The goal of a clinical analysis is to identify, from millions of patient's variants, a few ones that may explain the disease. Once selected a few variants, they are classified according to a pathogenicity or clinical significance criteria.
For each selected variant, OpenCGA creates a clinical variant that mainly, consists of a list of clinical variant evidences. And each evidence classifies the variant according to a tier, ACGM value, clinical significance, drug response, trait association and functional effect and more.
OpenCGA provides two types of clinical analysis depending on the outcome:
The tiering interpretation analysis creates and executes, in parallel (multithreaded execution), a variant query for each mode of inheritance (family segregation), those queries filter by a set of consequence types, protein coding biotype and population frequencies and calls the clinical variant creator in order to create clinical variants. In addition, it executes a secondary findings analysis. The tiering interpretation analysis returns a clinical analysis interpretation.
The following diagram shows how the tiering interpretation analysis:
The Zetta interpretation analysis executes an user-defined query in order to retrieve the variants that are processed by the clinical variant creator in order to create clinical variants. In addition, it executes a secondary findings analysis an. The Zetta interpretation analysis returns a clinical analysis interpretation.
The following diagram shows how the Zetta interpretation analysis:
The clinical variant creator creates clinical variant(s) from the input variant(s) according to certain parameters and configuration options. A clinical variant evidence is created for each combination of mode of inheritance, panel and trascript. See diagram below:
To assign the tier value of a selected variant is crucial in clinical analysis. OpenCGA considers three values:
OpenCGA implements two algorithms to assign tier values:
Default tier calculator sets the tier score for each clinical variant evidence taking into account:
The default tier calculator is used by the primary findings, secondary findings, Zetta interpretation and TEAM-based interpretation analysis.
The following diagram shows how the default tier calculator assigns a tier value:
GEL-based tier calculator sets the tier value for each reported event of a given reported variant taking into account:
The GEL-based tier calculator is used by the interpretation analysis based on GEL algorithms.
The following diagram shows how the GEL-based tier calculator assigns a tier value: