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1.  Electronic Health Record Design and Implementation for Pharmacogenomics: a Local Perspective 
Purpose
The design of electronic health records (EHR) to translate genomic medicine into clinical care is crucial to successful introduction of new genomic services, yet there are few published guides to implementation.
Methods
The design, implemented features, and evolution of a locally developed EHR that supports a large pharmacogenomics program at a tertiary care academic medical center was tracked over a 4-year development period.
Results
Developers and program staff created EHR mechanisms for ordering a pharmacogenomics panel in advance of clinical need (preemptive genotyping) and in response to a specific drug indication. Genetic data from panel-based genotyping were sequestered from the EHR until drug-gene interactions (DGIs) met evidentiary standards and deemed clinically actionable. A service to translate genotype to predicted drug response phenotype populated a summary of DGIs, triggered inpatient and outpatient clinical decision support, updated laboratory records, and created gene results within online personal health records.
Conclusion
The design of a locally developed EHR supporting pharmacogenomics has generalizable utility. The challenge of representing genomic data in a comprehensible and clinically actionable format is discussed along with reflection on the scalability of the model to larger sets of genomic data.
doi:10.1038/gim.2013.109
PMCID: PMC3925979  PMID: 24009000
2.  Systematic comparison of phenome-wide association study of electronic medical record data and genome-wide association study data 
Nature biotechnology  2013;31(12):1102-1110.
Candidate gene and genome-wide association studies (GWAS) have identified genetic variants that modulate risk for human disease; many of these associations require further study to replicate the results. Here we report the first large-scale application of the phenome-wide association study (PheWAS) paradigm within electronic medical records (EMRs), an unbiased approach to replication and discovery that interrogates relationships between targeted genotypes and multiple phenotypes. We scanned for associations between 3,144 single-nucleotide polymorphisms (previously implicated by GWAS as mediators of human traits) and 1,358 EMR-derived phenotypes in 13,835 individuals of European ancestry. This PheWAS replicated 66% (51/77) of sufficiently powered prior GWAS associations and revealed 63 potentially pleiotropic associations with P < 4.6 × 10−6 (false discovery rate < 0.1); the strongest of these novel associations were replicated in an independent cohort (n = 7,406). These findings validate PheWAS as a tool to allow unbiased interrogation across multiple phenotypes in EMR-based cohorts and to enhance analysis of the genomic basis of human disease.
doi:10.1038/nbt.2749
PMCID: PMC3969265  PMID: 24270849
3.  Stakeholder engagement: a key component of integrating genomic information into electronic health records 
Integrating genomic information into clinical care and the electronic health record can facilitate personalized medicine through genetically guided clinical decision support. Stakeholder involvement is critical to the success of these implementation efforts. Prior work on implementation of clinical information systems provides broad guidance to inform effective engagement strategies. We add to this evidence-based recommendations that are specific to issues at the intersection of genomics and the electronic health record. We describe stakeholder engagement strategies employed by the Electronic Medical Records and Genomics Network, a national consortium of US research institutions funded by the National Human Genome Research Institute to develop, disseminate, and apply approaches that combine genomic and electronic health record data. Through select examples drawn from sites of the Electronic Medical Records and Genomics Network, we illustrate a continuum of engagement strategies to inform genomic integration into commercial and homegrown electronic health records across a range of health-care settings. We frame engagement as activities to consult, involve, and partner with key stakeholder groups throughout specific phases of health information technology implementation. Our aim is to provide insights into engagement strategies to guide genomic integration based on our unique network experiences and lessons learned within the broader context of implementation research in biomedical informatics. On the basis of our collective experience, we describe key stakeholder practices, challenges, and considerations for successful genomic integration to support personalized medicine.
doi:10.1038/gim.2013.127
PMCID: PMC3909653  PMID: 24030437
electronic health records; genomics; health information technology; personalized medicine; stakeholder engagement; translational medical research
4.  Targeting glutamate synapses in schizophrenia 
Trends in molecular medicine  2011;17(12):689-698.
Although early clinical observations implicated dopamine dysfunction in the neuropathology of schizophrenia, accumulating evidence suggests that multiple neurotransmitter pathways are dysregulated. The psychotomimetic actions of NMDA receptor antagonists point to an imbalance of glutamatergic signaling. Encouragingly, numerous preclinical and clinical studies have elucidated several potential targets for increasing NMDA receptor function and equilibrating glutamatergic tone, including the metabotropic glutamate receptors 2, 3 and 5, the muscarinic acetylcholine receptors M1 and M4, and the glycine transporter GlyT1. Highly specific allosteric and orthosteric ligands have been developed that modify the activity of these novel target proteins, and in this review we summarize both the glutamatergic mechanisms and the novel compounds that are increasing promise for a multifaceted pharmacological approach to treat schizophrenia.
doi:10.1016/j.molmed.2011.08.004
PMCID: PMC3225651  PMID: 21955406
5.  Discovery, Synthesis, SAR Development of a Series of N-4-(2,5-dioxopyrrolidin-1-yl)-phenylpicolinamides (VU0400195, ML182): Characterization of a Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 (mGlu4) with Oral Efficacy in an anti-Parkinsonian Animal Model 
Journal of medicinal chemistry  2011;54(21):7639-7647.
There is an increasing amount of literature data showing the positive effects on preclinical anti-Parkinsonian rodent models with selective positive allosteric modulators of metabotropic glutamate receptor 4 (mGlu4).1 However, most of the data generated utilize compounds that have not been optimized for drug-like properties and, as a consequence, they exhibit poor pharmacokinetic properties and thus do not cross the blood-brain barrier. Herein, we report on a series of N-4-(2,5-dioxopyrrolidin-1-yl)-phenylpicolinamides with improved PK properties with excellent potency and selectivity as well as improved brain exposure in rodents. Finally, ML182 was shown to be orally active in the haloperidol induced catalepsy model, a well-established anti-Parkinsonian model.
doi:10.1021/jm200956q
PMCID: PMC3226828  PMID: 21966889
metabotropic glutamate receptors; mGlu4; positive allosteric modulators; Parkinson’s disease; haloperidol-induced catalepsy; structure-activity relationship (SAR); oral efficacy; brain penetration
6.  Discovery, Synthesis, and Structure Activity Relationship Development of a Series of N-(4-acetamido)phenylpicolinamides as Positive Allosteric Modulators of Metabotropic Glutamate Receptor 4 (mGlu4) with CNS Exposure in Rats 
Journal of medicinal chemistry  2011;54(4):1106-1110.
Herein we report the discovery, synthesis and evaluation of a series of N-(4-acetamido)-phenylpicolinamides as positive allosteric modulators of mGlu4.a Compounds from the series show submicromolar potency at both human and rat mGlu4. In addition, pharmacokinetic studies utilizing subcutaneous dosing demonstrated good brain exposure in rats.
doi:10.1021/jm101271s
PMCID: PMC3166797  PMID: 21247167
7.  Y95 and E444 Interaction Required for High-Affinity S-Citalopram Binding in the Human Serotonin Transporter 
ACS Chemical Neuroscience  2010;2(2):75-81.
The human serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT) is responsible for the reuptake of 5-HT following synaptic release, as well as for import of the biogenic amine into several non-5-HT synthesizing cells including platelets. The antidepressant citalopram blocks SERT and thereby inhibits the transport of 5-HT. To identify key residues establishing high-affinity citalopram binding, we have built a comparative model of hSERT and Drosophila melanogaster SERT (dSERT) based on the Aquifex aeolicus leucine transporter (LeuTAa) crystal structure. In this study, citalopram has been docked into the homology model of hSERT and dSERT using RosettaLigand. Our models reproduce the differential binding affinities for the R- and S-isomers of citalopram in hSERT and the impact of several hSERT mutants. Species-selective binding affinities for hSERT and dSERT also can be reproduced. Interestingly, the model predicts a hydrogen bond between E444 in transmembrane domain 8 (TM8) and Y95 in TM1 that places Y95 in a downward position, thereby removing Y95 from a direct interaction with S-citalopram. Mutation of E444D results in a 10-fold reduced binding affinity for S-citalopram, supporting the hypothesis that Y95 and E444 form a stabilizing interaction in the S-citalopram/hSERT complex.
doi:10.1021/cn100066p
PMCID: PMC3369724  PMID: 22778858
S-citalopram; hSERT; ligand; homology model; computational docking
8.  Structural determinants of species-selective substrate recognition in human and Drosophila serotonin transporters revealed through computational docking studies 
Proteins  2009;74(3):630-642.
To identify potential determinants of substrate selectivity in serotonin (5-HT) transporters (SERT), models of human and Drosophila serotonin transporters (hSERT, dSERT) were built based on the leucine transporter (LeuTAa) structure reported by Yamashita et al. (Nature 2005;437:215–223), PBDID 2A65. Although the overall amino acid identity between SERTs and the LeuTAa is only 17%, it increases to above 50% in the first shell of the putative 5-HT binding site, allowing de novo computational docking of tryptamine derivatives in atomic detail. Comparison of hSERT and dSERT complexed with substrates pinpoints likely structural determinants for substrate binding. Forgoing the use of experimental transport and binding data of tryptamine derivatives for construction of these models enables us to cHitically assess and validate their predictive power: A single 5-HT binding mode was identified that retains the amine placement observed in the LeuTAa structure, matches site-directed mutagenesis and substituted cysteine accessibility method (SCAM) data, complies with support vector machine derived relations activity relations, and predicts computational binding energies for 5-HT analogs with a significant correlation coefficient (R = 0.72). This binding mode places 5-HT deep in the binding pocket of the SERT with the 5-position near residue hSERT A169/dSERT D164 in transmembrane helix 3, the indole nitrogen next to residue Y176/Y171, and the ethylamine tail under residues F335/F327 and S336/S328 within 4 Å of residue D98. Our studies identify a number of potential contacts whose contribution to substrate binding and transport was previously unsuspected.
doi:10.1002/prot.22178
PMCID: PMC2782712  PMID: 18704946
sodium and chloride-dependent neurotransmitter transporters; support vector machine substitution sensitivity map; comparative modeling; ROSETTALIGAND; leucine transporter

Results 1-8 (8)