{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T08:15:47Z","timestamp":1783325747826,"version":"3.54.6"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T00:00:00Z","timestamp":1778457600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"New Frontiers in Research","award":["NFRFE-2023-00291"],"award-info":[{"award-number":["NFRFE-2023-00291"]}]},{"name":"Alberta Innovates LevMax-Health Program Bridge","award":["222300769"],"award-info":[{"award-number":["222300769"]}]},{"DOI":"10.13039\/501100000196","name":"Canada Foundation for Innovation","doi-asserted-by":"publisher","award":["36605"],"award-info":[{"award-number":["36605"]}],"id":[{"id":"10.13039\/501100000196","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NSERC Discovery","award":["RGPIN-2024-06154"],"award-info":[{"award-number":["RGPIN-2024-06154"]}]},{"name":"NSERC Discovery","award":["RGPIN-2024-04679"],"award-info":[{"award-number":["RGPIN-2024-04679"]}]},{"name":"Alberta Innovates Graduate Student Scholarships"},{"name":"Cumming School of Medicine Graduate Scholarship"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>In genetic association studies, permutation tests serve as a cornerstone to estimate P-values. This is because researchers may design new test statistics without a known closed-form distribution, or the assumption of a well-established test may not hold. However, permutation tests require a vast number of permutations, which is proportional to the magnitude of the actual P-values. When it comes to genome-wide association studies where multiple-test corrections are routinely conducted, the actual P-values are extremely small, requiring a daunting number of permutations that may be beyond the available computational resources. Existing models that reduce the required number of permutations all assume a specific format of the test statistic to exploit its specific statistical properties. We propose Kernel-smoothed permutation, which is a model-free method universally applicable to any statistic. Our tool forms the null distribution of test statistics using a kurtosis-driven transformation, followed by a kernel-based density estimation. We compared our Kernel-smoothed permutation to Na\u00efve permutation using statistics from known closed-form null distributions. Based on 3 frequently used test statistics in association studies, ie t-test, sequence kernel association test, and chi-squared test, we demonstrated that our model reduced the required number of permutations by a magnitude with similar or higher accuracy. Based on a real-world genome-wide association study analysis, we used Crohn's disease cohort to further confirm that our model substantially outperforms the Na\u00efve permutation.<\/jats:p>","DOI":"10.1093\/genetics\/iyag119","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T21:01:07Z","timestamp":1778533267000},"source":"Crossref","is-referenced-by-count":0,"title":["Kernel-smoothed permutation for extreme\n                    <i>P-<\/i>\n                    value estimation in genetic association studies"],"prefix":"10.1093","volume":"233","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-8873-4839","authenticated-orcid":false,"given":"Jiayi","family":"Bian","sequence":"first","affiliation":[{"name":"Department of Mathematics and Statistics, University of Calgary , Calgary, Alberta T2N 1N4 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4555-1490","authenticated-orcid":false,"given":"Jingjing","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Mathematics and Statistics, University of Calgary , Calgary, Alberta T2N 1N4 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5421-3536","authenticated-orcid":false,"given":"M","family":"Ethan MacDonald","sequence":"additional","affiliation":[{"name":"Department of Electrical and Software Engineering, University of Calgary , Calgary, Alberta T2N 1N4 ,","place":["Canada"]},{"name":"Hotchkiss Brain Institute, University of Calgary , Calgary, Alberta T2N 1N4 ,","place":["Canada"]},{"name":"Alberta Children's Hospital Research Institute, University of Calgary , Calgary, Alberta T2N 1N4 ,","place":["Canada"]},{"name":"Department of Biomedical Engineering, University of Calgary , Calgary, Alberta T2N 1N4 ,","place":["Canada"]},{"name":"Department of Radiology, University of Calgary , Calgary, Alberta T2N 1N4 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9938-3627","authenticated-orcid":false,"given":"Lang","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Interdisciplinary Oncology and Department of Genetics, LSU-LCMC Health Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, Louisiana State University , New Orleans, LA 70112 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3795-1873","authenticated-orcid":false,"given":"Quan","family":"Long","sequence":"additional","affiliation":[{"name":"Department of Mathematics and Statistics, University of Calgary , Calgary, Alberta T2N 1N4 ,","place":["Canada"]},{"name":"Hotchkiss Brain Institute, University of Calgary , Calgary, Alberta T2N 1N4 ,","place":["Canada"]},{"name":"Alberta Children's Hospital Research Institute, University of Calgary , Calgary, Alberta T2N 1N4 ,","place":["Canada"]},{"name":"Department of Biochemistry and Molecular Biology, University of Calgary , Calgary, Alberta T2N 1N4 ,","place":["Canada"]},{"name":"Department of Medical Genetics, University of Calgary , Calgary, Alberta T2N 1N4 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9157-367X","authenticated-orcid":false,"given":"Caifeng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Mathematics and Statistics, University of Calgary , Calgary, Alberta T2N 1N4 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