Cost-effectiveness Evaluation of the 2021 US Preventive Services Task Force Recommendation for Lung Cancer Screening

Key Points

Question  Is the 2021 US Preventive Services Task Force (USPSTF) recommendation on lung cancer screening cost-effective?

Findings  In this economic evaluation of the cost-effectiveness of the 2021 USPSTF recommendation on lung cancer screening, a comparative modeling analysis found that relative to the 2013 USPSTF recommendation, the 2021 recommendation was cost-effective despite the expansion of screening eligibility to include younger smokers and those who had at least 20 pack-years of smoking exposure. However, alternative screening strategies that maintained a minimum cumulative smoking exposure of 20 pack-years but expanded screening eligibility to former smokers who had not smoked for more than 15 years were estimated to be more cost-effective than the 2021 USPSTF recommendation.

Meaning  This study found that the 2021 USPSTF recommendation for lung cancer screening was cost-effective relative to the 2013 USPSTF recommendation but that expanding screening eligibility to include former smokers who have not smoked for more than 15 years might further improve the cost-effectiveness of the screening program and warrants further evaluation.

Importance  The US Preventive Services Task Force (USPSTF) issued its 2021 recommendation on lung cancer screening, which lowered the starting age for screening from 55 to 50 years and the minimum cumulative smoking exposure from 30 to 20 pack-years relative to its 2013 recommendation. Although costs are expected to increase because of the expanded screening eligibility criteria, it is unknown whether the new guidelines for lung cancer screening are cost-effective.

Objective  To evaluate the cost-effectiveness of the 2021 USPSTF recommendation for lung cancer screening compared with the 2013 recommendation and to explore the cost-effectiveness of 6 alternative screening strategies that maintained a minimum cumulative smoking exposure of 20 pack-years and an ending age for screening of 80 years but varied the starting ages for screening (50 or 55 years) and the number of years since smoking cessation (≤15, ≤20, or ≤25).

Design, Setting, and Participants  A comparative cost-effectiveness analysis using 4 independently developed microsimulation models that shared common inputs to assess the population-level health benefits and costs of the 2021 recommended screening strategy and 6 alternative screening strategies compared with the 2013 recommended screening strategy. The models simulated a 1960 US birth cohort. Simulated individuals entered the study at age 45 years and were followed up until death or age 90 years, corresponding to a study period from January 1, 2005, to December 31, 2050.

Exposures  Low-dose computed tomography in lung cancer screening programs with a minimum cumulative smoking exposure of 20 pack-years.

Main Outcomes and Measures  Incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) of the 2021 vs 2013 USPSTF lung cancer screening recommendations as well as 6 alternative screening strategies vs the 2013 USPSTF screening strategy. Strategies with a mean ICER lower than $100 000 per QALY were deemed cost-effective.

Results  The 2021 USPSTF recommendation was estimated to be cost-effective compared with the 2013 recommendation, with a mean ICER of $72 564 (range across 4 models, $59 493-$85 837) per QALY gained. The 2021 recommendation was not cost-effective compared with 6 alternative strategies that used the 20 pack-year criterion. Strategies associated with the most cost-effectiveness included those that expanded screening eligibility to include a greater number of former smokers who had not smoked for a longer duration (ie, ≤20 years and ≤25 years since smoking cessation vs ≤15 years since smoking cessation). In particular, the strategy that screened former smokers who quit within the past 25 years and began screening at age 55 years was associated with screening coverage closest to that of the 2021 USPSTF recommendation yet yielded greater cost-effectiveness, with a mean ICER of $66 533 (range across 4 models, $55 693-$80 539).

Conclusions and Relevance  This economic evaluation found that the 2021 USPSTF recommendation for lung cancer screening was cost-effective; however, alternative screening strategies that maintained a minimum cumulative smoking exposure of 20 pack-years but included individuals who quit smoking within the past 25 years may be more cost-effective and warrant further evaluation.

In March 2021, the US Preventive Services Task Force (USPSTF) updated its recommendation on lung cancer screening.^1,2 Compared with the 2013 USPSTF criteria,³ the new recommendation lowered the starting age for screening from 55 to 50 years and the minimum cumulative smoking exposure from 30 to 20 pack-years, but maintained the annual screening frequency, the stopping age for screening at 80 years, and the time since smoking cessation at 15 years.

The USPSTF periodically updates its recommendations on preventive services to reflect up-to-date evidence on the effectiveness of available interventions and technological advancements. A comparative decision analysis framework was developed by the Cancer Intervention and Surveillance Modeling Network (CISNET) Lung Working Group to inform the USPSTF’s recommendation by estimating the potential health benefits and harms of several lung cancer screening strategies.^4,5 The CISNET Lung Working Group estimated that approximately 23% of the US population born in 1960 will be eligible for lung cancer screening based on the 2021 USPSTF recommendation, which is an increase from the approximately 14% of individuals who were eligible under the 2013 USPSTF recommended screening strategy. As a result, the number of low-dose computed tomographic (LDCT) examinations was estimated to increase by 85% (from approximately 227 000 to 419 000 examinations over the lifetime of 100 000 individuals). Whether the projected increase in health benefits accrued from using the 2021 screening recommendation will be sufficient to offset the expected additional costs remains uncertain because costs were not considered in the decision analysis.⁶

The decision analysis identified 6 consensus-efficient strategies, including the 2021 USPSTF strategy; each strategy maintained the 20 pack-year minimum cumulative smoking exposure eligibility criterion but varied the starting age of screening (50 or 55 years) and the number of years since smoking cessation (≤15, ≤20, or ≤25). However, it is unknown which of these 20 pack-year strategies would be optimal from a cost-effectiveness perspective.

A previous analysis compared the cost-effectiveness of the 2013 USPSTF eligibility criteria with those of the National Lung Screening Trial⁷ and the Centers for Medicare & Medicaid Services, which start screening at age 55 years and have a 30 pack-year minimum eligibility criterion but differ in their ending age for screening.⁸ This analysis estimated that all 3 programs were cost-effective at a willingness-to-pay threshold of $100 000 per quality-adjusted life-year (QALY).⁸ However, it did not evaluate the cost-effectiveness of strategies using the 20 pack-year minimum eligibility criterion or strategies that start screening at age 50 years.

In this economic evaluation, we assessed the cost-effectiveness of the 2021 USPSTF recommendation to examine whether the expected increase in the costs associated with expanded screening eligibility was justified by the expected health benefits. As part of this analysis, we assessed the relative impacts of reducing the minimum pack-years to 20 compared with changing the starting age of screening to 50 years. Moreover, we evaluated the relative cost-effectiveness of the 6 alternative 20 pack-year screening strategies identified by the CISNET decision analysis to identify the strategies that were cost-effective.⁵

A comparative modeling approach involving 4 independently developed and validated microsimulation models from the CISNET Lung Working Group was used to assess the cost-effectiveness of the following screening strategies, all of which were based on annual screening frequency: (1) 2021 recommended strategy: age 50 years at screening start, age 80 years at screening end, minimum cumulative smoking exposure of 20 pack-years, and maximum of 15 years since smoking cessation (abbreviated as 50-80-20-15); (2) alternative strategy 1: age 50 years at screening start, age 80 years at screening end, minimum cumulative smoking exposure of 30 pack-years, and maximum of 15 years since smoking cessation (abbreviated as 50-80-30-15); (3) alternative strategy 2: age 55 years at screening start, age 80 years at screening end, minimum cumulative smoking exposure of 20 pack-years, and maximum of 15 years since smoking cessation (abbreviated as 55-80-20-15); (4) alternative strategy 3: age 55 years at screening start, age 80 years at screening end, minimum cumulative smoking exposure of 20 pack-years, and maximum of 20 years since smoking cessation (abbreviated as 55-80-20-20); (5) alternative strategy 4: age 55 years at screening start, age 80 years at screening end, minimum cumulative smoking exposures of 20 pack-years, and maximum of 25 years since smoking cessation (abbreviated as 55-80-20-25); (6) alternative strategy 5: age 50 years at screening start, age 80 years at screening end, minimum cumulative smoking exposure of 20 pack-years, and maximum of 20 years since smoking cessation (abbreviated as 50-80-20-20); and (7) alternative strategy 6: age 50 years at screening start, age 80 years at screening end, minimum cumulative smoking exposure of 20 pack-years, and maximum of 25 years since smoking cessation (abbreviated as 50-80-20-25). These strategies were compared with the 2013 USPSTF recommended strategy (age 55 years at screening start, age 80 years at screening end, minimum cumulative smoking exposure of 30 pack-years, and maximum of 15 years since smoking cessation [abbreviated as 55-80-30-15]). The models used in this analysis were the same as those used to inform the 2013 and 2021 USPSTF recommendations on lung cancer screening.^4,5,9

The cost-effectiveness of screening strategies was evaluated from the perspective of the US health care sector, assuming 100% adherence to screening, as in previous studies.^5,8,9 Lung cancer–associated events for 1 million men and women were separately simulated using smoking patterns of a 1960 US birth cohort because this cohort was representative of the US population targeted by lung cancer screening. Simulated individuals entered our study at age 45 years and were followed up until death or age 90 years, whichever occurred first, corresponding to a study period from January 1, 2005, to December 31, 2050.

The 4 microsimulation models of the CISNET Lung Working Group were independently developed to evaluate screening and differed in their mathematical formulations of lung cancer development. These models included the Microsimulation Screening Analysis–Lung Model from Erasmus University Medical Center,¹⁰ the Lung Cancer Policy Model from Massachusetts General Hospital,¹¹ the Lung Cancer Outcomes Simulation from Stanford University,¹² and the University of Michigan model.¹³ The models were calibrated to lung cancer incidence and mortality data from the National Lung Screening Trial⁷ and the prostate, lung, colorectal, and ovarian cancer screening study.¹⁴

Despite the differences in underlying modeling assumptions, the models share a similar overall structure. First, dose-response functions use individual smoking histories to model lung carcinogenesis, and a natural history component is used to simulate disease progression in the absence of interventions. Then the same individual is evaluated in the presence of the intervention of interest, and the 2 life histories are compared to assess the impact of the intervention. The models have been updated to reflect the current practice and management of screening-detected pulmonary nodules.^5,15,16 An overview of the models and their assumptions is provided in eTable 1 in the Supplement and in the literature.^5,9,14,17

Smoking histories representative of the 1960 US birth cohort were obtained through the CISNET smoking history generator.^18-20 The smoking history generator provides standardized age-specific, sex-specific, and birth cohort–specific smoking histories that include ages at smoking initiation and cessation, smoking frequency, and age at death from causes other than lung cancer. The 4 models use individual-level smoking histories to simulate lung cancer–associated events over the lifetime of individuals, including age at diagnosis, histological features and stage of disease, disease progression, and survival time from diagnosis.

The life-years of simulated individuals were adjusted for quality of life using published health utilities associated with aging, lung cancer stage at diagnosis, and terminal care (eTable 2 in the Supplement).^21-23 Costs associated with screening and diagnostic procedures were obtained from the Centers for Medicare & Medicaid Services 2020 reimbursement rates²⁴ based on their corresponding Current Procedural Terminology²⁵ codes (eTable 3 in the Supplement). Downstream treatment costs associated with specific phases of lung cancer treatment were obtained from a published analysis of data from the Surveillance, Epidemiology, and End Results–Medicare database²⁶ and converted to 2020 US dollars using a 3% annual inflation rate (eTable 4 in the Supplement). Health utilities and costs were standardized and shared across the 4 CISNET models.

Each model estimated the sex-specific health benefits and costs of screening and derived overall population outcomes by aggregating the sex-specific results. Future health and cost outcomes were equally discounted using an annual rate of 3%. A $100 000 per QALY willingness-to-pay threshold was used to define cost-effective strategies.²⁷

Primary outcome measures included the incremental cost-effectiveness ratios (ICERs) of the different screening strategies compared with 2013 USPSTF strategy, with ICER calculated as the cost of the i-th strategy minus the cost of the 2013 USPSTF strategy divided by the difference of the QALY of the i-th strategy minus the QALY of the 2013 USPSTF strategy (in which i-th denotes one of the strategies included in our analysis). The costs and QALYs for each strategy were estimated by calculating the arithmetic mean of the results derived from each of the 4 CISNET models. A cost-effectiveness efficiency frontier (in which line segments connect strategies that yield the highest health benefit at a given level of cost) was derived, and ICERs were calculated for each strategy compared with the strategy preceding it on the efficiency frontier. A weakly dominated strategy was defined as a strategy dominated by a linear combination of 2 other strategies, and a strongly dominated strategy was defined as a strategy for which another strategy existed that yielded better health benefit at lower cost.

Secondary outcome measures included reduction in lung cancer mortality, unadjusted life-years gained from screening, ICERs based on unadjusted life-years, number of LDCT screenings, and overdiagnosis rates. Results were presented per 100 000 individuals alive at age 45 years, unless otherwise specified. Individuals were from the general population; thus, individuals who were not eligible for screening were included in the analyses.

Univariate sensitivity analyses were conducted to assess the sensitivity of the results to changes in the value of important model input parameters, and efficiency frontiers associated with each set of inputs were identified. We varied the costs of LDCT, downstream treatment by phase of care (initial, continuous, and terminal), and health utilities associated with cancer stages and histological subtypes by 25% higher and lower than their base-case values (eTable 2 and eTable 3 in the Supplement). We also evaluated the cost-effectiveness of screening strategies in which individuals with short life expectancy (<5 years from the time of LDCT screening) were deemed ineligible for screening. The geometric (vs arithmetic) means of model results were also examined. A 2-fold increase in the treatment cost of de novo advanced non–small cell lung cancer was evaluated to measure the impact of using more expensive immunotherapies.

Probabilistic sensitivity analyses were conducted to assess the robustness of our findings to simultaneous changes in the values of input parameters using 100 000 iterations.²⁸ At each iteration, the value of all cost parameters and lung cancer health utilities were concurrently varied by independently sampling their values from the corresponding uniform distribution defined by the boundaries of 25% lower and higher than their base-case values (0.75 multiplied by base-case value and 1.25 multiplied by base-case value, respectively). The probability that each screening strategy was cost-effective at a given willingness-to-pay threshold was calculated by counting the number of times per 100 000 iterations that the ICER was below the specified threshold.

All simulations were performed using R software, version 3.0 (R Foundation for Statistical Computing). Data aggregation and analysis was conducted using Microsoft Excel, version 1902 (Microsoft Corp).

The 2021 USPSTF recommended screening strategy (50-80-20-15) was cost-effective, with an estimated mean ICER of $72 564 (range across 4 models, $59 493 to $85 837) per QALY gained compared with the 2013 USPSTF recommended strategy (55-80-30-15) (Table 1; eTables 5-8 and eFigure 1 in the Supplement). Similar results were obtained when the geometric mean was used to consolidate model-specific results (eg, the estimated geometric mean ICER per QALY gained for 2021 recommended strategy was $73 600 [range across 4 models, $59 493-$85 837] vs the 2013 recommended strategy) (eTable 9 in the Supplement). Lung cancer–specific reductions in mortality, number of screening-detected lung cancer cases, overdiagnosis rates, and the required number of LDCT screenings for each strategy are shown in Table 2.

When all 6 screening strategies that used the 20 pack-year criterion (ie, the 2021 recommended strategy plus alternative strategies 2-6) were analyzed together with the USPSTF 2013 recommended strategy, the 2021 USPSTF strategy was not on the cost-effectiveness efficiency frontier (Figure 1; eFigure 2 in the Supplement). The efficiency frontier (based on mean results across the 4 CISNET models) consisted of 4 strategies: alternative strategy 2 (55-80-20-15), alternative strategy 3 (55-80-20-20), alternative strategy 4 (55-80-20-25), and alternative strategy 6 (50-80-20-25). Three of those strategies began screening at age 55 years (alternative strategies 2-4) vs 50 years, and 3 of those strategies were expanded to include former smokers who quit smoking within 20 years (alternative strategy 3) and 25 years (alternative strategies 4 and 6) vs 15 years. Notably, alternative strategy 1 (50-80-30-15) was not on the cost-effectiveness efficiency frontier (mean ICER per QALY gained, $71 205 [range across 4 models, $58 567-$81 788] vs 2013 recommended strategy), whereas alternative strategy 2 (55-80-20-15) was on the efficiency frontier (mean ICER per QALY gained, $63 719 [range across 4 models, $52 619-$77 930] vs 2013 recommended strategy); this finding suggested that the cost-effectiveness of the 2021 USPSTF program was largely associated with lowering the minimum pack-years to 20 rather than lowering the start of screening to age 50 years.

The 2 strategies on the efficiency frontier with the greatest health benefits were those in which screening eligibility was expanded to include former smokers who quit within 25 years and started screening at ages 55 and 50 years (alternative strategy 4 [55-80-20-25]: mean additional QALYs accrued, 574 [range across 4 models, 444-718] and alternative strategy 6 [50-80-20-25]: mean additional QALYs accrued, 898 [range across 4 models, 736-1103]). Notably, alternative strategy 4 (55-80-20-25) had a more favorable mean ICER per QALY gained ($66 533 [range across 4 models, $55 693-$80 539]) than the 2021 recommended strategy ($72 564 [range across 4 models, $59 493-$85 837]) and provided screening coverage to a proportion of the US population identical to that of the 2021 recommended strategy (23.0% for both strategies) (Table 2). Of the 4 strategies on the efficiency frontier (ie, alternative strategies 2, 3, 4, and 6), alternative strategy 6 (50-80-20-25) was the only strategy that started screening at age 50 years. Screening eligibility levels as a function of age for each screening strategy by smoking status are shown in eFigure 3 in the Supplement.

The 2021 USPSTF recommendation was associated with cost-effectiveness compared with the 2013 USPSTF recommendation for both men and women, but the 2021 recommendation was not on the sex-specific cost-effectiveness efficiency frontiers when considering all strategies (eTable 10 and eTable 11 in the Supplement). In general, screening was more cost-effective for women vs men. The 2021 USPSTF recommendation was not on the efficiency frontier when the health benefit was quantified according to lung cancer deaths averted (eFigure 4 in the Supplement). When unadjusted life-years were used to estimate the cost-effectiveness of the strategies, the respective ICERs were lower, but the efficiency frontier and general patterns were similar to those observed using QALYs (eFigure 5 and eFigure 6 in the Supplement). Treatment was the main factor associated with cost, accounting for 73% to 84% of the total cost associated with screening programs (eFigure 7 in the Supplement).

The cost-effectiveness of the 2021 USPSTF strategy compared with the 2013 USPSTF strategy was robust to changes in the value of important input parameters (Figure 2). Univariate sensitivity analyses revealed that the cost-effectiveness efficiency frontier remained identical to the base-case frontier in all scenarios (eTables 12-23 in the Supplement). The ICERs of screening strategies were most sensitive to changes in health utilities for stage I non–small cell lung cancer followed by cost of LDCT screening.

When screening was restricted to individuals with at least 5 years of life expectancy, the cost-effectiveness efficiency frontier comprised strategies that provided screening coverage to former smokers who had quit smoking within 20 and 25 years (eTable 24 in the Supplement). When we conducted a within-strategy comparison, which compared each strategy with vs without the life expectancy restriction (eTable 25 in the Supplement), the 2021 USPSTF recommendation without the life expectancy restriction cost $6.95 million more per 100 000 individuals and yielded 56 more QALYs vs the same strategy with the life expectancy restriction. This result corresponded to an ICER of $123 327, suggesting that screening eligible individuals without considering their life expectancy may not be cost-effective. When assuming a 2-fold increase from base-case value for the treatment cost during the initial and continuous disease phases of advanced non–small cell lung cancer (to account for the high cost of modern immunotherapies), the efficiency frontier remained unchanged, despite estimating lower ICERs than the base-case analysis (eTable 26 in the Supplement).

The probabilistic sensitivity analysis revealed that the cost-effectiveness of the 4 strategies on the base-case efficiency frontier was robust to simultaneous changes in important input parameters (eFigure 8 in the Supplement). The 2021 USPSTF recommendation compared with the strategy preceding it on the efficiency frontier (ie, alternative strategy 4 [55-80-20-25]) had a 24% likelihood of being cost-effective when the willingness-to-pay threshold was $100 000.

This economic evaluation assessed the cost-effectiveness of the 2021 USPSTF recommendation on lung cancer screening using a comparative modeling approach. When directly compared with the 2013 USPSTF recommendation, the 2021 USPSTF recommendation was cost-effective based on a willingness-to-pay threshold of $100 000 per QALY gained. We found that the cost-effectiveness of the 2021 USPSTF recommendation was largely associated with lowering the minimum cumulative smoking exposure to 20 pack-years rather than lowering the starting age for screening to 50 years. The main findings of this study were robust to changes in the values of input parameters and modeling assumptions and were most sensitive to changes in health utilities for early-stage lung cancer and the cost of LDCT screening.

It is notable that when we included the 5 alternative 20 pack-year strategies in our analysis, the 2021 USPSTF recommendation was not on the efficiency frontier; the frontier consisted of strategies that expanded screening eligibility by including former smokers who had not smoked for more than 15 years. Alternative strategy 4 (55-80-20-25) was estimated to provide screening coverage to a portion of the US population that was similar to that of the 2021 USPSTF recommendation,^4,5 yet it was associated with greater cost-effectiveness, improvements in lung cancer–specific mortality, and reductions in the number of LDCT screenings but increases in overdiagnosis. Providing screening coverage to former smokers who have not smoked for more than 15 years has been supported by data from previous studies.^29-31

The USPSTF decision to lower the starting age for screening to 50 years and the minimum cumulative smoking exposure to 20 pack-years was made in part to address racial disparities in screening eligibility that were associated with the 2013 USPSTF recommendation.^2,32-34 According to the CISNET decision analysis, the 2021 USPSTF strategy (50-80-20-15) and the 2 strategies on the efficiency frontier that included former smokers who quit smoking within 25 years (ie, alternative strategy 4 [55-80-20-25] and alternative strategy 6 [50-80-20-25]) would reduce racial and sex disparities in screening eligibility.^4,5 Whether expanding screening to former smokers who had not smoked for more than 15 years could further reduce racial disparities in practice is unknown and warrants further evaluation.^31,35

The findings of this study were notable given that the decision analysis that informed the 2021 USPSTF recommendation did not consider costs. Although previous cost-effectiveness analyses reported that existing lung cancer screening programs requiring at least 30 pack-years of smoking history were cost-effective, the cost-effectiveness of 20 pack-year strategies was not examined.^8,36 The ICERs derived from the present analysis were within the range of those published in similar studies.^37-40 Our sex-specific analyses were consistent with previous studies reporting more favorable results for women compared with men.^15,36 Downstream treatment costs were the main factor associated with the cost of a lung cancer screening program.⁸ Although clinicians may, in practice, consider life expectancy when making decisions about lung cancer screening for patients, our findings suggest that formally including life expectancy in the eligibility criteria of a screening program may further improve its cost-effectiveness.

This study has limitations. Despite low screening uptake (estimated 5%-17% of eligible individuals),^41-46 we assumed 100% uptake and adherence, thereby potentially overestimating the health benefits and costs associated with lung cancer screening. Incorporating adherence into modeling is challenging given its potential heterogeneity by age, sex, race and ethnicity, socioeconomic status, smoking status, and access to care.^47-50 Moreover, we did not consider potential issues regarding availability of resources to satisfy the expected increase in screening demand based on the 2021 USPSTF recommendation.⁵¹ Our current models are unable to produce race-specific and ethnicity-specific screening outcomes; thus, caution is warranted when generalizing the present results to specific racial and ethnic groups. The models in this study do not consider the increase in risk of developing other cancers (eg, breast cancer⁵²) associated with exposure to screening radiation or the benefits of smoking cessation interventions at the time of lung cancer screening, which have been reported to improve the cost-effectiveness of the overall screening program.^23,53-56 Although a 2014 study found differential cost-effectiveness of lung cancer screening by smoking status,³⁶ we were unable to conduct a subgroup analysis by smoking status because we followed up individuals over their entire life span, and smoking status changes over time. In addition, we did not consider the health benefits and costs associated with modern lung cancer immunotherapies. Incorporating these new treatments will likely improve the cost-effectiveness of screening programs because, as screening programs expand, more lung cancers will be diagnosed at earlier stages when alternative, equally beneficial, and less costly treatment options are available.

This economic evaluation found that the 2021 USPSTF recommendation for lung cancer screening was cost-effective when directly compared with the 2013 USPSTF recommendation. However, the cost-effectiveness of lung cancer screening may be improved if screening coverage is expanded to include former smokers with 20 pack-year smoking histories who have not smoked for more than 15 years; this expansion of screening eligibility warrants further consideration.

Accepted for Publication: July 20, 2021.

Published Online: October 21, 2021. doi:10.1001/jamaoncol.2021.4942

Corresponding Authors: Summer S. Han, PhD, Quantitative Sciences Unit, School of Medicine, Stanford University, 1701 Page Mill Rd, Room 234, Stanford, CA 94304 (summer.han@stanford.edu); Sylvia K. Plevritis, PhD, Department of Biomedical Data Sciences, Stanford University, Medical School Office Building (MSOB), 1265 Welch Rd, Stanford, CA 94305-5464 (sylvia.plevritis@stanford.edu).

Author Contributions: Drs Toumazis and Han had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Han and Plevritis contributed equally. Mr de Nijs, Ms Cao, and Dr Bastani contributed equally.

Concept and design: Toumazis, ten Haaf, Jeon, Gazelle, de Koning, Meza, Kong, Han, Plevritis.

Acquisition, analysis, or interpretation of data: Toumazis, de Nijs, Cao, Bastani, Munshi, ten Haaf, Gazelle, Feuer, Meza, Kong, Han, Plevritis.

Drafting of the manuscript: Toumazis, Kong, Han, Plevritis.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Toumazis, de Nijs, Cao, Bastani, Munshi, ten Haaf, Gazelle, Kong, Plevritis.

Obtained funding: Gazelle, de Koning, Meza, Kong, Plevritis.

Administrative, technical, or material support: Cao, Gazelle, Plevritis.

Supervision: ten Haaf, Jeon, Gazelle, de Koning, Meza, Han, Plevritis.

Conflict of Interest Disclosures: Dr ten Haaf reported receiving grants from Cancer Research UK, the Horizon 2020 Program of the European Union, and the University of Zurich; personal fees from Erasmus University Medical Center, the International Association for the Study of Lung Cancer, and the Russian Society of Clinical Oncology; and nonfinancial support from the International Association for the Study of Lung Cancer and the Russian Society of Clinical Oncology outside the submitted work. Dr de Koning reported receiving personal fees from Ipsos MORI, Merck Sharp & Dohme, Teva Pharmaceutical Industries, and The Menarini Group outside the submitted work. Dr Plevritis reported receiving personal fees from GRAIL outside the submitted work. No other disclosures were reported.

Funding/Support: This study was supported by grants U01CA199284 (Drs de Koning, Meza, Kong, and Plevritis) and U01CA253858 (Drs Gazelle, de Koning, Meza, Kong, and Plevritis) from the National Cancer Institute.

Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.