical care, further education is warranted to help overcome these perception barriers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/life10040032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235993PMC
March 2020

Cost-effectiveness of CYP2C19-guided antiplatelet therapy in patients with acute coronary syndrome and percutaneous coronary intervention informed by real-world data.

Pharmacogenomics J 2020 10 11;20(5):724-735. Epub 2020 Feb 11.

Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.

Current guidelines recommend dual antiplatelet therapy (DAPT) consisting of aspirin and a P2Y12 inhibitors following percutaneous coronary intervention (PCI). CYP2C19 genotype can guide DAPT selection, prescribing ticagrelor or prasugrel for loss-of-function (LOF) allele carriers (genotype-guided escalation). Cost-effectiveness analyses (CEA) are traditionally grounded in clinical trial data. We conduct a CEA using real-world data using a 1-year decision-analytic model comparing primary strategies: universal empiric clopidogrel (base case), universal ticagrelor, and genotype-guided escalation. We also explore secondary strategies commonly implemented in practice, wherein all patients are prescribed ticagrelor for 30 days post PCI. After 30 days, all patients are switched to clopidogrel irrespective of genotype (nonguided de-escalation) or to clopidogrel only if patients do not harbor an LOF allele (genotype-guided de-escalation). Compared with universal clopidogrel, both universal ticagrelor and genotype-guided escalation were superior with improvement in quality-adjusted life years (QALY's). Only genotype-guided escalation was cost-effective ($42,365/QALY) and demonstrated the highest probability of being cost-effective across conventional willingness-to-pay thresholds. In the secondary analysis, compared with the nonguided de-escalation strategy, although genotype-guided de-escalation and universal ticagrelor were more effective, with ICER of $188,680/QALY and $678,215/QALY, respectively, they were not cost-effective. CYP2C19 genotype-guided antiplatelet prescribing is cost-effective compared with either universal clopidogrel or universal ticagrelor using real-world implementation data. The secondary analysis suggests genotype-guided and nonguided de-escalation may be viable strategies, needing further evaluation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41397-020-0162-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417282PMC
October 2020

Nephrotoxicity in a Patient With Inadequate Pain Control: Potential Role of Pharmacogenetic Testing for Cytochrome P450 2D6 and Apolipoprotein L1.

Front Pharmacol 2019 8;10:1511. Epub 2020 Jan 8.

Indiana University Department of Medicine, Indianapolis, IN, United States.

A case is presented which demonstrates the perils of opioid inefficacy and how pharmacogenomic testing may have prevented nonsteroidal anti-inflammatory drug (NSAID)-induced nephrotoxicity and progression to chronic kidney disease (CKD). A 62 year-old female with back pain was treated with tramadol and hydrocodone; however, neither proved effective. Consequently, to control her pain, she resorted to cocaine, marijuana, and high dose nonsteroidal anti-inflammatory drugs (NSAIDs). She eventually developed CKD. To identify CKD contributors, she underwent genotyping for Apolipoprotein L1 (), a known risk factor of CKD, as well as relevant pharmacogenomic genes. Her genotype was , placing her at increased risk of CKD progression. Her genotype was , consistent with intermediate metabolism, making opioid drugs reliant on CYP2D6 activation, such as tramadol and hydrocodone, relatively ineffective in this patient. Thus, this patient was at genetic risk for CKD and reduced opioid efficacy. We conclude that this genetic combination likely contributed to opioid inefficacy and the eventual progression to CKD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2019.01511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960206PMC
January 2020

Influence of Uridine Diphosphate Glucuronosyltransferase Family 1 Member A1 and Solute Carrier Organic Anion Transporter Family 1 Member B1 Polymorphisms and Efavirenz on Bilirubin Disposition in Healthy Volunteers.

Drug Metab Dispos 2020 03 30;48(3):169-175. Epub 2019 Dec 30.

Department of Medicine, Division of Clinical Pharmacology (K.S.C., I.F.M., B.T.G., J.L., T.C.S., Z.D.), and Department of Medical and Molecular Genetics (E.B.M., V.M.P.), Indiana University School of Medicine, Indianapolis, Indiana

Chronic administration of efavirenz is associated with decreased serum bilirubin levels, probably through induction of We assessed the impact of efavirenz monotherapy and UGT1A1 phenotypes on total, conjugated, and unconjugated serum bilirubin levels in healthy volunteers. Healthy volunteers were enrolled into a clinical study designed to address efavirenz pharmacokinetics, drug interactions, and pharmacogenetics. Volunteers received multiple oral doses (600 mg/day for 17 days) of efavirenz. Serum bilirubin levels were obtained at study entry and 1 week after completion of the study. DNA genotyping was performed for [ (C>T), (G>A), (TA), (TA), and (TA)] and for [ (521T>C) and (388A>G] variants. Diplotype predicted phenotypes were classified as normal, intermediate, and slow metabolizers. Compared with bilirubin levels at screening, treatment with efavirenz significantly reduced total, conjugated, and unconjugated bilirubin. After stratification by UGT1A1 phenotypes, there was a significant decrease in total bilirubin among all phenotypes, conjugated bilirubin among intermediate metabolizers, and unconjugated bilirubin among normal and intermediate metabolizers. The data also show that genotype predicts serum bilirubin levels at baseline, but this relationship is lost after efavirenz treatment. genotypes did not predict bilirubin levels at baseline or after efavirenz treatment. Our data suggest that efavirenz may alter bilirubin disposition mainly through induction of UGT1A1 metabolism and efflux through multidrug resistance-associated protein 2. SIGNIFICANCE STATEMENT: Efavirenz likely alters the pharmacokinetics of coadministered drugs, potentially causing lack of efficacy or increased adverse effects, as well as the disposition of endogenous compounds relevant in homeostasis through upregulation of UGT1A1 and multidrug resistance-associated protein 2. Measurement of unconjugated and conjugated bilirubin during new drug development may provide mechanistic understanding regarding enzyme and transporters modulated by the new drug.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1124/dmd.119.089052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011111PMC
March 2020

RegSNPs-intron: a computational framework for predicting pathogenic impact of intronic single nucleotide variants.

Genome Biol 2019 11 28;20(1):254. Epub 2019 Nov 28.

Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.

Single nucleotide variants (SNVs) in intronic regions have yet to be systematically investigated for their disease-causing potential. Using known pathogenic and neutral intronic SNVs (iSNVs) as training data, we develop the RegSNPs-intron algorithm based on a random forest classifier that integrates RNA splicing, protein structure, and evolutionary conservation features. RegSNPs-intron showed excellent performance in evaluating the pathogenic impacts of iSNVs. Using a high-throughput functional reporter assay called ASSET-seq (ASsay for Splicing using ExonTrap and sequencing), we evaluate the impact of RegSNPs-intron predictions on splicing outcome. Together, RegSNPs-intron and ASSET-seq enable effective prioritization of iSNVs for disease pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13059-019-1847-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883696PMC
November 2019

MicroRNA 362-3p Reduces hERG-related Current and Inhibits Breast Cancer Cells Proliferation.

Cancer Genomics Proteomics 2019 Nov-Dec;16(6):433-442

Department of Pharmacy Practice, College of Pharmacy, Purdue University, West Lafayette, IN, U.S.A.

Background/aim: hERG potassium channels enhance tumor invasiveness and breast cancer proliferation. MicroRNA (miRNA) dysregulation during cancer controls gene regulation. The objective of this study was to identify miRNAs that regulate hERG expression in breast cancer.

Materials And Methods: Putative miRNAs targeting hERG were identified by bioinformatic approaches and screened using a 3'UTR luciferase assay. Functional assessments of endogenous hERG regulation were made using whole-cell electrophysiology, proliferation assays, and cell-cycle analyses following miRNA, hERG siRNA, or control transfection.

Results: miR-362-3p targeted hERG 3'UTR and was associated with higher survival rates in patients with breast cancer (HR=0.39, 95%CI=0.18-0.82). Enhanced miR-362-3p expression reduced hERG expression, peak current, and cell proliferation in cultured breast cancer cells (p<0.05).

Conclusion: miR-362-3p mediates the transcriptional regulation of hERG and is associated with survival in breast cancer. The potential for miR-362-3p to serve as a biomarker and inform therapeutic strategies warrants further investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21873/cgp.20147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885367PMC
March 2020

Allele-specific expression and high-throughput reporter assay reveal functional genetic variants associated with alcohol use disorders.

Mol Psychiatry 2021 04 2;26(4):1142-1151. Epub 2019 Sep 2.

Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.

Genome-wide association studies (GWAS) of complex traits, such as alcohol use disorders (AUD), usually identify variants in non-coding regions and cannot by themselves distinguish whether the associated variants are functional or in linkage disequilibrium with the functional variants. Transcriptome studies can identify genes whose expression differs between alcoholics and controls. To test which variants associated with AUD may cause expression differences, we integrated data from deep RNA-seq and GWAS of four postmortem brain regions from 30 subjects with AUD and 30 controls to analyze allele-specific expression (ASE). We identified 88 genes with differential ASE in subjects with AUD compared to controls. Next, to test one potential mechanism contributing to the differential ASE, we analyzed single nucleotide polymorphisms (SNPs) in the 3' untranslated regions (3'UTR) of these genes. Of the 88 genes with differential ASE, 61 genes contained 437 SNPs in the 3'UTR with at least one heterozygote among the subjects studied. Using a modified PASSPORT-seq (parallel assessment of polymorphisms in miRNA target-sites by sequencing) assay, we identified 25 SNPs that affected RNA levels in a consistent manner in two neuroblastoma cell lines, SH-SY5Y and SK-N-BE(2). Many of these SNPs are in binding sites of miRNAs and RNA-binding proteins, indicating that these SNPs are likely causal variants of AUD-associated differential ASE. In sum, we demonstrate that a combination of computational and experimental approaches provides a powerful strategy to uncover functionally relevant variants associated with the risk for AUD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41380-019-0508-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050407PMC
April 2021

Effects of polymorphisms on plasma estrogen concentrations in women with breast cancer receiving aromatase inhibitors exemestane and letrozole.

Pharmacogenomics 2019 06;20(8):571-580

Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI 48109-1065, USA.

This study tested for associations between polymorphisms and circulating estrogen levels in women with breast cancer treated with letrozole or exemestane. Postmenopausal women with hormone-receptor positive breast cancer were genotyped for (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. was associated with elevated pretreatment estrone sulfate and an increased risk of detectable estrone concentrations after 3 months of AI treatment. These findings suggest polymorphisms may have an effect on estrogenic response to AI treatment, and therefore may adversely impact the anticancer effectiveness of these agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/pgs-2019-0020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891932PMC
June 2019

Multi-site investigation of strategies for the clinical implementation of CYP2D6 genotyping to guide drug prescribing.

Genet Med 2019 10 21;21(10):2255-2263. Epub 2019 Mar 21.

Department of Medicine, Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, USA.

Purpose: A number of institutions have clinically implemented CYP2D6 genotyping to guide drug prescribing. We compared implementation strategies of early adopters of CYP2D6 testing, barriers faced by both early adopters and institutions in the process of implementing CYP2D6 testing, and approaches taken to overcome these barriers.

Methods: We surveyed eight early adopters of CYP2D6 genotyping and eight institutions in the process of adoption. Data were collected on testing approaches, return of results procedures, applications of genotype results, challenges faced, and lessons learned.

Results: Among early adopters, CYP2D6 testing was most commonly ordered to assist with opioid and antidepressant prescribing. Key differences among programs included test ordering and genotyping approaches, result reporting, and clinical decision support. However, all sites tested for copy-number variation and nine common variants, and reported results in the medical record. Most sites provided automatic consultation and had designated personnel to assist with genotype-informed therapy recommendations. Primary challenges were related to stakeholder support, CYP2D6 gene complexity, phenotype assignment, and sustainability.

Conclusion: There are specific challenges unique to CYP2D6 testing given the complexity of the gene and its relevance to multiple medications. Consensus lessons learned may guide those interested in pursuing similar clinical pharmacogenetic programs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-019-0484-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754805PMC
October 2019

Analytical Validation of Variants to Aid in Genotype-Guided Therapy for Oncology.

J Mol Diagn 2019 05 20;21(3):491-502. Epub 2019 Feb 20.

Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana.

The Clinical Laboratory Improvement Amendments of 1988 require that pharmacogenetic genotyping methods need to be established according to technical standards and laboratory practice guidelines before testing can be offered to patients. Testing methods for variants in ABCB1, CBR3, COMT, CYP3A7, C8ORF34, FCGR2A, FCGR3A, HAS3, NT5C2, NUDT15, SBF2, SEMA3C, SLC16A5, SLC28A3, SOD2, TLR4, and TPMT were validated in a Clinical Laboratory Improvement Amendments-accredited laboratory. Because no known reference materials were available, existing DNA samples were used for the analytical validation studies. Pharmacogenetic testing methods developed here were shown to be accurate and 100% analytically sensitive and specific. Other Clinical Laboratory Improvement Amendments-accredited laboratories interested in offering pharmacogenetic testing for these genetic variants, related to genotype-guided therapy for oncology, could use these publicly available samples as reference materials when developing and validating new genetic tests or refining current assays.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jmoldx.2019.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504676PMC
May 2019

Drug-gene and drug-drug interactions associated with tramadol and codeine therapy in the INGENIOUS trial.

Pharmacogenomics 2019 04 20;20(6):397-408. Epub 2019 Feb 20.

Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

Tramadol and codeine are metabolized by CYP2D6 and are subject to drug-gene and drug-drug interactions. This interim analysis examined prescribing behavior and efficacy in 102 individuals prescribed tramadol or codeine while receiving pharmaco-genotyping as part of the INGENIOUS trial (NCT02297126). Within 60 days of receiving tramadol or codeine, clinicians more frequently prescribed an alternative opioid in ultrarapid and poor metabolizers (odds ratio: 19.0; 95% CI: 2.8-160.4) as compared with normal or indeterminate metabolizers (p = 0.01). After adjusting the CYP2D6 activity score for drug-drug interactions, uncontrolled pain was reported more frequently in individuals with reduced CYP2D6 activity (odds ratio: 0.50; 95% CI: 0.25-0.94). Phenoconversion for drug-drug and drug-gene interactions is an important consideration in pharmacogenomic implementation; drug-drug interactions may obscure the potential benefits of genotyping.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/pgs-2018-0205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562829PMC
April 2019

Analytical validity of a genotyping assay for use with personalized antihypertensive and chronic kidney disease therapy.

Pharmacogenet Genomics 2019 01;29(1):18-22

Departments of Medicine.

Hypertension and chronic kidney disease are inextricably linked. Hypertension is a well-recognized contributor to chronic kidney disease progression and, in turn, renal disease potentiates hypertension. A generalized approach to drug selection and dosage has not proven effective in managing these conditions, in part, because patients with heterogeneous kidney disease and hypertension etiologies are frequently grouped according to functional or severity classifications. Genetic testing may serve as an important tool in the armamentarium of clinicians who embrace precision medicine. Increasing scientific evidence has supported the utilization of genomic information to select efficacious antihypertensive therapy and understand hereditary contributors to chronic kidney disease progression. Given the wide array of antihypertensive agents available and diversity of genetic renal disease predictors, a panel-based approach to genotyping may be an efficient and economic means of establishing an individualized blood pressure response profile for patients with various forms of chronic kidney disease and hypertension. In this manuscript, we discuss the validation process of a Clinical Laboratory Improvement Amendments-approved genetic test to relay information on 72 genetic variants associated with kidney disease progression and hypertension therapy. These genomic-based interventions, in addition to routine clinical data, may help inform physicians to provide personalized therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/FPC.0000000000000361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358457PMC
January 2019

Qualitative study of system-level factors related to genomic implementation.

Genet Med 2019 07 23;21(7):1534-1540. Epub 2018 Nov 23.

Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA, USA.

Purpose: Research on genomic medicine integration has focused on applications at the individual level, with less attention paid to implementation within clinical settings. Therefore, we conducted a qualitative study using the Consolidated Framework for Implementation Research (CFIR) to identify system-level factors that played a role in implementation of genomic medicine within Implementing GeNomics In PracTicE (IGNITE) Network projects.

Methods: Up to four study personnel, including principal investigators and study coordinators from each of six IGNITE projects, were interviewed using a semistructured interview guide that asked interviewees to describe study site(s), progress at each site, and factors facilitating or impeding project implementation. Interviews were coded following CFIR inner-setting constructs.

Results: Key barriers included (1) limitations in integrating genomic data and clinical decision support tools into electronic health records, (2) physician reluctance toward genomic research participation and clinical implementation due to a limited evidence base, (3) inadequate reimbursement for genomic medicine, (4) communication among and between investigators and clinicians, and (5) lack of clinical and leadership engagement.

Conclusion: Implementation of genomic medicine is hindered by several system-level barriers to both research and practice. Addressing these barriers may serve as important facilitators for studying and implementing genomics in practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-018-0378-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533158PMC
July 2019

Report of Confirmation of the rs7853758 and rs885004 Haplotype in SLC28A3.

Genet Test Mol Biomarkers 2018 Nov 23;22(11):652-655. Epub 2018 Oct 23.

1 Department of Medical and Molecular Genetics and Indiana University School of Medicine , Indianapolis, Indiana.

Aims: To validate a laboratory-developed test for the nucleoside transporter, SLC28A3, which has been associated with an increased risk of anthracycline-induced cardiomyopathy.

Methods: We used Taqman allele discrimination to test for two variants of the SLC28A3 gene: rs7853758 (c.1381C>T) and rs885004 (c.862-360C>T).

Results: During the validation process, we noted that several DNA samples obtained from the Coriell Cell Repository (Camden, NJ) were positive for both the c.1381 C > T and c.862-360C>T variants and another variant allele for either c.1381 C > T or c.862-360C>T (e.g., c.1381C>T homozygous/c.862-360C>T heterozygous, c.1381C>T homozygous/c.862-360C>T homozygous). We used de-identified DNA samples from trios of family members (mother, father, and child) to establish that the c.1381 C > T and c.862-360C>T variant alleles could be inherited in cis on the same chromosome.

Conclusions: Samples containing three variant alleles suggest that the c.1381 C > T and c.862-360C>T are in cis on the chromosome in some individuals and may have implications when calculating anthracycline-induced cardiomyopathy risk. In this study, we confirm a novel haplotype of SLC28A3 using familial studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/gtmb.2018.0194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249667PMC
November 2018