Abstract
Integration of multimodal, multi-omics data is critical for advancing precision medicine, yet its application is frequently limited by incomplete datasets where one or more modalities are missing. To address this challenge, we developed a generative framework capable of synthesizing any missing modality from an arbitrary subset of available modalities. We introduce Coherent Denoising, a novel ensemble-based generative diffusion method that aggregates predictions from multiple specialized, single-condition models and enforces consensus during the sampling process. We compare this approach against a multi-condition, generative model that uses a flexible masking strategy to handle arbitrary subsets of inputs. The results show that our architectures successfully generate high-fidelity data that preserve the complex biological signals required for downstream tasks. We demonstrate that the generated synthetic data can be used to maintain the performance of predictive models on incomplete patient profiles and can leverage counterfactual analysis to guide the prioritization of diagnostic tests. We validated the framework's efficacy on a large-scale multimodal, multi-omics cohort from The Cancer Genome Atlas (TCGA) of over 10,000 samples spanning across 20 tumor types, using data modalities such as copy-number alterations (CNA), transcriptomics (RNA-Seq), proteomics (RPPA), and histopathology (WSI). This work establishes a robust and flexible generative framework to address sparsity in multimodal datasets, providing a key step toward improving precision oncology.