Selecting variant masks to improve power and replicability of gene-level burden tests Article Swipe
Jason Flannick
,
Trang Thi Huyen Nguyen
,
Ryan Koesterer
,
Sean J. Jurgens
,
Peter Dornbos
,
Satoshi Yoshiji
,
Armando Llamas
,
Dongkeun Jang
,
Patrick Smadbeck
,
Annie Moriondo
,
Quy Hoang
,
Oliver Ruebenacker
,
Patrick T. Ellinor
,
Noël P. Burtt
·
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.21203/rs.3.rs-6322956/v1
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.21203/rs.3.rs-6322956/v1
Rare coding variant association studies typically perform gene-level association tests in which variants are filtered (or “masked”) and aggregated based on functional annotation and allele frequency. As there is little research and no consensus regarding masking strategies to use, we investigated the impact of masking strategies on gene-level burden tests, the most widely used and interpretable type of aggregate association test. A systematic review of 234 studies catalogued 664 masks and masking strategies that rarely repeated across studies. Analyzing 54 traits within 189,947 UK Biobank exomes, we show that the number of significant associations greatly depends on the masking strategy employed (ranging from 58 to 2,523 associations) and, consequently, separate published analyses of this dataset report minimally overlapping associations (<30%). By empirically determining mask combinations that maximize the number of significant associations, we propose masking strategies that detect twice as many significant low-frequency and rare variant associations as the “average” strategies previously employed, with consistent performance across many traits. Our analyses demonstrate the inconsistency of previously used variant masking strategies and provide a simple solution to increase power and replicability in future studies.
Related Topics
Concepts
Masking (illustration)
Biobank
Association test
Association (psychology)
Genetic association
Coding (social sciences)
Computer science
Statistical power
Computational biology
Biology
Genetics
Statistics
Single-nucleotide polymorphism
Gene
Psychology
Mathematics
Genotype
Visual arts
Art
Psychotherapist
Metadata
- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.21203/rs.3.rs-6322956/v1
- https://www.researchsquare.com/article/rs-6322956/latest.pdf
- OA Status
- gold
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4409461002
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4409461002Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.21203/rs.3.rs-6322956/v1Digital Object Identifier
- Title
-
Selecting variant masks to improve power and replicability of gene-level burden testsWork title
- Type
-
preprintOpenAlex work type
- Language
-
enPrimary language
- Publication year
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2025Year of publication
- Publication date
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2025-04-15Full publication date if available
- Authors
-
Jason Flannick, Trang Thi Huyen Nguyen, Ryan Koesterer, Sean J. Jurgens, Peter Dornbos, Satoshi Yoshiji, Armando Llamas, Dongkeun Jang, Patrick Smadbeck, Annie Moriondo, Quy Hoang, Oliver Ruebenacker, Patrick T. Ellinor, Noël P. BurttList of authors in order
- Landing page
-
https://doi.org/10.21203/rs.3.rs-6322956/v1Publisher landing page
- PDF URL
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https://www.researchsquare.com/article/rs-6322956/latest.pdfDirect link to full text PDF
- Open access
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YesWhether a free full text is available
- OA status
-
goldOpen access status per OpenAlex
- OA URL
-
https://www.researchsquare.com/article/rs-6322956/latest.pdfDirect OA link when available
- Concepts
-
Masking (illustration), Biobank, Association test, Association (psychology), Genetic association, Coding (social sciences), Computer science, Statistical power, Computational biology, Biology, Genetics, Statistics, Single-nucleotide polymorphism, Gene, Psychology, Mathematics, Genotype, Visual arts, Art, PsychotherapistTop concepts (fields/topics) attached by OpenAlex
- Cited by
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0Total citation count in OpenAlex
- Related works (count)
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10Other works algorithmically related by OpenAlex
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