Assessment of the functionality and usability of open-source rare variant analysis pipelines

Area of Science:

• Genetics and Genomics
• Bioinformatics
• Computational Biology

Background:

• Large-scale sequencing studies increasingly identify rare genetic variants.
• Rare variants are crucial for understanding complex traits but challenging to analyze computationally.
• A lack of comprehensive overviews hinders the selection of appropriate rare variant analysis tools.

Purpose of the Study:

• To systematically review and assess available open-source rare variant analysis pipelines.
• To provide researchers with guidance on selecting suitable tools for their specific genetic analyses.
• To identify gaps and opportunities for future pipeline development.

Main Methods:

• Systematic literature search of MEDLINE and Google Scholar up to November 27, 2023.
• Inclusion of open-source pipelines accepting cohort/case-control genotype data and grouping variants.
• Assessment of 17 identified pipelines based on functionality and usability criteria.

Main Results:

• Seventeen rare variant analysis pipelines were identified, supporting diverse trait types, association tests, and variant weighting schemes.
• No single pipeline currently offers comprehensive scalability and flexibility for all data types.
• Specific pipelines were recommended: STAARpipeline (user-friendly), REGENIE (scalable, maintained), Ravages (multinomial traits), and OrdinalGWAS (ordinal traits).

Conclusions:

• The current landscape of rare variant analysis pipelines is diverse, with no one-size-fits-all solution.
• Tool selection should be guided by specific analysis needs, trait types, and desired scalability.
• Development of a highly flexible, scalable, and user-friendly pipeline is needed to fully leverage rare variants for complex trait discovery.