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. 2023 Nov 22;25(1):bbad522.
doi: 10.1093/bib/bbad522.

A granularity-level information fusion strategy on hypergraph transformer for predicting synergistic effects of anticancer drugs

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A granularity-level information fusion strategy on hypergraph transformer for predicting synergistic effects of anticancer drugs

Wei Wang et al. Brief Bioinform. .

Abstract

Combination therapy has exhibited substantial potential compared to monotherapy. However, due to the explosive growth in the number of cancer drugs, the screening of synergistic drug combinations has become both expensive and time-consuming. Synergistic drug combinations refer to the concurrent use of two or more drugs to enhance treatment efficacy. Currently, numerous computational methods have been developed to predict the synergistic effects of anticancer drugs. However, there has been insufficient exploration of how to mine drug and cell line data at different granularity levels for predicting synergistic anticancer drug combinations. Therefore, this study proposes a granularity-level information fusion strategy based on the hypergraph transformer, named HypertranSynergy, to predict synergistic effects of anticancer drugs. HypertranSynergy introduces synergistic connections between cancer cell lines and drug combinations using hypergraph. Then, the Coarse-grained Information Extraction (CIE) module merges the hypergraph with a transformer for node embeddings. In the CIE module, Contranorm is a normalization layer that mitigates over-smoothing, while Gaussian noise addresses local information gaps. Additionally, the Fine-grained Information Extraction (FIE) module assesses fine-grained information's impact on predictions by employing similarity-aware matrices from drug/cell line features. Both CIE and FIE modules are integrated into HypertranSynergy. In addition, HypertranSynergy achieved the AUC of 0.93${\pm }$0.01 and the AUPR of 0.69${\pm }$0.02 in 5-fold cross-validation of classification task, and the RMSE of 13.77${\pm }$0.07 and the PCC of 0.81${\pm }$0.02 in 5-fold cross-validation of regression task. These results are better than most of the state-of-the-art models.

Keywords: anticancer drugs; granularity-level information fusion; hypergraph; predicting synergistic effects; transformer.

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Figures

Figure 1
Figure 1
Architecture of HypertranSynergy. (1) Initialize hypergraph node feature. We initialize hypergraph node features using MLP and GINs. Here, formula image and formula image correspond to the cell line feature matrix and drug feature matrix, respectively. (2) Constructing the drug synergy hypergraph. This section describes the process of constructing the drug synergy hypergraph. (3) CIE based on hypergraph transformer. formula image and formula image represent the embedding matrices of cell lines and drugs processed by CIE, respectively. (4) Fine-grained information extraction. formula image denotes the number of attention network layers, formula image represents the weight parameters, and formula image denotes the nonlinear activation function, formula image and formula image represent the informative similarity-aware matrix. The formula image matrix is used in conjunction with the formula image matrix to calculate the loss of FIE. (5) Fusion of Granularity-LevelInformation and Prediction. formula image represents the decoded embedding, while formula image and formula image correspond the loss functions of CIE and FIE, respectively. formula image represents the total loss.
Figure 2
Figure 2
Scatter plot of the predicted synergy scores and the ground truth.
Figure 3
Figure 3
Result of parameter sensitivity analysis. (A, B) Parameter analysis of embedding dimension processed by CIE. (C,D) Parameter analysis of the number of transformer multi-head attention. (E, F) Parameter analysis of transformer layers.
Figure 4
Figure 4
Illustration of the three datasets partitioning scenarios and the performance of each scenario in classification and regression tasks. Each data point consists of two drugs and a cell line. The blue and green data samples represent the training/validation data set and test dataset, respectively. (A) Random five-fold cross-validation. In this scenario, the dataset was randomly divided into equal parts, one portion was colored green and held out as test dataset. (B) Leave-cell line-out scenario. In this scenario, the dataset was randomly divided into equal parts at the cell line level, one portion was colored green and held out as test dataset. (C) Leave-drug combination-out scenario. In this scenario, the dataset was randomly divided into equal parts at the drug combination level, one portion was colored green and held out as test dataset. (D–I) Performance of the model in the three scenarios. The classification task is evaluated using AUC, AUPR and ACC, while the prediction task is evaluated using RMSE and PCC.
Figure 5
Figure 5
Variation in model performance with different contributions of coarse-grained and fine-grained information. The optimal model performance is achieved with formula image value of 4.
Figure 6
Figure 6
Subnetwork of the hypergraph composed of partial prediction results. Green nodes represent drugs, and orange nodes represent cell lines. Blue lines indicate the certain predicted synergies align with experimentally confirmed findings, and red lines indicate newly predicted synergies.
Figure 7
Figure 7
Synergistic inhibition analysis heatmap of ETOPOSIDE-GEMCITABINE on SK-MEL-30 and MITOMYCIN-PACLITAXEL on HT-29.

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