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We reported elsewhere that the primary endpoint of a reduction in the incidence of stage III\/IV cancer diagnoses in the intervention arm versus control arm was not met. Here we report prespecified secondary test performance endpoints among evaluable intervention arm participants across three annual screening rounds. These analyses were descriptive; there was no hypothesis testing. Participants aged 50\u221277\u2009years (\n                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u2009142,250) were randomized 1:1 into intervention (MCED) or control arms. Intervention arm participants with positive MCED results were referred to National Health Service (NHS) standard-of-care pathways for diagnostic workup, with referrals informed by the predicted cancer signal origin (CSO). Positive test results were returned for 722 of 70,325 (1.03%), 518 of 64,498 (0.80%) and 561 of 62,323 (0.90%) participants in rounds 1\u22123, respectively. In aggregate, 937 participants had MCED-detected primary cancers. Respective by-round cancer detection rates were 0.60%, 0.40% and 0.41%; positive predictive values were 58.0% (419\/722), 50.4% (261\/518) and 45.8% (257\/561); and negative predictive values were 98.98% (68,895\/69,603), 98.90% (63,278\/63,980) and 98.86% (61,058\/61,762). Across rounds, specificity ranged from 99.50% to 99.60%; episode sensitivity ranged from 26.7% to 37.2% for all cancers and from 47.6% to 63.4% for 12 prespecified types; and CSO accuracy ranged from 91.1% to 93.6%. These data provide insights on the performance of the MCED test in population screening within the NHS setting. 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S.D. has no competing interests to disclose. P.J. has no competing interests to disclose. H.J. has no competing interests to disclose. H.K. is employed by and owns stock in GRAIL. L.Y.W.L. has no competing interests to disclose. Y.L.\u2019s salary is supported by research funding from GRAIL. W.L. is employed by GRAIL and owns stock in GRAIL. T.R. has received research funding from GRAIL. R.S. is employed by GRAIL and owns stock in GRAIL. J.W.\u2019s salary is supported by research funding from GRAIL. P.S. has consulting\/advisory roles with GRAIL Bio UK Ltd. and MEDIAN Technologies (institution); has received research funding from GlaxoSmithKline UK Ltd. (institution), GRAIL Bio UK Ltd. (institution) and Merck (institution); and has a patent pending related to HPV testing. C.S. acknowledges grant support from Invitae (previously Archer Dx Inc., collaboration in minimal residual disease sequencing technologies) and Personalis. He is Co-Chief Investigator of the NHS-Galleri trial funded by GRAIL and is a paid member of GRAIL\u2019s Scientific Advisory Board. C.S. is a nonexecutive director of Novartis from March 2026 and was a paid board member for Bicycle Therapeutics and Chair of Bicycle Therapeutics\u02bc Clinical Advisory Group. He has received or receives consultant or advisory fees from Genentech and China Innovation Center of Roche (CICoR)-Shanghai; Medicxi Ventures; Relay Therapeutics (Scientific Advisory Board member); Saga Diagnostics (Scientific Advisory Board member); and Sarah Cannon Research Institute. He has undertaken an uncompensated advisory role for AstraZeneca and has received consultancy fees, advisory fees or honoraria from Pfizer and Achilles Therapeutics. C.S. has equity and\/or stock options in Bicycle Therapeutics, Novartis, Relay Therapeutics and Saga Diagnostics. He has previously held stock and was co-founder of Achilles Therapeutics. C.S. declares a patent application for methods for lung cancer detection (PCT\/US2017\/028013); targeting neoantigens (PCT\/EP2016\/059401); identifying patient response to immune checkpoint blockade (PCT\/EP2016\/071471); methods for lung cancer detection (US20190106751A1); identifying patients who respond to cancer treatment (PCT\/GB2018\/051912); determining HLA LOH (PCT\/GB2018\/052004); predicting survival rates of patients with cancer (PCT\/GB2020\/050221); methods and systems for tumor monitoring (PCT\/EP2022\/077987); analysis of HLA alleles transcriptional deregulation (PCT\/EP2023\/059039); technique for detecting minimal residual disease (PCT\/EP2023\/065074); and relating to the use of plasma proteomics for risk prediction of lung cancer (PCT\/EP2025\/086701). C.S. is an inventor on a European patent application (PCT\/GB2017\/053289) relating to assay technology to detect tumor recurrence. This patent has been licensed to a commercial entity, and, under their terms of employment, C.S. is due a revenue share of any revenue generated from such license(s).","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}