Thursday, October 10, 2019

Public comment period for CPIC allele function assignment SOP

CPIC is inviting public comments on their draft SOP for assigning function to pharmacogenomic alleles.

CPIC has been assigning “function” to pharmacogenomic alleles since its inception. This has already led to a Delphi process and consensus publication on standardizing terms used for allele function and pharmacogenetic phenotypes for some genes. The unique contribution of CPIC is to assign an allele function that leads to a phenotype assignment that can drive clinical prescribing actionability. Now that several types of genes involved in drug pharmacokinetics and pharmacodynamics have been included in CPIC guidelines, CPIC leadership considers it timely to establish written SOPs that describe the criteria used for assigning pharmacogenetic allele function in greater detail. Many elements of this SOP have been tested in preparation of recent guidelines.

The SOP can be downloaded from the Resources section of the CPIC website. Comments and feedback should be sent to Kelly Caudle ( by October 23rd 2019.

Tuesday, October 1, 2019

PharmGKB releases automated annotations

We are excited to announce that automated annotations of pharmacogenomic information in the scientific literature are now available from PharmGKB. These annotations have been produced using the PGxMine project, the result of a collaboration with Dr. Jake Lever at Stanford University.

PGxMine uses a supervised machine learning algorithm to carry out text mining of PubMed abstracts and full-text articles from PubMed Central. Sentences which contain a chemical and a variant are found using the PubTator Central resource and subsequently identified as being highly likely to contain PGx information are highlighted as an automated annotation. Automated annotations will also be used by PharmGKB curators to identify papers for manual curation.

The new automated annotations tab can now be found on drug, gene, variant and haplotype pages on the PharmGKB website. Each automated annotation displays the relevant sentence identified by PGxMine as well as information about the article where the sentence was found. PGxMine was deliberately designed to have a high level of precision at the expense of a lower recall rate. This means that PGx associations that are mentioned in multiple papers should be captured by the algorithm while associations mentioned in only one paper may be missed.

Unlike variant annotations or clinical annotations, which are manually curated by PharmGKB curators, automated annotations are found using computational methods only. The accuracy or relevance of these annotations has not been checked by PharmGKB staff. Users should therefore be aware that there is some noise associated with these annotations. Users should also note that this is not a comprehensive annotation of all published articles. Articles which are only accessible through a journal subscription cannot be annotated by PGxMine and will not be displayed in the automated annotations section.

A paper describing PGxMine in greater detail has been accepted by the Pacific Symposium on Biocomputing and will be available online soon. We will add the URL as a comment to this blog post as soon as it is available. An FAQ page about automated annotations and the PGxMine project can be found on the PharmGKB website.

Future updates of our automated annotations will be tied to the update schedule of PubTator Central. The PGxMine code is open source and can be accessed at GitHub while a full data dump can be accessed at Zenodo.

Thursday, September 26, 2019

CYP2D6 Gene Review by PharmVar published in CPT

The Pharmacogene Variation (PharmVar) Consortium just published the inaugural article of a gene-centered series of review papers in Clinical Pharmacology & Therapeutics

The reviews are covering clinical relevance, genetic variability, allele frequencies and function, ethnic differences, gene nomenclature before and within PharmVar, curation efforts, particular gene-specific challenges, PharmVar features and tools with gene-specific examples, new variants defined by PharmVar, methods suitable for gene characterization and templates to report genotyping methods and translation into phenotype, and more. 

The first Gene Review, accessible at Clinical Pharmacology & Therapeuticsprovides a comprehensive overview and summary of CYP2D6 genetic variations, which impact the metabolism  of numerous drugs and thus can impact drug efficacy and safety. The article also describes how the information provided by PharmVar is utilized by the Pharmacogenomics Knowledgebase (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC).

Each review also provides a set of spreadsheets (Supplemental Materials which will also be available through the PharmVar and PharmGKB websites) to facilitate the reporting of genotyping methods as well as allele and genotype frequencies. Adopting these templates will not only make it easier for authors, but also for PharmGKB curators to retrieve published information.

Friday, September 20, 2019

ACLA writes to the FDA about PGx testing

The American Clinical Laboratory Association (ACLA) has written a letter to the US Food and Drug Administration (FDA) regarding the FDA’s recent communications about pharmacogenomic (PGx) testing. The letter details the ACLA’s concerns that the FDA’s actions will have a significant impact on both patients and the field of PGx. The ACLA state their support for a legislative framework specifically for laboratory diagnostic tests (LDTs) and request a meeting with FDA leadership to discuss the matter further. You can read the full letter at the ACLA website.

Similarly, the Association of Molecular Pathology (AMP) has released a position statement on PGx testing, discussing the role of PGx in the precision medicine era and the standards which AMP believes that PGx tests should be held to. The full statement can be accessed at the AMP website.

Tuesday, September 10, 2019

Michelle Whirl-Carrillo -- Director of the PharmGKB!

We are happy to announce that Dr. Michelle Whirl-Carrillo has agreed to take on the position of Director of PharmGKB. Michelle has worked with the PharmGKB for over 15 years (not including a 1.5 year “sabbatical” at 23andme). She has served as lead curator, Assistant Director, and (since 2014) Associate Director. The PharmGKB grant has recently been renewed and Michelle has been named Director, effective at the start of September. Michelle has her undergraduate degree in Biology from MIT, and a PhD (working with Russ)in Biophysics from Stanford. Congratulations to Michelle and thanks for her willingness to help lead the PharmGKB into its 3rd decade! Teri and Russ (Co-PIs)

Wednesday, August 14, 2019

Pilot study from Genomics England to report on DPYD variants

A pilot study from Genomics England is now reporting back DPYD variants in cancer patients as part of the 100,000 Genomes Project.

The DPYD protein is responsible for degrading fluoropyrimidine drugs, which include 5-fluorouracil and capecitabine. These drugs are commonly used in the treatment of cancer. Decreased activity of the DPYD protein is associated with an increased risk for severe or fatal toxicity from standard doses of fluoropyrimidine drugs. Guidelines from the Clinical Pharmacogenetics Implementation Consortium (CPIC) recommend reducing the starting dose of fluorouracil and capecitabine in patients with decreased DPYD activity, and avoiding use of the drugs in patients with absent DPYD activity.

For cancer patients recruited into the 100,000 Genomes Project, Genomics England is prospectively analyzing germline whole genome sequence (WGS) data for the presence of the rs3918290 (1905+1G>A; DPYD*2A), rs55886062 (1679T>G; DPYD*13), rs67376798 (2846A>T) and rs56038477/rs75017182 (1236G>A/1129-5923C>G; haplotype B3) variants. rs3918290 and rs55886062 are associated with absent DPYD activity, while rs67376798 and rs56038477/rs75017182 confer decreased DPYD activity. If any of these DPYD variants are discovered in the analysis, the genome analysis report for those variants includes a link out to the PharmGKB website for more information.

The WGS results are made available to Genomic Medicine Centres, allowing clinicians to assess whether adjusting treatment regimens may help reduce toxicity risk. Feedback on any actions taken by clinicians will be recorded and analyzed to determine the clinical effectiveness of reporting these variants within the National Health Service (NHS). The program aims to demonstrate how WGS results can help cancer patients receive effective treatment with a lower risk for severe toxicity.


Read the Genomics England blogpost
Read the CPIC guideline for fluoropyrimidines and DPYD

Monday, July 29, 2019

PharmCAT article published in Clinical Pharmacology & Therapeutics

The article describing the Pharmacogenomics Clinical Annotation Tool (PharmCATand a pilot validation using GeT-RM samples was recently published in Clinical Pharmacology & Therapeutics
PharmCAT (1) extracts variants specified in guidelines from a genetic dataset derived from sequencing or genotyping technologies; (2) infers haplotypes and diplotypes; and (3) generates a report containing genotype/diplotype-based annotations and guideline recommendations. 
In this initial version, the tool only considers variants contained in the allele definition files, which are based on CPIC guidelines and provides CPIC recommendations in the output. PharmCAT assumes the sample VCF file has already undergone extensive quality control. Requirements for the VCF files are accessible in GitHub.
PharmCAT was highly concordant with the GeT-RM data and discordant results are discussed in detail in the article and supplemental material [add link to journal or to, if we post it there].

Seeking community input and testing. With this initial beta release of PharmCAT, the pharmacogenomics community is asked to support the continuing evaluation of this freely available tool by running VCF samples, documenting issues and successfully identifying variants. GitHub can be used to communicate feedback. 

PharmCAT is available under the Mozilla Public License (MPL 2.0) for the scientific and clinical community to review, test, and improve. 

Wednesday, July 10, 2019

CYP2C9, CYP2C19, and CYP2D6 core alleles

We recently blogged about the use of PharmVar core alleles as the basis for the PharmGKB/CPIC CYP2D6CYP2C19, and CYP2C9 allele definition tables, which are available as part of the gene-specific information tables. In addition to the core variant(s), the definition includes ambiguous nucleotides to reflect variation present in some suballeles of an allele which are also core variants of other alleles. The allele definitions are now used by the PharmGKB database for all annotations for these 3 genes.

CYP2D6 example:
CYP2D6 100C>T (P34S) is part of some but not all CYP2D6*4 suballeles. Therefore, it is not present in the CYP2D6*4 core allele. However, 100 C>T is part of core allele definitions of a number of CYP2D6 star alleles such as CYP2D6*10.
To reflect the possible presence of 100C>T in the *4 allele, the variant is represented as a “R” using IUPAC nucleotide code. "R" reflects that either a “G” or “A” (positive strand) can be present at the 100C>T position in *4. This is shown on the PharmGKB CYP2D6*4 overview page, which lists 100C>T positions and others next to the *4 key splicing variant 1847G>A (rs3892097).

CYP2C19 example:
For CYP2C19*1, the genomic reference sequence at position GRCh38 NC_000010.11:g.94842866 (rs3758581) is "A", which is present in CYP2C19*1.001(*1A), however all other *1 suballeles have a "G" (I331V) at this position. All suballeles of a star (*) are assumed to have similar functional status. The I331V is prominent in CYP2C19 and part of many alleles.  To reflect the possibility of either base at this position, the NC_000010.11:g.94842866 position is included as "R" for the CYP2C19*1 allele at PharmGKB.

For more information about cytochrome P450 star alleles and suballeles, see PharmVar .

PharmGKB has been updated to contain annotations on main star alleles such as *2, *3, etc. and not individual suballeles. If a publication specifically mentions a suballele, this association will be annotated on the main star allele and the suballele will be mentioned in the annotation notes.

Tuesday, July 2, 2019

CPIC to issue guidance on non-actionable pharmacogenes

The Clinical Pharmacogenetics Implementation Consortium (CPIC) hopes to provide more guidance in the future about gene-drug pairs which have a weak evidence base and are not clinically actionable, despite being heavily marketed to healthcare providers and the public. Many of these gene-drug pairs have already been curated by CPIC staff and assigned a CPIC level of C or D, indicating low or highly conflicting evidence.

The plan was announced at CPIC’s 2019 open meeting in Memphis by Dr. Mary Relling, co-leader of CPIC. It is hoped that this new initiative will improve standardization of pharmacogenomic (PGx) testing, particularly in the face of increased scrutiny from the FDA.

Other CPIC projects announced at the meeting include the development of a CPIC database and API, incorporation of the CPIC guidelines into external resources such as ClinVar and ClinGen and a second phase of the PGx term standardization project which will focus on receptors and other pharmacodynamic genes.

You can find out more about CPIC’s future plans in this GenomeWeb article.