Background: Low-dose CT lung cancer screening (LDCT LCS) reduces lung cancer mortality by ~20%, but its effect on allcause mortality (ACM) remains uncertain. The top two trials showed a statistically significant ~4% ACM reduction and a non-significant ~1% ACM increase, respectively. Overdiagnosis (OD) screen-detected cancers that would not have caused harm within a person’s lifetime—has been proposed as a mechanism by which harms could offset benefit. However OD estimates range from 2% to 49%—largely due to methodological heterogeneity—which limits their policy usefulness. Datasets: Analyses will use individual-level data from two major LCS trials: NLST (USA; n≈53,000) and NELSON (Netherlands/Belgium; n≈15,800). Methods will be developed in NLST and validated in NELSON. Irish population inputs will be derived from CSO census data, CRADLE primary care records, and NCRI incidence data.
Methods:
- WP1 will map and critique methodological drivers of OD variation and specify a standardised excess incidence OD estimand suitable for policy use.
- WP2 will quantify heterogeneity in excess incidence using discrete-time and competing-risk time-to-event models as a function of age, sex, smoking exposure, comorbidity, and screening history, selecting parsimonious models that generalise across trials.
- WP3 will test whether OD risk (derived from WP2) explains variation in lung cancer–specific and non–lung cancer mortality among screened participants and will develop a process map linking excess incidence to observed mortality dynamics.
- WP4 will estimate the mortality offset attributable to excess incidence using counterfactual risk-set matching and difference-in-differences decomposition, with uncertainty characterised by stochastic resampling and robustness analyses.
- WP5 will translate NELSON-validated estimates to Ireland via reweighting/standardisation, producing uncertainty-aware subgroup classifications indicating whether OD is unlikely, possible, or likely to threaten net mortality benefit, alongside clinician-facing communication tools.
Impact: This programme will deliver a defensible OD estimand, quantify the extent to which OD can erode mortality benefit, and inform risk-stratified LCS eligibility policy in Ireland.