NAMD: Virtual Follow-up Computed Tomography Synthesis via Nodule-Aligned Multimodal Diffusion Models for Early Lung Cancer Diagnosis

Lung cancer remains the leading cause of cancer-related mortality worldwide, with survival outcomes critically dependent on early and accurate detection. When low-dose computed tomography (LDCT) findings are indeterminate, clinicians typically defer diagnosis pending follow-up CT imaging obtained up to 12 months later, inevitably delaying treatment for patients with malignant nodules. To address this clinical gap, we propose Nodule-Aligned Multimodal (Latent) Diffusion (NAMD), a novel generative framework that synthesizes one-year follow-up nodule CT images conditioned on the baseline CT scan, quantitative nodule biomarkers, and patient-level Electronic Health Records (EHR), enabling timely prediction of nodule malignant progression without requiring actual follow-up scans. NAMD introduces two key contributions: (i) a nodule-aligned latent space regularized so that embedding distances reflect clinically meaningful biomarker changes, and (ii) an LLM-driven multimodal conditioning mechanism encoding heterogeneous EHR data into the diffusion backbone. Evaluated on the National Lung Screening Trial (NLST), our method's synthetic follow-up images achieve an AUROC of 0.805 and an AUPRC of 0.346 for lung nodule malignancy prediction, outperforming both the baseline LDCT performance without virtual follow-up generation, and existing state-of-the-art conditional generation methods, while maintaining competitive image quality. These findings suggest that NAMD enables earlier and more accurate lung cancer diagnosis by capturing clinically meaningful features of nodule progression.