This study is a multi-center, observational study aiming to develop an early screening multi-model for detecting lung cancer signals through the integration of imaging (non-contrast CT) and blood testing (cfDNA methylation).

This study aims to develop three modality -based models for lung cancer early screening, incuding a CT-based imaging model, a blood-based cfDNA methylation model, and a multimodal framework. First, 10,700 retrospective non-contrast CT scans will be collected to construct the CT imaging-based model. This model will extract multi- scale structural features through a hierarchical modeling framework, enabling the learning of interpretable spatial representations. Second, cfDNA methylation data from lung cancer patients and healthy individuals enrolled in the ProFound study (NCT06217900) wll be used to develop the blood-based model. Third, subjects with paired CT imaging and cfDNA methylation data from the ProFound study will be included to construct a multimodal model by integrating information across modalities. The performance of models based on different modalities will be systematically compared to evaluate their respective and complementary contributions to lung cancer early screening.

Inclusion Criteria:

• 40-74 years old
• Clinically and/or pathologically diagnosed cancer
• No prior or undergoing any systemic or local antitumor therapy, including but not limited to surgical resection, radiochemotherapy, endocrinotherapy, targeted therapy, immunotherapy, interventional therapy, etc.
• Able to provide a written informed consent and willing to comply with all part of the protocol procedures

Exclusion Criteria:

• Pregnancy or lactating women
• Known prior or current diagnosis of other types of malignancies comorbidities
• Severe acute infection (e.g. severe or critical COVID-19, sepsis, etc.) or febrile illness (body temperature of ≥ 38.5 °C) within 14 days prior to screen
• Recipients of organ transplant or prior bone marrow transplant or stem cell transplant
• Recipients of blood transfusion within 30 days prior to screen
• Recipients of therapy in past 14 days prior to screen, including oral or IV antibiotics, glucocorticoid, azacitidine, decitabine, procainamide, hydrazine, arsenic trioxide
• Unsuitable for this trial determined by the researchers
• Low-quality samples: images only partially showing the lungs or in lateral decubitus position, unreadable due to severe motion artifacts/metal artifacts, or with missing critical metadata

Inclusion Criteria for Control Arm Participants:

• 40-74 years old
• Without confirmed cancer diagnosis
• Able to provide a written informed consent and willing to comply with all part of the protocol procedures

Exclusion Criteria for Control Arm Participants:

• Pregnancy or lactating women
• Known prior or current diagnosis of other types of malignancies comorbidities
• Severe acute infection (e.g. severe or critical COVID-19, sepsis, etc.) or febrile illness (body temperature of ≥ 38.5 °C) within 14 days prior to screen
• Recipients of organ transplant or prior bone marrow transplant or stem cell transplant
• Recipients of blood transfusion within 30 days prior to screen
• Recipients of therapy in the past 14 days prior to screen, including oral or IV antibiotics, glucocorticoid, azacitidine, decitabine, procainamide, hydrazine, arsenic trioxide
• Unsuitable for this trial determined by the researchers
• Low-quality samples: images only partially showing the lungs or in lateral decubitus position, unreadable due to severe motion artifacts/metal artifacts, or with missing critical metadata

lung cancers or healthy individuals who can provide imaging data meeting the inclusion and exclusion criteria