Angelina Ning | Searcharxiv

arXiv2025

Interpretable Perturbation Modeling Through Biomedical Knowledge Graphs

Understanding how small molecules perturb gene expression is essential for uncovering drug mechanisms, predicting off-target effects, and identifying repurposing opportunities. While prior deep learning frameworks have integrated multimodal embeddings into biomedical knowledge graphs (BKGs) and further improved these representations through graph neural network message-passing paradigms, these models have been applied to tasks such as link prediction and binary drug-disease association, rather than the task of gene perturbation, which may unveil more about mechanistic transcriptomic effects. To address this gap, we construct a merged biomedical graph that integrates (i) PrimeKG++, an augmentation of PrimeKG containing semantically rich embeddings for nodes with (ii) LINCS L1000 drug and cell line nodes, initialized with multimodal embeddings from foundation models such as MolFormerXL and BioBERT. Using this heterogeneous graph, we train a graph attention network (GAT) with a downstream prediction head that learns the delta expression profile of over 978 landmark genes for a given drug-cell pair. Our results show that our framework outperforms MLP baselines for differentially expressed genes (DEG) -- which predict the delta expression given a concatenated embedding of drug features, target features, and baseline cell expression -- under the scaffold and random splits. Ablation experiments with edge shuffling and node feature randomization further demonstrate that the edges provided by biomedical KGs enhance perturbation-level prediction. More broadly, our framework provides a path toward mechanistic drug modeling: moving beyond binary drug-disease association tasks to granular transcriptional effects of therapeutic intervention.

cs.LG↗

arXiv2025

Negative Pre-activations Differentiate Syntax

Modern large language models increasingly use smooth activation functions such as GELU or SiLU, allowing negative pre-activations to carry both signal and gradient. Nevertheless, many neuron-level interpretability analyses have historically focused on large positive activations, often implicitly treating the negative region as less informative, a carryover from the ReLU-era. We challenge this assumption and ask whether and how negative pre-activations are leveraged by models. We address this question by studying a sparse subpopulation of Wasserstein neurons whose output distributions deviate strongly from a Gaussian baseline and that functionally differentiate similar inputs. We show that this negative region plays an active role rather than reflecting a mere gradient optimization side effect. A minimal, sign-specific intervention that zeroes only the negative pre-activations of a small set of Wasserstein neurons substantially increases perplexity and sharply degrades grammatical performance on BLiMP and TSE, whereas both random and perplexity-matched ablations of many more non-Wasserstein neurons in their negative pre-activations leave grammatical performance largely intact. Conversely, on a suite of non-grammatical benchmarks, the perplexity-matched control ablation is more damaging than the Wasserstein neuron ablation, yielding a double dissociation between syntax and other capabilities. Part-of-speech analysis localizes the excess surprisal to syntactic scaffolding tokens, layer-specific interventions show that small local degradations accumulate across depth, and training-dynamics analysis reveals that the same sign-specific ablation becomes more harmful as Wasserstein neurons emerge and stabilize. Together, these results identify negative pre-activations in a sparse subpopulation of Wasserstein neurons as an actively used substrate for syntax in smooth-activation language models.

cs.LG↗