Development and Validation of a Multivariable Lung Cancer Risk Prediction Model That Includes Low-Dose Computed Tomography Screening Results: A Secondary Analysis of Data From the National Lung Screening Trial

Abstract

Importance: Low-dose computed tomography lung cancer screening is most effective when applied to high-risk individuals.

Objectives: To develop and validate a risk prediction model that incorporates low-dose computed tomography screening results.

Design, setting, and participants: A logistic regression risk model was developed in National Lung Screening Trial (NLST) Lung Screening Study (LSS) data and was validated in NLST American College of Radiology Imaging Network (ACRIN) data. The NLST was a randomized clinical trial that recruited participants between August 2002 and April 2004, with follow-up to December 31, 2009. This secondary analysis of data from the NLST took place between August 10, 2013, and November 1, 2018. Included were LSS (n = 14 576) and ACRIN (n = 7653) participants who had 3 screens, adequate follow-up, and complete predictor information.

Main outcomes and measures: Incident lung cancers occurring 1 to 4 years after the third screen (202 LSS and 96 ACRIN). Predictors included scores from the validated PLCOm2012 risk model and Lung CT Screening Reporting & Data System (Lung-RADS) screening results.

Results: Overall, the mean (SD) age of 22 229 participants was 61.3 (5.0) years, 59.3% were male, and 90.9% were of non-Hispanic white race/ethnicity. During follow-up, 298 lung cancers were diagnosed in 22 229 individuals (1.3%). Eight result combinations were pooled into 4 groups based on similar associations. Adjusted for PLCOm2012 risks, compared with participants with 3 negative screens, participants with 1 positive screen and last negative had an odds ratio (OR) of 1.93 (95% CI, 1.34-2.76), and participants with 2 positive screens with last negative or 2 negative screens with last positive had an OR of 2.66 (95% CI, 1.60-4.43); when 2 or more screens were positive with last positive, the OR was 8.97 (95% CI, 5.76-13.97). In ACRIN validation data, the model that included PLCOm2012 scores and screening results (PLCO2012results) demonstrated significantly greater discrimination (area under the curve, 0.761; 95% CI, 0.716-0.799) than when screening results were excluded (PLCOm2012) (area under the curve, 0.687; 95% CI, 0.645-0.728) (P < .001). In ACRIN validation data, PLCO2012results demonstrated good calibration. Individuals who had initial negative scans but elevated PLCOm2012 six-year risks of at least 2.6% did not have risks decline below the 1.5% screening eligibility criterion when subsequent screens were negative.

Conclusions and relevance: According to this analysis, some individuals with elevated risk scores who have negative initial screens remain at elevated risks, warranting annual screening. Positive screens seem to increase baseline risk scores and may identify high-risk individuals for continued screening and enrollment into clinical trials.

Trial registration: ClinicalTrials.gov Identifier: NCT00047385.

Figure 1.. Schema Showing PLCO2012results Model Development Plan

Lung-RADS indicates Lung CT Screening Reporting & Data System developed by the American College of Radiology; NLST, National Lung Screening Trial; PLCOm2012, risk prediction model described by Tammemägi et al; PLCOm2012_bu, PLCOm2012 model with predictors age, smoking duration in current smokers, and quit time in former smokers updated to the start of study follow-up (T3) by adding 3 years to baseline values (the PLCOm2012_bu is estimated for a 3-year period, not the original 6-year period); T0, baseline screen; T1, first annual screen; and T2, annual screen at year 2.

Figure 2.. Cumulative Incidence of Lung Cancer in the National Lung Screening Trial Low-Dose Computed Tomography Group Occurring 1 to 4 Years After the Last Low-Dose Computed Tomography Screen Among 23 227 Participants^a

Stratified by Lung CT Screening Reporting & Data System screen results (positive vs negative) at baseline, 1-year, and 2-year annual screenings categorized into 4 groups. ^aCompeting risks (ie, non–lung cancer deaths) were taken into account according to the method by Fine and Gray. Included in the analysis were 298 incident lung cancer cases and 735 competing-cause deaths during the 3-year follow-up period.