{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T04:35:47Z","timestamp":1787978147945,"version":"build-2784847793"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:00:00Z","timestamp":1776816000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008899","name":"University of South Carolina","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008899","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100019550","name":"SPARC","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100019550","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Many biomarkers have been evaluated as potential early detection markers for ovarian cancer. Better understanding of factors associated with inter-individual variation in circulating concentrations of these biomarkers is useful for optimizing their clinical utility for early detection. The study objective was to characterize the associations of sociodemographic-, lifestyle-, and health-related factors in relation to circulating ovarian biomarker concentrations in cancer-free women.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The associations between the independent variables and concentrations of 20 biomarkers were examined in a cross-sectional study of 913 women without ovarian cancer who participated in the ovarian cancer screening arm of the Prostate Lung Colorectal and Ovarian (PLCO) Cancer Screening Trial.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Older age was significantly associated with trends in concentrations of ten biomarkers, eight that increased with age (human epididymis protein 4 [HE4], beta-2-microglobulin [B2M], epidermal growth factor receptor [EGFR], insulin-like growth factor binding protein 2 [IGFBPII], kallikrein-related peptidase [KLK6], mesothelin [MSLN], matrix metalloproteinase-3 [MMP3], and spondin 2 [SPON2]) and two that decreased with age (insulin-like growth factor 2 [IGFII] and inter-alpha-trypsin inhibitor heavy chain H4 [ITIH4]). Compared to women with no family history of breast or ovarian cancer, those with a positive family history had significantly higher concentrations of B2M, EGFR, and hepcidin and lower concentrations of cancer antigen 125 (CA125) and cancer antigen 72.4 (CA72.4). Post hoc case-control comparisons showed case-control heterogeneity concentrated in specific biomarkers; for example, case-control differences for cancer antigen 15.3 (CA15.3) were statistically significant for all 11 independent variables.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Significant trends were observed between age and circulating concentrations of 10 of the 20 biomarkers studied. The strong, consistent findings with age support the need to consider age when assigning thresholds for biomarkers being evaluated for the early detection of ovarian cancer. Integrating data from cancer cases provides valuable context for assessing the generalizability of findings.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/jalm\/jfag044","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T12:21:23Z","timestamp":1774268483000},"page":"806-821","source":"Crossref","is-referenced-by-count":1,"title":["Correlates of Serum Concentrations of Biomarkers Relevant to Ovarian Cancer Screening"],"prefix":"10.1093","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0869-1219","authenticated-orcid":false,"given":"Maxwell","family":"Akonde","sequence":"first","affiliation":[{"name":"Department of Epidemiology and Biostatistics, University of South Carolina Arnold School of Public Health , Columbia, SC ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Whitney Spannuth","family":"Graybill","sequence":"additional","affiliation":[{"name":"Department of Gynecologic Oncology, Medical University of South Carolina , Charleston, SC ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyssa","family":"Clay-Gilmour","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, University of South Carolina Arnold School of Public Health , Columbia, SC ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4566-0822","authenticated-orcid":false,"given":"Jiajia","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, University of South Carolina Arnold School of Public Health , Columbia, SC ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony J","family":"Alberg","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, University of South Carolina Arnold School of Public Health , Columbia, SC ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,4,22]]},"reference":[{"key":"2026070109522528100_jfag044-B1","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1038\/s41416-021-01697-z","article-title":"Prospective evaluation of 92 serum protein biomarkers for early detection of ovarian cancer","volume":"126","author":"Mukama","year":"2022","journal-title":"Br J Cancer"},{"key":"2026070109522528100_jfag044-B2","doi-asserted-by":"crossref","first-page":"81","DOI":"10.31557\/apjcb.2024.9.1.81-85","article-title":"Biomarkers for early detection of ovarian cancer: a review","volume":"9","author":"Bindu","year":"2024","journal-title":"Asia Pacific J Cancer Biol"},{"key":"2026070109522528100_jfag044-B3","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.cca.2012.10.058","article-title":"Detection and monitoring of ovarian cancer","volume":"415","author":"Su","year":"2013","journal-title":"Clin Chim Acta"},{"key":"2026070109522528100_jfag044-B4","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1097\/IGC.0000000000000586","article-title":"Clinical use of cancer biomarkers in epithelial ovarian cancer: updated guidelines from the European Group on Tumor Markers","volume":"26","author":"S\u00f6l\u00e9tormos","year":"2016","journal-title":"Int J Gynecol Cancer"},{"key":"2026070109522528100_jfag044-B5","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1136\/jcp.2004.018077","article-title":"The role of CA125 in clinical practice","volume":"58","author":"Moss","year":"2005","journal-title":"J Clin Pathol"},{"key":"2026070109522528100_jfag044-B6","first-page":"1","article-title":"HE4 in ovarian cancer: from discovery to clinical application","volume":"55","author":"Montagnana","year":"2011","journal-title":"Adv Clin Chem"},{"key":"2026070109522528100_jfag044-B7","doi-asserted-by":"crossref","first-page":"452","DOI":"10.3390\/diagnostics13030452","article-title":"Evaluation of HE4 use in the diagnosis of ovarian cancer: first and second recurrence, and an analysis of HE4 concentration during second- and third-line chemotherapy","volume":"13","author":"Chudecka-G\u0142az","year":"2023","journal-title":"Diagnostics"},{"key":"2026070109522528100_jfag044-B8","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1373\/clinchem.2009.140855","article-title":"A recipe for proteomics diagnostic test development: the OVA1 test, from biomarker discovery to FDA clearance","volume":"56","author":"Fung","year":"2010","journal-title":"Clin Chem"},{"key":"2026070109522528100_jfag044-B9","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s13048-017-0315-6","article-title":"Correlates of circulating ovarian cancer early detection markers and their contribution to discrimination of early detection models: results from the EPIC cohort","volume":"10","author":"Fortner","year":"2017","journal-title":"J Ovarian Res"},{"key":"2026070109522528100_jfag044-B10","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1158\/1055-9965.EPI-12-0616","article-title":"Interpretation of single and serial measures of HE4 and CA125 in asymptomatic women at high risk for ovarian cancer","volume":"21","author":"Urban","year":"2012","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"key":"2026070109522528100_jfag044-B11","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/0024-3205(84)90330-8","article-title":"The effects of smoking on acth and cortisol secretion","volume":"34","author":"Seyler","year":"1984","journal-title":"Life Sci"},{"key":"2026070109522528100_jfag044-B12","doi-asserted-by":"crossref","first-page":"1622","DOI":"10.3390\/cancers14071622","article-title":"Does inflammation contribute to cancer incidence and mortality during aging? A conceptual review","volume":"14","author":"Guerville","year":"2022","journal-title":"Cancers (Basel)"},{"key":"2026070109522528100_jfag044-B13","doi-asserted-by":"crossref","first-page":"100054","DOI":"10.1016\/j.addicn.2022.100054","article-title":"Biomarkers of improved health outcomes after smoking cessation","volume":"5","author":"Benowitz","year":"2023","journal-title":"Addict Neurosci"},{"key":"2026070109522528100_jfag044-B14","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1016\/j.ygyno.2015.06.021","article-title":"A novel diagnostic index combining HE4, CA125 and age may improve triage of women with suspected ovarian cancer\u2014an international multicenter study in women with an ovarian mass","volume":"138","author":"Karlsen","year":"2015","journal-title":"Gynecol Oncol"},{"key":"2026070109522528100_jfag044-B15","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1007\/s13277-011-0256-4","article-title":"Human epididymis protein 4 reference limits and natural variation in a Nordic reference population","volume":"33","author":"Bolstad","year":"2012","journal-title":"Tumor Biol"},{"key":"2026070109522528100_jfag044-B16","doi-asserted-by":"crossref","first-page":"349.e1","DOI":"10.1016\/j.ajog.2011.12.028","article-title":"Serum levels of the ovarian cancer biomarker HE4 are decreased in pregnancy and increase with age","volume":"206","author":"Moore","year":"2012","journal-title":"Am J Obstet Gynecol"},{"key":"2026070109522528100_jfag044-B17","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1093\/jnci\/djr359","article-title":"Potential role of HE4 in multimodal screening for epithelial ovarian cancer","volume":"103","author":"Urban","year":"2011","journal-title":"J Natl Cancer Inst"},{"key":"2026070109522528100_jfag044-B18","doi-asserted-by":"crossref","first-page":"e12977","DOI":"10.7717\/peerj.12977","article-title":"Biomarkers of non-communicable chronic disease: an update on contemporary methods","volume":"10","author":"Al-Hadlaq","year":"2022","journal-title":"PeerJ"},{"key":"2026070109522528100_jfag044-B19","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1158\/1055-9965.EPI-18-0203","article-title":"Chronic medical conditions and CA125 levels among women without ovarian cancer","volume":"27","author":"Akinwunmi","year":"2018","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"key":"2026070109522528100_jfag044-B20","doi-asserted-by":"crossref","first-page":"273S","DOI":"10.1016\/S0197-2456(00)00098-2","article-title":"Design of the prostate, lung, colorectal and ovarian (PLCO) cancer screening trial","volume":"21","author":"Prorok","year":"2000","journal-title":"Control Clin Trials"},{"key":"2026070109522528100_jfag044-B21","doi-asserted-by":"crossref","first-page":"251S","DOI":"10.1016\/S0197-2456(00)00097-0","article-title":"The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial of the National Cancer Institute: history, organization, and status","volume":"21","author":"Gohagan","year":"2000","journal-title":"Control Clin Trials"},{"key":"2026070109522528100_jfag044-B22","first-page":"147","article-title":"Methods for etiologic and early marker investigations in the PLCO trial","volume":"592","author":"Hayes","year":"2005","journal-title":"Mutat Res"},{"key":"2026070109522528100_jfag044-B23","author":"National Cancer Institute"},{"key":"2026070109522528100_jfag044-B24","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1158\/1940-6207.CAPR-10-0195","article-title":"Ovarian cancer biomarker performance in prostate, lung, colorectal, and ovarian cancer screening trial specimens","volume":"4","author":"Cramer","year":"2011","journal-title":"Cancer Prev Res"},{"key":"2026070109522528100_jfag044-B25","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/0021-9681(87)90171-8","article-title":"A new method of classifying prognostic in longitudinal studies: development and validation","volume":"40","author":"Charlson","year":"1987","journal-title":"J Chronic Dis"},{"key":"2026070109522528100_jfag044-B26","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1200\/JCO.2003.02.022","article-title":"Human kallikrein 6 (hK6): a new potential serum biomarker for diagnosis and prognosis of ovarian carcinoma","volume":"21","author":"Diamandis","year":"2003","journal-title":"J Clin Oncol"},{"key":"2026070109522528100_jfag044-B27","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.ygyno.2008.09.043","article-title":"A serum based analysis of ovarian epithelial tumorigenesis","volume":"112","author":"Nolen","year":"2009","journal-title":"Gynecol Oncol"},{"key":"2026070109522528100_jfag044-B28","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1530\/EJE-18-0422","article-title":"IGFBP-2 and aging: a 20-year longitudinal study on IGFBP-2, IGF-I, BMI, insulin sensitivity and mortality in an aging population","volume":"180","author":"Van Den Beld","year":"2019","journal-title":"Eur J Endocrinol"},{"key":"2026070109522528100_jfag044-B29","doi-asserted-by":"crossref","first-page":"314","DOI":"10.4082\/kjfm.18.0057","article-title":"Usefulness of carbohydrate antigen 19-9 test in healthy people and necessity of medical follow-up in individuals with elevated carbohydrate antigen 19-9 level","volume":"40","author":"Lee","year":"2019","journal-title":"Korean J Fam Med"},{"key":"2026070109522528100_jfag044-B30","doi-asserted-by":"crossref","first-page":"2015","DOI":"10.1016\/j.bbamcr.2017.05.007","article-title":"The role of matrix metalloproteinases in aging: tissue remodeling and beyond","volume":"1864","author":"Freitas-Rodr\u00edguez","year":"2017","journal-title":"Biochim Biophys Acta Mol Cell Res"},{"key":"2026070109522528100_jfag044-B31","doi-asserted-by":"crossref","first-page":"101245","DOI":"10.1016\/j.molmet.2021.101245","article-title":"Insulin-like growth factors: ligands, binding proteins, and receptors","volume":"52","author":"LeRoith","year":"2021","journal-title":"Mol Metab"},{"key":"2026070109522528100_jfag044-B32","first-page":"299","article-title":"Racial\/ethnic differences in average CA125 and CA15.3 values and its correlates among postmenopausal women in the USA","volume":"32","author":"Sasamoto","year":"2021","journal-title":"Cancer Causes Control"},{"key":"2026070109522528100_jfag044-B33","author":"American Psychological Association"},{"key":"2026070109522528100_jfag044-B34","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1111\/j.1749-6632.1999.tb08111.x","article-title":"Socioeconomic status and chronic stress. Does stress account for SES effects on health?","volume":"896","author":"Baum","year":"1999","journal-title":"Ann N Y Acad Sci"},{"key":"2026070109522528100_jfag044-B35","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1161\/01.CIR.101.10.1206","article-title":"Aspirin","volume":"101","author":"Awtry","year":"2000","journal-title":"Circulation"},{"key":"2026070109522528100_jfag044-B36","volume-title":"Statistical quality control for quantitative measurement procedures: principles and definitions","author":"Clinical and Laboratory Standards Institute Guideline","year":"2016","edition":"C24 4th ed"},{"key":"2026070109522528100_jfag044-B37","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1016\/S0015-0282(16)49390-8","article-title":"CA-125 levels in endometriosis","volume":"45","author":"Patton","year":"1986","journal-title":"Fertil Steril"},{"key":"2026070109522528100_jfag044-B38","doi-asserted-by":"crossref","first-page":"S107","DOI":"10.1007\/s00404-010-1717-5","article-title":"Highly elevated serum CA-125 levels in patients with non-malignant gynecological diseases","volume":"283","author":"He","year":"2011","journal-title":"Arch Gynecol Obstet"}],"container-title":["The Journal of Applied Laboratory Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jalm\/article-pdf\/11\/4\/806\/68136806\/jfag044.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jalm\/article-pdf\/11\/4\/806\/68136806\/jfag044.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T16:27:55Z","timestamp":1782923275000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jalm\/article\/11\/4\/806\/8660969"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,22]]},"references-count":38,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4,22]]},"published-print":{"date-parts":[[2026,7,1]]}},"URL":"https:\/\/doi.org\/10.1093\/jalm\/jfag044","relation":{},"ISSN":["2475-7241"],"issn-type":[{"value":"2475-7241","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,7]]},"published":{"date-parts":[[2026,4,22]]}}}