# Toxicity Assessment in Preclinical Histopathology via Class-Aware Mahalanobis Distance for Known and Novel Anomalies

arXiv: https://arxiv.org/abs/2602.02124 · HTML: https://mlsanity.com/paper/2602.02124/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 28 of its 49 references that are in the map.
- First posted on arXiv 2 Feb 2026.

## Builds on (most cited first, 28 of 28)

- [An Image is Worth 16x16 Words: Transformers for Image Recognition at Scale](https://mlsanity.com/paper/2010.11929/) (2020)
- [PyTorch: An Imperative Style, High-Performance Deep Learning Library](https://mlsanity.com/paper/1912.01703/) (2019)
- [DINOv2: Learning Robust Visual Features without Supervision](https://mlsanity.com/paper/2304.07193/) (2023)
- [A Baseline for Detecting Misclassified and Out-of-Distribution Examples in Neural Networks](https://mlsanity.com/paper/1610.02136/) (2016)
- [A Simple Unified Framework for Detecting Out-of-Distribution Samples and Adversarial Attacks](https://mlsanity.com/paper/1807.03888/) (2018)
- [DINOv3](https://mlsanity.com/paper/2508.10104/) (2025)
- [Enhancing The Reliability of Out-of-distribution Image Detection in Neural Networks](https://mlsanity.com/paper/1706.02690/) (2017)
- [Energy-based Out-of-distribution Detection](https://mlsanity.com/paper/2010.03759/) (2020)
- [Deep Anomaly Detection with Outlier Exposure](https://mlsanity.com/paper/1812.04606/) (2018)
- [Out-of-Distribution Detection with Deep Nearest Neighbors](https://mlsanity.com/paper/2204.06507/) (2022)
- [Memorizing Normality to Detect Anomaly: Memory-augmented Deep Autoencoder for Unsupervised Anomaly Detection](https://mlsanity.com/paper/1904.02639/) (2019)
- [ReAct: Out-of-distribution Detection With Rectified Activations](https://mlsanity.com/paper/2111.12797/) (2021)
- [Scaling Out-of-Distribution Detection for Real-World Settings](https://mlsanity.com/paper/1911.11132/) (2019)
- [GANomaly: Semi-Supervised Anomaly Detection via Adversarial Training](https://mlsanity.com/paper/1805.06725/) (2018)
- [Improving Unsupervised Defect Segmentation by Applying Structural Similarity to Autoencoders](https://mlsanity.com/paper/1807.02011/) (2018)
- [Adversarially Learned One-Class Classifier for Novelty Detection](https://mlsanity.com/paper/1802.09088/) (2018)
- [OCGAN: One-class Novelty Detection Using GANs with Constrained Latent Representations](https://mlsanity.com/paper/1903.08550/) (2019)
- [In or Out? Fixing ImageNet Out-of-Distribution Detection Evaluation](https://mlsanity.com/paper/2306.00826/) (2023)
- [Out-of-Distribution Detection Using an Ensemble of Self Supervised Leave-out Classifiers](https://mlsanity.com/paper/1809.03576/) (2018)
- [Towards Visually Explaining Variational Autoencoders](https://mlsanity.com/paper/1911.07389/) (2019)
- [Generative Probabilistic Novelty Detection with Adversarial Autoencoders](https://mlsanity.com/paper/1807.02588/) (2018)
- [Pixel-wise Energy-biased Abstention Learning for Anomaly Segmentation on Complex Urban Driving Scenes](https://mlsanity.com/paper/2111.12264/) (2021)
- [Residual Pattern Learning for Pixel-wise Out-of-Distribution Detection in Semantic Segmentation](https://mlsanity.com/paper/2211.14512/) (2022)
- [Segment Every Out-of-Distribution Object](https://mlsanity.com/paper/2311.16516/) (2023)
- [A Survey on Diffusion Models for Anomaly Detection](https://mlsanity.com/paper/2501.11430/) (2025)
- [Learning image representations for anomaly detection: application to discovery of histological alterations in drug development](https://mlsanity.com/paper/2210.07675/) (2022)
- [AI-based Anomaly Detection for Clinical-Grade Histopathological Diagnostics](https://mlsanity.com/paper/2406.14866/) (2024)
- [OOD-SEG: Exploiting out-of-distribution detection techniques for learning image segmentation from sparse multi-class positive-only annotations](https://mlsanity.com/paper/2411.09553/) (2024)

## Abstract (arXiv)

Drug-induced toxicity is a leading cause of preclinical and early-clinical failure, making early detection critical. Histopathology is the gold standard for toxicity assessment but relies on expert pathologists, creating a bottleneck for large-scale screening. We introduce an AI-based anomaly detection framework for whole-slide images (WSIs) of rodent liver that identifies healthy tissue and known pathologies (anomalies) and flags samples without training data as out-of-distribution (OOD). We evaluate OOD detection on two held-out categories: apoptosis (single-cell, near-OOD) and staining/processing artifacts (heterogeneous, far-OOD). We build a novel pixelwise-annotated dataset and fine-tune a pre-trained Vision Transformer (DINOv2) via Low-Rank Adaptation (LoRA) for segmentation, then use the Mahalanobis distance for OOD detection with class-specific thresholds. Optimizing the false positive rate subject to a predefined constraint on the false negative rate yields only 0.16% of pathological tissue classified as healthy and 0.35% of healthy tissue classified as pathological. Our false negative rate does not penalise cross-type errors, reflecting the safety-first objective of never overlooking a lesion; under the stricter correct-class criterion our method assigns 93.93% of ID and 89.38% of OOD findings to their own class. The study demonstrates technical feasibility of pixel-level anomaly detection for mouse liver histopathology, indicating possible applications in improving preclinical workflows and drug development efficiency.