Essentiality and Transcriptome-Enriched Pathway Scores Predict Drug-Combination Synergy
Abstract
:1. Introduction
2. Materials and Methods
2.1. Data Source
2.1.1. Data Regarding the Synergy of Drug Combinations
2.1.2. Transcriptome Data
2.1.3. Essentiality Data
2.1.4. Training and Validation Data
2.2. Features
2.3. Logistic Regression Models in Selecting Features for Drug-Synergy Prediction
2.4. Model Training and Validation
3. Results
3.1. In Overall Trend Analysis, Pathway Features Showed Stronger Statistical Correlation Evidence Than Gene Features with Drug-Combination Synergy Scores
3.2. Genome-Wide Association Analyses Revealed Significant Associations of Genes and Pathways with Scores of Drug Synergy
3.3. Overlap Was Limited between Significant Gene Expressions and Essentialities in Predicting Drug Synergy
3.4. No Statistically Significant Evidence Supported Relationship between Target and Non-Target Genes and Pathways in the Prediction of Drug Synergy
3.5. Feature Comparison in Pathway Analysis
3.6. Model Validation
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Data | Feature | Feature Description | Type |
---|---|---|---|
Drug-combination targets | nD_union_ab | Number of total drug targets for Drug A or Drug B | |
nD_intersection_ab | Number of total drug targets for both Drug A and Drug B | ||
KEGG pathways | nk | Number of genes in KEGG Pathway K | |
Cell lines | ncell_c_expression | Number of active genes in Cell Line C | 1 |
ncell_c_essentiality | Number of essential genes in Cell Line C | 1 | |
Drug-combination targets in cell lines based on gene expression | ncell_c_expression_D_union_ab | Number of total drug targets for Drug A or Drug B that are active in Cell Line C | 1 |
ncell_c_expression_D_intersection_ab | Number of total drug targets for both Drug A and Drug B that are active in Cell Line C | ||
ncell_c_expression_D_union_ab/ncell_c_expression | Ratio of the number of active drug targets for Drug A or Drug B to all active genes in Cell Line C | ||
ncell_c_expression_D_intersection_ab/ncell_c_expression | Ratio of the number of active drug targets for Drug A and Drug B to all active genes in Cell Line C | ||
Drug-combination targets and cell lines based on gene essentiality | ncell_c_ essentiality _D_union_ab | Number of total drug targets for Drug A or Drug B that are essential in Cell Line C | 1 |
ncell_c_essentiality _D_intersection_ab | Number of total drug targets for both Drug A and Drug B that are essential in Cell Line C | ||
ncell_c_essentiality_D_union_ab/ncell_c_essentiality | Ratio of the number of essential drug targets for Drug A or Drug B relative to all essential genes in Cell Line C | ||
ncell_c_essentiality_D_intersection_ab/ncell_c_essentiality | Ratio of the number of essential drug targets for Drug A and Drug B relative to all essential genes in Cell Line C | ||
KEGG pathways and cell lines based on gene expression | ncell_c_expression_kegg_k | Number of active genes in KEGG Pathway K for Cell Line C | 2 |
ncell_c_expression_kegg_k/ncell_c_expression | Ratio of the number of active genes in KEGG Pathway K relative to all active genes in Cell Line C | ||
KEGG pathways and cell lines Based on gene essentiality | ncell_c_essentiality_kegg_k | Number of essential genes in KEGG Pathway K for Cell Line C | 2 |
ncell_c_essentiality_kegg_k/ncell_c_essentiality | Ratio of the number of essential genes in KEGG Pathway K to all essential genes in Cell Line C |
Group | Gene Expression | Gene Essentiality | Combined Expression and Essentiality | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Threshold | Number Observed | Number Expected | FDR | Threshold | Number Observed | Number Expected | FDR | Threshold | Number Observed | Number Expected | FDR | ||
1 | 0.0001 | 0 | 0.01 | NA | 0.0001 | 1 | 0.01 | 0.01 | 0.0001 | 1 | 0.01 | 0.01 | |
0.001 | 0 | 0.11 | NA | 0.001 | 1 | 0.11 | 0.11 | 0.001 | 1 | 0.11 | 0.11 | ||
0.01 | 4 | 1.14 | 0.29 | 0.01 | 2 | 1.14 | 0.57 | 0.01 | 7 | 1.14 | 0.16 | ||
2 | DD * | 0.0001 | 7 | 0.01 | 1.43 × 10−3 | 0.0001 | 2 | 0.01 | 0.005 | 0.0001 | 11 | 0.01 | 9.09 × 10−4 |
0.001 | 25 | 0.11 | 4.4 × 10−3 | 0.001 | 15 | 0.11 | 7.33 × 10−3 | 0.001 | 35 | 0.11 | 3.14 × 10−3 | ||
0.01 | 72 | 1.14 | 0.016 | 0.01 | 77 | 1.14 | 0.015 | 0.01 | 85 | 1.14 | 0.013 | ||
DDP # | 0.0001 | 8 | 1.88 | 0.24 | 0.0001 | 3 | 1.88 | 0.63 | 0.0001 | 16 | 1.88 | 0.12 | |
0.001 | 43 | 18.81 | 0.44 | 0.001 | 25 | 18.81 | 0.75 | 0.001 | 78 | 18.81 | 0.24 | ||
0.01 | 443 | 188.1 | 0.42 | 0.01 | 311 | 188.1 | 0.60 | 0.01 | 519 | 188.1 | 0.36 | ||
3 | DD * | 0.0001 | 23 | 0.01 | 4.35 × 10−4 | 0.0001 | 13 | 0.01 | 7.69 × 10−4 | 0.0001 | 37 | 0.01 | 2.72 × 10−4 |
0.001 | 36 | 0.11 | 3.06 × 10−3 | 0.001 | 26 | 0.11 | 4.23 × 10−3 | 0.001 | 62 | 0.11 | 1.77 × 10−3 | ||
0.01 | 86 | 1.14 | 0.013 | 0.01 | 61 | 1.14 | 0.019 | 0.01 | 98 | 1.14 | 0.012 | ||
DDP # | 0.0001 | 50 | 1.88 | 0.038 | 0.0001 | 33 | 1.88 | 0.057 | 0.0001 | 253 | 1.88 | 7.43 × 10−3 | |
0.001 | 125 | 18.81 | 0.15 | 0.001 | 119 | 18.81 | 0.16 | 0.001 | 423 | 18.81 | 0.044 | ||
0.01 | 781 | 188.1 | 0.24 | 0.01 | 832 | 188.1 | 0.23 | 0.01 | 1257 | 188.1 | 0.15 |
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Li, J.; Huo, Y.; Wu, X.; Liu, E.; Zeng, Z.; Tian, Z.; Fan, K.; Stover, D.; Cheng, L.; Li, L. Essentiality and Transcriptome-Enriched Pathway Scores Predict Drug-Combination Synergy. Biology 2020, 9, 278. https://doi.org/10.3390/biology9090278
Li J, Huo Y, Wu X, Liu E, Zeng Z, Tian Z, Fan K, Stover D, Cheng L, Li L. Essentiality and Transcriptome-Enriched Pathway Scores Predict Drug-Combination Synergy. Biology. 2020; 9(9):278. https://doi.org/10.3390/biology9090278
Chicago/Turabian StyleLi, Jin, Yang Huo, Xue Wu, Enze Liu, Zhi Zeng, Zhen Tian, Kunjie Fan, Daniel Stover, Lijun Cheng, and Lang Li. 2020. "Essentiality and Transcriptome-Enriched Pathway Scores Predict Drug-Combination Synergy" Biology 9, no. 9: 278. https://doi.org/10.3390/biology9090278