Clinical performance and utility - A microsimulation model to inform the design of screening trials for a multi-cancer early detection test

Sep 21, 2026

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Designing cancer screening trials for multi-cancer early detection (MCED) tests presents a significant methodology challenge because the natural histories of cell-free DNA-shedding cancers are not yet fully known. A microsimulation model was developed to project MCED performance and utility under varied cancer latency assumptions. The model simulated preclinical progression across 23 cancer classes, ran annual screening rounds using a methylation-based MCED test (Galleri®), and estimated early-detection mortality effects via a stage-shift approach.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages10

Reading Time25 min

AccessFree to download

Abstract

Objectives

Methods

Results

Conclusions

Introduction

Background on cancer screening in the United States

Development of blood-based MCED tests

Early Detection Research Network phases

Role of randomized controlled trials

Clinical performance and utility: A microsimulation model to inform the design of screening trials for a multi-cancer early detection test James Y Dai 1 , Jing Zhang 1, Jerome V Braun2, Noah Simon3, Earl Hubbell 1 , and Nan Zhang 1 J Med Screen 2024, Vol. 31(3) 140–149 © The Author(s) 2024 Article reuse guidelines: [sagepub.com/journals-permissions](sagepub.com/journals-permissions)[ ](sagepub.com/journals-permissions)[DOI: 10.1177/09691413241228041](DOI: 10.1177/09691413241228041)[ ](DOI: 10.1177/09691413241228041)[journals.sagepub.com/home/msc](journals.sagepub.com/home/msc) Abstract Objectives: Designing cancer screening trials for multi-cancer early detection (MCED) tests presents a signiﬁcant methodology challenge, as natural histories of cell-free DNA-shedding cancers are not yet known. A microsimulation model was developed to project the performance and utility of an MCED test in cancer screening trials. Methods: Individual natural history of preclinical progression through cancer stages for 23 cancer classes was simulated by a stage-transition model under a broad range of cancer latency parameters. Cancer incidences and stage distributions at clinical presentation in simulated trials were set to match the data from Surveillance, Epidemiology, and End Results program. One or multiple rounds of annual screening using a targeted methylation-based MCED test (GalleriⓇ) was conducted to detect preclinical cancers. Mortality beneﬁt of early detection was simulated by a stage-shift model. Results: In simulated trials, accounting for healthy volunteer effect and varying test sensitivity, positive predictive value in the prevalence screening round reached 48% to 61% in 6 natural history scenarios. After 3 rounds of annual screening, the cumulative proportions of stage I/II cancers increased by approximately 9% to 14%, the incidence of stage IV cancers was reduced by 37% to 46%, the reduction of stages III and IV cancer incidences was 9% to 24%, and the reduction of mortality reached 13% to 16%. Greater reductions of late-stage cancers and cancer mortality were achieved by ﬁve rounds of MCED screening. Conclusions: Simulation results guide trial design and suggest that adding this MCED test to routine screening in the United States may shift cancer detection to earlier stages, and potentially save lives. Keywords Cancer screening, clinical utility, multi-cancer early detection test, microsimulation, randomized controlled trial, trial design Date received: 19 July 2023; revised: 14 December 2023; accepted: 29 December 2023 Introduction In the United States, screening tests are available for just ﬁve cancers: colorectal, breast, lung in high-risk individuals, cervical, and prostate cancer on an individual basis.1–5 For many other cancers, single-organ cancer screening in the general population is not cost-effective because of low incidence and/ or lack of an appropriate test. Yet, in 2020, approximately 76% of estimated cancer-related deaths in the US population aged 50–79 were from cancers without population screening 6 programs. Signiﬁcant progress has been made recently to develop bloodbased, multi-cancer early detection(MCED)tests, with some tests utilizing features of cell-free DNA (cfDNA), such as cancer methylation signatures or fragmentation patterns.7–10 The performance of these MCED tests has been evaluated in retrospectively identiﬁed cancers and controls. For example, one MCED test (GalleriⓇ; GRAIL, LLC) was reported to detect cancer signals from more than 50 types of cancer, with a low falsepositive rate of 0 .5%.9 By aggregating detection rates over multiple cancers in a single blood draw, MCED is a promising approach to improve the cost-effectiveness over single-organ 1 GRAIL, LLC, Menlo Park, CA, USA 2Independent Statistical Consultant, Davis, CA, USA 3Department of Biostatistics, University of Washington, Seattle, WA, USA JYD and JZ are joint lead authors. Corresponding aut

FAQs

What challenge does the study address in designing MCED screening trials?

The study targets the methodological difficulty of designing MCED trials because the natural histories of cell-free DNA-shedding cancers are not yet well understood.

How does the microsimulation model evaluate MCED trial performance?

It simulates preclinical progression through cancer stages for 23 cancer classes across a wide range of latency parameters, calibrates incidences and stage distributions to SEER data, and models annual screening using a methylation-based MCED test.

What impact does repeated MCED screening have in simulated trials?

Across scenarios, the proportion of early-stage (stage I/II) cancers increases after multiple annual rounds, stage IV incidence decreases, and mortality reductions are estimated to reach about 13% to 16% with further gains after five rounds.

Sep 21, 2026

Uploaded by Ezra