VA Profiles

VA Profiles extend generic Core Model classes with specializations to support a particular type of knowledge (e.g. a variant pathogenicity), and/or align with established community terminology and curation conventions (e.g. the ACMG-2015 Guidelines)

The VA-Spec provides a Profile authoring approach that specifies how profiles are defined as YAML-based specifications, from which machine-readable JSON Schema are derived and used by implementers to structure, validate, and exchange variant data in their systems.

The VA-Spec currently supports profiles of four Core Model classes:

  • Statement Profiles support assertions of general knowledge about a variant (e.g. classification of the PTEN:c.35A>T(p.Asn12Ile) variant as likely pathogenic in the ClinVar knowledgebase).

  • Evidence Line Profiles describe how information is interpreted as evidence supporting or disputing a proposition that may ultimately be asserted as true in a Statement (e.g. how data from an experimental functional impact analysis are interpreted to provide strong evidence supporting an assertion that PTEN:c.35A>T(p.Asn12Ile) is pathogenic).

  • Study Result Profiles capture collections of data items about a specific variant from a particular study or analysis, which often represent evidence for higher order Statements about the variant (e.g. functional impact data about PTEN:c.35A>T(p.Asn12Ile) from the MAVE dataset).

  • Proposition Profiles are used exclusively within Statement and Evidence Line objects - where they encapsulate the semantics of the possible fact that may be asserted in a Statement, or against which evidence may be assessed in an Evidence Line (e.g. a proposition that “PTEN:c.35A>T(p.Asn12Ile) is causal for Hamartoma Tumor Syndrome”).

The data example here illustrates how profiles of these different types can be used together to represent a variant pathogenicity classification and the evidence supporting it.

In version 1.0 of the VA-Spec, we distinguish between two categories of profiles:

Base Profiles:

  • Specialize generic VA core classes for a particular type of knowledge, through formal definition of concrete subclasses.

  • This Base Profiling approach is used to create Proposition Profiles and Study Result Profiles, which can be used/referenced within Statement and Evidence Line profiles.

Community Profiles:

  • Layer additional constraints on top of VA core classes to enforce alignment with terminology conventions of a specific community guideline (e.g. ACMG 2015).

  • These constraints are defined using a schema composition approach, which does not result in creation of concrete subclasses for each profile.

  • This approach is used to define Statement and Evidence Line profiles - which incorporate Propositions to specify the possible fact they assert to be true or evaluate evidence against, respectively.

  • Notably, it is possible to define more than one Community Profile for a given knowledge type, each of which aligns with a different community guideline. For example, separate Pathogenicity community profiles may end up being defined to align with current ACMG 2015 Guidelines, and a forthcoming updated version of these guidelines.

For technical guidance around how these types of profiles are authored and implemented, see the Developer Guide section.

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