# CADD: Context aware disease deviations via restoration of brain images using normative conditional diffusion models

arXiv: https://arxiv.org/abs/2508.03594 · HTML: https://mlsanity.com/paper/2508.03594/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Placed in Medical imaging and segmentation, one of 14 directions in Diffusion models.
- Builds on 40 of its 57 references that are in the map.
- First posted on arXiv 5 Aug 2025.

## Placed in

- Diffusion models / [Medical imaging and segmentation](https://mlsanity.com/diffusion/medical-imaging-and-segmentation/)

## Builds on (most cited first, 30 of 40)

- [Attention Is All You Need](https://mlsanity.com/paper/1706.03762/) (2017)
- [An Image is Worth 16x16 Words: Transformers for Image Recognition at Scale](https://mlsanity.com/paper/2010.11929/) (2020)
- [Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2006.11239/) (2020)
- [U-Net: Convolutional Networks for Biomedical Image Segmentation](https://mlsanity.com/paper/1505.04597/) (2015)
- [High-Resolution Image Synthesis with Latent Diffusion Models](https://mlsanity.com/paper/2112.10752/) (2021)
- [Very Deep Convolutional Networks for Large-Scale Image Recognition](https://mlsanity.com/paper/1409.1556/) (2014)
- [The Unreasonable Effectiveness of Deep Features as a Perceptual Metric](https://mlsanity.com/paper/1801.03924/) (2018)
- [Denoising Diffusion Implicit Models](https://mlsanity.com/paper/2010.02502/) (2020)
- [Deep Unsupervised Learning using Nonequilibrium Thermodynamics](https://mlsanity.com/paper/1503.03585/) (2015)
- [Scalable Diffusion Models with Transformers](https://mlsanity.com/paper/2212.09748/) (2022)
- [SqueezeNet: AlexNet-level accuracy with 50x fewer parameters and <0.5MB model size](https://mlsanity.com/paper/1602.07360/) (2016)
- [Unsupervised Anomaly Detection with Generative Adversarial Networks to Guide Marker Discovery](https://mlsanity.com/paper/1703.05921/) (2017)
- [Memorizing Normality to Detect Anomaly: Memory-augmented Deep Autoencoder for Unsupervised Anomaly Detection](https://mlsanity.com/paper/1904.02639/) (2019)
- [Latte: Latent Diffusion Transformer for Video Generation](https://mlsanity.com/paper/2401.03048/) (2024)
- [The RSNA-ASNR-MICCAI BraTS 2021 Benchmark on Brain Tumor Segmentation and Radiogenomic Classification](https://mlsanity.com/paper/2107.02314/) (2021)
- [Brain Imaging Generation with Latent Diffusion Models](https://mlsanity.com/paper/2209.07162/) (2022)
- [Diffusion Models for Medical Anomaly Detection](https://mlsanity.com/paper/2203.04306/) (2022)
- [Autoencoders for Unsupervised Anomaly Segmentation in Brain MR Images: A Comparative Study](https://mlsanity.com/paper/2004.03271/) (2020)
- [MedSegDiff-V2: Diffusion based Medical Image Segmentation with Transformer](https://mlsanity.com/paper/2301.11798/) (2023)
- [Denoising diffusion models for out-of-distribution detection](https://mlsanity.com/paper/2211.07740/) (2022)
- [Fast Unsupervised Brain Anomaly Detection and Segmentation with Diffusion Models](https://mlsanity.com/paper/2206.03461/) (2022)
- [Unsupervised Detection of Lesions in Brain MRI using constrained adversarial auto-encoders](https://mlsanity.com/paper/1806.04972/) (2018)
- [Improving Reconstruction Autoencoder Out-of-distribution Detection with Mahalanobis Distance](https://mlsanity.com/paper/1812.02765/) (2018)
- [Unsupervised Lesion Detection via Image Restoration with a Normative Prior](https://mlsanity.com/paper/2005.00031/) (2020)
- [Context-encoding Variational Autoencoder for Unsupervised Anomaly Detection](https://mlsanity.com/paper/1812.05941/) (2018)
- [Rethinking Reconstruction Autoencoder-Based Out-of-Distribution Detection](https://mlsanity.com/paper/2203.02194/) (2022)
- [Encoding Structure-Texture Relation with P-Net for Anomaly Detection in Retinal Images](https://mlsanity.com/paper/2008.03632/) (2020)
- [Mask, Stitch, and Re-Sample: Enhancing Robustness and Generalizability in Anomaly Detection through Automatic Diffusion Models](https://mlsanity.com/paper/2305.19643/) (2023)
- [Unsupervised Brain Anomaly Detection and Segmentation with Transformers](https://mlsanity.com/paper/2102.11650/) (2021)
- [Diffusion Models with Implicit Guidance for Medical Anomaly Detection](https://mlsanity.com/paper/2403.08464/) (2024)

## Abstract (arXiv)

Applying machine learning to real-world medical data, e.g. from hospital archives, has the potential to revolutionize disease detection in brain images. However, detecting pathology in such heterogeneous cohorts is a difficult challenge. Normative modeling, a form of unsupervised anomaly detection, offers a promising approach to studying such cohorts where the ``normal'' behavior is modeled and can be used at subject level to detect deviations relating to disease pathology. Diffusion models have emerged as powerful tools for anomaly detection due to their ability to capture complex data distributions and generate high-quality images. Their performance relies on image restoration; differences between the original and restored images highlight potential abnormalities. However, unlike normative models, these diffusion model approaches do not incorporate clinical information which provides important context to guide the disease detection process. Furthermore, standard approaches often poorly restore healthy regions, resulting in poor reconstructions and suboptimal detection performance. We present CADD, the first conditional diffusion model for normative modeling in 3D images. To guide the healthy restoration process, we propose a novel inference inpainting strategy which balances anomaly removal with retention of subject-specific features. Evaluated on three challenging datasets, including clinical scans, which may have lower contrast, thicker slices, and motion artifacts, CADD achieves state-of-the-art performance in detecting neurological abnormalities in heterogeneous cohorts.