Medical Genetics Summaries on the NCBI Bookshelf – a pharmacogenomics resource for clinicians

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Good afternoon. This is Peter Cooper from the customer service
division of NCBI . Today’s webinar is on Medical Genetics Summaries on the NCBI Boolshelf. With me as Adrianna Malheiro who is a genetic
counselor NCBI and she will be talking you about the Medical Genetics Summaries. If you have a question during the webinar,
write it into the question pod. The answers are going to be available after
the webinar, linked to our webinars page. In their will be the slide set and materials
directly as well. I’m goint to pass this over to Adrianna. Thank you, Peter. Welcome to the NCBI minute! It is with great pleasure that I am introducing
you to your new best friend for actionable pharmacogenetic information, the Medical Genetics
Summaries In the clinic, a physician, genetic counselor,
nurse or pharmacist may want to efficiently access authoritative information about genetic
testing to guide therapeutic decision making. This is where the MGS come in. You can use them to find pharmacogenomic information
about drug efficacy, dosing, or adverse event risk. The Medical Genetics Summaries were created
by NCBI to bring a clinician a trustworthy, quickly digestible resource that summarizes
the latest pharmacogenomic information in an actionable format. Each chapter is written in house by a doctor
with pharmacology background, edited in-house by clinical geneticists, and then sent for
outside editing by an impressive list of expert reviewers – they are all acknowledged in
each chapter so you can see whose input contributed to the summary. Summaries are updated regularly. You can access Medical Genetics Summaries
for free from the Bookshelf which is where NCBI stores its free books like GeneReviews
that you may be familiar with. You can use it to find the over 300 pharmacogenetic
tests currently in GTR. And access information in MedGen. These clinical genetics resources at NCBI
all link to each other. The main page lists all summaries and you
can expand to see links to specific sections of each chapter for quick access to the specific
information you need. There is a search box where you can look for
summaries by drug or gene. The MGS is a collection of currently 37 chapters
or summaries and this number is growing. Each summary has the same format. Each chapter or summary starts with a concise
introduction that describes the drug and its metabolism, how the genetic variation influences
the drug response, and the take-home messages from FDA and other authoritative sources. The introduction also shows dosing guidelines,
giving quick access to actionable information. The Drug, Gene, and Therapeutic recommendations
sections go into more detail. The allele Nomenclature table is your Rosetta
stone for variants, to translate common start alleles, alternate variant names, dbSNP rs
identifiers, and HGVS expressions – HGVS is the standardized nomenclature for human
variation. So, what is in the MGS? The MGS includes the relevant statement from
the FDA drug label. Professional practice standards from authoritative
pharmacogenomic societies like CPIC the Clinical Pharmacogenetics Implementation Consortium. It also includes relevant practice guidelines
from professional medical societies like the American College of Medical Genetics and Genomics
(ACMG) It has information from the Pharmacogenomics
Knowledgebase, PharmGKB, like potentially clinically actionable gene-drug associations. We perform literature searches from PubMed
to include the latest papers, reviews, and guidelines which gives you a curated set of
references for a more efficient workflow in your clinic. Also included is input and review from experts
in the field. The MGS are accessible from other resources
at NCBI. Here you can see how you can access the summaries
from the NIH Genetic Testing Registry or GTR, which is a free database of orderable clinical
and research genetic tests provided by labs from around the world. And MedGen, which is a portal to information
about phenotypes with a genetic component. These are the 37 chapters available so far
– each chapter is for a drug and the genes that affect its metabolism or efficiency. I’ll use the summary on Codeine Therapy
and CYP2D6 as my example. Here is the layout of the codeine summary. It starts with a descriptive introduction
of the chapter. On the right-hand side, there are links to
valuable information. For example, you can see that the GTR search
on the drug response and gene are already set up for you to click on. When you click on these links you are taken
to GTR and a page that lists all relevant tests. Deeper in the chapter you’ll find more details
about genetic testing and how test results are given, for example as diplotypes of star
alleles that need to be translated into a predicted metabolizer phenotype. Let’s say you ordered a CYP2D6 test. Or, a patient is coming to you with the results
of the test their doctor ordered for them, and the doctor wants your advice on translating
the result into clinical decisions. Here is what the report may look like. This report lists a set of markers that were
assayed, defined with rs identifiers from dbSNP. The genotype is given for each marker. The genetic result is then described as a
diplotype of two star alleles, in this case ‘star 1 and star 41. This laboratory report translates the diplotype
into a metabolic phenotype – in this example ‘extensive metabolizer’. Now let’s go back to the Medical Genetic
Summary. Here is the translation table for different
ways used to report variations by for example labs and the literature. Here you can see what the HGVS expression
is for a star allele, a piece of information that is not always easy to find. The star 41 allele in our example lab report
is at the bottom. This table shows the activity status of each
relevant alleles for the CYP2D6 gene: star 1 is a normal function allele and star 41
is a decreased function allele. These are the Codeine therapy recommendations
based on CYP2D6 phenotype, these recommendations have been adapted from CPIC. The MGS uses the new published recommended
standardized terminology from CPIC. So, you may notice some discrepancy in the
terminology when comparing with other resources. Here is the star 1 / star 41 diplotype and
how it relates to the enzyme activity score. This result is one normal function allele
(star 1) and one decreased function allele (star 41) so the patient is considered to
be a normal metabolizer and dosing should not be affected; so you can use label-recommended,
age or weight specific dosing. Translating the test results into clinical
actions takes some dedication. The MGS is more efficient than a literature
search or wading through an FDA label because everything you may need is in one place. The codeine summary displays excerpts from
the FDA, CPIC, and the Canadian Pharmacogenetics Network for drug safety (CPNDS). In conclusion, a clinician can use MedGen
to consider a differential diagnosis, to find clinical, molecular, and research information
about a condition or phenotype along with links to relevant information. They can use GTR to find a suitable test for
specific genes or diseases. And they can use the MGS to find: Therapeutic
dosing recommendations by phenotype; Enzymatic activity status of significant alleles; Assignment
of likely phenotype based on genotypes And to translate terms used in published literature
with terms used in the laboratory and the clinic by using the allele nomenclature table. Here is the url for the Medical Genetics Summaries. A little tip: a google search will also work. We are on Twitter, you can follow us for notifications
on new summaries being published and updates to existing summaries. We are working on getting these summaries
indexed in PubMed and expect this to be done soon. Thank you for your attention. I can now take questions. Thanks Adrianna. The only real question that is in the pod
right now is a question about the genetic test chart that you showed that had the rs
id’s in it. The person wants to know where that came from. It was definitely in the book but I think
this question was more about what would be the source of something like that? Yes, the lab report with the CYP2D6 alleles
in it. For the allele nomenclature table we actually
do this ourselves. We just read the literature and we try to
find the allele on the dbSNP and for the CYP enzymes, there is a website that actually
gathers all of the information for the CYP enzymes. So I don’t have the exact URL but that is
definitely something that should be at the end of the summaries and if not, I can send
them to you. Now, if you are referring to the rs numbers
for the genetic test reports, this is adapted from an actual report that comes from a testing
laboratory. For that, I can’t answer because I didn’t
know where they did it. So a follow-up question for that table, he
wants to know if that is not in the medical genetics summary that allele nomenclature? The allele nomenclature table is in the medical
genetics summaries, yes. This we do ourselves. We actually create this table ourselves. Great. Thank you. Another question is about when was the first
medical genetics summary done, what date? It was back in 2012. So when you first go to the medical genetics
summary, the book, we have the dates in there. So there is the date that a chapter was created
and there’s a date when the chapter was updated and all the updates after that will be dated
as well. Thank you, Adriana. Laura Dean who is the author of this book
is commenting on the questions pot and I will send her answers out to people later on when
we get the Q&A document together. Another question is, for a given drug example
can you cross-reference to other targets that influenced metabolism for example a drug may
be metabolized by CYP2D6 and CYP3A4 and so on. Yes, so each summary is for a drug and all
of the genes or enzymes that affect it’s metabolism. So some of the summaries have discussed more
than one gene. So you can see for instance, Clozapine Therapy
discusses CYP2D6 CYP1A2 and CYP3A4. So we definitely can have discussions of more
than one gene for summary. Are there any examples were the medical genetics
summaries disagree with CPIC conclusions. We display all of the recommendations from
FDA and CPIC, the Dutch pharmacology workgroup, the Canadian group. So we display all of those. And sometimes they don’t agree with each other. So it’s one of the reasons why we created
the summarises was to show that when you are in a clinic and you need to know what all
of the professional societies and what FDA has to say about it, sometimes some of the
medical societies as well like a ACMG or ASCO they will have recommendations as well. So we’ve display all of those that are available. We don’t formulate an opinion here. We just show and display all of the recommendations
from all of the groups that publish on that drug. Thank you, Adriana. I don’t see any more questions. I want to go ahead and close the webinar now
and remind you that the slides will be available on the ftp site that I sent in the chat pod
to everybody. So thank you everybody for coming and we will
see you next time.

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