Evidence map›Paper›PMID 40321767›Full record

ArticleResearch square2025

Selecting variant masks to improve power and replicability of gene-level burden tests.

Trang Nguyen, Ryan Koesterer, Sean J Jurgens, Peter Dornbos, Satoshi Yoshiji, Alex Llamas, Dongkeun Jang, Patrick Smadbeck, Annie Moriondo, Quy Hoang and 4 more

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PubMed Full text at PMC Publisher
In one paragraph

Article in Research square, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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0cells of the map it votes in
0citing papers in PubMed
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1 · What the graph read from it

What it found

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2 · The registry

The trial behind it

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3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

14 authors.

Trang NguyenProgram in Medical & Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID 0009-0004-9413-5965
Ryan KoestererProgram in Medical & Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Sean J JurgensCardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID https://orcid.org/0000-0002-1605-9782
Peter DornbosProgram in Medical & Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Satoshi YoshijiProgram in Medical & Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID https://orcid.org/0000-0001-8863-2413
Alex LlamasProgram in Medical & Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Dongkeun JangProgram in Medical & Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Patrick SmadbeckProgram in Medical & Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Annie MoriondoProgram in Medical & Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Quy HoangProgram in Medical & Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Oliver RuebenackerProgram in Medical & Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Patrick EllinorCardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.ORCID https://orcid.org/0000-0002-2067-0533
Noël BurttProgram in Medical & Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Jason FlannickProgram in Medical & Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID 0000-0002-3618-795X

Funding

The next iteration of the AMP-T2D Knowledge PortalUM1DK105554 · NIDDK · BROAD INSTITUTE, INC. · PI BOEHNKE, MICHAEL L, BURTT, NOEL P · 2020 to 2025
$18.5M
In vivo and in vitro rare coding variant analyses to identify modulations of the adipocyte differentiation pathway that affect T2D riskR01DK125490 · NIDDK · BOSTON CHILDREN'S HOSPITAL · PI Jason Flannick · 2020 to 2026
$3.9M
The Association to Function Knowledge Portal: a genomic data resource for translating GWAS associations to biological effectsU24HG011453 · NHGRI · BROAD INSTITUTE, INC. · PI BURTT, NOEL P, FLANNICK, JASON · 2021 to 2025
$3.4M
NHGRI NIH HHS U24 HG011453NIDDK NIH HHS R01 DK125490NIDDK NIH HHS UM1 DK105554
6 · The paper itself

Abstract

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.

Identifiers

PMID40321767
PMCPMC12047983

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.