Multi-Beholder: Biomarker Prediction for Low-Grade Glioma with Multiple Instance Learning and One-Class Classification

Biomarker detection is an indispensable part of the diagnosis and treatment of low-grade glioma (LGG). However, current LGG biomarker detection methods rely on expensive and complex molecular genetic testing, for which professionals are required to analyze the results, and intra-rater variability is often reported. To overcome these challenges, we propose an interpretable deep learning pipeline, named Multi-Biomarker Histomorphology Discoverer (Multi-Beholder), to predict the status of five biomarkers in LGG using only hematoxylin and eosin-stained whole slide images. Specifically, Multi-Beholder incorporates one-class classification into the multiple instance learning framework to achieve accurate instance-level pseudo-labeling, thereby complementing slide-level labels and improving prediction performance. Multi-Beholder demonstrates high performance on two LGG cohorts with diverse races and scanning protocols, with area under the receiver operating characteristic curve up to 0.973 on the internal-validated TCGA-LGG dataset and 0.820 on the external-validated Xiangya cohort. Moreover, the interpretability of Multi-Beholder allows for discovering quantitative and qualitative correlations between biomarker status and histomorphology characteristics. Our pipeline not only provides a novel approach for biomarker prediction, enhancing the applicability of molecular treatments for LGG patients but also facilitates the discovery of new mechanisms in molecular functionality and LGG progression. Code can be accessed at https://github.com/Vison307/Multi-Beholder.