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Publications

Journal Article Review Ahead of print 1 citation

PubMed: 42508231 DOI: 10.1016/j.ebiom.2026.106407

Common analysis pitfalls in longitudinal ctDNA studies: lead time, sensitivity and immortal time bias.

EBioMedicine 130:106407

Authors: Dominik Hlauschek, Nadia Dandachi, Michael Gnant, Heather Parsons, Angela DeMichele, Ellen Heitzer, Gabriel Rinnerthaler, Marija Balic

Affiliations

  • Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; Austrian Breast and Colorectal Cancer Study Group [ABCSG], Vienna, Austria.
  • Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; Institute of Human Genetics, Diagnostic & Research Center for Molecular BioMedicine, Medical University of Graz, Graz, Austria.
  • Austrian Breast and Colorectal Cancer Study Group [ABCSG], Vienna, Austria; Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
  • Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
  • Medical Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Institute of Human Genetics, Diagnostic & Research Center for Molecular BioMedicine, Medical University of Graz, Graz, Austria.
  • Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; Austrian Breast and Colorectal Cancer Study Group [ABCSG], Vienna, Austria.
  • Austrian Breast and Colorectal Cancer Study Group [ABCSG], Vienna, Austria; Division of Oncology, Hillmans Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.

Abstract

Circulating tumour DNA (ctDNA) has emerged as one of the most promising biomarkers in oncology, with potential applications from detection of minimal residual disease (MRD) and diagnosis to prognosis, treatment guidance, and response monitoring. This personal view critically examines recurring methodological and statistical pitfalls in ctDNA studies with longitudinal measurements. We highlight important issues with lead time definition and demonstrate that performance metrics like sensitivity and specificity are inherently time-dependent. Furthermore, we show why immortal time bias arises when classifying patients incorrectly as always positive, based on becoming positive during surveillance in MRD related studies. With a combination of toy data examples, simulations, and re-analysis of published data we provide practice-oriented guidance to support the design, analysis, and reporting of ctDNA trials. This viewpoint paper aims to sensitise the community and raise awareness of pitfalls in longitudinal ctDNA analysis, rather than offer definitive solutions-more evidence is needed first.

MeSH

Bias, Biomedical Research