Biomarker detection is an indispensable part in 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, a Multi-Biomarker Histomorphology Discoverer
(Multi-Beholder) model based on the multiple instance learning (MIL) framework,
to predict the status of five biomarkers in LGG using only hematoxylin and
eosin-stained whole slide images and slide-level biomarker status labels.
Specifically, by incorporating the one-class classification into the MIL
framework, accurate instance pseudo-labeling is realized for instance-level
supervision, which greatly complements the slide-level labels and improves the
biomarker prediction performance. Multi-Beholder demonstrates superior
prediction performance and generalizability for five LGG biomarkers
(AUROC=0.6469-0.9735) in two cohorts (n=607) with diverse races and scanning
protocols. Moreover, the excellent interpretability of Multi-Beholder allows
for discovering the 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.

通过基于多重实例学习框架的多生物标志物组织形态学发现者（Multi-Beholder）模型，我们提出了一种可解释的深度学习流程，仅使用血液和嗜酸性染色全切片图像和切片级生物标志物状态标签，预测低级别胶质瘤中五种生物标志物的状况，从而克服了当前昂贵且复杂的分子遗传学测试所依赖的专业人员分析结果以及常常报告的内观者差异。