Monday, May 28, 2018

Curators' Favorite Papers

A critical component of pharmacogenetic/pharmacogenomics (PGx) implementation into clinical care is the integration of PGx data in clinical decision support (CDS) and electronic health records (EHRs). A new article in the journal Human Molecular Genetics (Genomics and electronic health record systems) discusses the benefits of, and current challenges to, the integration of genomics and PGx data, into EHRs. In particular, the article discusses how PGx data in EHRs relates to questions of standards and evidence generation, and how data should be represented so as not to be overwhelming for clinicians. The article adeptly outlines specific components of CDS pertaining to whole genome sequencing (WGS) (e.g. ordering and interpreting a test, importing data, trigger alerts and warning in EHRs, and evaluating outcomes) and describes existing tools, such as application programming interfaces (APIs), that link knowledgebases (including PharmGKB) to EHRs to assist with CDS.  The authors conclude that with continued developments in technology, and ambitious research programs with large, diverse cohorts, such as the NIH-sponsored All of Us program, the “goals of generating new knowledge and clinically relevant discoveries using population-based genomics data can someday be achieved by using EHRs”.

A patient’s diagnosis and medical treatment is frequently guided by where that patient’s laboratory values fall along a range of established “normal” values. A new “Viewpoint” (In the Era of Precision Medicine and Big Data, Who Is Normal?) in the Journal of the American Medical Association (JAMA) raises an important question in the context of laboratory values and precision medicine: if medicine is personalized, to what do we compare an individual’s laboratory values if “normal” is actually relative? The authors consider solutions to ensure that test results “be interpreted in reference to a population of ‘similar’, ‘healthy’ individuals”. For example, the authors propose 1) that longitudinal data on individual outcomes be accessible to researchers to determine whether selected reference values are truly useful 2) that large-scale analyses be carried out across data sets 3) that reference values be tailored to patients and delivered at point of care, and 3) that “computationally derived genetic ancestry” be linked to laboratory test values, so that race is not used as a proxy.

Tuesday, May 22, 2018

New PharmVar Downloads

PharmVar is delighted to announce a new feature that just went live!  Variants of genes in the PharmVar database can now be downloaded in sequence (FASTA and VCF) and table (TSV) formats. Options include to the download variants of interest, all variants of a gene or the entire PharmVar database. 

Check out the link “Additional Data Download Information” on the gene page for more information.

There are currently three genes in the database, CYPs 2C9, 2C19 and 2D6 – additional genes will be transitioned soon.

The PharmVar Team

Friday, May 4, 2018

Dr. Francis Collins discusses All of Us on CBS This Morning


The National Institutes of Health (NIH) director Dr. Francis Collins appeared on CBS This Morning to promote the All of Us program, a part of the Precision Medicine Initiative, which launches this Sunday, May 6th. 

When asked about what it hopes to accomplish, he explained:

“Do you ever feel when somebody is making recommendations to you about how to stay healthy or when you need a prescription and you’re wondering 'is this the right drug for me at the right dose?' A lot of what we do in medicine is one-size-fits-all. Precision medicine is this opportunity to make things much more individualized and more precise and more likely to result in a good outcome, but to get to that point we need to collect a lot of data on a lot of people…”

All of Us hopes to recruit 1 million Americans, and is particularly interested in recruiting subjects from communities that are typically underrepresented in biomedical research. Dr. Collins addressed questions about privacy concerns by explaining that all data will be de-identified, researchers pledged to not re-identify subjects and that data will be protected from use by law enforcement as a result of new legislation. 

You can find more information about pharmacogenomics (PGx) such as PGx-guided dosing/prescribing guidelines at CPIC and PharmGKB where you can also find curated information about drugs and genes, from the literature as well as from drug labels and other sources.

Tuesday, April 24, 2018

Curators' Favorite Papers


The first paper comes from the journal Pharmacogenomics (Clinical pharmacogenetics: how do we ensure a favorable future for patients?) and it discusses the factors that have impeded the implementation of pharmacogenomic (PGx) testing into routine clinical care. Randomized clinical trials (RCT) are the current gold-standard for clinical research for new drug approvals, but the nature of PGx studies is ill-suited to the RCT format. The authors propose alternatives to RCTs such as demonstration of non-inferiority to standard of care, N-of-1 trials for individuals or “hybrid effectiveness-implementation” clinical trials (trials that blend design components investigating clinical effectiveness with implementation research). They also emphasize that implementation of PGx data would require comprehensive, pre-emptive testing, population specific PGx considerations, and storage of results in electronic medical records (EMR) with adequate clinical decision support (CDS) tools. Finally, they make the case for testing for genetic variants with robust evidence of a PGx association, and specifically cite the Clinical Pharmacogenenomics Implementation Consortium (CPIC) as a “promising place to start” in selecting PGx genes to test as well as PharmGKB as a resource for information on gene-drug PGx associations.

The second paper, authored by the International Society for Biocuration (Biocuration: Distilling data into knowledge), comes from the journal PLoS Biology. It explains the specific role that biocurators play within teams that manage biological information resources and databases. Beginning with the premise that data is an asset whose value increases each time it is shared, the authors argue that biocurators maximize value by assuring the “accuracy, comprehensiveness, integration, accessibility, and reuse” of data through the process of extracting knowledge (such as data) from unstructured forms (usually publications) into structured and machine readable forms to enhance its usability and sharing. The authors note that there is encouraging development with regard to data reporting tools, an increase in demand and support for data standards and a growth in the use of biocuration tools by researchers, and all of these are expected to facilitate data curation, data sharing and ultimately, scientific progress.

Wednesday, April 18, 2018

The Clobazam Pathway on the Cover of Pharmacogenetics and Genomics

One of our newest pathways, the Clobazam Pathway, Pharmacokinetics, is featured on the cover of the April issue of the journal Pharmacogenetics and Genomics. PharmGKB Scientific Curator Dr. Rachel Huddart is the first author on this pathway. Clobazam is a benzodiazepine and is used primarily as an anti-epileptic.  The primary metabolizing enzyme is CYP2C19, but additional metabolizing enzymes include CYP3A4CYP2B6 and CYP2C18. You can now view the interactive Clobazam Pathway, Pharmacokinetics on PharmGKB.

Thursday, April 5, 2018

Curator's Favorite Papers


Genetics has been shown to have a profound effect on response to treatment in patients with major depressive disorder (MDD) and may account for as much as 42% of the variability in treatment response, according to some studies. In addition, personality traits, as defined by “the Big-Five" (openness, conscientiousness, extraversion, agreeableness, and neuroticism), which are likely to also be influenced by genetics, may also associate with response to anti-depression treatment. A new study (Association of the Polygenic Scores for Personality Traits and Response to Selective Serotonin Reuptake Inhibitors in Patients with Major Depressive Disorder) intended to uncover gene variants associated with the cross-trait associations between “the Big-Five” and treatment response using data from the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (N = 529) and the International SSRI Pharmacogenomics Consortium (N = 865). Evidence points to an overlap in association between specific personality traits and SSRI treatment outcomes and that the association is partly due to genetics. Specifically, the study evaluated the combined effect of multiple genes (polygenic score, PGS) and their association with one of the five personality traits, as well as response and remission in patients with MDD who are prescribed SSRIs. The PGS for openness personality with treatment response was statistically significant in the ISPC cohort and statistically significant with remission in the PGRN-AMPS sample. PGS for conscientiousness was associated with response, but not remission. Cross-trait meta-analysis of GWAS uncovered eight overlapping genetic loci with previously reported associations with response to SSRIs as well as certain personality traits, particularly neuroticism.  Of note, several PharmGKB members were co-authors on this study: Katrin Sangkuhl, Scientific Curator, Ryan Whaley, Technical Lead, Russ Altman, Co-PI of PharmGKB and Teri Klein, Director and Co-PI of PharmGKB. 


You can find more information about pharmacogenetic guided dosing for SSRIs on cpicpgx.org as well as on the PharmGKB annotation of the CPIC Guideline for SSRIs and CYP2D6 and CYP2C19.

Wednesday, March 21, 2018

PharmVar Launches CYP2D6, CYP2C9 and CYP2C19 Interactive DB

PharmVar has launched its interactive database for CYP2D6, CYP2C9 and CYP2C19. One cool feature is the ability to now easily find the position of each SNP on different reference sequences. The user can now also choose to count from the beginning of a sequence or the ATG start codon. And by clicking on a SNP of interest  a new page will display on which alleles a SNP is located, its respective positions on each reference sequence and the link to dbSNP. Before getting started, the user is advised to read the STANDARDS Document under the GENES tab describing the conventions used for storing and displaying allelic data. Once on the genes page users are encouraged to check out the READ ME and CHANGE LOG documents – these provide important information for each gene and list the changes that have been made as each gene was transferred into the database. These documents can be found on top of the bar showing the reference sequences.  PharmVar is keeping busy adding more CYP genes into the database and developing additional features. 

PharmGKB and CPIC have updated the Allele Definition Tables for CYP2C9 and CYP2C19, part of the PGx Gene Specific Information Tables, to harmonize with PharmVar.  The CYP2D6 Allele Definition Table will be updated soon.