Shadowing Practice: Sequence Variant Literature Search Tips and Tricks - Learn English Speaking with Video

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Hi, my name is Jessica Mester.

I'm a genetic counselor at GeneDx and a member of the ClinGen Education Workgroup.

This presentation will provide a brief introduction into performing a literature search for sequence variant interpretation.

Our time today will focus on three main points relevant to

both bio curators working to classify variants as well as clinicians

might be searching for additional information on a variant picked up in one of their patients.

We'll discuss how to incorporate nomenclature into an effective literature search, what resources to use to find articles,

and we'll also talk about some common speed bumps you may hit during your literature search and ways to overcome them. But first,

let's talk about the purpose of doing a literature search to help us wrap our heads around what we're looking for.

As a biocurator, you're looking for articles that provide evidence for the purpose of applying ACMG criteria.

These include papers describing functional studies or that characterize the potential molecular impact of the variant, as well as clinically focused papers giving patient phenotype,

describing families that provide segregation evidence, or case control studies.

Remember that you're looking for evidence that could either support or refute pathogenicity.

As a clinician, in addition to helping you get a sense for what information about a variant may support a laboratory's classification,

you may also do a literature search to help you understand more about the phenotypic spectrum associated with the disease,

the types of variants associated with the disease, or one specific variant of interest.

Before we begin, I also want to enforce the idea that there is no such thing as the perfect literature search tool.

Using a combination of sources is generally necessary to be thorough and get the job done.

However, there are a few resources

that have already done some of the heavy lifting regarding compiling publications

that describe a specific variant that provide a helpful starting point.

HGMD, the human gene mutation database, has both a professional and a public version that provides variant level data with PubMed IDs and links to articles.

The free version isn't as up - to -date as the paid version.

Also, be aware

that HGMD tends to be very generous with labeling variants seen in any patient with a phenotype as being disease -associated,

but did not classify variants using the ACMG -AMP criteria.

As such, HGMG is best used as a source to help you find literature that may help you classify a variant,

but should not be considered a repository of curated pathogenic variants.

There are also gene -specific databases, many listed at the link provided or you can find via a Google search,

which may have compiled critical literature about a specific gene as well as variant -level evidence.

If you expect to be curating

or investigating a number of variants for a particular gene and a gene -specific database is available,

I highly encourage you to familiarize yourself with this resource

so you can fully understand where they get their information from and how to best utilize it.

Finally, some ClinVar submitters provide citations with PubMed IDs or links to other evidence that support their classification.

However, be cautious, as sometimes they'll link to an article not because it contains information on your variant,

but because it describes a pathogenic variant at the same residue that was used as evidence to support classification.

There are also tools that are working to try and simplify the literature search process.

Two I wanted to highlight are Mastermind, for which ClinGen curators get access to the full version for a few months trial period,

and LitVar, which is an NCBI tool, and other similar tools are in development.

While searching PubMed for articles on a specific variant will find articles where the variant appears in the abstract or title,

often for papers that list a number of variants identified in a population with a specific phenotype, the variant information is only contained within a table,

sometimes just in supplemental data, and wouldn't be picked up on a PubMed search.

As a result, the two tools

that I've personally found to be the most effective for finding variant -specific literature are Google and Google Scholar.

Now, I will say there is a bit of a learning curve with using Google search results, but with time and experience you'll start to recognize

which search hits are worth looking into further and which don't lead you to useful links.

For example, searching ATM variants finds scientific publications as well as local ATM machine locations.

But sometimes you'll find a link that looks really helpful, such as a supplemental table to an article, but the source article isn't clearly specified.

We'll walk through an example of that later in this talk.

Google Scholar is more specific than Google

because it is limited to published academic literature

and tends to be more effective at finding variants listed in a table within the actual paper,

but it may not find you publications where your variant is only in a supplemental table.

When building your search term, you want to include the name of your gene as well as several versions of the variant nomenclature.

I have some specific examples on the next slide, but want to preview a few helpful hints here.

Using quotation marks and the Boolean operators AND and OR can help make sure your search output is comprehensive,

but not so extensive that you're spending hours digging through search hits for a single variant.

Quotation marks help you specifically find an exact match for the text within the marks.

While we hope that publications will stick to defined HGVS nomenclature, sometimes it helps to be a little creative,

especially for older publications, and use genomic position as well as variant nomenclature in your search string.

If your gene has aliases or historic names, including those may help.

You also need to be aware of alternate transcripts or nomenclature that might have been commonly used in addition to HGVS.

Now, I won't belabor this point, as it could certainly merit its own separate talk,

but you might be able to identify alternate transcripts or nomenclature on a laboratory report in ClinVar,

or for biocurators who are curating in the variant curation interface, this information may also appear in the evidence view.

I'll also direct you towards Dr. Marino DeStefano's excellent article

and talks on alternate transcripts on the ClinGen YouTube channel for more information on this topic.

So, here are examples of search strings you might use for specific types of variants.

In addition to quotation marks and the AND or Boolean operators, you'll also see an asterisk here and there.

In search language, this is called a wildcard operator, and will return anything that starts with the preceding text.

Looking at a few examples, you'll see in the first row for the P10 nonsense variant ARG335 -TER,

the CD nomenclature 1003C2T is used without the C that is a part of HGVS nomenclature,

as some articles do not include the CDOT even though they should.

You'll also see two versions of the CDOT nomenclature, one with a space between the nucleotide position and the nucleotide change, and one with no space.

In addition to TER as the HGVS termination for a stop codon, I also included ARCH335 -STOP because,

again, that nomenclature might be used for nonsense variants, particularly in older publications.

And finally, the genomic position of the nucleotide change is included for good measure.

Looking through the other examples, you'll see more of the same.

Each includes nomenclature referring to the nucleotide change, protein change, and genomic position.

Bringing your attention to the in -frame indel row, while the HGVS nomenclature specifies the nucleotides deleted .

An author might have shortened this to say instead to save column space in a table.

Now I want to take you through an example of Google search results for the MYBPC3 frameshift variant in the previous table.

At first, you might think, oh no, I have to review 113 articles?

I promise you, although that looks intimidating, it's actually not that bad.

Trying this out, you'll see that the search output includes multiple links from the same source,

many of which you'll instantly recognize as ClinVar entries for the variant, Nomad links, or other databases you might have already reviewed.

Also note that these searches will pull up articles where your gene is mentioned and your variant is mentioned, but they don't line up.

Many genes were looked at in the study and a variant with the same cDNA nomenclature was found in a different gene.

When you first start learning this process, I do think it's helpful to explore most of the links,

especially on the first few pages of your search result, to familiarize yourself with the kinds of search hits that are returned.

Over time, you'll recognize which search hits are likely to lead you to useful information and really need to be explored.

So using the search string for that MYBPC3 frameshift variant, one of your first Google hits looks really promising and and indeed,

takes you directly to the actual article in PLAS 1 that contains your variant.

This is the best case scenario.

Other links you'll often see are to database entries for your variant in ClinVar, which tends to be at the top of Google search results.

You may also find links to an LOVD entry, which when you click on the link, takes you into LOVD.

Here for this variant, we see there is a reference cited which we'd want to find and review if we hadn't already.

Clicking on this link takes you to the PubMed entry for the article, which you'd hopefully then be able to access to look for your variant.

100

Another possible result of a Google search takes you on a bit of a treasure hunt.

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This link takes you to a Word document, which is a supplementary table to an article that appears to contain your specific variant.

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However, the name of the article, year of publication, etc. aren't clearly specified, but clues are given within the name of the word document.

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Taking these clues to the Genetics in Medicine journal website, journal websites typically have a search tool at the top of the page.

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Clicking this, let's add our possible author name, Funke, and possible publication date of 2010 to see what we get.

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And, lo and behold, it looks like we might have a match.

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And when you look at this article, indeed, it has our variant and the supplemental table matches what we found in Google.

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This same search phrase in Google Scholar only gives us one article, which is different from the other three we found using Google,

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but still looks like it might include a patient with our variant and HCM.

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Words of caution when looking at variant -specific literature.

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Although it's good practice as an author to state

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when a patient included in your paper has previously been published elsewhere and then cite that publication,

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perhaps an author did not realize the patient was already published, resulting in the same patient or family being presented in multiple separate publications.

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This is important, as seeing a variant in multiple independent probands might lead an expert panel to apply a higher level of phenotype -related evidence.

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Use your common sense.

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If the authors between the articles have some overlap, if the same study cohort is being utilized,

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or if specific clinical details like age diagnosis and phenotype are highly aligned, chances are it's just one family or patient that was reported multiple times.

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In these situations, it's best to err on the side of caution

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and take a conservative approach by only counting apparently similar probands or families once.

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In summary, I hope you come away from this talk knowing

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that developing literature search skills isn't something that you become highly skilled at overnight, but is a learning process that improves with time and practice.

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I hope you'll look to available database resources to increase your efficiency,

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as well as be able to build search strings to perform comprehensive searches using Google and Google Scholar.

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Finally, always look at the source publication to make sure your variant of interest is present

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and to understand how the information contained in the article relates to your needs.

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I hope this has been a useful introduction to literature searches for sequence variant interpretation.

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Please visit www .clinicalgenome .org for additional educational resources and to learn more about ClinGen initiatives.

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Our funding sources are listed at the bottom of this slide.

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Please feel free to contact ClinGen by email at ClinGen at clinicalgenome .org with questions or feedback.

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Thank you.

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Woordenschat en spreektips bij deze les

Deze spreekles is gebaseerd op de video “Sequence Variant Literature Search Tips and Tricks”. Deze woorden komen het vaakst terug: variant, search, article, Google, literature. Deze video bevat 5 zinnen en 2136 woorden om na te spreken. Het gesproken deel duurt 12:34. De spreker praat in een natuurlijk tempo van ongeveer 170 woorden per minuut, dicht bij een alledaags gesprek. Slechts 79% van de woorden hoort bij de 3.000 meest gebruikte Engelse woorden, dus de woordenschat is pittig.

Belangrijke woorden in deze video

15 woorden uit de video die het leren waard zijn, met uitspraak en betekenis:

Woord	Uitspraak	Betekenis
variant zelfstandig naamwoord	/ˈvæɹi.ənt/	variant
publication zelfstandig naamwoord	/ˌpʌblɪˈkeɪʃ(ə)n/	publicatie
gene zelfstandig naamwoord	/d͡ʒiːn/	gen
database zelfstandig naamwoord	/ˈdeɪtəˌbeɪs/	database, databank
helpful bijvoeglijk naamwoord	/ˈhɛlp.fl̩/	behulpzaam
string zelfstandig naamwoord	/stɹɪŋ/	draad, koord
curator zelfstandig naamwoord	/kjʊəˈɹeɪtə(ɹ)/	conservator, conservatrice
operator zelfstandig naamwoord	/ˈɑpəˌɹeɪtɚ/	bediener
classification zelfstandig naamwoord	/ˌklæsɪfɪˈkeɪʃən/	classificatie
specify werkwoord	/ˈspɛs.əˌfaɪ/	specificeren
quotation zelfstandig naamwoord	/kwoʊˈteɪʃn̩/	offerte
output zelfstandig naamwoord	/ˈaʊtpʊt/	productie
comprehensive bijvoeglijk naamwoord	/ˌkɑm.pɹəˈhɛn.sɪv/	omvattend, alomvattend
sequence zelfstandig naamwoord	/ˈsiː.kwəns/	volgorde, reeks
explore werkwoord	/ɪkˈsploɹ/	onderzoeken, bestuderen

Grammatica in deze video

De structuren die de spreker het meest gebruikt, met de exacte woorden uit de video:

Structuur	In de video
Lijdende vorm be + voltooid deelwoord — het gaat om wat er gebeurt, niet om wie het doet	should not be considered · was used · is only contained
Present perfect have/has + voltooid deelwoord — iets uit het verleden dat nu nog telt	have already done · I've personally found · has previously been published
Betrekkelijke bijzinnen who / which + zin — extra informatie over een persoon of ding	LitVar, which is · document, which is · article, which is

Uitspraak om op te letten

De spreker gebruikt 34 samentrekkingen en verkorte vormen, zoals you'll, we'll, you're. Spreek ze kort uit, zoals je ze hoort.

De “th”-klanken: thorough /ˈθʌɹoʊ/, pathogenic /pæθəˈd͡ʒɛnɪk/, pathogenicity /ˌpæθəd͡ʒəˈnɪsɪti/
De klanken “sh” en “zh”: publication /ˌpʌblɪˈkeɪʃ(ə)n/, classification /ˌklæsɪfɪˈkeɪʃən/, quotation /kwoʊˈteɪʃn̩/, interpretation /ɪnˌtɜːpɹəˈteɪʃən/, caution /ˈkɔːʃ(ə)n/
Lange woorden — let op de klemtoon: publication /ˌpʌblɪˈkeɪʃ(ə)n/, operator /ˈɑpəˌɹeɪtɚ/, classification /ˌklæsɪfɪˈkeɪʃən/, comprehensive /ˌkɑm.pɹəˈhɛn.sɪv/, laboratory /ˈlæb(ə)ɹəˌtɔɹi/

Klanken die Nederlandstaligen lastig vinden:

Stemhebbende eindmedeklinker — /b/, /d/, /g/, /z/, /v/ niet verscherpen: comprehensive /ˌkɑm.pɹəˈhɛn.sɪv/, encourage /ɪnˈkʌɹ.ɪd͡ʒ/, initiative /ɪˈnɪʃ.ə.tɪv/, phrase /ˈfɹeɪ̯z/, slide /ˈslaɪ̯d/
/æ/ — opener dan de Nederlandse “e”: variant /ˈvæɹi.ənt/, classification /ˌklæsɪfɪˈkeɪʃən/, transcript /ˈtɹæn.skɹɪpt/, laboratory /ˈlæb(ə)ɹəˌtɔɹi/, feedback /ˈfiːdˌbæk/
/g/ — een harde plofklank, geen Nederlandse “g”: investigate /ɪnˈvɛs.tə.ɡeɪt/, dig /dɪɡ/, diagnosis /daɪəɡˈnəʊsɪs/, segregation /sɛɡɹəˈɡeɪ̯ʃən/, workgroup /ˈwəːkɡɹuːp/

Zo oefen je met deze video

Luister de hele video één keer zonder te spreken en noteer de woorden die je niet kent.
Begin op 0,75× snelheid, spreek zin voor zin na en ga terug naar normale snelheid zodra het makkelijk gaat.
Neem jezelf op en vergelijk met het origineel; let daarbij op woorden als variant, publication, gene.

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Shadowing Practice: Sequence Variant Literature Search Tips and Tricks - Learn English Speaking with Video

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