Regression is all you need for medical image translation

While Generative Adversarial Nets (GANs) and Diffusion Models (DMs) have achieved impressive results in natural image synthesis, their core strengths - creativity and realism - can be detrimental in medical applications, where accuracy and fidelity are paramount. These models instead risk introducing hallucinations and replication of unwanted acquisition noise. Here, we propose YODA (You Only Denoise once - or Average), a 2.5D diffusion-based framework for medical image translation (MIT). Consistent with DM theory, we find that conventional diffusion sampling stochastically replicates noise. To mitigate this, we draw and average multiple samples, akin to physical signal averaging. As this effectively approximates the DM's expected value, we term this Expectation-Approximation (ExpA) sampling. We additionally propose regression sampling YODA, which retains the initial DM prediction and omits iterative refinement to produce noise-free images in a single step. Across five diverse multi-modal datasets - including multi-contrast brain MRI and pelvic MRI-CT - we demonstrate that regression sampling is not only substantially more efficient but also matches or exceeds image quality of full diffusion sampling even with ExpA. Our results reveal that iterative refinement solely enhances perceptual realism without benefiting information translation, which we confirm in relevant downstream tasks. YODA outperforms eight state-of-the-art DMs and GANs and challenges the presumed superiority of DMs and GANs over computationally cheap regression models for high-quality MIT. Furthermore, we show that YODA-translated images are interchangeable with, or even superior to, physical acquisitions for several medical applications.