Research Directions in the Clinical Implementation of Pharmacogenomics: An Overview of US Programs and Projects

Response to a drug often differs widely among individual patients. This variability is frequently observed not only with respect to effective responses but also with adverse drug reactions. Matching patients to the drugs that are most likely to be effective and least likely to cause harm is the goal of effective therapeutics. Pharmacogenomics (PGx) holds the promise of precision medicine through elucidating the genetic determinants responsible for pharmacological outcomes and using them to guide drug selection and dosing. Here we survey the US landscape of research programs in PGx implementation, review current advances and clinical applications of PGx, summarize the obstacles that have hindered PGx implementation, and identify the critical knowledge gaps and possible studies needed to help to address them

A Sustainable Future In The Implementation Of Clinical Pharmacogenomics

Purpose: The sustainability of clinical pharmacogenomics requires further study of clinical education on the topic, its effects on clinical workflow, and the responsibilities of different providers for its delivery. Tools from the discipline of implementation science were utilized herein to help achieve the purposes of the three studies. The broad purpose of this dissertation is to advance the work of clinical pharmacogenomic implementation through a more rigorous convergence with implementation science. Methods: Three studies constitute the whole of this dissertation. The first is a scoping review that provides a broad characterization of the methods utilized in available peer-revieliterature focusing on provider use of and experience with using pharmacogenomics in practice or the study setting. The second study used semi-structured in-depth interviews to elicit strategies and perspectives from leadership in current implementation programs using the Consolidated Framework for Implementation Science (CFIR) Process Domain. The third used a cross-sectional quantitative survey with experimental vignettes to explore the potential for pharmacist-physician collaboration using newly developed implementation science outcomes. Results: The scoping review included 25 studies, with many focused on the interactions of providers with clinical decision support systems and adherence to therapeutic recommendations represented. Results from the interviews were extensive but several highlights included a focus on understanding pharmacogenomic use prior to implementation, high-touch informal communication with providers, and the power of the patient case. The survey analysis revealed that the primary care physicians believe that it is more appropriate to deliver clinical pharmacogenomics when a pharmacist is physically located in a clinic and is responsible for managing and modifying a drug therapy based on these results. Conclusion: These three studies further the convergence of implementation science and genomic medicine, with particular focus on pharmacogenomics and the foundational concept of implementation science, sustainability. The scoping review should provide future researchers with a landscape of available and previously used methodologies for interventional pharmacogenomic studies. The interview results will help new implementers of pharmacogenomics steer around avoidable hurdles or make them easier to address. The survey results showcase the potential for pharmacist-physician collaboration in clinical pharmacogenomics

Personalized Medicine: the Future of Health Care

BACKGROUND: Most medical treatments have been designed for the “average patients”. As a result of this “one-size-fits-all-approach”, treatments can be very successful for some patients but not for others. The issue is shifting by the new innovation approach in diseases treatment and prevention, precision medicine, which takes into account individual differences in people\u27s genes, environments, and lifestyles. This review was aimed to describe a new approach of healthcare performance strategy based on individual genetic variants.CONTENT: Researchers have discovered hundreds of genes that harbor variations contributing to human illness, identified genetic variability in patients\u27 responses to different of treatments, and from there begun to target the genes as molecular causes of diseases. In addition, scientists are developing and using diagnostic tests based on genetics or other molecular mechanisms to better predict patients\u27 responses to targeted therapy.SUMMARY: Personalized medicine seeks to use advances in knowledge about genetic factors and biological mechanisms of disease coupled with unique considerations of an individual\u27s patient care needs to make health care more safe and effective. As a result of these contributions to improvement in the quality of care, personalized medicine represents a key strategy of healthcare reform

Multidisciplinary Workflow Implementation for ctDNA Kit Collection to Decrease Inefficiencies for Patients and Staff: A Quality Improvement Initiative

Background: Circulating tumor DNA testing in the oncologic clinic setting is used to detect residual disease and genetic mutations for targeted therapy options. Local Problem: This quality initiative was developed to standardize circulating tumor DNA kit (ctDNA kit) collection in a rural academic medical cancer center. The use of third-party ctDNA testing kits within the clinic has increased in the last three years to detect genetic markers for targeted therapy. Methods: The use of a plan-do-study-act framework was utilized to revise the workflow for the ctDNA kit collection process to decrease total collection time and increase staff satisfaction. Intervention: With key stakeholder support a revised workflow was implemented to address the need for ctDNA kit collection process. Test requisition forms and test kits were relocated within the clinic to improve ease of access. Results: Staff satisfaction increased from a mean of 1.17 pre-intervention to a mean of 2.7 of post-intervention in those surveyed and total collection time decreased from a mean of 37 to a mean of 19 minutes following implementation. Conclusion: The global aim to reduce total collection time was met and to increase staff satisfaction, however, the specific aim to decrease total collection to 15 minutes was not met. Future implementation cycles could include contractual development with the kit vendors to ensure proper billing and electronic health record integration to improve access to results. Keywords: quality initiative, ctDNA, circulating tumor DNA, workflow implementation, process developmen

Facilitating and Enhancing Biomedical Knowledge Translation: An in Silico Approach to Patient-centered Pharmacogenomic Outcomes Research

Current research paradigms such as traditional randomized control trials mostly rely on relatively narrow efficacy data which results in high internal validity and low external validity. Given this fact and the need to address many complex real-world healthcare questions in short periods of time, alternative research designs and approaches should be considered in translational research. In silico modeling studies, along with longitudinal observational studies, are considered as appropriate feasible means to address the slow pace of translational research. Taking into consideration this fact, there is a need for an approach that tests newly discovered genetic tests, via an in silico enhanced translational research model (iS-TR) to conduct patient-centered outcomes research and comparative effectiveness research studies (PCOR CER). In this dissertation, it was hypothesized that retrospective EMR analysis and subsequent mathematical modeling and simulation prediction could facilitate and accelerate the process of generating and translating pharmacogenomic knowledge on comparative effectiveness of anticoagulation treatment plan(s) tailored to well defined target populations which eventually results in a decrease in overall adverse risk and improve individual and population outcomes. To test this hypothesis, a simulation modeling framework (iS-TR) was proposed which takes advantage of the value of longitudinal electronic medical records (EMRs) to provide an effective approach to translate pharmacogenomic anticoagulation knowledge and conduct PCOR CER studies. The accuracy of the model was demonstrated by reproducing the outcomes of two major randomized clinical trials for individualizing warfarin dosing. A substantial, hospital healthcare use case that demonstrates the value of iS-TR when addressing real world anticoagulation PCOR CER challenges was also presented

Pharmacogenomics of sickle cell disease therapeutics: pain and drug metabolism associated gene variants and hydroxyurea-induced post-transcriptional expression of miRNAs

Sickle cell disease (SCD) is a common blood disease caused by a single nucleotide substitution (c.20T>A, p.Glu6Val) in the beta globin gene on chromosome 11. The prevalence of the disease is high throughout large areas in sub-Saharan Africa, the Mediterranean basin, the Middle East, and India due to the level of protection that the sickle cell trait, provides against severe malaria. Approximately 300,000 infants are born per year with sickle cell anemia, which is defined as homozygosity for the sickle hemoglobin (HbS). The majority (nearly 75%) of these births occur in sub-Saharan Africa, particularly in two countries: Nigeria, and the Democratic Republic of the Congo where there are poorly resourced healthcare systems. Early diagnosis, penicillin prophylaxis, blood transfusions, hydroxyurea, and hematopoietic stem-cell transplantation can dramatically improve survival and quality of life for patients with SCD. However, our understanding of the role of genetic and clinical factors in explaining the complex phenotypic diversity of this disease is still limited. Early prediction of the severity, and patients' responses to specific therapeutics of SCD could lead to more precise treatment and management. Beyond well-known modifiers of disease severity, such as fetal hemoglobin (HbF) levels and αthalassemia, other genetic variants might influence specific sub-phenotypes. New treatments and management strategies accounting for these genetic and nongenetic factors could substantially and rapidly improve the quality of life and reduce health care costs for patients with SCD. Patients with SCD are subjected to long term administration of drugs and there is a limited data on pharmacogenomics of SCD therapeutics. Vaso-occlusive crisis (VOC) are the main clinical events of SCD and are associated with recurrent and long-term use of antalgics/opioids and HU. This project aimed to investigate the clinical and genetic predictors of painful vaso-occlusive crisis (VOC) among SCD Cameroon patients by exploring pharmacokinetic determinants of treatment responses as well as post-transcriptional signatures triggered by hydroxyurea treatment, particularly, miRNA expression. SCD patients were recruited from Yaounde Central Hospital and Laquintinie Hospital in Douala (Wonkam et al., 2018, Mnika et al., 2019 (b)), and recent migrants SCD patients from the DRC, recruited at the Haematology Clinic, Groote Schuur Hospital in Cape Town, South Africa (Mnika et al., 2019 (a) and Mnika et al., 2019 (b)). Sociodemographic and clinical data were collected by means of a structured questionnaire. Patients' medical records were reviewed to extract their clinical features over the past 3 years. Specifically, the occurrences of VOC, hematological parameters, hospital outpatient visits, hospitalisation, overt strokes, blood transfusions, and administration of hydroxyurea were recorded. Height, weight, body mass index (BMI), systolic and diastolic blood pressures (SBP and DBP) were measured. Detailed descriptions of patients and sampling methods used in the Cameroonian patients have been reported previously (Wonkam et al., 2018 Mnika et al., 2019 (a) and Mnika et al., 2019 (b)). For the purpose of comparing frequencies of variants, ethnically matched Cameroonian controls were randomly recruited from apparently healthy blood donors in Yaounde for participation in the study. All blood samples were collected for genomic characterisation and analysis. DNA was extracted from peripheral blood, following instructions on the available commercial kit [QIAamp DNA Blood Maxi Kit ® (Qiagen, United States)]. Genotyping (TaqMan and MassArray) was performed for 40 variants in 17 pain-related genes, three fetal haemoglobin (HbF)-promoting loci, two kidney dysfunction-related genes, and HBA1/HBA2 genes for 436 patients. A subset of these samples was also genotyped to analyse 32 core and 267 extended pharmacogenes using commercially available PharmacoScan® platform for characterisation of pharmacokinetic determinant of response. We also compared the pharmacogenes variants from these African groups, to data extracted from the 1000 genomes Project. Moreover, association studies were carried out on pharmacogenes variants with SCD clinical variability. Additionally, protein-protein interaction (PPI) network and enriched biological processes and pathways were investigated. For association studies, statistical models using regression frameworks to analyse 40 variants were performed in R®. For miRNA expression, total RNA was isolated using the miRNeasy kit according to protocol of the Manufacturer (QIAGEN, Hilden, Germany); and sequenced by the Genomic and RNA Profiling Core at Baylor College of Medicine, United States, using the NanoString Platform (NanoString Technologies, Inc., Seattle, WA, United States), according to manufacturer's instructions. Genes with statistically significant changes in expression were analysed using the significance analyses of microarrays (SAM) tools. Female sex, body mass index, Hb/HbF, blood transfusions, leucocytosis and consultation or hospitalisation rates significantly correlated with VOC. Three painrelated gene variants correlated with VOC (CACNA2D3-rs6777055, P = 0·025; DRD2- rs4274224, P = 0·037; KCNS1-rs734784, P= 0·01). Five pain-related gene variants correlated with hospitalization/consultation rates (COMT-rs6269, P = 0·027; FAAHrs4141964, P = 0·003; OPRM1- rs1799971, P = 0·031; ADRB2-rs1042713; P < 0·001; UGT2B7-rs7438135, P = 0·037). The 3·7 kb HBA1/HBA2 deletion correlated with increased VOC (P = 0·002). HbF-promoting loci variants correlated with decreased hospitalisation (BCL11A-rs4671393, P = 0·026; HBS1L-MYB-rs28384513, P = 0·01). APOL1 G1/G2 correlated with increased hospitalisation (P = 0·048). A commercial genotyping array platform (PharmacoScan®) with 4627 markers located in 1191 genes was used to investigate 299 pharmacogenes (32 ADME core and 267 extended pharmacogenes). Based on the PharmacoScan analyses, no statistically significant differences in allele frequencies were detected between SCD cases and controls from Cameroon. A principal component analysis (PCA) revealed that Cameroonians' data clustered with other Africans, but this population is significantly distinct from American, European and Asian populations data. Variant allele frequencies in 21/32 core pharmacogenes were significantly different between the two SCD groups (Cameroon vs. Congo). No correlation between clinical variability and variants in the core genes was detected for both populations under study. An association study of the core and extended PharmacoScan variants to VOC identified statistically significant associations between two single nucleotide polymorphisms (SNPs) to VOC after correction of multiple testing. These two SNPs mapped to 50 genes, with two SNPs located in core pharmacogenes (SLCO4A1- rs118042746, p=1.21e-07; UGT1A10, UGT1A8- rs10176426, p=1.22e-07). Functional enrichment analyses revealed that these 50 genes are involved in three biological processes and four pathways relevant to SCD pathophysiology, including xenobiotic glucuronidation (GO:0052697, p = 2.3e-03), and drug metabolism - other enzymes (p = 2.1e-02). Further analyses of the 50 genes, identified key genes in human proteinprotein networks: NTSR1, LRMDA, SMAD SMAD4 and CDH2. These four genes also interacted with three core pharmacogenes associated with VOC: UGT1A8, UGT1A10 and SLCO4A1. We found 22/798 miRNAs to be differentially expressed under HU treatment, with the majority (13/22) being functionally associated with HbF-regulatory genes, including BCL11A (miR-148b-3p, miR-32-5p, miR-340-5p, miR-29c-3p), MYB (miR-105-5p), KLF-3 (miR-106b-5), and SP1 (miR-29b-3p, miR-625-5p, miR-324-5p, miR-125a-5p, miR-99b-5p, miR-374b-5p, miR-145-5p). The present thesis started by highlighting the scarcity of studies investigating variable responses to pain in SCD patients and then proceeded to addressing this research gap. To our knowledge this is the first body of from Africa to provide evidence supporting the possible development of a genetic risk model for pain in SCD. This is also the first body of work to report an association between these two SNPs and VOC in core and extended pharmacogenes. Our data reveals that the commercial pharmacogenes arrays investigated might need additional evidence for appropriateness among Africans. Therefore, it advocates the need to invest in research exploring population-specific arrays, drug design, targeting, and efficacy, for improved clinical management of patients of African descent. Previous studies have investigated various mechanisms to understand the genomic variations affecting responses to HU, but full understanding of the variable HU-mediated HbF production among individuals affected by SCD remains elusive. The present study showed that mechanisms of HbF production in response to HU, could particularly be mediated through miRNA regulation. The data reveals some alternative perspectives and routes towards identifying new therapeutic targets and approaches for SCD. However, this study needs to be replicated in larger samples in multiple African populations

The ENIGMA-Epilepsy working group: Mapping disease from large data sets

Epilepsy is a common and serious neurological disorder, with many different constituent conditions characterized by their electro clinical, imaging, and genetic features. MRI has been fundamental in advancing our understanding of brain processes in the epilepsies. Smaller‐scale studies have identified many interesting imaging phenomena, with implications both for understanding pathophysiology and improving clinical care. Through the infrastructure and concepts now well‐established by the ENIGMA Consortium, ENIGMA‐Epilepsy was established to strengthen epilepsy neuroscience by greatly increasing sample sizes, leveraging ideas and methods established in other ENIGMA projects, and generating a body of collaborating scientists and clinicians to drive forward robust research. Here we review published, current, and future projects, that include structural MRI, diffusion tensor imaging (DTI), and resting state functional MRI (rsfMRI), and that employ advanced methods including structural covariance, and event‐based modeling analysis. We explore age of onset‐ and duration‐related features, as well as phenomena‐specific work focusing on particular epilepsy syndromes or phenotypes, multimodal analyses focused on understanding the biology of disease progression, and deep learning approaches. We encourage groups who may be interested in participating to make contact to further grow and develop ENIGMA‐Epilepsy

Program and abstracts

We are pleased that the program in 2022 will be more interesting than ever and it will include the following topics: Mathematical Modeling in Cancer Therapy, Gene Therapy, Archaeological Genetics, New perspectives in Human Forensic Molecular Biology, Genomics in Medicine, Pharmacogenomics and Drug Development, Stem Cells in Medicine, Regenerative Medicine, Ribosomes in Medicine, Epigenomics, Crime Scene Investigation, Forensic Genetics, and Mass Catastrophes Managements. This year, the third "Nobel Spirit" will provide a forum to the three Nobel laureates to stimulate public discussion on the role of science in solving global health issues, acute regional problems such as brain drain, demographic decline, as well as cultural and social change. In addition, we are organizing a very stimulating Session on Bioanthropology and global health in the times of crisis, as well as Joint Event ISABS and Ministry of the Interior - Crime Scene Investigation Training Course: Mystery on the ship —Investigation of the water-related crime scene