Ciyue Shen

Nhat Minh Le, Ciyue Shen, Neel Patel et al.

Pathology plays an important role in disease diagnosis, treatment decision-making and drug development. Previous works on interpretability for machine learning models on pathology images have revolved around methods such as attention value visualization and deriving human-interpretable features from model heatmaps. Mechanistic interpretability is an emerging area of model interpretability that focuses on reverse-engineering neural networks. Sparse Autoencoders (SAEs) have emerged as a promising direction in terms of extracting monosemantic features from polysemantic model activations. In this work, we trained a Sparse Autoencoder on the embeddings of a pathology pretrained foundation model. We found that Sparse Autoencoder features represent interpretable and monosemantic biological concepts. In particular, individual SAE dimensions showed strong correlations with cell type counts such as plasma cells and lymphocytes. These biological representations were unique to the pathology pretrained model and were not found in a self-supervised model pretrained on natural images. We demonstrated that such biologically-grounded monosemantic representations evolved across the model's depth, and the pathology foundation model eventually gained robustness to non-biological factors such as scanner type. The emergence of biologically relevant SAE features was generalizable to an out-of-domain dataset. Our work paves the way for further exploration around interpretable feature dimensions and their utility for medical and clinical applications.

Weiqi Ji, Bo Yuan, Ciyue Shen et al.

Data-driven dynamic models of cell biology can be used to predict cell response to unseen perturbations. Recent work (CellBox) had demonstrated the derivation of interpretable models with explicit interaction terms, in which the parameters were optimized using machine learning techniques. While the previous work was tested only in a single biological setting, this work aims to extend the range of applicability of this model inference approach to a diversity of biological systems. Here we adapted CellBox in Julia differential programming and augmented the method with adjoint algorithms, which has recently been used in the context of neural ODEs. We trained the models using simulated data from both abstract and biology-inspired networks, which afford the ability to evaluate the recovery of the ground truth network structure. The resulting accuracy of prediction by these models is high both in terms of low error against data and excellent agreement with the network structure used for the simulated training data. While there is no analogous ground truth for real life biological systems, this work demonstrates the ability to construct and parameterize a considerable diversity of network models with high predictive ability. The expectation is that this kind of procedure can be used on real perturbation-response data to derive models applicable to diverse biological systems.