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This study evaluated whether next-generation sequencing (NGS)-based universal screening offers advantages over traditional cascade screening in this specific population. We enrolled 91,857 reproductive-age individuals in Ganzhou, a high-prevalence Hakka region, comparing 37,500 participants who underwent traditional screening (2019\u20132021) with 54,357 who received NGS-based screening. NGS-based screening detected thalassemia carriers at a rate 4.74 times higher than traditional screening (15.05% vs. 3.18%), particularly identifying silent \u03b1-thalassemia and \u03b2\n                    <jats:sup>++<\/jats:sup>\n                    -thalassemia variants that were substantially under-detected by the traditional approach. Crucially, while traditional screening identified 98.7% of \u03b2\u2011high\u2011severity couples, it detected only 71.4% of \u03b1\u2011high\u2011severity couples and missed 28.6% of those at risk for Hb Bart\u2019s hydrops fetalis, as well as 32.7% of couples at risk for severe non\u2011deletional Hb H disease. Traditional screening cost only USD 3.90 per person (versus USD 21.00 for NGS) and provided faster results (6.40 vs. 13.06 days). NGS-based universal screening provides a more accurate assessment of thalassemia burden and genotype diversity, offering critical advantages for prevention programs. Although traditional cascade screening is more cost-effective, its limited sensitivity for \u03b1-thalassemia variants leads to substantial underdetection. These findings underscore the need to tailor screening protocols to local epidemiological and genetic characteristics.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-53002-8","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T07:03:25Z","timestamp":1787036605000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comparing traditional and NGS-based screening strategies for thalassemia in a high-prevalence Hakka population: a population-based study"],"prefix":"10.1038","volume":"16","author":[{"given":"Haimei","family":"Qi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqiong","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulian","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shilian","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianping","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoying","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuling","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haijun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"JunKun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenzhong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shichun","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liyun","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"key":"53002_CR1","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1016\/j.hoc.2022.12.001","volume":"37","author":"N Tesio","year":"2023","unstructured":"Tesio, N. & Bauer, D. 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