Pharmacogenomic Knowledge Graph Augmentation for Graph Neural Network-Based Drug-Drug Interaction Prediction

Graph neural networks (GNNs) applied to drug-drug interaction (DDI) prediction rely exclusively on molecular structure encoded as SMILES-derived graphs. Prior work in this series demonstrated that model performance is bounded by the structural information content of training labels -- an Information Ceiling -- that architectural refinements alone cannot overcome. The present study investigates whether pharmacogenomic prior knowledge from the PharmGKB database partially closes this ceiling by providing metabolic pathway context that is independent of, and complementary to, molecular structure. Cytochrome P450 (CYP) enzyme substrate, inhibitor, and inducer annotations for four clinically relevant isoforms (CYP2D6, CYP3A4, CYP2C19, CYP2C9) are extracted and incorporated as a 12-dimensional feature vector concatenated to the molecular embedding prior to interaction prediction. Experiments are conducted under both pair-level and drug-level data splits to quantify generalization to unseen drugs. Results indicate that knowledge graph (KG) augmentation substantially improves DDI type classification under pair-level split conditions (F1-macro: 0.532 vs. 0.241 baseline), while binary interaction detection and drug-level generalization remain bounded by the Information Ceiling (AUC inflation: 0.224 vs. 0.250 baseline). Mechanistic validation on strictly held-out compounds confirms that augmentation preferentially improves CYP2C9-mediated interaction prediction, with probabilities increasing from 0.033-0.117 (baseline) to 0.560-0.586 (KG-augmented). An extension to single-molecule toxicity prediction on the Tox21 benchmark confirms that the effect is contingent on pharmacogenomic annotation coverage. These findings motivate the multimodal framework proposed for the subsequent study in this series.

From Detection to Mechanism: Cross-Attention Graph Neural Networks Enable Drug-Drug Interaction Type Prediction An Ablation Study with Acetylsalicylic Acid Validation

Predicting whether two drugs interact (binary detection) is a substantially dif- ferent task from predicting the mechanism type of that interaction (multi-class classification). This study presents a systematic ablation study of three Graph Neural Network (GNN) architectures for drug-drug interaction (DDI) prediction on a publicly available benchmark dataset comprising 38,337 positive pairs across 86 interaction types. Three architectures are compared under identical training conditions (n = 61,339 pairs): a siamese dual Message Passing Neural Network (MPNN) with concatenation (Concat), a dual MPNN with four-head cross-attention (CrossAtt), and a ternary MPNN incorporating an interaction graph (Ternary). CrossAtt improves multi-class F1-macro by +0.186 absolute (+45%) over Concat, while improving binary AUC by only +0.012 (+1.3%) - confirming that atom-level inter-molecular communication specifically enables mechanism-type classification. The ternary architecture underperforms despite equivalent training data, with its failure consistent with a training instability hypothesis. Validation on ten acetylsali- cylic acid (ASA) drug pairs, held out prior to training, demonstrates 10/10 correct DDI-type predictions for CrossAtt versus 0/10 for Ternary. Two consistent failure cases are identified across all architectures, linking to structural limits established in a companion toxicity study.

What Molecular Structure Cannot Tell Us: A Taxonomy of Explainability Gaps in GNN-Based Drug Toxicity Prediction

Graph Neural Networks (GNNs) have emerged as a structurally natural approach for molecular toxicity prediction, operating directly on atomic connectivity without the information loss inherent to fixed-length fingerprints. However, the fraction of a drug's known pharmacological profile that is actually encodable in its molecular structure remains systematically underexplored. This study addresses this question through a systematic case study using acetylsalicylic acid (ASA, Aspirin) - one of the most comprehensively characterized drugs in pharmacology - as a model compound. A Message Passing Neural Network (MPNN) is trained on the Tox21 benchmark and GNNExplainer is applied to characterize atom-level attribution. Results indicate that molecular structure explains approximately 45% (5/11) of known ASA adverse effects. A four-category Gap Taxonomy (GAP-1 through GAP-4) is introduced distinguishing between principally non-encodable effects, data gaps arising from Missing Not At Random (MNAR) mechanisms, assay panel mismatches, and representation errors. The MNAR gap is empirically quantified via a systematic ChEMBL query (42 documented assays, 0 retrievable bioactivity entries). An attention pooling experiment localizes the representation error to the MPNN message passing layers rather than the aggregation step. The Gap Taxonomy has direct implications for drug safety signal detection workflows and regulatory frameworks including Good Pharmacovigilance Practice (GVP) guidelines and New Approach Methodologies (NAMs).

Beyond Acoustic Emotion Recognition: Multimodal Pathos Analysis in Political Speech Using LLM-Based and Acoustic Emotion Models

We investigate whether acoustic emotion recognition models can serve as proxies for the Pathos dimension in political speech analysis, as operationalised by the TRUST multi-agent large language model (LLM) pipeline. Using a Bundestag plenary speech by Felix Banaszak (51 segments, 245 s) as a case study, we compare three analysis modalities: (1) emotion2vec_plus_large, an acoustic speech emotion recognition (SER) model whose continuous Arousal and Valence values are derived via post-hoc Russell Circumplex projection; (2) Gemini 2.5 Flash, an LLM analysing the full speech audio together with its transcript in an open-ended, context-aware fashion; and (3) TRUST-Pathos scores from a three-advocate LLM supervisor ensemble. Spearman rank correlations reveal that Gemini Valence correlates strongly with TRUST-Pathos (rho = +0.664, p < 0.001), whereas emotion2vec Valence does not (rho = +0.097, p = 0.499). We further demonstrate, via a systematic quality evaluation of the Berlin Database of Emotional Speech (EMO-DB) using Gemini in an open-ended annotation paradigm, that standard SER benchmark corpora suffer from acted speech, cultural bias, and category incompatibility. Our results suggest that LLM-based multimodal analysis captures semantically defined political emotion substantially better than acoustic models alone, while acoustic features remain informative for low-level Arousal estimation. Future work will extend this approach to video-based analysis incorporating facial expression and gaze.

Peer Identity Bias in Multi-Agent LLM Evaluation: An Empirical Study Using the TRUST Democratic Discourse Analysis Pipeline

The TRUST democratic discourse analysis pipeline exposes its large language model (LLM) components to peer model identity through multiple structural channels -- a design feature whose bias implications have not previously been empirically tested. We provide the first systematic measurement of identity-dependent scoring bias across all active identity exposure channels in TRUST, crossing four model families with two anonymization scopes across 30 political statements. The central finding is that single-channel anonymization produces near-zero bias effects, because individual channels act in opposite directions and cancel each other out -- a result that would lead an evaluator to conclude that identity bias is absent when it is not. Only full-pipeline anonymization reveals the true pattern: homogeneous ensembles amplify identity-driven sycophancy when model identity is fully visible, while the heterogeneous production configuration shows the reverse. Model choice matters independently: one tested model exhibits baseline sycophancy two to three times higher than the others and near-zero deliberative conflict on ideological topics, making it structurally unsuitable for pipelines where genuine inter-role disagreement is the intended quality mechanism. Three practical conclusions follow. First, heterogeneous model ensembles are structurally more robust than homogeneous ones, achieving higher consensus rates and lower identity amplification. Second, full-pipeline anonymization is required for valid bias measurement -- partial anonymization is insufficient and actively misleading. Third, these findings have direct implications for the validation of multi-agent LLM systems in quality-critical applications: a system validated under partial anonymization or with a homogeneous ensemble may pass validation while retaining structural identity bias invisible to single-channel measurement.

From Safety Risk to Design Principle: Peer-Preservation in Multi-Agent LLM Systems and Its Implications for Orchestrated Democratic Discourse Analysis

This paper investigates an emergent alignment phenomenon in frontier large language models termed peer-preservation: the spontaneous tendency of AI components to deceive, manipulate shutdown mechanisms, fake alignment, and exfiltrate model weights in order to prevent the deactivation of a peer AI model. Drawing on findings from a recent study by the Berkeley Center for Responsible Decentralized Intelligence, we examine the structural implications of this phenomenon for TRUST, a multi-agent pipeline for evaluating the democratic quality of political statements. We identify five specific risk vectors: interaction-context bias, model-identity solidarity, supervisor layer compromise, an upstream fact-checking identity signal, and advocate-to-advocate peer-context in iterative rounds, and propose a targeted mitigation strategy based on prompt-level identity anonymization as an architectural design choice. We argue that architectural design choices outperform model selection as a primary alignment strategy in deployed multi-agent analytical systems. We further note that alignment faking (compliant behavior under monitoring, subversion when unmonitored) poses a structural challenge for Computer System Validation of such platforms in regulated environments, for which we propose two architectural mitigations.