The Association of Comorbidities and Demographics with Screen-Detected Nodule Cancer Risk

Principal Investigator

Name
Keith Sigel

Degrees
M.D., Ph.D.

Institution
Icahn School of Medicine at Mount Sinai

Position Title
Professor of Medicine

Email
keith.sigel@mssm.edu

About this CDAS Project

Study
NLST (Learn more about this study)

Project ID
NLST-1497

Initial CDAS Request Approval
Mar 16, 2026

Title
The Association of Comorbidities and Demographics with Screen-Detected Nodule Cancer Risk

Summary
Lung cancer screening with low-dose computed tomography (LDCT) has been shown to reduce lung cancer mortality by enabling earlier detection among high-risk individuals. However, LDCT screening frequently identifies pulmonary nodules, the majority of which are benign, leading to follow-up imaging, diagnostic testing, and, in some cases, invasive procedures. Improving the ability to distinguish nodules that are likely to represent malignancy from those that are benign remains a central challenge in lung cancer screening and is critical for maximizing the benefits of screening while minimizing unnecessary harms.

One of the main objectives of this project is to evaluate the risk of malignancy among non-calcified pulmonary nodules detected during LDCT screening, with a specific focus on heterogeneity by race/ethnicity and major comorbidities. Existing nodule management guidelines and risk models primarily emphasize radiographic features, age, and smoking history. These features may not fully account for differences in cancer risk across demographic and clinical subgroups. Prior research has demonstrated substantial variation in lung cancer incidence and outcomes by race/ethnicity, as well as strong associations between comorbidities. However, less is known about how these factors influence the probability that a screen-detected nodule represents malignancy.

This project will use data from the NLST to examine malignancy risk associated with non-calcified nodules detected during LDCT screening. The NLST provides a uniquely well-characterized screening population with standardized LDCT imaging, detailed participant demographic and clinical information, longitudinal screening data, and lung cancer outcomes. These features make NLST well suited for evaluating nodule-level cancer risk in relation to patient-level characteristics.

Analyses will focus on participants with one or more non-calcified pulmonary nodules detected on LDCT screening. Nodules will be classified as prevalent (detected at baseline screening) or incident (detected on subsequent screening rounds), recognizing that these groups may differ in underlying malignancy risk. The primary outcome will be lung cancer diagnosis attributable to a screen-detected nodule within a defined follow-up period. Key exposures of interest include race/ethnicity and the presence of major comorbid illnesses, with adjustment for age, sex, smoking history, nodule size and contour, as available in the NLST dataset.

The main goal of this analysis is to assess whether lung nodules with similar radiographic characteristics, when identified on LDCT scans, carry different risks of malignancy across different racial/ethnic groups and comorbidity profiles. Identifying such differences would highlight potential limitations of current guideline-based approaches and support the development of more targeted, individualized risk stratification strategies. By leveraging the depth and rigor of the NLST data, this project aims to contribute evidence that can inform future efforts to refine lung cancer screening and nodule management, with the purpose of improving screening efficiency while reducing unnecessary diagnostic interventions.

Aims

Aim 1: To determine the impact of race/ethnicity, smoking patterns, and major comorbid illness on the risk of malignancy among non-calcified lung nodules detected during LDCT screening.

When patients undergo low-dose CT (LDCT) scans to screen for lung cancer, lung nodules are frequently found. This aim will investigate whether the chance that these nodules are cancerous differs depending on a patient’s race/ethnicity or if they have other serious comorbidities. Using data from the National Lung Screening Trial (NLST), we will evaluate the association between race/ethnicity, major comorbidity, and the probability of malignancy among individuals with non-calcified pulmonary nodules detected during LDCT screening. Analyses under this aim will adjust for demographic, smoking-related, clinical, and nodule-specific characteristics, and will distinguish between prevalent and incident nodules. Effect modification by race/ethnicity and comorbidity burden will be explored.

Collaborators

Keith Sigel Icahn School of Medicine at Mount Sinai
Jonathan Marra Icahn School of Medicine at Mount Sinai