{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T18:39:14Z","timestamp":1792694354231,"version":"4.5.0"},"reference-count":28,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"vor","delay-in-days":250,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Science Foundation of Hunan Province","award":["2023JJ30422"],"award-info":[{"award-number":["2023JJ30422"]}]},{"name":"Health Research Project of Hunan Provincial Health Commission","award":["W20243089"],"award-info":[{"award-number":["W20243089"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>STUDY QUESTION<\/jats:title>\n                    <jats:p>In best-prognosis preimplantation genetic testing (PGT) cycles\u2014defined by the availability of multiple transferable embryos\u2014can polygenic embryo screening (PES) provide meaningful, context-dependent stratification that may influence embryo prioritization?<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>SUMMARY ANSWER<\/jats:title>\n                    <jats:p>In a sister-pair breast cancer validation cohort, the polygenic risk score (PRS) showed modest predictive performance, and when applied retrospectively to embryos, differences in modelled susceptibility were context-dependent, primarily influenced by the number of available embryos, parental polygenic risk profile, the limited discriminative power of the PRS, and the presence of disease-related monogenic variants.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>WHAT IS KNOWN ALREADY<\/jats:title>\n                    <jats:p>The use of PES as an embryo-ranking tool within PGT remains controversial. Its potential utility depends on embryo availability and clinical context, yet empirical evaluations in real-world PGT settings remain limited.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>STUDY DESIGN, SIZE, DURATION<\/jats:title>\n                    <jats:p>This retrospective study combined (i) family-based validation using 184 affected\u2013unaffected sisters, and (ii) embryo-level analysis of 310 PGT for monogenic disorders (PGT-M) cycles comprising 1722 embryos. Simulation modelling estimated differences in modelled embryo-level PRS percentile ranking under varying clinical and genetic scenarios.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>PARTICIPANTS\/MATERIALS, SETTING, METHODS<\/jats:title>\n                    <jats:p>Family-based performance of a breast cancer PRS was evaluated using affected and unaffected sister pairs. Embryo genotype data from PGT-M cycles were used to model PES under varying conditions, including the number of transferable embryos, the presence of pathogenic monogenic variants, and parental PRS percentile strata.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>MAIN RESULTS AND THE ROLE OF CHANCE<\/jats:title>\n                    <jats:p>Within-family PRS discrimination was modest: sisters in the top 10% of the PRS distribution had 4.07-fold higher breast cancer odds than their siblings (95% CI: 1.55\u20136.33). In the PGT-M cohort, 55% of cycles produced \u22653 transferable embryos, with a median within-cycle spread of approximately 25 PRS percentiles. In BRCA1\/2-related cycles, PRS did not introduce distinct risk strata but revealed dispersion in modelled susceptibility among embryos sharing the same monogenic background. Embryo PRS distributions were concordant with parental profiles: 71% of embryos from couples with parental PRS \u226580th percentile were classified as high-PRS, compared with 7% when at least one parent was \u226420th percentile. Simulation analyses indicated that PRS-based embryo prioritization was associated with a 12-point lower mean embryo PRS percentile compared with morphology-based embryo prioritization in PGT-M cycles, attenuating to 10 points when PGT-A was incorporated. These differences reflect a statistical surrogate outcome only and do not demonstrate reduction in lifetime disease incidence or other clinical benefits.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>LARGE SCALE DATA<\/jats:title>\n                    <jats:p>N\/A<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>LIMITATIONS, REASONS FOR CAUTION<\/jats:title>\n                    <jats:p>These findings derive from high-prognosis PGT-M cycles and may not generalize to other PGT settings. Current PRS models have modest performance and variable transferability across ancestries. The retrospective design, limited subgroup sizes, and modelling assumptions (e.g. aneuploidy and sex distribution) further constrain interpretation. The primary simulation outcome\u2014PRS percentile shift\u2014is a hypothesis-generating surrogate endpoint, not a clinical outcome; clinical benefit was not assessed or demonstrated. These findings should not be interpreted as supporting routine clinical implementation of PES; premature use may increase parental anxiety, inequitable access, and pressure to rank embryos using predictions that remain unvalidated at the embryo level.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>WIDER IMPLICATIONS OF THE FINDINGS<\/jats:title>\n                    <jats:p>This study provides an empirical framework for evaluating the current limits of PES within PGT. The observed PRS percentile shifts appear concentrated in best-prognosis cycles with multiple transferable embryos and elevated parental PRS, whereas little change is observed when embryo numbers are limited or risk is dominated by high-penetrance monogenic variants. These findings are hypothesis-generating and may inform future prospective research and ethical discussion, while underscoring that clinical utility and implementation require further validation within appropriately governed settings.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>FUNDING<\/jats:title>\n                    <jats:p>This study was funded by Major Scientific Program of CITIC Group (No. 2023ZXKYB34100), the Science Foundation of Hunan Province (Grant 2023JJ30422), and Health Research Project of Hunan Provincial Health Commission (grant number: W20243089).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCLOSURES<\/jats:title>\n                    <jats:p>The authors declare no conflicts of interest.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/hropen\/hoag078","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T11:22:21Z","timestamp":1788780141000},"source":"Crossref","is-referenced-by-count":0,"title":["A context-specific evaluation of polygenic embryo screening in best-prognosis preimplantation genetic testing cycles"],"prefix":"10.1093","volume":"2026","author":[{"given":"Qi","family":"Wang","sequence":"first","affiliation":[{"name":"Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive & Genetic Hospital of CITIC-Xiangya , Changsha,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0111-8193","authenticated-orcid":false,"given":"SiCong","family":"Zeng","sequence":"additional","affiliation":[{"name":"Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive & Genetic Hospital of CITIC-Xiangya , Changsha,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"ZiXu","family":"Chen","sequence":"additional","affiliation":[{"name":"Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive & Genetic Hospital of CITIC-Xiangya , Changsha,","place":["China"]},{"name":"NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Xiangya School of Basic Medical Sciences, Central South University , Changsha,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Hu","sequence":"additional","affiliation":[{"name":"Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive & Genetic Hospital of CITIC-Xiangya , Changsha,","place":["China"]},{"name":"NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Xiangya School of Basic Medical Sciences, Central South University , Changsha,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Hu","sequence":"additional","affiliation":[{"name":"Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive & Genetic Hospital of CITIC-Xiangya , Changsha,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0865-9526","authenticated-orcid":false,"given":"PingYuan","family":"Xie","sequence":"additional","affiliation":[{"name":"Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive & Genetic Hospital of CITIC-Xiangya , Changsha,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5701-6703","authenticated-orcid":false,"given":"Juan","family":"Du","sequence":"additional","affiliation":[{"name":"Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive & Genetic Hospital of CITIC-Xiangya , Changsha,","place":["China"]},{"name":"NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Xiangya School of Basic Medical Sciences, Central South University , Changsha,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"XiLin","family":"Xu","sequence":"additional","affiliation":[{"name":"Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive & Genetic Hospital of CITIC-Xiangya , Changsha,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"GuangXiu","family":"Lu","sequence":"additional","affiliation":[{"name":"Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive & Genetic Hospital of CITIC-Xiangya , Changsha,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8359-4654","authenticated-orcid":false,"given":"YueQiu","family":"Tan","sequence":"additional","affiliation":[{"name":"Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive & Genetic Hospital of CITIC-Xiangya , Changsha,","place":["China"]},{"name":"NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Xiangya School of Basic Medical Sciences, Central South University , Changsha,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3877-2546","authenticated-orcid":false,"given":"Ge","family":"Lin","sequence":"additional","affiliation":[{"name":"Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive & Genetic Hospital of CITIC-Xiangya , Changsha,","place":["China"]},{"name":"NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Xiangya School of Basic Medical Sciences, Central South University , Changsha,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,9,8]]},"reference":[{"key":"2026102213581000700_hoag078-B1","first-page":"S0015","article-title":"Use of preimplantation genetic testing for polygenic disorders (PGT-P): an Ethics Committee opinion","author":"ASRM Ethics and Practice Committees","year":"2025","journal-title":"Fertil Steril"},{"key":"2026102213581000700_hoag078-B2","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1056\/NEJMoa1913948","article-title":"Breast cancer risk genes \u2013 association analysis in more than 113,000 women","volume":"384","author":"Breast Cancer Association Consortium","year":"2021","journal-title":"N Engl J Med"},{"key":"2026102213581000700_hoag078-B3","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1016\/j.ajhg.2018.07.015","article-title":"A one-penny imputed genome from next-generation reference panels","volume":"103","author":"Browning","year":"2018","journal-title":"Am J Hum Genet"},{"key":"2026102213581000700_hoag078-B4","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1093\/humupd\/dmae012","article-title":"Screening embryos for polygenic disease risk: a review of epidemiological, clinical, and ethical considerations","volume":"30","author":"Capalbo","year":"2024","journal-title":"Hum Reprod Update"},{"key":"2026102213581000700_hoag078-B5","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s13742-015-0047-8","article-title":"Second-generation PLINK: rising to the challenge of larger and richer datasets","volume":"4","author":"Chang","year":"2015","journal-title":"Gigascience"},{"key":"2026102213581000700_hoag078-B6","doi-asserted-by":"crossref","first-page":"hoaa018","DOI":"10.1093\/hropen\/hoaa018","article-title":"ESHRE PGT Consortium good practice recommendations for the detection of monogenic disorders","volume":"2020","author":"ESHRE PGT-M Working Group","year":"2020","journal-title":"Hum Reprod Open"},{"key":"2026102213581000700_hoag078-B7","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1016\/S0015-0282(00)00518-5","article-title":"Blastocyst score affects implantation and pregnancy outcome: towards a single blastocyst transfer","volume":"73","author":"Gardner","year":"2000","journal-title":"Fertil Steril"},{"key":"2026102213581000700_hoag078-B8","doi-asserted-by":"crossref","first-page":"hoab031","DOI":"10.1093\/hropen\/hoab031","article-title":"The International Fertility Education Initiative: research and action to improve fertility awareness","volume":"2021","author":"Harper","year":"2021","journal-title":"Hum Reprod Open"},{"key":"2026102213581000700_hoag078-B9","first-page":"586","article-title":"Polygenic risk scores for prediction of breast cancer risk in Asian populations","volume":"24","author":"Ho","year":"2022","journal-title":"Genet Med Off J Am Coll Med Genet"},{"key":"2026102213581000700_hoag078-B10","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1016\/j.cell.2019.10.033","article-title":"Screening Human Embryos for Polygenic Traits Has Limited Utility","volume":"179","author":"Karavani","year":"2019","journal-title":"Cell"},{"key":"2026102213581000700_hoag078-B11","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1016\/j.ajhg.2020.09.001","article-title":"Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk","volume":"107","author":"Kramer","year":"2020","journal-title":"Am J Hum Genet"},{"key":"2026102213581000700_hoag078-B12","doi-asserted-by":"crossref","first-page":"2402","DOI":"10.1001\/jama.2017.7112","article-title":"Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers","volume":"317","author":"Kuchenbaecker","year":"2017","journal-title":"JAMA"},{"key":"2026102213581000700_hoag078-B13","first-page":"1726","article-title":"The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant","volume":"23","author":"Lakeman","year":"2021","journal-title":"Genet Med Off J Am Coll Med Genet"},{"key":"2026102213581000700_hoag078-B14","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1038\/s41525-025-00546-9","article-title":"Clinical implications of rare and common variation in preimplantation genetic testing for breast cancer","volume":"11","author":"Lencz","year":"2026","journal-title":"NPJ Genomic Med"},{"key":"2026102213581000700_hoag078-B15","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s13073-020-00742-5","article-title":"Polygenic risk scores: from research tools to clinical instruments","volume":"12","author":"Lewis","year":"2020","journal-title":"Genome Med"},{"key":"2026102213581000700_hoag078-B16","author":"Li","year":"2013"},{"key":"2026102213581000700_hoag078-B17","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1016\/j.ajhg.2019.11.006","article-title":"Genomic Medicine Year in Review: 2019","volume":"105","author":"Manolio","year":"2019","journal-title":"Am J Hum Genet"},{"key":"2026102213581000700_hoag078-B18","doi-asserted-by":"crossref","first-page":"101662","DOI":"10.1016\/j.gim.2025.101662","article-title":"Challenges in clinical translation of polygenic risk score analyses: a systematic review","volume":"28","author":"Mart\u00ednez-Minguet","year":"2026","journal-title":"Genet Med"},{"key":"2026102213581000700_hoag078-B19","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.ajhg.2018.11.002","article-title":"Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes","volume":"104","author":"Mavaddat","year":"2019","journal-title":"Am J Hum Genet"},{"key":"2026102213581000700_hoag078-B20","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1101\/gr.107524.110","article-title":"The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data","volume":"20","author":"McKenna","year":"2010","journal-title":"Genome Res"},{"key":"2026102213581000700_hoag078-B21","first-page":"2825","article-title":"Scikit-learn: machine learning in Python","volume":"12","author":"Pedregosa","year":"2011","journal-title":"J Mach Learn Res"},{"key":"2026102213581000700_hoag078-B22","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.fertnstert.2018.01.002","article-title":"The use of preimplantation genetic testing for aneuploidy (PGT-A): a committee opinion","volume":"109","author":"Penzias","year":"2018","journal-title":"Fertil Steril"},{"key":"2026102213581000700_hoag078-B23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12687-021-00573-w","article-title":"A systematic review of the views of healthcare professionals on the scope of preimplantation genetic testing","volume":"13","author":"Siermann","year":"2022","journal-title":"J Community Genet"},{"key":"2026102213581000700_hoag078-B24","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1016\/j.gim.2022.03.001","article-title":"A review of normative documents on preimplantation genetic testing: recommendations for PGT-P","volume":"24","author":"Siermann","year":"2022","journal-title":"Genet Med"},{"key":"2026102213581000700_hoag078-B25","doi-asserted-by":"crossref","first-page":"845","DOI":"10.3389\/fendo.2019.00845","article-title":"Utility and First Clinical Application of Screening Embryos for Polygenic Disease Risk Reduction","volume":"10","author":"Treff","year":"2019","journal-title":"Front Endocrinol (Lausanne)"},{"key":"2026102213581000700_hoag078-B26","doi-asserted-by":"crossref","first-page":"648","DOI":"10.3390\/genes11060648","article-title":"Preimplantation genetic testing for polygenic disease relative risk reduction: evaluation of genomic index performance in 11,883 adult sibling pairs","volume":"11","author":"Treff","year":"2020","journal-title":"Genes (Basel)"},{"key":"2026102213581000700_hoag078-B27","doi-asserted-by":"crossref","first-page":"103647","DOI":"10.1016\/j.ejmg.2019.04.004","article-title":"Validation of concurrent preimplantation genetic testing for polygenic and monogenic disorders, structural rearrangements, and whole and segmental chromosome aneuploidy with a single universal platform","volume":"62","author":"Treff","year":"2019","journal-title":"Eur J Med Genet"},{"key":"2026102213581000700_hoag078-B28","doi-asserted-by":"crossref","first-page":"e2149030","DOI":"10.1001\/jamanetworkopen.2021.49030","article-title":"Incorporating Polygenic Risk Scores and Nongenetic Risk Factors for Breast Cancer Risk Prediction Among Asian Women","volume":"5","author":"Yang","year":"2022","journal-title":"JAMA Netw Open"}],"container-title":["Human Reproduction Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/hropen\/advance-article-pdf\/doi\/10.1093\/hropen\/hoag078\/70994278\/hoag078.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hropen\/article-pdf\/2026\/4\/hoag078\/70994278\/hoag078.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hropen\/article-pdf\/2026\/4\/hoag078\/70994278\/hoag078.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T17:58:19Z","timestamp":1792691899000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hropen\/article\/doi\/10.1093\/hropen\/hoag078\/8787926"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026]]},"references-count":28,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,9,17]]}},"URL":"https:\/\/doi.org\/10.1093\/hropen\/hoag078","relation":{},"ISSN":["2399-3529"],"issn-type":[{"value":"2399-3529","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026]]},"published":{"date-parts":[[2026]]},"article-number":"hoag078"}}