Cited by 328Computational Drug Discovery MethodsStatistical Methods in Clinical TrialsOptimal Experimental Design Methods

The DOI matches its Crossref record; 14 of the 14 references it cites were found in a registry or an index.

A New Bliss Independence Model to Analyze Drug Combination Data

Open access

Zhao, Wei, Sachsenmeier, Kris, Zhang, Lanju, Sult, Erin, Hollingsworth, Robert E., Yang, Harry·2014·SLAS Discovery

DOI 10.1177/1087057114521867

Open this paper in CoChat — free account Open PDF

Abstract

The Bliss independence model is widely used to analyze drug combination data when screening for candidate drug combinations. The method compares the observed combination response (Y(O)) with the predicted combination response (Y(P)), which was obtained based on the assumption that there is no effect from drug-drug interactions. Typically, the combination effect is declared synergistic if Y(O) is greater than Y(P). However, this method lacks statistical rigor because it does not take into account the variability of the response measures and can frequently cause false-positive claims. In this article, we introduce a two-stage response surface model to describe the drug interaction across all dose combinations tested. This new method enables robust statistical testing for synergism at any dose combination, thus reducing the risk of false positives. The use of the method is illustrated through an application describing statistically significant "synergy regions" for candidate drug combinations targeting epidermal growth factor receptor and the insulin-like growth factor 1 receptor.

Integrity signals

Registry

Crossref · 10.1177/1087057114521867

Cites

14 of 14 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

The search for synergy: a critical review from a response surface perspective.
Greco, W. R., Bravo, G., & Parsons, J. C. (1995) · Pharmacological Reviews · doi:10.1016/s0031-6997(25)06847-4 · Cited by 1,445
Probability Theory and Mathematical Statistics
(1996) · doi:10.1142/2898 · Cited by 1,406
Activation of Multiple Proto-oncogenic Tyrosine Kinases in Breast Cancer via Loss of the PTPN12 Phosphatase
Sun, T., Aceto, N., Meerbrey, K. L., Kessler, J. D., Zhou, C., Migliaccio, I., Nguyen, D. X., Pavlova, N. N., Botero, M. F., Huang, J., et al. (2011) · Cell · doi:10.1016/j.cell.2011.02.003 · Cited by 281 · cited 4×
“I Y Y M a b ab O ab P = − = + , , ( | , ) Γ ε, (3)”
BackgroundMethodInfluential
A global analysis of cross-talk in a mammalian cellular signalling network
Natarajan, M., Lin, K.-M., Hsueh, R. C., Sternweis, P. C., & Ranganathan, R. (2006) · Nature Cell Biology · doi:10.1038/ncb1418 · Cited by 235 · cited 1×
“Average percentage inhibition is usually used when replicates are available and a conclusion can be drawn by strictly following equations (1) and (2).”
Method
Probability Theory and Mathematical Statistics.
Bartholomew, D. J., & Fisz, M. (1964) · Biometrika · doi:10.2307/2334227 · Cited by 161
A stable IgG-like bispecific antibody targeting the epidermal growth factor receptor and the type I insulin-like growth factor receptor demonstrates superior anti-tumor activity
Dong, J., Sereno, A., Aivazian, D., Langley, E. J., Miller, B., Snyder, W. B., Chan, E., Cantele, M., Morena, R., Joseph, I. B. J., et al. (2011) · mAbs · doi:10.4161/mabs.3.3.15188 · Cited by 80
Activation of the Insulin-like Growth Factor-1 Receptor Induces Resistance to Epidermal Growth Factor Receptor Antagonism in Head and Neck Squamous Carcinoma Cells
Jameson, M. J., Beckler, A. D., Taniguchi, L. E., Allak, A., VanWagner, L. B., Lee, N. G., Thomsen, W. C., Hubbard, M. A., & Thomas, C. Y. (2011) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-11-0294 · Cited by 79
The EGF receptor interacts with the type 1 IGF receptor and regulates its stability
Riedemann, J., Takiguchi, M., Sohail, M., & Macaulay, V. M. (2007) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2007.02.012 · Cited by 77
Dual inhibition of epidermal growth factor receptor and insulin‐like growth factor receptor I: Reduction of angiogenesis and tumor growth in cutaneous squamous cell carcinoma
Galer, C. E., Corey, C. L., Wang, Z., Younes, M. N., Gomez‐Rivera, F., Jasser, S. A., Ludwig, D. L., El‐Naggar, A. K., Weber, R. S., & Myers, J. N. (2010) · Head & Neck · doi:10.1002/hed.21419 · Cited by 53
Rational Design of Cancer-Drug Combinations
Ramaswamy, S. (2007) · New England Journal of Medicine · doi:10.1056/nejmcibr072593 · Cited by 48 · cited 1×
“Average percentage inhibition is usually used when replicates are available and a conclusion can be drawn by strictly following equations (1) and (2).”
Method

Show all 14 references

Sorted by citations

Items 301–328 of 328

Predicting Synergistic Anticancer Drug Combinations via Graph Attention Network
Kim, S.-M., & Yoo, S. (2026) · Journal of Digital Contents Society · doi:10.9728/dcs.2026.27.3.831
Efficacy and synergy of low-dose radiotherapy combined with anti-PD-L1 based immunotherapy
Laurent, P.-A. (2023) · theses.fr (ABES) · doi:10.70675/e7695737z26a3z4747zafafzb19e3e74372b
WNT-driven chromosomal instability as a biomarker for PORCN inhibitionPreprint
Garcia-Lopez, D., Zoufir, A., Hernando, B., Santamarı́a, P. G., Cádiz, A., Terraube, H. D. G., Madrid, L., Cullen, A. E., Woodcock, S. A., Piskorz, A., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.04.13.718275
“…in monotherapy trials 17,52 ( Figure 4a ) and combination trials 45,53 ( Supplementary Figure 7 , PORCN inhibitors plus anti-PD1 immunotherapy) where we applied the Bliss Independence model 54 to mathematically infer the PORCN inhibitor-driven component of the clinical response (see Methods ).”
Proteome-anchored multi-omics of recurrent somatic alterations defines tumour states in cervical cancer and enables state-guided drug repurposingPreprint
Hamese, S., Takundwa, M. M., Prinsloo, E., & Raj, D. B. T. G. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.04.21.719801
The telomerase/shelterin system is impaired in acromegaly and Cushing´s disease: Potential pathophysiological relevance
G-García, M. E., la Rosa-Herencia, A. S. D., Gil-Duque, I., Arroyo-Millan, L., Venegas, E., Herrera-Martínez, A. D., Bellido, M., Núñez-Santos, M. Á., Montero‐Hidalgo, A. J., Gavilán, I., et al. (2026) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2026.119482
Synergistic effects of ionic photosensitizers and silver nanoparticles in PEGDA/gelatin hybrid hydrogels for advanced antibacterial photodynamic therapy
Raman, T. Ş., Kühnert, M., Konieczny, R., Lippmann, N., Kaiser, A., Werdehausen, R., Abel, B., & Schulze, A. (2026) · Biomaterials Advances · doi:10.1016/j.bioadv.2026.214946 · Cited by 1
Agent-based modeling demonstrates how target-independent processes supplement killing by antibody-drug conjugates in cancer therapy
Calopiz, M. C., Linderman, J. J., & Thurber, G. M. (2026) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1013872
“These cell-killing mechanisms are additive at the mechanistic level, but they would include overlapping killing, such as T cells killing a perivascular cell that already internalized a lethal dose of payload, similar to the Bliss model of independence [15].”
Glyphosate Promotes the Spread of Antibiotic Resistance Genes in the Intestine: An Overlooked Environmental Risk
Zheng, J., Chen, X., Jiang, J., & Wu, F. (2026) · Toxics · doi:10.3390/toxics14060506
“Additionally, the Bliss independence model was employed to determine the types of interaction present in the mixture groups [46].”
Cellular and molecular responses of Cryptococcus to brilacidin
Bezerra, B. T., Mellon, D. A., Souza, C. M., Castelli, R. F., Camillo-Andrade, A. C., Santos, M. H. S., Carvalho, P. C., Rodrigues, M. L., & de Oliveira, H. C. (2026) · Microbiology Spectrum · doi:10.1128/spectrum.00138-26
“Consider ing the differences in chemical nature and cellular targets of AmB and the test com pounds, the Bliss independence model (39) was used to calculate synergy scores via the SynergyFinder tool (40).”
Metabolic network homeostasis and antagonistic stress response drive rootstock-mediated tolerance to combined salinity and water-deficit in grapevine cv. Syrah
Wagaw, K., Lupo, Y., Sikron-Persi, N., Acuña, T., Lazarovitch, N., & Fait, A. (2026) · Plant Stress · doi:10.1016/j.stress.2026.101456 · Cited by 1
2H-chromen-2-one disrupts the Staphylococcus aureus biofilm matrix and potentiates moxifloxacin activity: In vitro and in silico analyses
Khanh, L. N., Anh, N. T. L., Quynh, N. T. N., Tùng, N. T., Hồ, Đ. V., Hoai, N. T., Huong, P. T., & Nguyen, T. K. (2026) · Microbial Pathogenesis · doi:10.1016/j.micpath.2026.108666
Model-informed prediction of antiviral drug combination synergy from sparse data using complementary mechanistic and pharmacodynamic approaches
Jeong, Y., & Byun, J. H. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1834793
BSA-functionalized MnFe2O4 nanoassemblies as a multifunctional platform for chemo-photodynamic therapy with magnetic heating and MRI contrast capabilities
Gupta, J., Shelar, S. B., Dutta, B., Ahirwar, S., Lawande, M. A., & Barick, K. C. (2026) · Journal of Photochemistry and Photobiology A Chemistry · doi:10.1016/j.jphotochem.2026.117538
DABPU-DE targeting host adipose triglyceride lipase provides broad-spectrum anti-coronavirus effects in vitro
FAROUK, R., Lee, D. J., Aboelmagd, S., Kwon, H., Jeong, S.-H., Han, S. I., Cheong, D., Ny, S., Seo, H.-R., Lee, C., et al. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1786048
“Data were imported into SynergyFinder 3.0 in the replicate-example format to ensure appropriate curve-fitting and synergy analysis (Zhao et al., 2014; Wagoner et al., 2022).”
Influential
U2 snRNP inhibition hampers pancreatic cancer cell viability by disrupting DNA repair proficiency and mitotic checkpoint integrity
Panzeri, V., Pieraccioli, M., Ruta, V., Manno, M. V., Caggiano, C., Hartem, D., Riente, A., Milletti, G., Quero, G., Alfieri, S., et al. (2026) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-026-03795-3
“Values were expressed as the difference between the expected and the observed effect, the cutoff of 0.10 was used as threshold for synergy between drugs, while values between 0 and 0.1 indicated additivity between the drugs [38].”
Influential
Physiological and gut microbial responses of Apis cerana to sub‐chronic exposure to binary pesticide mixtures at environmentally relevant concentrations
Song, B., Zhang, H., Long, Y., Zhu, X., Huang, M., Liao, G., Chen, M., Qin, L., Chen, X., & Zhu, F. (2026) · Pest Management Science · doi:10.1002/ps.71212
Combination of Melittin and Clinacanthus nutans Extract Enhances Antiviral Efficacy Against Dengue Virus Serotype 2 Infection
Boonsatit, N., Fungfueang, S., Thongyim, S., Tragoolpua, Y., Disayathanoowat, T., Baillie, G. S., & Panya, A. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27177782
“The interaction between melittin and C. nutans extract was evaluated using the Bliss independence model [64].”
Integrative proteomics reveals MSH6 to modulate PARP inhibitor sensitivity in BRCA1/2-proficient ovarian cancer
Deng, O., Nepomuceno, T. C., Fang, B., Welsh, E. A., Izumi, V., Martin, R. H., George, E. M., Koomen, J. M., Monteiro, A. N., & Rix, U. (2026) · PLoS ONE · doi:10.1371/journal.pone.0357365
NRF2/SLC7A11/GPX4 Antioxidant Axis Suppression by Camel Milk Whey Protein Sensitizes MCF-7 Breast Cancer Cells to Cisplatin
Civelek, İ. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27188241
“This approach avoids the requirement of multi-parameter analysis of concentration–response curves in serial dilution experiments [46,47].”
2,4-dichlorophenoxyacetic acid (2,4-D) potentiates vanadium-induced Parkinsonian neurodegeneration: Evidence from mitochondrial bioenergetic dysfunction and dopaminergic and GABAergic neurodegeneration
Babalola, A. A., da Silva, A. F., da Silva, S. W., Soares, M. V., Aschner, M., & Soares, F. A. A. (2026) · NeuroToxicology · doi:10.1016/j.neuro.2026.103576
A Clinical Evidence-Guided Bioinformatics Framework for Expanding Cisplatin-Based Combination Therapies in Cervical CancerPreprint
Hamese, S., Takundwa, M. M., Prinsloo, E., & Raj, D. B. T. G. (2026) · Research Square · doi:10.21203/rs.3.rs-10926147/v1
Immunomodulatory Potential of KSTM in Activating Natural Killer Cells for Cancer Cell Elimination
Pianmak, T., Panya, A., Boonsatit, N., Tabtimmai, L., & Choowongkomon, K. (2026) · Pharmaceuticals · doi:10.3390/ph19101525
“The interactions between NK cells and each herbal extract (KERRA, KS, and Minoza) were evaluated separately using the Bliss independence model [44].”
Radiosensitizing Effect of Gold Nanoparticles Stabilized with Sodium Citrate and Thioglycolic Acid on MDA-MB-231 and MCF7 Breast Cancer Cells
Smirnova, A., Kontareva, E., Nofal, Z., Kryuchikhin, V., Chigasova, A., Drozhzhin, N. A., Andreev, E. V., Fadeikina, I. N., Mutali, A., Nechaev, A., et al. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27198632
“We used the Bliss independence method to see if irradiation and adding NPs to the cells worked together in any way [18].”
Synergistic Photothermal‐Chemical Rescue of Single Injured Neuron via Optical Fiber‐Guided Nanomotors
Liu, X., Zhou, H., Chen, S., Zeng, H., Liu, H., Shi, W., Li, B., & Xin, H. (2026) · Laser & Photonics Review · doi:10.1002/lpor.72014
A host-directed hypothesis for recurrent bacterial vaginosis: paeonol and luteolin as candidate microenvironment normalizers
Wang, Q., Song, Q., Wang, D., Lee, S.-P., & Wu, W.-Y. (2026) · Medical Hypotheses · doi:10.1016/j.mehy.2026.112200
New Organic Compounds Against Scedosporium and Mucorales: Antifungal Activity and Mechanisms of Cell Wall and Membrane Disruption
Rollin‐Pinheiro, R., de Castro-Almeida, Y., Xisto, M. I. D. D. S., de Souza-Santos, J., de Moraes, D. C., Vicente, B., Midlej, V. D. V. P., Toledo, F. T., Ferrarini, R., Ferreira, G. M., et al. (2026) · Molecules · doi:10.3390/molecules31203691
“Bliss independence model was performed according to Meletiadis and colleagues and Zhao and colleagues [46,64].”
Celecoxib or diallyl trisulfide topical emulgels, alone or in combination, reduce pruritus and inflammatory cascades in a BALB/c mouse model of imiquimod-induced psoriasis
Kamel, M. M., Zaki, H. F., Saleh, R. A., Henry, S. R., Ibrahim, M. K., Bakr, M. M., Abouhussein, D. M. N., & Rabie, M. A. (2026) · Pharmacia · doi:10.3897/pharmacia.73.e205623
“Using the Bliss Independence Model, Y P = 0.23 + 0.18 – (0.23 * 0.18) = 0.3686, Y O = 0.42, since Y O > Y P , the combined treat-ment had synergistic effects.”
Influential
BindingDB Entry 50021582: 5-(Trifluoromethyl)-1,2,4-oxadiazole (TFMO)-based highly selective class IIa HDAC inhibitors exhibit synergistic anticancer activity in combination with bortezomib.
BindingDB (2025) · UC San Diego · doi:10.7270/q2988cn8

Authors: Zhao, W., Sachsenmeier, K., Zhang, L., Sult, E., Hollingsworth, R. E., & Yang, H.
Affiliations: AbbVie (United States) (US)
Corresponding author: Zhao, Wei
ORCID: Zhao, Wei
Sachsenmeier, Kris
Zhang, Lanju
Hollingsworth, Robert E.
Yang, Harry
Venue: SLAS Discovery
Publisher: Elsevier BV
Published: 2014-06
Volume: 19
Issue: 5
Pages: 817-821
ISSN: 2472-5552 (ISSN-L)
DOI: 10.1177/1087057114521867
OpenAlex: W1980181290
Cited by: 322
References: 14
Citations by year: 2026: 46 · 2025: 33 · 2024: 29 · 2023: 45 · 2022: 40 · 2021: 19 · 2020: 26 · 2019: 23 · 2018: 17 · 2017: 17 · 2016: 14 · 2015: 11 · 2014: 2
FWCI: 15.18
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor, 2866 d)
Locations: SLAS DISCOVERY (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
Topics: Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
Social Sciences › Decision Sciences › Management Science and Operations Research › Optimal Experimental Design Methods
Keywords: Bliss independence model, drug synergy, drug-drug interactions, false positive reduction, epidermal growth factor receptor, IGF-1 receptor, drug combination screening
MeSH terms: Algorithms, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Dose-Response Relationship, Drug, Drug Combinations, Drug Interactions, Drug Synergism, Humans, Lung Neoplasms, Models, Chemical, Neoplasms, Regression Analysis, Technology, Pharmaceutical, Signal Transduction, Receptor, IGF Type 1, Drug Resistance, Neoplasm, ErbB Receptors

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

A New Bliss Independence Model to Analyze Drug Combination Data

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Citations

Cites

Cited by

Related

Metadata

Record

About these checks