Dan Roden - US grants

Prolongation of cardiac repolarization (increased QT duration) is linked to provocation of serious ventricular arrhythmias in some settings, but to arrhythmia suppression in others. Up to 11% of patients started on quinidine develop marked increases in QT and potentially fatal polymorphic ventricular tachycardia ("Torsades de Pointes"). On the other hand, marked QT increases are an invariable accompaniment of arrhythmia suppression by amiodarone, which only very rarely causes Torsades de Pointes. The research proposed will test the hypothesis that a specific in vitro electrophysiologic abnormality, bradycardia-dependent early afterdepolarization (EADs), triggers Torsades de Pointes in vivo. This hypothesis has its foundation in a series of clinical and laboratory studies we have conducted on quinidine-induced prolonged repolarization. In patients, we found that the occurrence of Torsades de Pointes was associated with a high incidence of hypokalemia and invariably started after an abrupt increase in cycle length. In canine Purkinje fibers superfused with low concentrations of quinidine, lowering potassium during slow stimulation consistently triggered EADs. Furthermore, interventions abolishing EADs (increasing potassium or stimulation rate) were the same as those which are most effective in Torsades de Pointes. The hypothesized role of EADs in triggering Torsades de Pointes will be further explored in three ways in this proposal. First, agents thought to cause Torsades de Pointes (disopyramide, procainamide, quinidine metabolites) will be tested in canine Purkinje fibers for their ability to induce EADs; interventions which prolong action potential but do not induce this arrhythmia (amiodarone, hypocalcemia) will be similarly evaluated. Second, ventricular monophasic action potentials will be recorded in an animal model of Torsades de Pointes, hypokalemic dogs with slow heart rates (AV block) treated with quinidine or other agents reported to induce EADs in vitro (N-acetylprocainamide, cesium). We have observed abnormalities in monophasic action potentials in such animals which we believe to represent EADs. The relationship of such abnormalities to previous cycle length, Torsades de Pointes onset, and drugs which prevent Torsades de Pointes will be evaluated to confirm this finding, thereby strengthening the link between the in vitro and in vivo abnormalities. Third, monophasic action potential will be recorded in patients receiving action potential prolonging drugs and in patients with previous Torsades de Pointes. In this way, methods to identify patients at risk for Torsades de Pointes will be improved. This research will identify circumstances under which prolongation of cardiac repolarization induces arrhythmias, thereby providing the basis for improved antiarrhythmic drug therapy.

Although the interaction between antiarrhythmic drugs and cardiac sodium channels has been intensively studied in vitro, the effects of these agents on sodium channel-dependent phenomena in the cardiac syncytium is less well-characterized. Factors known to alter the fast inward sodium current include drug concentration, stimulation frequency, transmembrane potential and factors in the extracellular milieu such as pH. The hypothesis we will test is that such information on the sodium channel blocking properties of antiarrhythmic drugs can be successfully exploited to study these agents in vivo. In preliminary studies, we have developed methods to measure, as a function of stimulation frequency and the extracellular environment, both direction-dependent conduction times and excitability in the intact heart. We ill use these methods, as well as HV time and QRS duration, as indices of the effect of drugs on sodium channel function in a series of animal preparations and in patients. The specific questions which we will address have arisen during both in vitro and patient studies. The in vitro studies focused on development and application of the Modulated Receptor Theory (MRT) of drug-ionic channel interactions. We will test several hypotheses based on the MRT: that certain drug combinations exert antagonistic effects on in vivo indices of sodium channel function, while others are synergistic; that MRT-based structure-activity relation studies can be used to identify agents with high potential for clinical utility; that alterations in the extracellular milieu (hyperkalemia, acidosis) affect drug action in a predictable fashion; that incorporation of the MRT into computer models of cardiac propagation results in faithful simulation of in vivo experimental data. The impetus for other studies we propose was the outcome of drug therapy in patients. Marked QRS widening by a new subclass of drugs (such as encainide and flecainide) has been associated with arrhythmia exacerbation. In preliminary studies, we have found that sodium salts reverse such QRS and HV increases in dogs; we will conduct studies to elucidate the mechanism and potential clinical applicability of this observation. We will also evaluate the possibility that drug metabolites may enhance or blunt the antiarrhythmic actions of parent drugs during chronic therapy. An actively collaborating group of basic and clinical scientists with overlapping interests have generated the preliminary data leading to this proposal and will continue to work together closely to address the questions posed in the proposal. This research will increase our understanding of the basic mechanisms of actions of antiarrhythmic drugs in the whole heart and has the potential to immediately improve care of patients with life-threatening arrhythmias.

Although beta-receptor antagonists have been proven effective in preventing sudden death and suppressing ventricular arrhythmias, both actions of these drugs are poorly understood. The possible contribution of non-beta-receptor-mediated electrophysiologic changes demonstrable in vitro is controversial. Our initial observation that a subset of patients required plasma propranolol concentrations for suppression of ventricular arrhythmias well in excess of those producing substantial beta-blockade led us to hypothesize that propranolol produced electrophysiologic effects in vivo independant of beta-blockade. Subsequent animal work provided support for this hypothesis since isoproterenol did not reverse all of propranolol's electrophysiologic effects. Comparison of the electrophysiologic effects of low and high plasma propranolol concentrations in patients indicated the presence of such a non-beta-receptor-mediated effect in man. In animal models and in human volunteers these electrophysiologic changes were produced by the d-isomer of propranolol and proven to be unrelated to its weak beta-blocking action. To further evaluate the possible role of non-beta-mediated actions of other beta-blockers, we assessed the dose-antiarrhythmic relationships of timolol and sotalol in patients with ventricular arrhythmias. Timolol, an agent whose effects are thought to be mediated exclusively by beta-blockade, was effective in only a minority of patients and incremental efficacy beyond that produced by beta-blockade was not demonstrable. On the other hand, a subset of patients with beta-blocker-resistant arrhythmias was found to respond to sotalol, a beta-blocker with the additional property of refractory period prolongation similar to the highly effective and frequently toxic agent, amiodarone. We will now extend our electrophysiologic observations to evaluate the antiarrhythmic efficacy of the d-isomers of propranolol and sotalol. Preliminary data indicate that d-propranolol can effectively suppress ventricular arrhythmias in man without producing clinically significant beta-blockade. Both d-propranolol and d-sotalol will be evaluated in this patient population as well as in patients with sustained ventricular tachycardia inducible by programmed stimulation. Racemic and d-sotalol (at concentrations producing equal suppression of isoproterenol-induced tachycardia) will be compared in a canine model of inducible sustained ventricular tachycardia. To assess the clinical significance of sotalol's non-beta-mediated refractory period prolongation, sotalol will be substituted for amiodarone in patients with life-threatening arrhythmias. The proposed studies will evaluate the importance of the non-beta-mediated effects of this class of drugs and so allow design of safer and better tolerated therapies for ventricular arrhythmias and sudden cardiac death.

Antiarrhythmic drugs are widely used in the management of rhythm disturbances as diverse as simple palpitations to recurrent ventricular fibrillation, the cause of the sudden cardiac death syndrome which kills half a million Americans per year. Response to this group of drugs is notoriously variable, with some patients experiencing clearcut benefit, while other, apparently similar individuals may develop new or worsening arrhythmias as a consequence of treatment. Moreover, response is often not static, but changes over time. The initial results of the Cardiac Arrhythmia Suppression Trial (CAST) highlight this problem: in CAST, drug therapy to suppress isolated ectopic beats after a myocardial infarction was associated with a 2-3-fold increase in mortality over the following year. This Program will test the central hypothesis that the effect of antiarrhythmic drugs is not static, but is determined by the changing intracellular and extracellular milieu in which drugs interact with target proteins in the heart. The effect of factors such as transmembrane potential, stimulation frequency, neurohormones, intracellular calcium and stretch on antiarrhythmic drug action will be studied by investigators with expertise in a wide range relevant fields, including ion channel physiology, the molecular biology of ion channels, control of intracellular calcium, modelling the biology of excitable tissues, and in assessment of drug action in vitro and in the intact heart. The central hypothesis will be tested in parallel studies in the intact heart, in myocytes, and in tissue culture lines and Xenopus oocytes expressing native or mutated mammalian (including human) ion channels. The programmatic approach will facilitate transfer of the results of hypothesis testing in one system to other systems. Moreover, because the Program brings together investigators with a wide range of skills, new strategies for the study of drug action and its modulation will be implemented. This Program will provide a basis for improved understanding of the acute and chronic modulation of ion channels and their block by drugs. In this way, more effective ways to use available agents and strategies for developing newer and safer compounds will be developed.

sodium channel; potassium channel; heart function; heart pharmacology; electrophysiology; messenger RNA; cardiotoxin; gene expression; antiarrhythmic agent; molecular cloning; genetic transcription; heart rate; northern blottings; laboratory mouse; laboratory rat; heart cell; genetically modified animals; tissue /cell culture;

The electrophysiologic behavior of the heart is highly heterogeneous. It has been, and continues to be, the goal of this Program to define mechanisms underlying this heterogeneity. In the last period of support, substantial progress has been made toward this goal. The present renewal application has been restructured to focus specifically on cardiac potassium channels, testing the overall working hypothesis that variability in expression or function of these channels is an important determinant of heterogenous repolarization both in health and in disease. The studies proposed will incorporate both conventional molecular and electrophysiologic techniques as well as new techniques in which Program investigators and collaborators have developed considerable expertise in the last period of support; these include generation of genetically-modified mice, in situ hybridization, the molecular genetics of cardiac ion channels, and spin labeling/EPR technology. In each Project, preliminary data that attest to feasibility are presented, and specific hypotheses relating to the mechanisms underlying heterogeneous function or expression of cardiac K plus channels are proposed for testing. The experimental models include wild-type and mutant channels in heterologous expression systems, the use of genetically-modified animals, and studies in human subjects. The focus of the central theme of cardiac potassium channels allows a high degree of scientific interchange among Projects; this includes the use of shared reagents, as well as the likelihood that results in one Project influence the scientific direction in others. Dysfunction of cardiac potassium channels is increasingly recognized to play a role in the genesis of cardiac arrhythmias. The studies proposed in this Program will help elucidate mechanisms underlying this dysfunction, and therefore point to novel approaches to therapy.

A number of lines of evidence strongly suggest that the disposition kinetics of digoxin are determined largely by the activity of the MDR1 gene product, the P-glycoprotein efflux pump. Recent studies in human subjects indicate that expression of MDR1 can vary 50-fold among individuals and in animal models is induced to a variable extent by exposure to environmental carcinoogens such as those contained in tobacco smoke. The overall objective of this study, therefore, is to determine the distrubition of P-glycoprotein-dependent efflux mechanisms in the disposition of digoxin in a population of human subjects (smokers and nonsmokers).

We will test the hypothesis that quinidine-induced changes in QT interval are blunted by elevation of serum potassium. Prolongation of cardiac repolarization, which is manifest on the surface electro- cardiogram as an increase in the QT interval, has been viewed as a desirable mode of antiarrhythnic drug action.

This Project will use genetically-modified mice to study the overall hypothesis that cardiac K plus channels are expressed in a cell-specific fashion, and that this expression has important functional consequences. Two K plus channel genes are proposed for study: minK and Kv1.5, whose expression is thought to result in Iks and Ikur respectively. Program investigators have generated a mouse in which the minK gene has been removed, and replaced by a reporter (lacZ) whose expression is therefore driven by minK regulatory elements. Preliminary studies in the knockout indicate that, unexpectedly, expression of minK is highly restricted in the adult mouse heart, to the conducting system. Specific Aim 1 of this Project will determine the functional consequences of deletion of the minK gene. These studies will test not only the hypothesis that minK expression is required to recapitulate native Iks, but also related hypotheses such as whether expression is similarly restricted in other animals, and whether the electrophysiologic effects of deleting minK extend to altered expression or function of other cardiac ion channels. In the second Specific Aim, DNA regulatory elements responsible for restricted expression of minK to the conducting system will be identified using transgenic approaches. In the third Specific Aim, the gene structure of Kv1.5 will be modified by adding a new pharmacologic signature and an epitope tag. Mice carrying the modified gene will then be generated to test the hypothesis that Kv1.5 expression is similarly regionally determined, and to evaluate the resultant functional consequences. These new approached to studying cellular localization and function of ion channels should provide important new information on the mechanisms underlying the heterogeneous electrophysiologic behavior of the heart, the overall goal of this Program.

Studies at our Center have indicated that subjects receiving a high salt diet had lower plasma concentrations of quinidine than they were receiving a low salt diet. We will assess systemic clearance, renal clearance and non renal clearance. P-glycoprotein mediated processes, nonrenal clearance and secretion clearance, will be modulated by dietary sodium. We were having recruitment problems and have had to adjust the protocol to make recruitment easier. It is anticipated that we will be able to continue without any problems.

DESCRIPTION (provided by applicant): We submit here a proposal for renewal of the Pharmacogenomics of Arrhythmia Therapy (PAT) node of the PGRN. The studies we propose combine candidate, genome-wide, and targeting resequencing approaches to identify the genomic basis for arrhythmia drug response phenotypes of major public health importance. In addition, each Specific Aim includes a major focus on multi-institutional accumulation of large numbers of patients with well-defined drug response phenotypes. Studies In Specific Aim 1 further define the genomic basis underlying susceptibility to drug-induced long QT-related arrhythmias, a continuing challenge In clinical drug use and In drug development. In Specific Aim 2, we build on previous work to prospectively assess the relationships among drug response, genotypes, and clinical endophenotypes in patients with atrial fibrillation (AF). While AF therapy often includes warfarin anticoagulation whose major complication is bleeding, pharmacogenomic studies of warfarin response to date have focused on determinants of dose. In Specific Aim 3, we will identify a large set of cases of major warfarin-related bleeding in BioVU, our DNA repository linked to de-identified electronic medical records, and undertake a case-control study of the genomic determinants of this complication. We include here two proposals for network resources: (1) PGPop (PharmacoGenomic discovery and replication in very large patient Populations) that brings together multiple healthcare system-based nodes, including BioVU, that each Include extensive drug response phenotypes and extant or planned large DNA collections. PGPop will serve as a "real-world" platform for pharmacogenomic discovery;one initial project will be generation of a replication set for warfarin-related bleeding. (2) P-STAR (PGRN Statistical Analysis Resource), that will provide statistical support to PGRN sites and develop advanced methods in the field. These studies build on progress within our own site, across PGRN, and reach out beyond the network to develop expanded populations and new tools to enable application of pharmacogenetic knowledge to clinical care.

DESCRIPTION (provided by applicant): Epidemiologic studies implicate family history as a distinct risk factor for sudden cardiac death, and multiple lines of evidence implicate SCN5A, encoding the cardiac sodium channel -subunit, as a candidate gene. These include in vitro experiments, molecular genetic studies, and large clinical trials (CAST) that converge on decreased sodium channel availability as a common cause for arrhythmias. The goal of this Project is to delineate new mechanisms determining this reduced channel availability. Preliminary studies have identified enhanced slow inactivation of the channel with oxidative or drug stress, cloned and undertaken initial characterization of the 5'-flanking region driving expression of SCN5A, and identified non-coding and coding region polymorphisms. The latter do not alter channel availability at baseline but do under oxidative or other stress conditions. Specific Aims 1 will identify structural domains in the channel underlying enhanced slow inactivation with oxidative stress, and Specific Aim 2 will delineate enhancer and repressor elements controlling SCN5A transcription; both aims will include studies of the functional effects of DNA polymorphisms. Specific Aim 3 will directly test the hypothesis that DNA variants are arrhythmogenic at baseline or with stress by studying the electrophysiologic properties of mice generated by recombination-mediated cassette exchange to carry a series of variant sodium channels. The identification of DNA variants that enhance arrhythmic risk will be an important step in stratification of risk for sudden death, while delineation of domains of the channel crucial for arrhythmogenic behavior will identify new targets for drug intervention. By advancing our understanding of this aspect of the biology of arrhythmia susceptibility, these studies mesh well with the overall theme of this Program.

[unreadable] DESCRIPTION (provided by applicant): The aim of studies supported by this grant has been the elucidation of mechanisms underlying variability in cardiac repolarization, and its role in arrhythmogenesis and arrhythmia suppression. A major conceptual advance during the last period of support has been the increasing recognition that normal and abnormal electrogenesis in heart and in other excitable tissues is driven not only by pore-forming ion channel proteins, but also requires the coordinated activity of multiple other proteins, subserving functions as diverse as gating modulation, post-translational modification, trafficking, and anchoring. IKs serves a key role in maintaining normal repolarization, particularly in the face of adrenergic stimulation, and its recapitulation requires coexpression of at least KvLQT1 and minK. Preliminary data we and others have generated strongly suggest the working hypothesis that 'Ks represents a macromolecular complex that includes multiple other proteins. The overall goal of the research proposed here is testing specific hypotheses to identify' such components and define their function. We identified fhl2 as a potential minK-interacting protein in a yeast 2-hybrid assay, and have developed further in vitro data supporting an fhl2-minK interaction in heart; in Specific Aim 1 we will extend this concept in vivo by defining the electrophysiologic phenotype of fhl2 null mice. Mistrafficking is an increasingly recognized mechanism underlying dysfunction of membrane proteins, including ion channels; in Specific Aim 2, we will use a combination of electrophysiology, confocal imaging, and assay of cell surface protein expression -methods that are all in hand - to identify KvLQT1 domains driving normal and abnormal channel trafficking. We have identified both the PP2A phosphatase subunit B56a and the cardiac A Kinase Anchoring Protein mAXAP as potential KvLQT1 protein partners in a yeast 2-hybrid assay; in Specific Aim 3, we will use biochemical and electrophysiologic approaches to determine interactions among channel subunits and regulatory mechanisms that specify response of 'Ks to adrenergic signaling. The results of these studies will elucidate mechanisms modulating 'Ks, further develop the tools necessary for studying how integrated multimolecular interactions modulate cardiomyocyte electrophysiology, and thereby promote the long-term goal of identifying new targets for safer, more effective antiarrhythmic intervention.

DESCRIPTION (provided by applicant): Cardiac arrhythmias extract a huge public health cost in morbidity and mortality, they are becoming more prevalent as the population ages, and available drug therapies are only partially effective and cause serious adverse effects, including proarrhythmia. The last decade has seen a quantum increase in our understanding of the molecular mechanisms underlying cardiac arrhythmias, due in large part to identification of the genes whose expression results in pore-forming ion channel subunits. However, as our understanding of arrhythmia mechanisms has advanced, it is becoming clear that electrical activity in the heart is driven not by ion channels alone, but by the complex biologic context in which these channels are expressed. Cloning of human and mouse genomes offers an new opportunity to determine the way in which this context - including components such transcription, protein-protein interactions, and post-translational modification by activation of intracellular signaling - can be disrupted to cause arrhythmias. In this Program, a highly interactive group of scientists propose 5 Projects to test a series of specific hypotheses relating arrhythmia susceptibility to dysfunction of myocyte biology. Themes that cross Projects include studies of decreased channel availability, channel interactions with known and new subunits, and altered channel function by activation of intracellular signaling. Scientific tasks common to multiple Projects will be supported in two Cores: a cellular and mouse surgical Core and a microarray Core. This Program, by applying a new, genomic/systems approach to arrhythmias, will improve available therapies through identification of new targets for risk stratification and for antiarrhythmic intervention.

[unreadable] DESCRIPTION (provided by applicant): Transporters are increasingly recognized as important processes in drug disposition. More recently, functional characterization of drug uptake transporters has revealed that a family of drug uptake transporters known as the Organic Anion Transporting Polypeptides (OATPs), are critical to the cellular uptake of drugs into organs such as the liver, intestine, and brain. Studies have revealed that certain human OATPs such as OATP-C and OATP-8 may be the key hepatic drug uptake transporters, while OATP-A expression at the level of the blood brain barrier may be responsible for the CNS entry of certain drugs. We are now able to show that OATP-A is expressed in the small intestines, and may be a key transporter responsible enhancing the gastrointestinal absorption of various drugs in clinical use. It is our hypothesis that intersubject variability in the expressed level and activity of OATP transporters affects drug disposition and responsiveness. However, the extent of our knowledge regarding human OATP transporters is limited. Studies carried out from this laboratory have identified a number of single nucleotide polymorphisms (SNPs) in OATP transporters importantly associated with drug disposition and response. Accordingly, in this application, studies on the role of genetic variability in certain human OATP transporters to transporter function, both in vitro and in vivo, are outlined. Specific Aim 1 is focused studies on the in vitro functional characterization of allelic variants newly identified by this laboratory in OATP-A, OATP-8 and OATP-C. In Specific Aim 2, to better understand the interplay between OATP-mediated drug uptake versus P-glycoprotein (MDR1) or MRP2 (cMOAT)-mediated drug efflux, studies are proposed on the creation of model cell lines expressing an OATP transporter along with P-glycoprotein or MRP2, in combinations reflective of organs such as the liver, intestine and brain. In Specific Aim 3, the role of commonly occurring SNPs in OATP-C, which studies from this laboratory had shown to be functionally significant in vitro, will be tested in human subjects using the well-known OATP-C-specific substrate, pravastatin, and a newly identified substrate, rifampin, as in vivo probes for this transporter. Moreover, variability in the extent of rifampin-mediated induction of the drug metabolizing enzyme, CYP3A, among subjects with variant OATP-C alleles, will also be tested. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): VGER: The Vanderbilt Genome-Electronic Record project An important potential enabling resource for Personalized Medicine is the combination of a DNA repository with Electronic Medical Record (EMR) systems sufficiently robust to provide excellence in clinical care and to serve as resources for analysis of disease susceptibility and therapeutic outcomes across patient populations. The Vanderbilt EMR is a state of the art clinical and research tool (that includes >1.4 million records), and is associated with a DNA repository which has been in development for over 3 years;these are the key components of VGER, the Vanderbilt Genome-Electronic Records project proposed here. The VGER model acquires DNA from discarded blood samples collected from routine patient care, and can link these to de-identified data extracted and readily updated from the EMR. The phenotype we will analyze here is the QRS duration on the electrocardiogram, since slow conduction (indicated by longer QRS duration) is a marker of arrhythmia susceptibility. This will not only exploit the power of Genome-Wide Association (GWA) approaches to generate new biologic knowledge that impacts an area of public health concern, but also provides a platform for the development of tools, such as Natural Language Processing approaches, to optimally mine EMRs. This project brings together a team of investigators with nationally recognized records of accomplishment in genome science, medical ethics, bioinformatics, de-identification science, and translational and cardiovascular medicine to address four Specific Aims: (1) perform a GWA comparing samples from subjects with QRS durations at the extremes of the normal range, and validate by genotyping high likelihood associations in prospectively ascertained clinical trial sets for QRS duration and for arrhythmia susceptibility;(2) evaluate the validity and utility of structured and unstructured components of EMR data for genome-phenome correlations;(3) assess the ethical, scientific, and societal advantages and disadvantages of the VGER model, and determine best practices for oversight, community involvement, and communication as the resource grows;and (4) develop and evaluate formal privacy protection models for data derived from databanks and EMRs, establishing data sharing and integration practices. We also include here a proposal to develop the Administrative Coordinating Center whose mission will be to facilitate communication and collaboration among nodes in this network, the NHGRI, and external advisors. We subscribe to a vision of Personalized Medicine in which genomic and other patient-specific information drives personalized, predictive, preemptive, and participatory health care, and VGER represents an important step in that direction.

[unreadable] DESCRIPTION (provided by applicant): The creation of high-dimensional resources, such as human and other genome sequences and their variants, is propelling new opportunities for basic, clinical, and translational science. Realization of the vision of Personalized Medicine - in which therapies are predictive, personalized, preventive, and participatory - would represent the successful implementation of these resources to improve human health. Vanderbilt University Medical Center (VUMC) has internationally-recognized strengths in areas of translational science, such as basic and clinical pharmacology and genetics, required to accomplish this vision and accordingly the current VUMC research strategic plan identifies Personalized Health and Healthcare as a priority area for investment in the upcoming decade. A key intermediate step to realizing the vision of Personalized Medicine is the conduct of studies associating genetic variants with a range of human phenotypes, from disease susceptibility to beneficial drug responses to common and rare adverse drug effects. Such studies require generation of large databases that include detailed human phenotypes associated with DNA samples. At VUMC, management of multi-user, expensive, and mission-critical functions such as DNA sample handling, is operated under a institutional Core Resource approach; the DNA Resource Core allows a wide community of users high quality storage and rapid access to appropriately formatted sample sets. The Core has handled 90,000 samples since its inception in 1997, including multiple large sample sets generated with current NIH support by major users of the proposed instrument. Moreover, the scale of DNA collections at VUMC is now changing very rapidly: in February 2007, we launched the Vanderbilt DNA databank and it is now accruing 900 samples/week. By May 2008 the collection will approach 50,000 samples, and by early 2011, it will contain 200,000 samples. The databank is unique in its design, scale, and flexibility, and will be an enabling resource for genotype-phenotype associations across the disciplines in the medical center. The project has been funded to date by an institutional commitment of $3.4 million. A critical need in successful use of such large DNA collections to propel translation between the bench and the bedside is a mechanism for sample handling that ensures both timely generation of sample sets for analysis as well as data and sample integrity. Accordingly, this proposal requests funding for the purchase of a compound Storage System, that includes modules and software for sample storage, arraying, delivery, decapping, and stacking. This represents an enabling instrument for the conduct of cutting edge translational science. PUBLIC HEALTH RELEVANCE: The sequencing of the human genome is enabling science to address the way in which variation in DNA sequence determines important human traits, such as disease susceptibility or variable response to drugs. An important step in this research is accumulation of extremely large collections of DNA samples to detect and validate relationships between genetic variants and human traits. Using these collections in research, however, is not possible unless robust systems to acquire, store, and deliver selected samples can be deployed. Accordingly, this proposal requests a high end instrument to accomplish these goals, and to thereby enable a new era of Personalized Medicine. [unreadable] [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): An important potential enabling resource for Personalized Medicine is the combination of a DNA repository with Electronic Medical Record (EMR) systems sufficiently robust to provide excellence in clinical care and to serve as resources for analysis of disease susceptibility and therapeutic outcomes across patient populations. The Vanderbilt EMR is a state of the art clinical and research tool (that includes >1.7 million records), and is associated with BioVU, a DNA repository which has been in development for over 3 years;these are the key components of VESPA, the Vanderbilt Electronic Systems for Pharmacogenomic Assessment project proposed here. The BioVU model acquires DNA from discarded blood samples collected from routine patient care, and can link these to de-identified data extracted and readily updated from the EMR. The VESPA project will include a robust EHR system that includes point of care decision support;an extensive pharmacogenetic database linking genotypes to drug response phenotypes;and high-throughput, reliable, and increasingly inexpensive genotyping capabilities that allow dense genomic information to populate an EHR. Establishing platforms and approaches such as the one we propose here is a necessary first step to a genomic future in which these data are routinely incorporated into personalized, predictive, and preemptive healthcare. A fundamental question for progress in this area is whether Electronic Health Record (EHR) systems that are designed to provide excellence in clinical care can also serve as reliable resources for analysis of drug response phenotypes representing a range of therapeutic outcomes across patient populations. Multiple factors conspire to make drawing scientific conclusions from EHR data more challenging than data collected specifically to answer research hypotheses: examples are that sicker subjects tend to be monitored more closely and to receive different medications than healthier ones, or that clinical events are misclassified due to time pressure on clinicians or incentives to maximize reimbursement. Accordingly, we propose in Specific Aim 1 to validate BioVU, the Vanderbilt repository linking DNA to a de- identified EHR image, as a tool for pharmacogenomic research. Formal models are needed to represent the relative contribution and reliability of the classes of information elements present in EHRs, and their effects on the certainty of inferring associations between genotypes and heterogeneously documented clinical phenotypes. Therefore, the goal of Specific Aim 2 is to model the relative contributions of clinical data and genomic data to clinical event prediction. RELEVANCE: The Vanderbilt Electronic Systems for Pharmacogenomic Assessment (VESPA) project will use de-identified data from electronic health records coupled with a large DNA repository as a resource for investigating the genetic component of individual response to medications. The project will investigate the relative contribution and reliability of the classes of information elements present in EHRs, and their effects on the certainty of inferring associations between genotypes and heterogeneously documented clinical phenotypes.

DESCRIPTION (provided by applicant): This is a request for the purchase of specialized instrumentation to expand acquisition of samples for BioVU, the Vanderbilt DNA databank, into the pediatric population. The challenges to improve child health surround us - regionally, nationally, and globally. Eleven million children die each year before 5 years of age, with 4 million of these deaths occurring within the first month of life. Long-term disabilities compromise the lives of countless others. Personalized Medicine, a mechanism to optimize human health based upon knowledge of an individual's genetic composition, environmental exposures, behaviors, and therapeutic options, holds unparalleled promise to prevent, anticipate, or intervene in, disease throughout the lifespan and promote the well-being of future generations. Vanderbilt University Medical Center (VUMC) has embraced the concept of Personalized Medicine, and will utilize its internationally recognized basic and clinical research expertise in genetics, bioinformatics, pharmacology, medicine, pediatrics, obstetrics, neurology and related clinical disciplines, to bring this dream into practice. VUMC has established an innovative platform to facilitate medical research, and the implementation of Personalized Medicine, BioVU. BioVU is a DNA biobank that is linked to the de-identified electronic medical record (EMR) of the individual from which the sample was obtained. The resource is currently accruing ~500 adult samples/week, and as of February 2009 contains more than 50,000 samples. By early 2011, the collection will exceed 100,000 samples. Information from the EMR has been systematically extracted and de- identified to form the Synthetic Derivative (SD) database. The SD incorporates health information from pregnancy, the perinatal period, infancy, childhood, and adulthood on patients cared for at VUMC, including those only seen at Vanderbilt Children's Hospital. The ability to acquire pediatric DNA samples linked to the SD will be essential to afford the same opportunities to improve outcomes in pediatric disorders as in those afflicting adults. Expansion of BioVU to incorporate pediatric biobanking requires a mechanism for small volume DNA extraction that ensures both timely generation of sample sets for analysis as well as sample integrity. Accordingly, this proposal requests funding for the purchase of a QIAsymphony SP, a compact integrated system that includes modules and software for DNA sample preparation and quantification. This represents an enabling instrument for the conduct of cutting edge translational science.

DESCRIPTION (provided by applicant): The Vanderbilt Genome-Electronic Records project was one of five sites in the first phase of the Electronic Medical Records and Genomics (eMERGE-l) network. The VGER team contributed importantly to progress in multiple areas across eMERGE-l, including developing and deploying algorithms for phenotypes at Vanderbilt and across the network; developing and managing the genotype quality control pipeline for the network; discovering new genotype-phenotype relations in Vanderbilt and cross-network datasets; actively participating in the community consultation and return of results initiatives; developing methods to resolve tensions between data access and individual privacy; and developing new software tools for the field, including for de-identification and for the phenome-wide association study paradigm (PheWAS). Vanderbilt has identified Personalized Healthcare as a key strategic priority for investment in basic discovery, translation, and implementation across the institution; resources developed at Vanderbilt (directed by VGER team members) include StarChart, an electronic medical record (EMR) system with comprehensive patient-specific clinical decision support functionality that includes data on >1.7 million patients; BioVU, the DNA repository that links >100,000 DNA samples to a de-identified image of the EMR; and the PREDICT project which has created a framework for evaluating genotype-phenotype relations and is depositing clinically actionable genotypes into the EMR. BioVU currently includes 5,186 samples with GWAS data, projected to >16,500 by fall 2011. The present proposal to participate as a site in eMERGE-ll builds on this record of accomplishment and on institutional investments. We propose 4 specific aims that will be accomplished by collaborations among scientists with expertise in diverse disciplines (clinical medicine, basic science, genomics, statistics, informatics, privacy science, and ethics) at our site and across the network: (1) to accelerate development and validation of algorithms for phenotype extraction from EMRs. (2) To exploit the results of GWAS in BioVU and other datasets to identify combinations of genotypes highly predictive of disease or drug response outcomes. (3) To engage patients as we implement prospective clinical genotyping in PREDICT. (4) To develop new tools to maximize our ability to effectively share genomic information and ensure patient confidentiality. We subscribe to a vision of Personalized Medicine in which genomic and other patient-specific information drives healthcare, and VGER and eMERGE-ll represent important steps in that direction. RELEVANCE: Descriptions of how genetic variation determines variability in clinically important conditions like disease susceptibility or drug responses represent the first fruits of the Human Genome Project. A challenge - that this proposal addresses - is how to analyze and use this torrent of information to improve human health. Our proposal to join the eMERGE-ll network addresses this challenge by identifying genetic variants important for human health and beginning to use these in a systems approach to personalized healthcare that is robust and scalable in the face of the escalating volume and complexity of clinically relevant data.

DESCRIPTION (provided by applicant): The creation of high-dimensional resources to facilitate proteomics and genomics research propels basic, clinical and translational sciences forward in the effort to realize the vision of Personalized Medicine. Vanderbilt University Medical has internationally-recognized strengths in translational sciences and has identified the advancement of Personalized Medicine as an effort of highest priority and as an institutional platform for excellence across clinical and basic science departments. A key step in the realization of Personalized Medicine is the facilitation of studies to associate biomarkers with disease risk or progression and response to drug therapy. These studies require generation of large databases with detailed human phenotype information linked to plasma samples. BioVU, Vanderbilt's large-scale biorepository, contains detailed de-identified human phenotype information linked to de-identified DNA samples and genotypes. BioVU is expanding the biorepository to collect plasma samples and link them to de- identified clinical information. The plasma bank will have broad utility among a diverse set of scientific investigators. The greatest value will be for the screening of candidate biomarkers associated with disease risk or response to drug therapy, including efficacy, adverse reactions and toxicity. The availability of plasma samples linked to de-identified clinical records will enable the development of more sophisticated designs to evaluate real world utility of biomarkers and also support an increasing number of biomarker development studies. To meet this goal, specialized instrumentation for sample storage and retrieval is necessary to handle the thousands of resultant plasma samples. To preserve the integrity of the plasma samples and prevent degradation, an automated freezer is required to process samples at -20oC, and store the samples at - 80oC, thereby preventing repeated freeze-thaw cycles that can diminish sample quality. This automated instrument will be an enabling device to further cutting edge translational science research toward the goal of Personalized Medicine.

DESCRIPTION (provided by applicant): Opening of the primary cardiac sodium channel, encoded by SCN5A, is responsible for rapid myocyte depolarization that initiates the cardiac cycle and underlies fast conduction in the heart. Mutations in the gene have been associated with a range of phenotypes, including long QT syndrome, Brugada syndrome, conduction disease, dilated cardiomyopathy (DCM) and atrial fibrillation. Out of hundreds of mutations linked to these disease states, only a handful have been clearly associated with DCM and heart failure and the underlying mechanisms are not understood. This proposal builds on our work establishing murine models of sodium channel-related disease to test the overall hypothesis that SCN5A mutations initiate the DCM phenotype through mechanisms directly related to electrophysiologic dysfunction; notably, this distinguishes SCN5A-related DCM from other forms of the disease. In mice with D1275N, a mutation associated with human DCM, our major findings are decreased peak sodium current, near normal gating, striking conduction delay by ECG and optical mapping, decreased abundance of the channel protein especially along the lateral myocyte border, and age-dependent development of DCM. By contrast, other mouse lines with equivalent or greater decreases in peak sodium current do not display conduction abnormalities or DCM. Accordingly, in Specific Aim 1, we will test multiple competing hypotheses to explain this apparent paradox: specific experiments will address the roles of intracellular ionic homeostasis versus abnormalities in conduction, and their underlying mechanisms, as generators of the DCM phenotype. Unlike D1275N, the DCM-associated R222Q mutation displays striking gating changes in vitro and patients display very frequent drug-sensitive ventricular ectopic activity and develop DCM. In Specific Aim 2, we will contrast mechanisms whereby R222Q and D1275N cause DCM and test the hypothesis that suppression of ectopic activity improves or reverses the DCM phenotype. Heart failure affects more that 4 million people in the United States and studies to identify molecular subsets represent an important step to tailoring mechanism-based therapy.

Analytical and Administrative Support Core The Analytical and Administrative Support Core will provide to the Center and all Projects administrative management, data management, and analysis support in order to facilitate progress toward achieving the Center's short and long term goals. The management plan includes a four member Internal Advisory Board (IAB) that has been assembled to advise Center leadership as needed in difficult program issues and for conflict resolution. In addition, a five member External Advisory Board will meet annually with investigators and the IAB for a day and a half site visit every 1-2 years to assess progress and scientific opportunities and to make recommendations. Data management and analysis capabilities to be supported here include advanced capabilities in statistics and statistical genetics and analysis of high-dimensional datasets to identity networks and pathways modulating drug response. The Core's management plan is designed to facilitate interactions between investigators and projects and to determine priorities consistent with Center aims and goals, including managing, evaluating, and sharing large diverse data sets generated by the Center.

Age; base; care providers; Clinical; clinical care; Clinical Data; clinical decision support; Collection; Complex; Computerized Medical Record; design; Electronic Health Record; England; Environment; Evaluation; Family; Family health status; flexibility; Future; genetic risk assessment; Genome; Genomic medicine; Genomics; Goals; Health; health care delivery; health organization; Health system; Healthcare Systems; implementation research; implementation science; improved; Individual; Informatics; informatics infrastructure; innovation; International; Intervention; Interview; Measures; Medical; method development; Methods; new technology; Outcome; Patients; Primary Health Care; prospective; Protocols documentation; Provider; Recording of previous events; Records; Regulation; Research Infrastructure; Research Methodology; Risk; Risk Assessment; screening; Security; sharing data; simulation; Site; Specialist; Standardization; Structure; System; tailored health care; Technology; Test Result; Testing; tool; Vertebral column;

? DESCRIPTION (provided by applicant): Improving prediction of drug action Drugs are variably effective and cause adverse drug reactions (ADRs). ADRs extract major costs at individual and societal levels, leading to medication non-compliance, inefficacy, toxicity, hospitalization, and death. They can be on-target or off-target, they occur across the spectrum of therapies, and they have an important, and increasing, impact not only on the way in which drugs are used in individual subjects and across healthcare systems but on the way in which new candidate molecules are developed. This Center of Excellence has as its major goal the elucidation of new mechanisms underlying variability in drug action and ADRs. We bring to this effort a unique collection of new tools and resources that enable us to confidently predict rapid development of entirely new classes of knowledge that will be a paradigm-shift from current norms of slow, incremental progress. Project 1 focuses on QT interval prolongation by drugs, a major cause for drug relabeling and withdrawals over the last two decades. Conventional wisdom has focused on the drug block of the HERG channel as the major mechanism, but we present compelling data that other pathways play a critical role. We will integrate the results of our previous genomic, molecular, cellular, and clinical studies in the field, exciting new data on the role of P3 kinase in this ADR, and the capability of generating cardiomyocytes from individuals whose drug response phenotypes we have established to develop new paradigms to identity risk in new drug candidates and across patient populations. Project 2 focuses on immunologically-mediated ADRs, and uses a unique resource of cells and DNA from patients with drug hypersensitivity or drug tolerance in the face of a specific HLA risk allele to define associations between HLA alleles, specific T-cell receptor usage and severe T-cell mediated drug hypersensitivity. Our goal is to test a new heterologous immunity model of drug hypersensitivity to explain this phenotypic variability and inform the development of new predictive models. Project 3 applies the new technology of phenome-wide scanning that we have pioneered to a large cohort of subjects with genomic and longitudinal electronic medical record data to broadly repurpose drugs for new indications and refine prediction of long QT-related, HLA-related, and other ADRs. The results of work in the Center will thus advance our long term goal of improving the outcome of drug therapy by reducing the burden of ADRs, improving prediction in an individual subject, repurposing available drugs, and providing new tools to the drug development process to reduce ADR risk.

A new paradigm for identifying patients and drugs at risk for QT prolongation The drug-induced long QT syndrome (diLQTS) continues to be a problem for clinicians balancing risk and benefits across multiple therapeutic areas, and for pharmaceutical scientists and regulators evaluating new drug candidates. The prevalent view is that block of a specific ion current, the rapid component of the cardiac delayed rectifier (IKr), encoded by KCNH2 (also known as HERG), is the common mechanism predisposing to diLQTS across drug classes and that patients with mutations in ion channel genes are at especially increased risk. We present here a body of clinical, genomic, and cellular studies that call these assumptions into question. For example, one important and unexplained clinical feature of diLQTS is that not all IKr blocking drugs confer the same risk; the risk with antiarrhythmics such as sotalol or dofetilide can be 1- 3%, while the risk with IKr-blocking antibiotics such as moxifloxacin is much lower, <1/20,000. Moreover, some drugs, notably phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitors developed for cancer, prolong QT interval but do not block IKr. We and others have recently shown that prolonged (hours) exposure of cardiomyocytes to high risk drugs such as dofetilide generates striking prolongation of action potentials (the in vitro correlate of the QT interval) and arrhythmogenic afterdepolarizations. Importantly, this effect is IKr- independent, does not occur with low risk drugs, and is rapidly and completely reversed by intracellular perfusion with PIP3, implicating inhibition of PI3K as a critical and heretofore unrecognized mechanism contributing to diLQTS risk across drugs. Further, analyses of large international cohorts (whose collection we have led) show that variants in ion channel genes contribute only modestly to risk. Thus a fundamental issue that this Project will address is the extent to which diLQTS risk is predictable in an individual patient. In Specific Aim 1, we will generate cardiomyocytes from induced pluripotent stem cells obtained from patients with a history of diLQTS and from a large cohort of drug-tolerant controls we have ascertained. We will then compare genomic, electrophysiologic, and transcriptomic profiles at baseline (Specific Aim 2) and after drug challenge (Specific Aim 3; PI3K inhibitors; IKr blockers) in cardiomyocytes from subjects with diLQTS and from drug-tolerant controls. The results of these experiments will not only inform the drug development process but will also lead to new methods to screen individual subjects for diLQTS risk.

The concept of Precision Medicine builds on the age-old understanding that humans vary in their disease susceptibility, presentation, progression, and therapeutic response. Modern large data analytics reveal that most of us have ?average? susceptibility for most diseases, but each of us has high risk for a few. This finding provides the opportunity and challenge ? addressed by this eMERGE Genomic Risk Assessment and Management (eMERGEgram) initiative ? to identify people at high risk for common diseases to promote prevention or early treatment. We propose here a program that builds on over a decade of growth and knowledge in key enabling disciplines including informatics, genomics, bioethics, participant and community engagement, and clinical medicine, and of experience as productive participants in eMERGE since the network's inception. In Specific Aim 1, we will develop and validate Genomic Risk Assessment tools to identify people at high risk for common diseases. The Genomic Risk Assessments will incorporate polygenic risk scores, family health history, and clinical disease predictors. We propose that the eMERGEgram Steering Committee select diseases that are heritable; display variable impact across ancestries; are associated with available early detection, prevention or treatment interventions; and in which large multi-ancestry genome wide association studies are available to develop polygenic risk scores. Using these criteria, we present data that support a focus on coronary artery disease, chronic kidney disease, type 2 diabetes, uterine fibroids, and colorectal cancer. In Specific Aim 2, we will build on experience in eMERGE-3, All of Us, and our NIH-supported Recruitment Innovation Center to execute a program that will engage, recruit, and retain 2,500 subjects (>35% from populations under-represented in biomedical research), including family dyads or trios. We will compute Genomic Risk Assessments for network- selected target conditions; return results to participants, their healthcare providers, and their electronic health records; and track healthcare outcomes including disease detection or healthcare utilization and deliver these to the Coordinating Center. In Specific Aim 3, we will use the eMERGEgram experience to improve our ability to deliver Genomic Risk Assessment. We will assess the uptake and impact of Genomic Risk Assessments and the extent to which the components of the Genomic Risk Assessment provide independent information across populations and within subgroups. We will use a shared DNA segment map across >100,000 records in our biobank to develop the concept of a genetically-informed family history, a tool that can inform health risk in the absence of a large pedigree, as is the case for small or adoptive families. Additional research goals will be driven by participants, developed through community engagement by focus groups in Years 1-2 and highly intentional participant interaction throughout the project.

As clinical genetic testing is becoming widely deployed for patients with suspected Mendelian diseases as well as in the broad population, a major emerging challenge is the accurate prediction of pathogenicity of DNA variants. Multiple features, including allele frequencies across populations, family history, and functional studies, are currently being used to assign known or new variants to three broad categories: benign, pathogenic, or (most commonly) variant of uncertain significance (VUS). We propose here to test the hypothesis that deploying novel phenotyping methods will improve variant classification, and we will focus here on SCN5A, encoding the cardiac sodium channel. Despite the fact that this channel plays a critical role in normal heart function, SCN5A variants are surprisingly common and have been associated with serious and occasionally life-threatening phenotypes including type 1 Brugada Syndrome (BrS1), type 3 Long QT Syndrome (LQT3), conduction system disease, heart failure, and atrial fibrillation. In aim 1, we will determine the utility of phenotyping in the electronic health record (EHR) coupled to functional studies to assess SCN5A VUS pathogenicity. The Electronic Medical Records and Genomics (eMERGE) network in which we are participants is completing sequencing of 109 Mendelian disease genes, including SCN5A, in 25,000 subjects with EHRs. We will assess VUS pathogenicity by analyzing SCN5A-related EHR phenotypes in subjects with and without SCN5A rare variants and establishing in vitro function for newly-detected variants using multiplexed semi-automated electrophysiologic methods. In aim 2, we will build on preliminary data using deep mutational scanning (DMS) ? a high-throughput method to mutagenize each nucleotide in a target genomic sequence and establish its functional consequences ? to identify SCN5A coding variants with BrS1 or LQT3 features. In a pilot experiment, we developed a drug challenge that biases survival toward cells that do not express sodium current at their surface (the BrS phenotype) and against cells that display enhanced sustained sodium current (LQT3). We then generated all 252 possible non-synonymous or nonsense single amino acid (aa) variants across a 12aa regon of SCN5A, exposed a pool of cells transfected with one mutant/cell to the drug challenge, used next-generation sequencing pre- and post-drug challenge to identify variants with BrS1 and LQT3 features, and validated predictions with conventional patch clamp methods. We will now scale up to scan larger regions, starting with the 253 aa encoding transmembrane domain IV, known to harbor dozens of pathogenic variants. Further, we will map DMS results onto a model of the channel to probe the structural basis of loss and gain of function variants. We will incorporate DMS data into available and new statistical models to build an improved model of SCN5A variant disease risk. The result of this work will be new approaches to establish functional consequences of rare variants in SCN5A (and ultimately other genes), and thus enable genomic medicine.

PLEDGE Abstract The Precision Medicine Initiative?s (PMI?s) overarching goal is to transform our understanding of the factors that contribute to health and disease, and ultimately, to leverage this understanding to information how we prevent and treat disease. This bold objective will be operationalized in the creation of a longitudinal cohort of 1 million individuals. The PMI?s coordinating center (CC) (called Partnership in Learning around Engagement, Data, Genomics, and Environment, or ?PLEDGE?) operationalizes this vision, serving as a hub for the PMI Network leading the optimization of participant engagement strategies, robust data infrastructure, facilitative support of researchers, coordination and communication between the diverse stakeholders of the Network, and responsibility for enrollment of the Cohort?s direct volunteers. PLEDGE?s goals are illustrated by four proposed specific aims: 1) Support the network and its Steering Committee to establish, implement, monitor and reach its programmatic goals. Serve as a visible national home for the PMI, representing its mission and value to participants and to health; provide a ?one stop shop? storefront for all needs, inquiries, and provision of data access for high caliber research; 2) Enroll a diverse group of highly engaged direct volunteers without sacrificing inclusiveness for quantity; 3) Harmonize technical practices among Healthcare Provider Organizations including data standards, elements, and models, while nurturing innovation from network sites when conformity is not beneficial. Apply stringent privacy and security safeguards; and finally, 4) Generate support for PMI beyond the network?s personnel to continuously incorporate new knowledge and tools, by deploying innovative contests, crowd sourcing, and matchmaking services.

PROJECT SUMMARY This application seeks to renew the Vanderbilt Genomic Medicine (VGM) training program at Vanderbilt University Medical Center (VUMC). VGM fellows are trained in data science, bioinformatics, laboratory science, and genomic discovery; the program also instructs fellows on the practice of genomic medicine. VGM builds on decades-long strengths in critical enabling resources and infrastructure within VUMC including: 1) BioVU, the largest biobank linking DNA samples to electronic medical records (EMRs) at a single academic institution (now >244,000 subjects), 2) Participation in three NHGRI-funded networks: the Electronic Medical Records and Genomics (eMERGE) network and eMERGE coordinating center, the Implementing Genomics in Practice (IGNITE) Network, and the Undiagnosed Disease Network (UDN), 3) The Pharmacogenomic Resource for Enhanced Decisions In Care and Treatment (PREDICT) project which embeds pharmacogenomic testing within electronic health records (EHRs) to guide drug and dosage choices 4) a Precision Oncology program that applies tumor genome sequencing to identify actionable mutations in cancers and to personalized target therapy, and 6) the largest Department of Biomedical Informatics in the country, with strong research, education, and support programs in clinical information technology. The program has 35 highly collaborative and well-funded faculty preceptors who team up to provide both basic and clinical research opportunities to Ph.D.-level and M.D.-level postdoctoral fellows. Trainees will participate in rotations, seminars, journal clubs, and retreats and interact with other clinical and research fellows and faculty. Under Vanderbilt?s Biomedical Research Education and Training (BRET) Office, the program will provide Responsible Conduct in Research (RCR) training, high-standard Individual Development Plans (IDP), and Career Development programs with the goal of developing fellows to be next-generation leaders in genomic medicine. A Scientific Advisory Committee and an External Advisory Committee provide valuable advice on VGM program development and enhancement. The program actively seeks candidates from diverse populations and professional and research backgrounds. Our fundamental model is to enhance multidisciplinary training through a curriculum tailored for each trainee based on prior experience, coupled to paired mentoring to provide both clinical and methodological expertise.