# Asymmetric Focal Loss Improves Graph Neural Network Prediction of Drug-Drug Interactions

arXiv: https://arxiv.org/abs/2607.07611 · HTML: https://mlsanity.com/paper/2607.07611/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 16 of its 32 references that are in the map.
- First posted on arXiv 8 Jul 2026.

## Builds on (most cited first, 16 of 16)

- [Attention Is All You Need](https://mlsanity.com/paper/1706.03762/) (2017)
- [RoBERTa: A Robustly Optimized BERT Pretraining Approach](https://mlsanity.com/paper/1907.11692/) (2019)
- [Learning Phrase Representations using RNN Encoder-Decoder for Statistical Machine Translation](https://mlsanity.com/paper/1406.1078/) (2014)
- [A Comprehensive Survey on Graph Neural Networks](https://mlsanity.com/paper/1901.00596/) (2019)
- [Optuna: A Next-generation Hyperparameter Optimization Framework](https://mlsanity.com/paper/1907.10902/) (2019)
- [BioBERT: a pre-trained biomedical language representation model for biomedical text mining](https://mlsanity.com/paper/1901.08746/) (2019)
- [Modeling Relational Data with Graph Convolutional Networks](https://mlsanity.com/paper/1703.06103/) (2017)
- [Training Region-based Object Detectors with Online Hard Example Mining](https://mlsanity.com/paper/1604.03540/) (2016)
- [Generalized Focal Loss: Learning Qualified and Distributed Bounding Boxes for Dense Object Detection](https://mlsanity.com/paper/2006.04388/) (2020)
- [Asymmetric Loss For Multi-Label Classification](https://mlsanity.com/paper/2009.14119/) (2020)
- [Modeling polypharmacy side effects with graph convolutional networks](https://mlsanity.com/paper/1802.00543/) (2018)
- [SkipGNN: Predicting Molecular Interactions with Skip-Graph Networks](https://mlsanity.com/paper/2004.14949/) (2020)
- [SumGNN: Multi-typed Drug Interaction Prediction via Efficient Knowledge Graph Summarization](https://mlsanity.com/paper/2010.01450/) (2020)
- [Stacked Bidirectional and Unidirectional LSTM Recurrent Neural Network for Forecasting Network-wide Traffic State with Missing Values](https://mlsanity.com/paper/2005.11627/) (2020)
- [Drug-Drug Interaction Prediction Based on Knowledge Graph Embeddings and Convolutional-LSTM Network](https://mlsanity.com/paper/1908.01288/) (2019)
- [CASTER: Predicting Drug Interactions with Chemical Substructure Representation](https://mlsanity.com/paper/1911.06446/) (2019)

## Abstract (arXiv)

Background: Graph neural networks improve computational prediction of polypharmacy side effects, but standard binary cross-entropy training allocates equal capacity to well-classified and difficult examples, potentially missing clinically significant interactions. We evaluated whether an asymmetric focal objective could improve multi-relational drug-drug interaction (DDI) prediction by emphasizing difficult positive interactions. Methods: ClinicalFocal loss was integrated into a relation-aware graph convolutional network using molecular fingerprints, physicochemical descriptors, and learned embeddings. The model was evaluated on TWOSIDES using five-fold cross-validation with identical experimental conditions (architecture, features, data partitions, hyperparameters, and random seeds) for ClinicalFocal loss and binary cross-entropy baseline. Results: ClinicalFocal loss increased accuracy from 0.699 to 0.892 (+19.3 percentage points) and F1 score from 0.700 to 0.894 (+19.4 percentage points). AUROC increased from 0.766 to 0.914, and AUCPR increased from 0.714 to 0.860. The false-negative rate decreased from 29.8% to 9.1%, while specificity increased from 69.6% to 87.5%. Overall classification error decreased from 30.1% to 10.8%, corresponding to a 64.1% relative reduction. Improvements were consistent across all five folds. Conclusions: Asymmetric focal optimization improved classification and ranking performance while achieving 90.9% recall for observed interaction triples, without modifying the underlying architecture. Loss-function design is a direct, tunable lever for improving graph-based DDI prediction.