{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T05:45:19Z","timestamp":1790315119194,"version":"4.1.0"},"reference-count":49,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T00:00:00Z","timestamp":1783641600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["clinicalkey.com","clinicalkey.com.au","clinicalkey.es","clinicalkey.fr","clinicalkey.jp","thelancet.com","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["eBioMedicine"],"published-print":{"date-parts":[[2026,8]]},"DOI":"10.1016\/j.ebiom.2026.106407","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T13:06:58Z","timestamp":1785157618000},"page":"106407","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":1,"special_numbering":"C","title":["Common analysis pitfalls in longitudinal ctDNA studies: lead time, sensitivity and immortal time bias"],"prefix":"10.1016","volume":"130","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-1009-3777","authenticated-orcid":false,"given":"Dominik","family":"Hlauschek","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Dandachi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1002-2118","authenticated-orcid":false,"given":"Michael","family":"Gnant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Parsons","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"DeMichele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Heitzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7438-1465","authenticated-orcid":false,"given":"Gabriel","family":"Rinnerthaler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9482-9191","authenticated-orcid":false,"given":"Marija","family":"Balic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.ebiom.2026.106407_bib1","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1002\/1878-0261.13671","article-title":"Clinical applications of next-generation sequencing-based ctDNA analyses in breast cancer: defining treatment targets and dynamic changes during disease progression","volume":"19","author":"Klocker","year":"2025","journal-title":"Mol Oncol"},{"key":"10.1016\/j.ebiom.2026.106407_bib2","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1016\/j.jmoldx.2023.09.004","article-title":"Recommendations for cell-free DNA assay validations: a joint consensus recommendation of the Association for molecular pathology and college of American pathologists","volume":"25","author":"Lockwood","year":"2023","journal-title":"J Mol Diagn"},{"key":"10.1016\/j.ebiom.2026.106407_bib3","doi-asserted-by":"crossref","DOI":"10.3390\/cancers13225698","article-title":"Advantages and challenges of using ctDNA NGS to assess the presence of minimal residual disease (MRD) in solid tumors","volume":"13","author":"Larrib\u00e8re","year":"2021","journal-title":"Cancers (Basel)"},{"key":"10.1016\/j.ebiom.2026.106407_bib4","doi-asserted-by":"crossref","first-page":"7375","DOI":"10.1038\/s41598-018-25810-0","article-title":"Evaluation of pre-analytical factors affecting plasma DNA analysis","volume":"8","author":"Markus","year":"2018","journal-title":"Sci Rep"},{"key":"10.1016\/j.ebiom.2026.106407_bib5","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1007\/s10549-024-07508-2","article-title":"Longitudinal monitoring of circulating tumor DNA to detect relapse early and predict outcome in early breast cancer","volume":"209","author":"Garcia-Murillas","year":"2025","journal-title":"Breast Cancer Res Treat"},{"key":"10.1016\/j.ebiom.2026.106407_bib6","first-page":"167","article-title":"Circulating tumor DNA as a biomarker of prognosis prediction in colorectal cancer: a systematic review and meta-analysis","volume":"5","author":"Zhou","year":"2025","journal-title":"J Natl Cancer Cent"},{"key":"10.1016\/j.ebiom.2026.106407_bib7","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.ygyno.2022.09.004","article-title":"Circulating tumor DNA monitoring for early recurrence detection in epithelial ovarian cancer","volume":"167","author":"Hou","year":"2022","journal-title":"Gynecol Oncol"},{"key":"10.1016\/j.ebiom.2026.106407_bib8","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1158\/1078-0432.CCR-23-2326","article-title":"Comparison of circulating tumor DNA assays for molecular residual disease detection in early-stage triple-negative breast cancer","volume":"30","author":"Coakley","year":"2024","journal-title":"Clin Cancer Res"},{"key":"10.1016\/j.ebiom.2026.106407_bib9","article-title":"Real-world utilization and performance of circulating tumor DNA monitoring to predict recurrence in solid tumors","volume":"2","author":"Hoang","year":"2025","journal-title":"JCO Oncol Adv"},{"key":"10.1016\/j.ebiom.2026.106407_bib10","doi-asserted-by":"crossref","DOI":"10.1111\/cts.70185","article-title":"Establishing a common lexicon for circulating tumor DNA analysis and molecular residual disease: insights from the BLOODPAC consortium","volume":"18","author":"Hadd","year":"2025","journal-title":"Clin Transl Sci"},{"key":"10.1016\/j.ebiom.2026.106407_bib11","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.annonc.2022.11.005","article-title":"Results of the c-TRAK TN trial: a clinical trial utilising ctDNA mutation tracking to detect molecular residual disease and trigger intervention in patients with moderate- and high-risk early-stage triple-negative breast cancer","volume":"34","author":"Turner","year":"2023","journal-title":"Ann Oncol"},{"key":"10.1016\/j.ebiom.2026.106407_bib12","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1016\/j.ccell.2023.04.008","article-title":"Clinical significance and biology of circulating tumor DNA in high-risk early-stage HER2-negative breast cancer receiving neoadjuvant chemotherapy","volume":"41","author":"Magbanua","year":"2023","journal-title":"Cancer Cell"},{"key":"10.1016\/j.ebiom.2026.106407_bib13","doi-asserted-by":"crossref","DOI":"10.1016\/j.esmoop.2024.102390","article-title":"Circulating tumor DNA for predicting recurrence in patients with operable breast cancer: a systematic review and meta-analysis","volume":"9","author":"Nader-Marta","year":"2024","journal-title":"ESMO Open"},{"key":"10.1016\/j.ebiom.2026.106407_bib14","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/j.annonc.2025.01.021","article-title":"Whole genome sequencing-powered ctDNA sequencing for breast cancer detection","volume":"36","author":"Garcia-Murillas","year":"2025","journal-title":"Ann Oncol"},{"key":"10.1016\/j.ebiom.2026.106407_bib15","doi-asserted-by":"crossref","first-page":"4255","DOI":"10.1158\/1078-0432.CCR-18-3663","article-title":"Personalized detection of circulating tumor DNA antedates breast cancer metastatic recurrence","volume":"25","author":"Coombes","year":"2019","journal-title":"Clin Cancer Res"},{"key":"10.1016\/j.ebiom.2026.106407_bib16","doi-asserted-by":"crossref","first-page":"2556","DOI":"10.1158\/1078-0432.CCR-19-3005","article-title":"Sensitive detection of minimal residual disease in patients treated for early-stage breast cancer","volume":"26","author":"Parsons","year":"2020","journal-title":"Clin Cancer Res"},{"key":"10.1016\/j.ebiom.2026.106407_bib17","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1111\/j.0006-341X.2000.00337.x","article-title":"Time-dependent ROC curves for censored survival data and a diagnostic marker","volume":"56","author":"Heagerty","year":"2000","journal-title":"Biometrics"},{"key":"10.1016\/j.ebiom.2026.106407_bib18","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1186\/s12874-017-0332-6","article-title":"Time-dependent ROC curve analysis in medical research: current methods and applications","volume":"17","author":"Kamarudin","year":"2017","journal-title":"BMC Med Res Methodol"},{"key":"10.1016\/j.ebiom.2026.106407_bib19","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1002\/sim.4443","article-title":"Performance of binary markers for censored failure time outcome: nonparametric approach based on proportions","volume":"31","author":"Antolini","year":"2012","journal-title":"Stat Med"},{"key":"10.1016\/j.ebiom.2026.106407_bib20","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1111\/j.0006-341X.2005.030814.x","article-title":"Survival model predictive accuracy and ROC curves","volume":"61","author":"Heagerty","year":"2005","journal-title":"Biometrics"},{"key":"10.1016\/j.ebiom.2026.106407_bib21","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1177\/0272989X18801312","article-title":"A tutorial on evaluating the time-varying discrimination accuracy of survival models used in dynamic decision making","volume":"38","author":"Bansal","year":"2018","journal-title":"Med Decis Mak"},{"key":"10.1016\/j.ebiom.2026.106407_bib22","series-title":"ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical principles for clinical trials","year":"2020"},{"key":"10.1016\/j.ebiom.2026.106407_bib23","doi-asserted-by":"crossref","first-page":"2963","DOI":"10.1200\/JCO.2013.49.5283","article-title":"Challenges of guarantee-time bias","volume":"31","author":"Giobbie-Hurder","year":"2013","journal-title":"J Clin Oncol"},{"key":"10.1016\/j.ebiom.2026.106407_bib24","doi-asserted-by":"crossref","first-page":"237","DOI":"10.4174\/astr.2024.106.4.237","article-title":"Commentary on \u201cPrognosis according to the timing of recurrence in breast cancer\u201d (Ann Surg Treat Res 2023;104:1-9)","volume":"106","author":"Hlauschek","year":"2024","journal-title":"Ann Surg Treat Res"},{"key":"10.1016\/j.ebiom.2026.106407_bib25","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1001\/jama.2020.9151","article-title":"Immortal time bias in observational studies","volume":"325","author":"Yadav","year":"2021","journal-title":"JAMA"},{"key":"10.1016\/j.ebiom.2026.106407_bib26","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1001\/jamaoncol.2019.1838","article-title":"Assessment of molecular relapse detection in early-stage breast cancer","volume":"5","author":"Garcia-Murillas","year":"2019","journal-title":"JAMA Oncol"},{"key":"10.1016\/j.ebiom.2026.106407_bib27","article-title":"Serial postoperative circulating tumor DNA assessment has strong prognostic value during long-term Follow-Up in patients with breast cancer","volume":"8","author":"Shaw","year":"2024","journal-title":"JCO Precision Oncology"},{"key":"10.1016\/j.ebiom.2026.106407_bib28","doi-asserted-by":"crossref","first-page":"2786","DOI":"10.1038\/s41467-025-57988-z","article-title":"Dynamic ctDNA tracking stratifies relapse risk for triple negative breast cancer patients receiving neoadjuvant chemotherapy","volume":"16","author":"Li","year":"2025","journal-title":"Nat Commun"},{"key":"10.1016\/j.ebiom.2026.106407_bib29","doi-asserted-by":"crossref","first-page":"2968","DOI":"10.1158\/2159-8290.CD-21-0634","article-title":"Detecting liquid remnants of solid tumors: circulating tumor DNA minimal residual disease","volume":"11","author":"Moding","year":"2021","journal-title":"Cancer Discovery"},{"key":"10.1016\/j.ebiom.2026.106407_bib30","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1111\/tri.13081","article-title":"An unjustified benefit: immortal time bias in the analysis of time-dependent events","volume":"31","author":"Gleiss","year":"2018","journal-title":"Transplant Int"},{"key":"10.1016\/j.ebiom.2026.106407_bib31","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1002\/sim.6765","article-title":"Survival probabilities with time-dependent treatment indicator: quantities and non-parametric estimators","volume":"35","author":"Bernasconi","year":"2016","journal-title":"Stat Med"},{"key":"10.1016\/j.ebiom.2026.106407_bib32","doi-asserted-by":"crossref","first-page":"2024","DOI":"10.1002\/sim.8888","article-title":"Displaying survival of patient groups defined by covariate paths: extensions of the Kaplan-Meier estimator","volume":"40","author":"Jay","year":"2021","journal-title":"Stat Med"},{"key":"10.1016\/j.ebiom.2026.106407_bib33","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1002\/sim.4780030106","article-title":"A non-parametric graphical representation of the relationship between survival and the occurrence of an event: application to responder versus non-responder bias","volume":"3","author":"Simon","year":"1984","journal-title":"Stat Med"},{"key":"10.1016\/j.ebiom.2026.106407_bib34","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.1080\/02664763.2018.1558187","article-title":"Graphical representation of survival curves in the presence of time-dependent categorical covariates with application to liver transplantation","volume":"46","author":"Smith","year":"2019","journal-title":"J Appl Stat"},{"key":"10.1016\/j.ebiom.2026.106407_bib35","first-page":"1","article-title":"Using time dependent covariates and time dependent coefficients in the cox model","volume":"2","author":"Therneau","year":"2017","journal-title":"Surv Vignettes"},{"key":"10.1016\/j.ebiom.2026.106407_bib36","doi-asserted-by":"crossref","first-page":"2796","DOI":"10.1200\/JCO.2009.25.0654","article-title":"Basic concepts and methods for joint models of longitudinal and survival data","volume":"28","author":"Ibrahim","year":"2010","journal-title":"J Clin Oncol"},{"key":"10.1016\/j.ebiom.2026.106407_bib37","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1186\/s12874-017-0405-6","article-title":"Statistical methods for elimination of guarantee-time bias in cohort studies: a simulation study","volume":"17","author":"Cho","year":"2017","journal-title":"BMC Med Res Methodol"},{"key":"10.1016\/j.ebiom.2026.106407_bib38","doi-asserted-by":"crossref","first-page":"4824","DOI":"10.1002\/sim.7019","article-title":"Use of the landmark method to address immortal person-time bias in comparative effectiveness research: a simulation study","volume":"35","author":"Mi","year":"2016","journal-title":"Stat Med"},{"key":"10.1016\/j.ebiom.2026.106407_bib39","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1007\/s12561-016-9157-9","article-title":"Understanding landmarking and its relation with time-dependent cox regression","volume":"9","author":"Putter","year":"2017","journal-title":"Stat Biosci"},{"key":"10.1016\/j.ebiom.2026.106407_bib40","series-title":"A tutorial for joint modeling of longitudinal and time-to-event data in R","author":"Cekic","year":"2019"},{"key":"10.1016\/j.ebiom.2026.106407_bib41","series-title":"JM: Joint Modeling of Longitudinal and Survival Data","author":"Rizopoulos","year":"2022"},{"key":"10.1016\/j.ebiom.2026.106407_bib42","series-title":"joineR: Joint Modelling of Repeated Measurements and Time-to-event Data","author":"Philipson","year":"2026"},{"key":"10.1016\/j.ebiom.2026.106407_bib43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v072.i07","article-title":"The R package JMbayes for fitting joint models for longitudinal and time-to-event data using MCMC","volume":"72","author":"Rizopoulos","year":"2016","journal-title":"J Stat Softw"},{"key":"10.1016\/j.ebiom.2026.106407_bib44","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1038\/s41591-022-02115-4","article-title":"Molecular residual disease and efficacy of adjuvant chemotherapy in patients with colorectal cancer","volume":"29","author":"Kotani","year":"2023","journal-title":"Nat Med"},{"key":"10.1016\/j.ebiom.2026.106407_bib45","doi-asserted-by":"crossref","first-page":"2162","DOI":"10.1158\/1078-0432.CCR-24-3612","article-title":"ctDNA clearance as an early indicator of improved clinical outcomes in advanced NSCLC treated with TKI: findings from an aggregate analysis of eight clinical trials","volume":"31","author":"Andrews","year":"2025","journal-title":"Clin Cancer Res"},{"key":"10.1016\/j.ebiom.2026.106407_bib46","doi-asserted-by":"crossref","first-page":"6770","DOI":"10.1038\/s41467-021-27022-z","article-title":"Dynamic recurrence risk and adjuvant chemotherapy benefit prediction by ctDNA in resected NSCLC","volume":"12","author":"Qiu","year":"2021","journal-title":"Nat Commun"},{"key":"10.1016\/j.ebiom.2026.106407_bib47","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.annonc.2023.11.016","article-title":"Early breast cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up","volume":"35","author":"Loibl","year":"2024","journal-title":"Ann Oncol"},{"issue":"Suppl 6","key":"10.1016\/j.ebiom.2026.106407_bib48","doi-asserted-by":"crossref","first-page":"vi64","DOI":"10.1093\/annonc\/mdt354","article-title":"Early colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"24","author":"Labianca","year":"2013","journal-title":"Ann Oncol"},{"key":"10.1016\/j.ebiom.2026.106407_bib49","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1161\/CIRCULATIONAHA.115.017719","article-title":"Introduction to the analysis of survival data in the presence of competing risks","volume":"133","author":"Austin","year":"2016","journal-title":"Circulation"}],"container-title":["eBioMedicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S2352396426002914?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S2352396426002914?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T08:17:45Z","timestamp":1786522665000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S2352396426002914"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8]]},"references-count":49,"alternative-id":["S2352396426002914"],"URL":"https:\/\/doi.org\/10.1016\/j.ebiom.2026.106407","relation":{},"ISSN":["2352-3964"],"issn-type":[{"value":"2352-3964","type":"print"}],"subject":[],"published":{"date-parts":[[2026,8]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Common analysis pitfalls in longitudinal ctDNA studies: lead time, sensitivity and immortal time bias","name":"articletitle","label":"Article Title"},{"value":"eBioMedicine","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.ebiom.2026.106407","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2026 The Authors. Published by Elsevier B.V.","name":"copyright","label":"Copyright"}],"article-number":"106407"}}