Deep Learning Time-Series Prediction of Long-Term Growth Patterns of Pulmonary Ground-Glass Nodules Using Serial CT

Pulmonary ground-glass nodules (GGNs), including pure ground-glass nodules (pGGN) and mixed ground-glass nodules (mGGN), span a biological spectrum from atypical adenomatous hyperplasia and adenocarcinoma in situ to invasive lung adenocarcinoma. Current management guidelines (Fleischner Society, BTS, NCCN) rely primarily on cross-sectional CT features (diameter, density, consolidation-to-tumor ratio); these features do not capture the non-linear long-term behavior of GGNs. Long-term cohorts show that a meaningful fraction of GGNs remain indolent for years and then accelerate, demonstrating the limits of single-timepoint assessment.

Existing GGN management algorithms emphasize cross-sectional features measured on a single CT scan. Cross-sectional features alone are known to lose discriminative performance at longer (3-5 year) prediction horizons, where the relevant signal is increasingly carried by how the nodule changes over time rather than how it looks at any single moment. The present study is designed around this observation. It shifts the modeling target from static single-CT classification to a long-term spatiotemporal deep-learning framework that explicitly encodes the full trajectory of the nodule across the entire available serial-CT record.

This study uses a mixed retrospective-prospective design and is reported under TRIPOD guidance. Four cohorts are pre-specified:

• Development Cohort (Cohort 1): n ≈ 2,700. Surgically resected patients at Peking University People's Hospital from January 2007 to June 2025, with ≥ 2 pre-operative thin-slice chest CT scans available for the resected GGN.
• Internal Test Cohort A (Cohort 2): n ≈ 350. Surgically resected patients at Peking University People's Hospital from July 2025 to January 2026, with ≥ 2 pre-operative thin-slice chest CT scans available for the resected GGN.
• Internal Test Cohort B (Cohort 3): n ≈ 1,200. Non-operated patients at Peking University People's Hospital from January 2020 to December 2025, with ≥ 3 thin-slice chest CT scans of the target GGN.
• Prospective External Validation Cohort (Cohort 4): n ≈ 500. Patients (operated or non-operated) prospectively enrolled at Peking University People's Hospital and additional co-sites after the AI model is locked, with serial thin-slice chest CT performed as part of routine surveillance. This cohort serves as independent external (in-time and multi-center) validation and is not used for any model training or hyperparameter tuning.

After resampling to 1 × 1 × 1 mm and lung-window normalization, serial CTs are spatiotemporally registered (rigid + deformable) to baseline. For each timepoint, two regions of interest (ROIs) are derived for every target GGN: (i) the intratumoral ROI, defined as the full 3D extent of the nodule itself, automatically segmented using a pre-trained 3D U-Net with expert review; and (ii) the peritumoral ROI, defined as the shell of lung parenchyma extending 5 mm outward from the segmented nodule boundary, with intervening vessels, airways, and pleural surfaces masked out, to capture the perinodular lung microenvironment around the nodule. Radiomic features (per the Image Biomarker Standardization Initiative, IBSI) are extracted separately from each ROI, and deep features are extracted by a 3D convolutional neural network (e.g., 3D ResNet) applied independently to the intratumoral and peritumoral volumes. The two feature streams are concatenated at each timepoint to capture both intra-lesional heterogeneity and the perilesional microenvironment, which prior work from our team has shown to be informative.

The ordered sequence of per-timepoint feature vectors, together with the actual inter-scan time intervals, is fed into a time-aware sequence model (LSTM, GRU, or continuous-time Transformer) to model growth dynamics. Clinical covariates (age, sex, smoking history, family history of malignancy, emphysema score) are fused into a multimodal network. Temporal-attention maps and Shapley values are used for interpretability, with separate attribution reported for the intratumoral and peritumoral feature streams.

Model performance is reported with AUC and 95% CI for binary 1-, 3-, and 5-year progression endpoints, with DeLong testing against a single-baseline-CT radiomics benchmark; multi-class performance for the four-pattern trajectory task is reported with weighted / macro / micro F1 plus per-class precision and recall. Class imbalance, in particular the slow-then-rapid subgroup, is addressed with ADASYN oversampling and focal loss. For the subset of patients ultimately resected (Cohorts 1, 2, and the operated subset of Cohort 4), histopathological diagnosis serves as a secondary reference standard against which the imaging endpoints and the AI-predicted trajectory are compared.

Inclusion criteria

• Age ≥ 18 years.
• Persistent pulmonary ground-glass nodule (pGGN or mGGN, 5-30 mm) on thin-slice chest CT (slice thickness ≤ 1.5 mm).
• Baseline and follow-up thin-slice chest CTs of sufficient quality for 3D segmentation and registration.
• Minimum interval between any two consecutive CTs > 1 month.
• Complete baseline clinical data available (age, sex, smoking history, family history of malignancy, relevant comorbidities).

Cohort-specific inclusion

• Group 1 (Development): surgical resection of the target GGN at PKUPH between Jan 2007 - Jun 2025, with ≥ 2 pre-operative thin-slice CTs available.
• Group 2 (Surgical internal test): surgical resection at PKUPH between Jul 2025 - Jan 2026, with ≥ 2 pre-operative thin-slice CTs available.
• Group 3 (Non-surgical internal test): non-operative management at PKUPH between Jan 2020 - Dec 2025, with ≥ 3 thin-slice CTs of the target GGN available.
• Group 4 (Prospective external validation): prospective enrollment after model lock at participating centers, baseline CT plus ≥ 2 planned routine follow-up thin-slice CTs.

Exclusion criteria

• Coexisting severe pulmonary disease that obscures evaluation of the target GGN (e.g., active pulmonary tuberculosis, severe interstitial lung disease).
• Prior history of any other thoracic malignancy, or active extrathoracic malignancy under treatment within 5 years, that would confound interpretation of the target GGN.
• CT image quality insufficient for registration and feature extraction (severe motion artifact, slice thickness > 1.5 mm at any required timepoint, or extensive metallic artifact projecting over the target GGN).
• Pure solid nodule with no ground-glass component.
• Target GGN already received treatment (resection, ablation, or radiotherapy) prior to the baseline CT used in this study.