griffithlab / civic-meeting

Repo for advertising and organizing CIViC hackathon/meeting activities

VICC, CGC, CIViC, & ClinGen Somatic: Variant Curation & Coding Unconference

Advancing Cancer Precision Medicine with Community Collaboration

This repository is being used to organize pre-meeting suggestions for the VICC, CGC, CIViC, & ClinGen Somatic: Variant Curation & Coding Unconference, taking place before the 2024 CGC annual meeting. Hosted at the CGC meeting in St. Louis, August 3rd, 2024, the Unconference will focus on promoting the standardization and dissemination of knowledge of the clinical significance of cancer.

Registration can be found here.

Variant Curation

Molecular biologists, Pathologists and Oncologists (certified or in training), and genome scientists interested in the problem of sequence variant interpretation for cancer precision medicine should submit topics for the Curation. To propose a curation topic, visit the Issues page.

1. Select New Issue
2. Select Curation Project Proposal
3. Create a title and description for your issue
4. Fill out the fields in the form

Coding

Software developers, engineers and computational biologists interested in learning and applying back-end and front-end web development skills should submit topics for the Coding. To propose a coding topic, visit the Issues page.

1. Select New Issue
2. Select Coding Project Proposal
3. Create a title and description for your issue
4. Fill out the fields in the form

civic-meeting's Issues

Methods for assessing and comparing variant databases and AI technologies

I'm interested in methods for testing the accuracy of information in variant databases, with an eye to developing ways to assess the accuracy and utility of AI technologies for variant interpretation. Hoping to find other folks interested in these issues as well, and to share ideas about how to approach this both conceptually and technically.

Ian King, University Health Network (Toronto)

Biophysical modeling for interpreting functional impacts

Given the scale of potential variation, to what extent can protein-specific models of functional impact be used as evidence?

I've been developing a method to predict functional changes of missense mutations using simulations of protein structure.

https://www.cell.com/biophysj/fulltext/S0006-3495(20)33203-3

In short, molecular dynamics (MD) simulations are used to define the characteristic "wobble" using an all atom representation of a variant's protein structure. By projecting this variant specific profiles into a lower dimensional space (PCA), we find that variants cluster by their contribution to divergent disease mechanisms, which allows us to define a decision boundary for a classification model. That is to say, we can use these projections of variant dynamics to train an AI classifier that predicts the impact of novel variants based on the MD results.

An interesting result came when we applied this method to predict venetoclax resistance in BCL2. Shown below is a projection of resistant variants (red), sensitive variants (blue), and a re-sensitized double variant (rescue - first G101V, second E152A) into PCA space. The "rescue" variant becomes more wildtype, as also shown with the predicted Ki.

https://www.sciencedirect.com/science/article/pii/S0010482521008544?via%3Dihub

The Ki's were predicted by quantifying the distance of a given variant from the wildtype, and our preliminary data suggests the degree of divergence from the wildtype dynamics correlates to the degree of functional change in other proteins as well (see the Biophysical Journal article linked above).

So... to what degree can these methods be used as evidence? Or on the other hand, to what degree can curated evidence be used to label/train these sorts of models?

incorporation of pharmacogenomic and predisposing biomarkers

Biomarkers can have clinical implications as diagnostic, prognostic and predictive biomarkers. All of these can be found and created in CIViC. Yet, pharmacogenomic (genomic predictors of drug toxicity) and predisposing (genomic predictors of disease probability) are additional biomarker categories that might be worthwile to discuss as an addition to the database.

SOP and evidence codes for somatic variant oncogenicity/clinical actionability

add meeting location, times, details to CIViC Meetings page entry

save Add Evidence form state on exit from page, restore state upon return

Would be nice to have a feature where complex form's state (such as Add Evidence) were saved when a user exits a page, to be restored when they return.

Strategies for Variant Normalization & Representation

Hands-on CIViC curation workshop

Modeling Variant Interpretations in SEPIO

Elevator pitch to be lead by Matt Brush? @mbrush would you be able to give a ~3 minute elevator pitch on this and if there is interest help to lead a session on use of SEPIO?

Adopt WikiData drug concepts for CIViC drug entry

Germline vs. somatic mutations: how to distinguish and report them

Definition of new region types for expanded cancer variant representations

Using the CIViCpy module to query data

We should discuss the CIViCpy module and recipes for its use in querying data over the CIViC API.

Develop Template Components for CCGA in MediaWiki (Room 307)

• Automation of content generation
  • Generate links to external sources
  • Acquire basic information via API
• Implement page tags
  • Allow for version control
  • Specify page types

Motivating Participation for Scientific Curation of Somatic Variants for Clinical Actionability

Interested to discuss how to motivate people to participate in curation efforts. Wall of shame (or tracking participation), rewards associated with achieving levels, points, reminders of contributions, small completable tasks, goal setting/goal completions, any thoughts to tie this into health apps like vitality etc -- i.e. companies pay for healthy workers, maybe interested to pay for healthy science participation too?

Explore web applications for community contribution to knowledge networks

NGLY1 deficiency is an extreme congential rare disease. We built led by domain-experts feedback a disease knowledge network for this rare disease. This project aim at examining web applications to enable the community to contribute directly in the update and curation of this resource.

slides: https://docs.google.com/presentation/d/1KB6dK9GJj0XQpaTxEq_-EqiAS_jghd3X5y735l1y3nA/edit?usp=sharing

NGLY1 deficiency network: http://52.87.232.110:7474/browser/

Curation: Building a Fact-checking companion dataset for CIViC (Room 309)

I am planning to attend the upcoming meeting/jamboree and would like to propose backfilling/entering CIViC NLI selections if there is still room for proposals. This would involve curators selecting evidence sentences/spans in PMC/pumbed articles which are support for existing (or new if preferred) CIViC evidence items.

Secondary Task: Labelling pre-compiled examples in doccano: https://bcgsc-doccano.herokuapp.com/

CIViC networks available in NDEx

The following networks are available in NDEx (See link below)

Variant-Drug
Variant_Disease
Gene-Disease
Gene-Variant

http://public.ndexbio.org/#/user/77520e6b-816b-11e8-a4bf-0ac135e8bacf

interaction network diffusion of oncogenicity metric value of variants to find signalling neighborhoods

Interpret the potential interactions of variant genes using heat diffusion methodology.

Add initial heat of variants to corresponding nodes of a protein-protein interaction network, proportional to the oncogenicity metric value for each variant.

This will produce a subnetwork of the interaction network that is focused on the most relevant proteins/genes

Conjecture: this network could then be augmented via addition of drug-variant / drug-gene interaction links to suggest relevant therapies, one that may expose drug effects that affect multiple variants.

Discussion of curation standards

A group could be formed to discuss curation best practices, data model improvements, adoption of ClinGen (MVLD) and FDA proposals, ontologies, etc.

Best practices in annotating CNVs and fusions alongside variants in knowledgebases

One noted gap in many well-known knowledgebases is the coverage and searchability of copy number variants and fusions/structural variants. Many our our in-house tools are attempting to employ segment/coordinate based searches to link to relevant data/knowledge for clinical reporting of copy number variants. Fusions are another beast for us - each assay seems to annotate things a little differently. For example, are the fusion partners always listed 5' --> 3'? How do we document structural rearrangements (translocations/inversions/CNVs) that result in over/under expression by position effect (i.e. they don't result in a fusion product)?

Examine ways to incentivize the curation community

e.g. Zenodo, bioCADDIE for citable records

Discuss current and novel visual representations of structural rearrangements and copy number data (Room 307)

Capturing multiple scales of genomic variation in a single figure represents a unique challenge required for visualizing CCGA content.

An example of current CCGA efforts:

Improve CIViC WikiData integration

Elevator pitch to be lead by Greg Stupp (Su lab) @stuppie

Variant Interpretation Knowledgebase Interoperability

@ahwagner can you please edit the description with some more details?

discuss how to deal with variants of unknown significance in genes linked to clinical actions

Focus on clinically relevant fusions

Currently, clinically relevant fusions are under-represented in CIViC (and other knowledgebases) in relation to SNVs and other small mutations. Fusions represent a unique curation challenge in CIViC as they involve multiple genes and multiple (sometimes difficult to define) genomic coordinate sets. They also represent unique challenges for developing NGS sequencing panels and may require specific technologies (e.g., Archer) to identify them. However, many fusions have clear implications for prognosis, diagnosis, or drug response. I propose a working group to tackle the specific challenge of curating fusions in CIViC.

Propose, discuss, and implement 'badges', 'points', and other CIViC user incentives

• What activities in CIViC should be rewarded with a badge?
• What should we take into account when determining a user's activity/reputation score?

ClinGen VCI <-> Evidence Registry <-> CIViC Integration (VHL collaboration)

Some people from the Stanford VCI are coming and we would like to discuss technical details of how we could use the Evidence Registry (Baylor) to help VCI users leverage curation work previously done in CIViC to make final pathogenicity assertions in the VCI.

Improve WHO book representation in ontologies (Room 307)

• Work with NCI-Thesaurus to create entire WHO representations, similar to AML (https://nciterms.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&version=22.02d&code=C159157&ns=ncit)

• Establish list of relationships between who entities and the ICD codes

Incorporate myvariant.info into CIViC for basic variant annotations

This work is underway but it may still be in play when the meeting happens.

Related issue from civic-server repo: griffithlab/civic-server#171

Exporting CIViC data

This topic will include how to create a bed-format file or VCF file of CIViC variants.

Submit CIViC data to WikiData for incorporation into GeneWiki in collaboration with SWAT4LS

The 9th international Semantic Web Applications and Tools for Life Sciences (SWAT4LS) conference is occurring concurrently with the CIViC Hackathon Dec 5-8, also at the NKI in Amsterdam. In an effort to cross-pollinate between our two meetings/hackathons efforts will be made to provide CIViC data for SWAT4LS hacking. Specifically we will attempt to incorporate CIViC evidence statements into WikiData to allow semantic web applications.

what to do if the same variant has different interpretation in different databases?

e.g. some alert for the database responsibles so they can dig into the reasons behind that disagreement and try to solve it

predictive biomarkers in hepatocellular carcinoma

Currently only a few evidence items have been added for hepatocellular carcinoma - disease specific evidence mining could help to expand the database for this disease.

Improve coverage of high profile germline variants

Example: BRCA1 or BRCA2

Have experts recommend users

From Discussion:

Have a mechanism where an expert can suggest other experts to work on a specific gene or variant. Optionally specify a missing gene or variant.

Integrate CIViC with genome browsers (igv.js, JBrowse, ...)

Integrate the CIViC DB with genome browsers including igv.js, JBrowse, and possibly IGV. This integration could take 2 forms, not mutually exclusive

(1) Link out to CIViC from VCF and other variant track types (e.g. SnpDB) and provide variant details in a popup.

(2) When zoomed in to “gene” level, query the CIViC API for variants as genes come into view and display as a track. Clicking on a variant would query the API and bring up details in a popup.

The motivation is to give researchers browsing their own variants in the genome browser easy access to CIViC data. igv.js does a similar thing now with Cravat.

If there is interest in this proposal I could outline an implementation approach here, or save it for the hackathon.

Use HGVS nomenclature, and list the proper c.Nomen and p.Nomen with each variant

Write a VEP plugin that annotates a VCF with CIViC data

https://useast.ensembl.org/info/docs/tools/vep/script/vep_plugins.html

Integration of CRAVAT and CIViC

There is interest in integration of CRAVAT and CIViC (possibly bi-directional?). In what specific ways? To be discussed with the Karchin Lab (https://github.com/KarchinLab).

Resistance mutations to targeted agents

Review innate/ acquired genomic resistance mechanisms to targeted agents, how to interpret them and present the results of our curation in a schematic way.

contact wikidata about participating in hackathon

CNV / SV knowledge discussion

Proposed by Beth Pitel. This topic was the last one tackled in the afternoon session. 8 participants attended this discussion.

Curating the non-coding genome

A recent publication made recommendations for the curation of non-coding variants.
https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-022-01073-3

How do the germ-line recommendations apply to curation of somatic variants?

Benign SNV or not?

Which criteria are used to decide wether a SNP is benign?
(How) do you report a SNV, which is likely to be benign, but without enough conclusive evidence?

suggest source field doesn't indicate if an entered ID is invalid

Enter '0000000000' into the pubmed ID field and note that, even though the validation returned an error, the field does not show any error messages.

discuss a framework to match tumor's profiled alterations with available biomakers info

Make editing a recent submission more obvious

We currently have a small pencil next to the name to edit an evidence statement. One user stated that this wasn't intuitive, found it very frustrating. Maybe a bigger button, inside the evidence frame, that spells out edit this record. This may be clearer than what appears to be a means of editing the label of the evidence item.

Which kind of classifications of somatic variants are used? Pathogenic vs. "clinically relevant".