{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:07:30Z","timestamp":1786975650820,"version":"build-2736575974"},"reference-count":17,"publisher":"American Medical Association (AMA)","issue":"10","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"\n Importance<\/jats:title>\n Advancing research on fluid biomarkers associated with sport-related concussion (SRC) highlights the importance of detecting low concentrations using ultrasensitive platforms. However, common statistical practices may overlook replicate errors and specimen exclusion, emphasizing the need to explore robust modeling approaches that consider all available replicate data for comprehensive understanding of sample variation and statistical inferences.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To evaluate the impact of replicate error and different biostatistical modeling approaches on SRC biomarker interpretation.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n This cross-sectional study within the Surveillance in High Schools to Reduce the Risk of Concussions and Their Consequences study used data from healthy youth athletes (ages 11-18 years) collected from 3 sites across Canada between September 2019 and November 2021. Data were analyzed from November 2022 to February 2023.<\/jats:p>\n <\/jats:sec>\n \n Exposures<\/jats:title>\n Demographic variables included age, sex, and self-reported history of previous concussion.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n Outcomes of interest were preinjury plasma glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), neurofilament-light (NFL), total tau (t-tau) and phosphorylated-tau-181 (p-tau-181) assayed in duplicate. Bland-Altman analysis determined the 95% limits of agreement (LOAs) for each biomarker. The impact of replicate error was explored using 3 biostatistical modeling approaches assessing the associations of age, sex, and previous concussion on biomarker concentrations: multilevel regression using all available replicate data, single-level regression using the means of replicate data, and single-level regression with replicate means, excluding specimens demonstrating more than 20% coefficient variation (CV).<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n The sample included 149 healthy youth athletes (78 [52%] male; mean [SD] age, 15.74 [1.41] years; 51 participants [34%] reporting \u22651 previous concussions). Wide 95% LOAs were observed for GFAP (\u221217.74 to 18.20 pg\/mL), UCH-L1 (\u221213.80 to 14.77 pg\/mL), and t-tau (65.27% to 150.03%). GFAP and UCH-L1 were significantly associated with sex in multilevel regression (GFAP: effect size, 15.65%; \u03b2\u2009=\u2009\u22120.17; 95% CI, \u22120.30 to \u22120.04];\n P<\/jats:italic>\n \u2009=\u2009.02; UCH-L1: effect size, 17.24%; \u03b2\u2009=\u2009\u22120.19; 95% CI, \u22120.36 to \u22120.02];\n P<\/jats:italic>\n \u2009=\u2009.03) and single-level regression using the means of replicate data (GFAP: effect size, 15.56%; \u03b2\u2009=\u2009\u22120.17; 95% CI, \u22120.30 to \u22120.03];\n P<\/jats:italic>\n \u2009=\u2009.02; UCH-L1: effect size, 18.02%; \u03b2\u2009=\u2009\u22120.20; 95% CI, \u22120.37 to \u22120.03];\n P<\/jats:italic>\n \u2009=\u2009.02); however, there was no association for UCH-L1 after excluding specimens demonstrating more than 20% CV. Excluding specimens demonstrating more than 20% CV resulted in decreased differences associated with sex in GFAP (effect size, 12.29%; \u03b2\u2009=\u2009\u22120.14; 95% CI, \u22120.273 to \u22120.004];\n P<\/jats:italic>\n \u2009=\u2009.04) and increased sex differences in UCH-L1 (effect size, 23.59%; \u03b2\u2009=\u2009\u22120.27; 95% CI, \u22120.55 to 0.01];\n P<\/jats:italic>\n \u2009=\u2009.06), with the widest 95% CIs (ie, least precision) found in UCH-L1.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n In this cross-sectional study of healthy youth athletes, varying levels of agreement between SRC biomarker technical replicates suggested that means of measurements may not optimize precision for population values. Multilevel regression modeling demonstrated how incorporating all available biomarker data could capture replicate variation, avoiding challenges associated with means and percentage of CV exclusion thresholds to produce more representative estimates of association.<\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2023.39733","type":"journal-article","created":{"date-parts":[[2023,10,23]],"date-time":"2023-10-23T11:01:42Z","timestamp":1698058902000},"page":"e2339733","source":"Crossref","is-referenced-by-count":6,"title":["Use of Biostatistical Models to Manage Replicate Error in Concussion Biomarker Research"],"prefix":"10.1001","volume":"6","author":[{"given":"Jason B.","family":"Tabor","sequence":"first","affiliation":[{"name":"Sport Injury Prevention Research Centre, Faculty of Kinesiology, University of Calgary, Calgary, Alberta, Canada"},{"name":"Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada"},{"name":"Alberta Children\u2019s Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Michel","family":"Galarneau","sequence":"additional","affiliation":[{"name":"Sport Injury Prevention Research Centre, Faculty of Kinesiology, University of Calgary, Calgary, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linden C.","family":"Penner","sequence":"additional","affiliation":[{"name":"Sport Injury Prevention Research Centre, Faculty of Kinesiology, University of Calgary, Calgary, Alberta, Canada"},{"name":"Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada"},{"name":"Alberta Children\u2019s Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Cooper","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Ghodsi","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas D.","family":"Fraser","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Clinical Neurological Sciences, Western University, London, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheryl L.","family":"Wellington","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chantel T.","family":"Debert","sequence":"additional","affiliation":[{"name":"Sport Injury Prevention Research Centre, Faculty of Kinesiology, University of Calgary, Calgary, Alberta, Canada"},{"name":"Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada"},{"name":"Alberta Children\u2019s Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada"},{"name":"Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn A.","family":"Emery","sequence":"additional","affiliation":[{"name":"Sport Injury Prevention Research Centre, Faculty of Kinesiology, University of Calgary, Calgary, Alberta, Canada"},{"name":"Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada"},{"name":"Alberta Children\u2019s Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada"},{"name":"Departments of Pediatrics and Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","published-online":{"date-parts":[[2023,10,23]]},"reference":[{"issue":"12","key":"zoi231160r1","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1136\/bjsports-2022-106680","article-title":"Role of biomarkers and emerging technologies in defining and assessing neurobiological recovery after sport-related concussion: a systematic review.","volume":"57","author":"Tabor","year":"2023","journal-title":"Br J Sports Med"},{"issue":"19","key":"zoi231160r2","doi-asserted-by":"publisher","first-page":"2029","DOI":"10.1089\/neu.2019.6956","article-title":"Fluid biomarkers of pediatric mild traumatic brain injury: a systematic review.","volume":"37","author":"Mannix","year":"2020","journal-title":"J Neurotrauma"},{"issue":"12","key":"zoi231160r3","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1080\/14737159.2021.2005583","article-title":"Blood-based traumatic brain injury biomarkers\u2014clinical utilities and regulatory pathways in the United States, Europe and Canada.","volume":"21","author":"Wang","year":"2021","journal-title":"Expert Rev Mol Diagn"},{"issue":"9","key":"zoi231160r4","doi-asserted-by":"publisher","first-page":"782","DOI":"10.1016\/S1474-4422(18)30231-X","article-title":"Serum GFAP and UCH-L1 for prediction of absence of intracranial injuries on head CT (ALERT-TBI): a multicentre observational study.","volume":"17","author":"Bazarian","year":"2018","journal-title":"Lancet Neurol"},{"issue":"9","key":"zoi231160r5","doi-asserted-by":"publisher","first-page":"1063","DOI":"10.1001\/jamaneurol.2017.0655","article-title":"Comparing plasma phospho tau, total tau, and phospho tau\u2013total tau ratio as acute and chronic traumatic brain injury biomarkers.","volume":"74","author":"Rubenstein","year":"2017","journal-title":"JAMA Neurol"},{"issue":"11","key":"zoi231160r6","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1136\/bjsports-2016-097393","article-title":"What is the definition of sports-related concussion: a systematic review.","volume":"51","author":"McCrory","year":"2017","journal-title":"Br J Sports Med"},{"issue":"1","key":"zoi231160r7","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2019.19771","article-title":"Association of blood biomarkers with acute sport-related concussion in collegiate athletes: findings from the NCAA and Department of Defense CARE Consortium.","volume":"3","author":"McCrea","year":"2020","journal-title":"JAMA Netw Open"},{"issue":"8","key":"zoi231160r8","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2020.13191","article-title":"Plasma biomarker concentrations associated with return to sport following sport-related concussion in collegiate athletes\u2014a Concussion Assessment, Research, and Education (CARE) Consortium study.","volume":"3","author":"Pattinson","year":"2020","journal-title":"JAMA Netw Open"},{"issue":"1","key":"zoi231160r9","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1089\/neu.2017.5623","article-title":"Performance evaluation of a multiplex assay for simultaneous detection of four clinically relevant traumatic brain injury biomarkers.","volume":"36","author":"Korley","year":"2018","journal-title":"J Neurotrauma"},{"issue":"10","key":"zoi231160r10","doi-asserted-by":"publisher","first-page":"5582","DOI":"10.1007\/s00415-022-11223-7","article-title":"Investigating the use of plasma pTau181 in retired contact sports athletes.","volume":"269","author":"Vasilevskaya","year":"2022","journal-title":"J Neurol"},{"issue":"6","key":"zoi231160r11","doi-asserted-by":"publisher","first-page":"1249","DOI":"10.1016\/S0731-7085(99)00244-7","article-title":"Validation of immunoassays for bioanalysis: a pharmaceutical industry perspective.","volume":"21","author":"Findlay","year":"2000","journal-title":"J Pharm Biomed Anal"},{"key":"zoi231160r13","doi-asserted-by":"publisher","first-page":"179","DOI":"10.3389\/fneur.2015.00179","article-title":"A practical guide to immunoassay method validation.","volume":"6","author":"Andreasson","year":"2015","journal-title":"Front Neurol"},{"issue":"15-16","key":"zoi231160r14","doi-asserted-by":"publisher","first-page":"1638","DOI":"10.1089\/neu.2022.0501","article-title":"Characterizing factors influencing baseline plasma biomarkers for sport-related concussion in adolescents.","volume":"40","author":"Tabor","year":"2023","journal-title":"J Neurotrauma"},{"issue":"8476","key":"zoi231160r15","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1016\/S0140-6736(86)90837-8","article-title":"Statistical methods for assessing agreement between two methods of clinical measurement.","volume":"1","author":"Bland","year":"1986","journal-title":"Lancet"},{"issue":"2","key":"zoi231160r16","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1177\/096228029900800204","article-title":"Measuring agreement in method comparison studies.","volume":"8","author":"Bland","year":"1999","journal-title":"Stat Methods Med Res"},{"issue":"10","key":"zoi231160r17","doi-asserted-by":"publisher","first-page":"953","DOI":"10.1016\/S1474-4422(19)30282-0","article-title":"Association between plasma GFAP concentrations and MRI abnormalities in patients with CT-negative traumatic brain injury in the TRACK-TBI cohort: a prospective multicentre study.","volume":"18","author":"Yue","year":"2019","journal-title":"Lancet Neurol"},{"key":"zoi231160r12","volume-title":"Assay Guidance Manual","author":"Cox","year":"2019"}],"container-title":["JAMA Network Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/articlepdf\/2810981\/tabor_2023_oi_231160_1697472740.91779.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,23]],"date-time":"2023-10-23T11:01:45Z","timestamp":1698058905000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/fullarticle\/2810981"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,23]]},"references-count":17,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2023,10,2]]}},"URL":"https:\/\/doi.org\/10.1001\/jamanetworkopen.2023.39733","relation":{},"ISSN":["2574-3805"],"issn-type":[{"value":"2574-3805","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,23]]}}}