Front Pharmacol. 2023 Jan 18;13:931405. doi: 10.3389/fphar.2022.931405. eCollection 2022.

ABSTRACT

Background: Clopidogrel is frequently used in patients with ischemic stroke or transient ischemic attack (TIA), but its efficacy is hampered by inter-individual variability, due to genetic differences associated with clopidogrel metabolism. We conducted this randomized controlled trial to validate whether the personalized antiplatelet therapy based on clopidogrel pharmacogenomics and clinical characteristics leads to better clinical outcomes compared with standard treatment. Methods: Patients were randomly divided into the standard group or pharmacogenetic group, in which the pharmacogenetic group required the detection of the genotyping of CYP2C19*2, CYP2C19*3, and CYP2C19*17. Patients were followed up for 90 days for the primary efficacy endpoint of new stroke events, secondary efficacy endpoint of individual or composite outcomes of the new clinical vascular events, and the incidence of disability. The primary safety outcome was major bleeding. Results: A total of 650 patients underwent randomization, among which 325 were in the pharmacogenomics group while 325 were in the standard group. Our study found after a 90-day follow-up, the risk of stroke and composite vascular events in the pharmacogenomics group was lower than that in the standard group. The incidence of disability significantly decreased in the pharmacogenomics group. In addition, no statistically significant differences were observed in bleeding events between the two groups. Conclusion: The present study demonstrates that personalized antiplatelet therapy guided by clopidogrel pharmacogenomics and clinical characteristics can significantly improve the net clinical benefit of ischemic stroke or TIA patients during the 90-day treatment period without increasing bleeding risk.

PMID:36744212 | PMC:PMC9889636 | DOI:10.3389/fphar.2022.931405

Front Endocrinol (Lausanne). 2023 Jan 18;13:1034614. doi: 10.3389/fendo.2022.1034614. eCollection 2022.

ABSTRACT

OBJECTIVES: Endometriosis (EM) is an estrogen-dominant inflammatory disease linked to infertility that affects women of reproductive age. EM lesions respond to hormonal signals that regulate uterine tissue growth and trigger inflammation and pain. The objective of this study was to evaluate whether estradiol (E2) and its biologically active metabolites are differentially associated with EM given their estrogenic and non-estrogenic actions including proliferative and inflammatory properties.

DESIGN: We performed a retrospective study of 209 EM cases and 115 women without EM.

METHODS: Pain-related outcomes were assessed using surveys with validated scales. Preoperative serum levels of estradiol (E2) and estrone (E1), their 2-, 4- and 16- hydroxylated (OH) and methylated (MeO) derivatives (n=16) were measured by mass spectrometry. We evaluated the associations between estrogen levels and EM anatomic sites, surgical stage, risk of EM, and symptoms reported by women. Spearman correlations established the relationships between circulating steroids.

RESULTS: Of the sixteen estrogens profiled, eleven were detected above quantification limits in most individuals. Steroids were positively correlated, except 2-hydroxy 3MeO-E1 (2OH-3MeO-E1). Higher 2OH-3MeO-E1 was linked to an increased risk of EM (Odd ratio (OR)=1.91 (95%CI 1.09-3.34); P=0.025). Ovarian EM cases displayed enhanced 2-hydroxylation with higher 2MeO-E1 and 2OH-E1 levels (P< 0.009). Abdominal, pelvic and back pain symptoms were also linked to higher 2OH-3MeO-E1 levels (OR=1.86; 95%CI 1.06-3.27; P=0.032).

CONCLUSIONS: The 2-hydroxylation pathway emerges as an unfavorable feature of EM, and is associated with ovarian EM and pain related outcomes.

PMID:36743927 | PMC:PMC9891204 | DOI:10.3389/fendo.2022.1034614

ACS Omega. 2023 Jan 16;8(4):4146-4155. doi: 10.1021/acsomega.2c07129. eCollection 2023 Jan 31.

ABSTRACT

Substituted pyridinium bromides are prepared by conventional and solvent-free greener methods. The solvent-free solid-phase (greener) method is superior to the conventional method because of its nontoxic nature, simple reaction setup procedure, and twenty times less time consumption. Column chromatography and toxic organic solvents are avoided. Substituted pyridinium salts 1-2(a-c) show excellent catalytic response in the preparation of β-amino carbonyl derivatives using the conventional approach. Pharmacokinetics is very important in target validation and in shifting a lead compound into a drug. The physicochemical properties discussed here can be used effectively in the drug designing candidate, which is a cumbersome process in clinical research. In addition, molecular simulations are demonstrated, and compounds 1-2(a-c) possess the most potent VEGFR-2 kinase protein inhibitory activities, and most interestingly, compound 2a strongly binds and regulates the VEGFR-2 kinase activity in therapeutic approaches and cancer prevention.

PMID:36743060 | PMC:PMC9893258 | DOI:10.1021/acsomega.2c07129

Front Bioeng Biotechnol. 2023 Jan 20;11:982111. doi: 10.3389/fbioe.2023.982111. eCollection 2023.

ABSTRACT

Next-generation sequencing (NGS) is present in all fields of life science, which has greatly promoted the development of basic research while being gradually applied in clinical diagnosis. However, the cost and throughput advantages of next-generation sequencing are offset by large tradeoffs with respect to read length and accuracy. Specifically, its high error rate makes it extremely difficult to detect SNPs or low-abundance mutations, limiting its clinical applications, such as pharmacogenomics studies primarily based on SNP and early clinical diagnosis primarily based on low abundance mutations. Currently, Sanger sequencing is still considered to be the gold standard due to its high accuracy, so the results of next-generation sequencing require verification by Sanger sequencing in clinical practice. In order to maintain high quality next-generation sequencing data, a variety of improvements at the levels of template preparation, sequencing strategy and data processing have been developed. This study summarized the general procedures of next-generation sequencing platforms, highlighting the improvements involved in eliminating errors at each step. Furthermore, the challenges and future development of next-generation sequencing in clinical application was discussed.

PMID:36741756 | PMC:PMC9895957 | DOI:10.3389/fbioe.2023.982111

Front Pediatr. 2023 Jan 18;10:958622. doi: 10.3389/fped.2022.958622. eCollection 2022.

ABSTRACT

BACKGROUND: Methylphenidate is the most prescribed stimulant to treat attention deficit-hyperactivity disorder (ADHD). Despite its widespread usage, a fair proportion of children are classified as non-responders to the medication. Variability in response and occurrence of adverse events with methylphenidate use may be due to several factors, including drug-drug interactions as well as pharmacogenetic differences resulting in pharmacokinetic and/or pharmacodynamic variances within the general population. The objective of this study was to analyze the effect of carboxylesterase 1 (CES1) variants on the frequency of adverse effects and dosing requirements of methylphenidate in children with ADHD.

METHODS: This was a retrospective cohort study of children and adolescents who met the inclusion criteria and had a routine visit during the enrollment period were invited to participate. Inclusion criteria included: ADHD diagnosis by a healthcare provider, between 6 and 16 years of age at the time of permission/assent, had not previously been prescribed methylphenidate, and treatment with any methylphenidate formulation for at least three consecutive months. Three months of records were reviewed in order to assess changes in dose and frequency of discontinuing methylphenidate. Participants' ADHD symptoms, medication response, adverse effects, select vitals, and dose were extracted from the electronic health record. Saliva samples were collected by trained study coordinators. Haplotypes were assigned based on copy number in different portions of the CES1 gene. Due to limited numbers, diplotypes (combinations of two haplotypes) were grouped for analysis as CES1A1/CES1A1, CES1A1/CES1A1c and CES1A1c/CES1A1c.

RESULTS: A total of 99 participants (n = 30 female; n = 69 male) had both clinical data and CES1 sequencing data, with an average age of 7.7 years old (range 3-15 years). The final weight-based dose in all individuals was 0.79 mg/kg/day. The most common adverse effects reported were decreased appetite (n = 47), weight loss (n = 24), and sleep problems (n = 19). The mean final weight-based dose by haplotype was 0.92 mg/kg for CES1A2/CES1A2, 0.81 mg/kg for CES1A2/CES1P1, and 0.78 mg/kg for CES1P1/CES1P1. After correction for multiple hypothesis testing, only one SNV, rs114119971, was significantly associated with weight-based dosing in two individuals. The individuals with the rs114119971 SNV had a significantly lower weight-based dose (0.42 mg/kg) as compared to those without (0.88 mg/kg; p < 0.001).

DISCUSSION: Variation in CES1 activity may impact dose requirements in children who are prescribed methylphenidate, as well as other CES1 substrates. Although intriguing, this study is limited by the retrospective nature and relatively small sample size.

PMID:36741090 | PMC:PMC9890192 | DOI:10.3389/fped.2022.958622

Pharmacogenomics J. 2023 Feb 4. doi: 10.1038/s41397-023-00300-3. Online ahead of print.

ABSTRACT

BACKGROUND: Warfarin is an oral anticoagulant commonly used for treatment and prophylaxis against thromboembolic events. Warfarins's narrow therapeutic index window is one of the main challenges in clinical practice; thus, it requires frequent monitoring and dose adjustment to maintain patients' therapeutic range. Warfarin dose variation and response are attributed to several inter-and intra-individuals factors, including genetic variants in enzymes involved in warfarin pharmacokinetics (PK) and pharmacodynamics (PD) pathways. Thus, we aim to utilize the next-generation sequencing (NGS) approach to identify rare and common genetic variants that might be associated with warfarin responsiveness.

METHOD AND RESULTS: A predesigned NGS panel that included 16 genes involved in Warfarin PK/PD pathways was used to sequence 786 patients from the Saudi Warfarin Pharmacogenetic Cohort (SWAP). Identified variants were annotated using several annotation tools to identify the pathogenicity and allele frequencies of these variants. We conducted variants-level association tests with warfarin dose. We identified 710 variants within the sequenced genes; 19% were novel variants, with the vast majority being scarce variants. The genetic association tests showed that VKORC1 (rs9923231, and rs61742245), CYP2C9 (rs98332238, rs9332172, rs1057910, rs9332230, rs1799853, rs1057911, and rs9332119), CYP2C19 (rs28399511, and rs3758581), and CYP2C8 (rs11572080 and rs10509681) were significantly associated with warfarin weekly dose. Our model included genetics, and non-genetic factors explained 40.1% of warfarin dose variation.

CONCLUSION: The study identifies novel variants associated with warfarin dose in the Saudi population. These variants are more likely to be population-specific variants, suggesting that population-specific studies should be conducted before adopting a universal warfarin genotype-guided dosing algorithm.

PMID:36739459 | DOI:10.1038/s41397-023-00300-3

Lancet. 2023 Feb 4;401(10374):320-321. doi: 10.1016/S0140-6736(22)02461-8.

NO ABSTRACT

PMID:36739126 | DOI:10.1016/S0140-6736(22)02461-8

Lancet. 2023 Feb 4;401(10374):347-356. doi: 10.1016/S0140-6736(22)01841-4.

ABSTRACT

BACKGROUND: The benefit of pharmacogenetic testing before starting drug therapy has been well documented for several single gene-drug combinations. However, the clinical utility of a pre-emptive genotyping strategy using a pharmacogenetic panel has not been rigorously assessed.

METHODS: We conducted an open-label, multicentre, controlled, cluster-randomised, crossover implementation study of a 12-gene pharmacogenetic panel in 18 hospitals, nine community health centres, and 28 community pharmacies in seven European countries (Austria, Greece, Italy, the Netherlands, Slovenia, Spain, and the UK). Patients aged 18 years or older receiving a first prescription for a drug clinically recommended in the guidelines of the Dutch Pharmacogenetics Working Group (ie, the index drug) as part of routine care were eligible for inclusion. Exclusion criteria included previous genetic testing for a gene relevant to the index drug, a planned duration of treatment of less than 7 consecutive days, and severe renal or liver insufficiency. All patients gave written informed consent before taking part in the study. Participants were genotyped for 50 germline variants in 12 genes, and those with an actionable variant (ie, a drug-gene interaction test result for which the Dutch Pharmacogenetics Working Group [DPWG] recommended a change to standard-of-care drug treatment) were treated according to DPWG recommendations. Patients in the control group received standard treatment. To prepare clinicians for pre-emptive pharmacogenetic testing, local teams were educated during a site-initiation visit and online educational material was made available. The primary outcome was the occurrence of clinically relevant adverse drug reactions within the 12-week follow-up period. Analyses were irrespective of patient adherence to the DPWG guidelines. The primary analysis was done using a gatekeeping analysis, in which outcomes in people with an actionable drug-gene interaction in the study group versus the control group were compared, and only if the difference was statistically significant was an analysis done that included all of the patients in the study. Outcomes were compared between the study and control groups, both for patients with an actionable drug-gene interaction test result (ie, a result for which the DPWG recommended a change to standard-of-care drug treatment) and for all patients who received at least one dose of index drug. The safety analysis included all participants who received at least one dose of a study drug. This study is registered with ClinicalTrials.gov, NCT03093818 and is closed to new participants.

FINDINGS: Between March 7, 2017, and June 30, 2020, 41 696 patients were assessed for eligibility and 6944 (51·4 % female, 48·6% male; 97·7% self-reported European, Mediterranean, or Middle Eastern ethnicity) were enrolled and assigned to receive genotype-guided drug treatment (n=3342) or standard care (n=3602). 99 patients (52 [1·6%] of the study group and 47 [1·3%] of the control group) withdrew consent after group assignment. 652 participants (367 [11·0%] in the study group and 285 [7·9%] in the control group) were lost to follow-up. In patients with an actionable test result for the index drug (n=1558), a clinically relevant adverse drug reaction occurred in 152 (21·0%) of 725 patients in the study group and 231 (27·7%) of 833 patients in the control group (odds ratio [OR] 0·70 [95% CI 0·54-0·91]; p=0·0075), whereas for all patients, the incidence was 628 (21·5%) of 2923 patients in the study group and 934 (28·6%) of 3270 patients in the control group (OR 0·70 [95% CI 0·61-0·79]; p <0·0001).

INTERPRETATION: Genotype-guided treatment using a 12-gene pharmacogenetic panel significantly reduced the incidence of clinically relevant adverse drug reactions and was feasible across diverse European health-care system organisations and settings. Large-scale implementation could help to make drug therapy increasingly safe.

FUNDING: European Union Horizon 2020.

PMID:36739136 | DOI:10.1016/S0140-6736(22)01841-4

Int Immunopharmacol. 2023 Feb 2;116:109737. doi: 10.1016/j.intimp.2023.109737. Online ahead of print.

ABSTRACT

Gastric cancer (GC) is the most common form of gastrointestinal cancer, with a high mortality rate and limited treatment options. High levels of NEK2 are associated with malignant progression and a poor prognosis in several tumors; however, the role of NEK2 in GC remains unclear. We aimed to explore the potential role of NEK2 in the oncogenesis of GC and in the shaping of the tumor microenvironment (TME). The expression levels of NEK2 were analyzed using immunohistochemistry and real-time quantitative polymerase chain reaction. We found that NEK2 expression was upregulated in GC and was a predictor of a poor prognosis. Based on Kyoto Encyclopedia of Genes and Genomes pathway enrichment and gene set enrichment analyses, multiple tumor pathways were hyperactivated in patients with high NEK2 mRNA expression. Immunological characteristics indicated that NEK2 upregulation might lead to decreased immune cell infiltration and weakened immune activity in the cancer immunity cycle. Additionally, higher frequencies of amplifications and deletions were observed in the high NEK2 expression subpopulation. Based on the TME classification, patients with high expression of NEK2 were more susceptible to targeted therapy with drugs targeting the cell cycle and DNA replication. Following verification, a NEK2-derived genomic model reliably predicted the patient prognosis; A nomogram (radiation therapy, tumor/node/metastasis staging, and the NEK2-derived risk score) was used to better estimate an individual's survival probability. In summary, our findings indicate that NEK2 plays a vital role in the tumorigenesis of GC.

PMID:36738674 | DOI:10.1016/j.intimp.2023.109737

Clin Chim Acta. 2023 Jan 31:117239. doi: 10.1016/j.cca.2023.117239. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Highly sensitive technologies are available for molecular characterization of solid tumors, including digital PCR (dPCR). Liquid biopsy, based on the analysis of circulating free DNA (cfDNA), is often used to assess EGFR or RAS alterations in lung and colorectal cancers. Our study aimed to compare the results of two different dPCR platforms for the detection of mutations in cfDNA.

METHODS: Plasma samples from lung and colorectal cancer patients collected as per routinary procedures have been tested. CfDNA was extracted from plasma, and samples were screened on the droplet digital PCR (ddPCR) and dPCR Qiacuity.

RESULTS: A total of 42 samples were analyzed, 20 belonged to Non-Small Cell Lung Cancer (NSCLC) patients carrying an EGFR or a KRAS mutation on tissue at diagnosis, 22 samples belonged to colorectal cancer (CRC) patients, 10 of which presented a KRAS mutation. EGFR mutation detection was 58.8% for ddPCR and 100% for dPCR (κ= 0.54; 95% CI, 0.37-0.71), compared to tissue results. The detection rate for RAS mutations was 72.7% for ddPCR and 86.4% for dPCR (κ= 0.34; 95% CI, 0.01-0.68), compared to tissue results.

CONCLUSIONS: This study showed moderate agreement between dPCR and ddPCR. Sampling effect or threshold settings may potentially explain the differences in the cfDNA data between the two different platforms.

PMID:36736684 | DOI:10.1016/j.cca.2023.117239

J Oncol Pharm Pract. 2023 Feb 3:10781552231153814. doi: 10.1177/10781552231153814. Online ahead of print.

ABSTRACT

The intent of this review is to present basic genetic concepts key to understanding oncogenesis and the role receptor tyrosine kinase (RTK) inhibition plays in the targeted treatment of many cancer types. Oncogenic signaling by RTKs can result from genetic events such as point mutations, chromosomal rearrangements, structural variation, and gene amplification in the cancer genome. The cancer pharmacogenes discussed encode RTKs that exemplify the link between gene variation, the oncogenic process, and the basis of targeted approaches to treatment. Biochemical pathways often involved in oncogenesis and affected by RTK variation are reviewed. Molecular diagnostic testing for the presence of specific gene variants, alterations, and amplifications direct therapy to indicated tyrosine kinase inhibitors and monoclonal antibody drugs. As pharmacists are integral to the selection, preparation, and monitoring of chemotherapy, it is important that they understand the genetic basis for targeted therapies as well as the underlying disease process.

PMID:36734129 | DOI:10.1177/10781552231153814

Pharm Pract (Granada). 2022 Jul-Sep;20(3):2722. doi: 10.18549/PharmPract.2022.3.2722. Epub 2022 Sep 14.

ABSTRACT

BACKGROUND: Warfarin is well known as a narrow therapeutic index that has prodigious variability in response which challenges dosing adjustment for the maintenance of therapeutic international normalized ratio. However, an appreciated population not on new oral anticoagulants may still need to be stabilized with warfarin dosing.

OBJECTIVE: The current study's main objective was to validate and compare two models of warfarin clinical algorithm models namely the Gage and the International Warfarin Pharmacogenetics Consortium (IWPC) with warfarin 5 mg fixed standard dosing strategy in a sample of Sudanese subjects.

METHOD: We have conducted a cross-sectional study recruited from the out-patient clinic at a tertiary specialized heart center. We included subjects with unchanged warfarin dose (stabilized), and with therapeutic international normalized ratio. The predicted doses of warfarin in the two models were calculated by three different methods (accuracy, clinical practicality, and the clinical safety of the clinical algorithms).

MAIN OUTCOME MEASURE: The primary outcomes were the measurements of the clinical (accuracy, practicality, and safety) in each of the two clinical algorithms models compared to warfarin 5 mg fixed standard dose strategy.

RESULTS: We have enrolled 71 Sudanese subjects with mean age (51.7 ± 14 years), of which (49, 69.0%) were females. There was no significant difference between the warfarin 5 mg fixed standard dose strategy and the predicted doses of the two clinical algorithm models (MAE 1.44, 1.45, and 1.49 mg/day [P =0.4]) respectively. In the clinical practicality, all of the three models had a high percent of subjects (95.0%, 51.9%, and 66.7%) in the ideal dose range in middle dose group (3-7 mg/ day) for warfarin 5 mg fixed standard dosing strategy, Gage, and IWPC clinical algorithm models respectively. However, a small percent of subjects was exhibited in the warfarin low dose group ≤ 3 mg/day (0.0%, 15.0%, and 10.0%) and warfarin high dose group ≥ 7 mg/day (0.0%, 33.3%, and 33.3%) for warfarin 5 mg fixed standard dosing strategy, Gage, and IWPC clinical algorithms respectively. In terms of clinical safety, the percent of subjects with severely over-prediction were 28.2%, 22.5%, and 22.5% for warfarin 5 mg fixed standard dosing, Gage, and IWPC, respectively. While the percent of severely under-prediction was 12.7%, 7.0%, and 5.6% for the warfarin 5 mg fixed standard dosing, Gage, and IWPC, respectively.

CONCLUSION: The Gage and IWPC clinical algorithm models were accurate, more clinically practical, and clinically safe than warfarin 5 mg standard dosing in the study population. The cardiologist can use either models (Gage and IWPC) to stratify subjects for accurate, practical, and clinically safe warfarin dosing..

PMID:36733524 | PMC:PMC9851814 | DOI:10.18549/PharmPract.2022.3.2722

Aliment Pharmacol Ther. 2023 Feb 2. doi: 10.1111/apt.17406. Online ahead of print.

ABSTRACT

BACKGROUND: Zastaprazan (JP-1366) is a novel potassium-competitive acid blocker with favourable preclinical safety and efficacy profile being developed for the treatment of acid-related diseases.

AIMS: To investigate the safety, tolerability, pharmacodynamics and pharmacokinetics of zastaprazan.

METHODS: A randomised, open-label, placebo- and active-controlled, single and multiple ascending dose clinical trial was conducted in healthy Korean male subjects. Intragatric pH and serum gastrin were measured to assess the pharmacodynamics, while serial blood and urine samples were collected to assess the pharmacokinetics. Pharmacogenomic evaluation was conducted to explore genetic variants, which can affect the pharmacodynamics and pharmacokinetics. Safety and tolerability including hepatotoxicity were evaluated.

RESULTS: Suppression of gastric acid secretion increased as the dose of zastaprazan increased. The percentage of time that gastric pH was over 4 (%Time pH >4) with zastaprazan 20 mg (85.19%) and 40 mg (91.84%) were similar to or greater than that with esomeprazole 40 mg (72.06%). Zastaprazan was rapidly absorbed within 2 h and eliminated with a half-life of 6-10 h. Pharmacogenomic analysis found no genetic variant of drug metabolising enzymes including CYP2C19 or drug transporters associated with the exposure of zastaprazan. Zastaprazan was well tolerated with no clinically significant changes in safety and tolerability assessments.

CONCLUSIONS: Zastaprazan was safe and well tolerated after a single oral dose up to 60 mg and multiple oral doses up to 40 mg. It also showed rapid, potent suppression of gastric acid secretion. Pharmacodynamic and pharmacokinetic profile of zastaprazan was suitable for treatment of patients with acid-related diseases.

PMID:36732884 | DOI:10.1111/apt.17406

Comput Inform Nurs. 2022 Oct 14. doi: 10.1097/CIN.0000000000000960. Online ahead of print.

ABSTRACT

In previous work, a prototype clinical decision support mobile application was created that accepts a patient's genomic profile information and provides information and rationale for the prescription of certain oncology medications. The response to the instrument was overwhelmingly positive by healthcare providers in the oncology field who tested the instrument. This article reports on the interdisciplinary collaboration among nursing and computer science to redesign and reimplement a new version of the instrument with expanded functionality and improved usability. This article describes the functionality, usability considerations, and usability evaluation of the instrument over three versions. The current version is Web-based and responsive to different screen sizes (desktop, tablet, mobile), features improved usability, and expands the number of gene-drug recommendations provided based on Clinical Pharmacogenetics Implementation Consortium dosing guidelines. This project represents a successful new collaboration between the nursing and computer science disciplines.

PMID:36731048 | DOI:10.1097/CIN.0000000000000960

Pharmacogenet Genomics. 2022 Dec 12. doi: 10.1097/FPC.0000000000000487. Online ahead of print.

ABSTRACT

Pharmacogenomics is a crucial piece of personalized medicine. Preemptive pharmacogenomic testing is only used sparsely in the inpatient setting and there are few models to date for fostering the adoption of pharmacogenomic treatment in the inpatient setting. We created a multi-institutional project in Chicago to enable the translation of pharmacogenomics into inpatient practice. We are reporting our implementation process and barriers we encountered with solutions. This study, 'Implementation of Point-of-Care Pharmacogenomic Decision Support Accounting for Minority Disparities', sought to implement pharmacogenomics into inpatient practice at three sites: The University of Chicago, Northwestern Memorial Hospital, and the University of Illinois at Chicago. This study involved enrolling African American adult patients for preemptive genotyping across a panel of actionable germline variants predicting drug response or toxicity risk. We report our approach to implementation and the barriers we encountered engaging hospitalists and general medical providers in the inpatient pharmacogenomic intervention. Our strategies included: a streamlined delivery system for pharmacogenomic information, attendance at hospital medicine section meetings, use of physician and pharmacist champions, focus on hospitalists' care and optimizing system function to fit their workflow, hand-offs, and dealing with hospitalists turnover. Our work provides insights into strategies for the initial engagement of inpatient general medicine providers that we hope will benefit other institutions seeking to implement pharmacogenomics in the inpatient setting.

PMID:36729768 | DOI:10.1097/FPC.0000000000000487

Pharmacogenomics. 2023 Feb 2. doi: 10.2217/pgs-2022-0120. Online ahead of print.

ABSTRACT

This case comparison illustrates pharmacogenetic testing in psychotropic and clinical management in relation to the ABCB1 gene, which encodes the P-glycoprotein transporter affecting blood-brain barrier (BBB) permeability. Two pediatric patients (9 and 11 years old) were selected for similar clinical presentations with opposing ABCB1 genotype, while they were identically matched for key CYP450, dopaminergic and serotonergic genes (CYP2C9, CYP2C19, DRD2, SLC6A4, 5HTR2A). Case A was functional for the ABCB1 gene (G/G rs1045642), suggesting that the BBB had a functional P-glycoprotein transporter. Case B was subfunctional for the ABCB1 gene (A/A rs1045642), suggesting that the patient's BBB may be permeable to psychotropic drugs. Case A had more medication trials and dose adjustments than Case B. Case A had two inpatient admissions and interspersed emergency room visits, while case B had none.

PMID:36727491 | DOI:10.2217/pgs-2022-0120

Bioinform Adv. 2023 Jan 20;3(1):vbac095. doi: 10.1093/bioadv/vbac095. eCollection 2023.

ABSTRACT

MOTIVATION: As genome sequencing becomes cheaper and more accurate, it is becoming increasingly viable to merge this data with electronic health information to inform clinical decisions.

RESULTS: In this work, we demonstrate a full pipeline for working with both PacBio sequencing data and clinical FHIR® data, from initial data to tertiary analysis. The electronic health records are stored in FHIR® (Fast Healthcare Interoperability Resource) format, the current leading standard for healthcare data exchange. For the genomic data, we perform variant calling on long-read PacBio HiFi data using Cromwell on Azure. Both data formats are parsed, processed and merged in a single scalable pipeline which securely performs tertiary analyses using cloud-based Jupyter notebooks. We include three example applications: exporting patient information to a database, clustering patients and performing a simple pharmacogenomic study.

AVAILABILITY AND IMPLEMENTATION: https://github.com/microsoft/genomicsnotebook/tree/main/fhirgenomics.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics Advances online.

PMID:36726729 | PMC:PMC9872570 | DOI:10.1093/bioadv/vbac095

Front Genet. 2023 Jan 16;13:1082985. doi: 10.3389/fgene.2022.1082985. eCollection 2022.

ABSTRACT

Introduction: While pharmacogenomic (PGx) testing is routine in urban healthcare institutions or academic health centers with access to existing expertise, uptake in medically-underserved areas is lagging. The primary objective of this workforce education program is to extend access to didactic, case-based and clinical PGx training for pharmacists serving rural Minnesota and populations experiencing health disparities in Minnesota. Methods: A PGx workforce training program funded through the Minnesota Department of Health was offered through the University of Minnesota College of Pharmacy (COP) to pharmacists working in rural and/or underserved areas in the state of Minnesota. Learning activities included a 16-week, asynchronous PGx didactic course covering PGx topics, a 15-min recorded presentation, an in-person PGx case-based workshop, and a live international PGx Conference hosted by the University of Minnesota COP and attendance at our PGx Extension of Community Health Outcomes (ECHO). Results: Twenty-nine pharmacists applied for the initial year of the program, with 12 (41%) being accepted. Four (33%) practiced in a hospital setting, four (33%) in retail pharmacy, two (17%) in managed care, and two (17%) in other areas. The majority had not implemented a PGx program as part of their practice, although nearly all responded definitely or probably yes when asked if they expected their organization to increase its use of PGx testing services over the next three years. All participants either strongly or somewhat agreed that this program helped them identify how and where to access clinical PGx guidelines and literature and improved their ability to read and interpret PGx test results. Eight participants (67%) strongly or somewhat agreed that they expected to increase the number of PGx consultations in their practice, while ten (83%) strongly or somewhat agreed they would be able to apply what they learned in this program to their practice in the next six months to a year. Discussion: This novel PGx training program focused exclusively on pharmacists in rural and/or underserved areas with a delivery method that could be accomplished conveniently and remotely. Although most participants' organizations had yet to implement PGx testing routinely, most anticipated this to change in the next few years.

PMID:36726715 | PMC:PMC9884975 | DOI:10.3389/fgene.2022.1082985

Front Genet. 2023 Jan 4;13:1027345. doi: 10.3389/fgene.2022.1027345. eCollection 2022.

ABSTRACT

With rapid advancements in high-throughput sequencing technologies, massive amounts of "-omics" data are now available in almost every biomedical field. Due to variance in biological models and analytic methods, findings from clinical and biological studies are often not generalizable when tested in independent cohorts. Meta-analysis, a set of statistical tools to integrate independent studies addressing similar research questions, has been proposed to improve the accuracy and robustness of new biological insights. However, it is common practice among biomarker discovery studies using preclinical pharmacogenomic data to borrow molecular profiles of cancer cell lines from one study to another, creating dependence across studies. The impact of violating the independence assumption in meta-analyses is largely unknown. In this study, we review and compare different meta-analyses to estimate variations across studies along with biomarker discoveries using preclinical pharmacogenomics data. We further evaluate the performance of conventional meta-analysis where the dependence of the effects was ignored via simulation studies. Results show that, as the number of non-independent effects increased, relative mean squared error and lower coverage probability increased. Additionally, we also assess potential bias in the estimation of effects for established meta-analysis approaches when data are duplicated and the assumption of independence is violated. Using pharmacogenomics biomarker discovery, we find that treating dependent studies as independent can substantially increase the bias of meta-analyses. Importantly, we show that violating the independence assumption decreases the generalizability of the biomarker discovery process and increases false positive results, a key challenge in precision oncology.

PMID:36726714 | PMC:PMC9885264 | DOI:10.3389/fgene.2022.1027345

Front Pharmacol. 2023 Jan 16;14:1096816. doi: 10.3389/fphar.2023.1096816. eCollection 2023.

ABSTRACT

Aims: Genetic variants increase the susceptibility to anti-drug antibodies (ADA) in response to anti-TNF therapy in chronic inflammatory diseases. However, little is known about genetic variants in Chinese populations. This study aimed to identify genetic variants contributing to the risk of the development of antibodies to infliximab (ATI) in Chinese patients with Crohn's disease (CD). Methods: CD patients (n = 104) treated with infliximab (IFX) during the maintenance therapy were enrolled in this cross-sectional study. ATI was assessed by an in-house developed drug-tolerant ELISA method. ATI titers of 1:20 and ≥1:60 were considered a low titer and a high titer, respectively. Thirteen types of single nucleotide polymorphisms (SNPs) within 13 genes involved in the immune process, the susceptibility to chronic inflammatory diseases, cytokines and apoptosis pathways were investigated. Results: The median trough levels of infliximab (TLI) in patients with clinical remission (CR) were higher than those in patients without CR (3.80 vs. 1.50 μg/mL, p < .001). The median TLI in patients with high-titer ATI was significantly lower than that in ATI-negative patients (1.15 vs. 4.48 μg/mL, p < .001) or those with low-titer ATI (1.15 vs. 2.95 μg/mL, p = .03). The HLA-DQA1*05 rs2097432 GG and GA genotypes were more frequent in patients with ATI (GG and AG vs. AA, 27/38 = 71.05% vs. 29/66 = 43.94%, OR 2.94, 95% CI 1.19-7.30, p = .02). Patients carrying the CC and AC genotypes of rs396991 in FCGR3A were associated with a higher frequency of ATI formation (CC and AC vs. AA, 37/57 = 64.91% vs. 19/47 = 40.43%, OR 2.94, 95% CI 1.24-6.96, p = .01). According to the number of variants in rs2097432 and rs393991, patients with two variants had a higher proportion of producing ATI (two variants vs. no variant, 17/21 = 80.95% vs. 9/30 = 30.00%, OR 9.92, 95% CI 2.59-37.87, p = .001; single variant vs. no variant, 30/53 = 56.60% vs. 9/30 = 30.00%, OR 3.04, 95% CI 1.18-7.88, p = .02). No association was found between other SNPs and ATI production. Conclusion: Rs2097432 in HLA-DQA1*05 and rs396991 in FCGR3A are associated with ATI production in Chinese patients with CD. A pharmacogenomic strategy could help with the clinical management of CD.

PMID:36726584 | PMC:PMC9885127 | DOI:10.3389/fphar.2023.1096816