Assessing interactions for fixed-dose drug combinations in tumor xenograft studies
Open accessAbstract
Statistical methods for assessing the joint action of compounds administered in combination have been established for many years. However, there is little literature available on assessing the joint action of fixed-dose drug combinations in tumor xenograft experiments. Here an interaction index for fixed-dose two-drug combinations is proposed. Furthermore, a regression analysis is also discussed. Actual tumor xenograft data were analyzed to illustrate the proposed methods.
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Zhao and colleagues derived a Bliss independence index using differential equations to model tumor growth, which is equivalent to the interaction index in Wu and colleagues.
“Zhao and colleagues used differential equations to model tumor growth and derived a Bliss independence index (26), which is equivalent to interaction index in Wu and colleagues (24).”
From Statistical Assessment of Drug Synergy from <i>In Vivo</i> Combination Studies Using Mouse Tumor Models (2023) · cites this paper as [24]
Section 2 (INTERACTION INDEX; page unavailable) defines Wu and colleagues’ interaction index using a Bliss independence model, supporting the characterization of their index. Our copy does not discuss Zhao’s differential-equation model or establish that Zhao’s index is equivalent to Wu’s, so the equivalence is not verified by this source. (LLM, conf=0.82)
Experimental — accuracy not yet measuredExisting methods use only TV data from a single day to calculate CI, and local CI values may fluctuate excessively such that they may indicate synergy and antagonism at different days.
“or use only TV data from a single day to calculate CI (local CI values may fluctuate excessively such that they may indicate synergy and antagonism at different days)”
From Statistical Assessment of Drug Synergy from <i>In Vivo</i> Combination Studies Using Mouse Tumor Models (2023) · cites this paper as [24]
Section 2 (page unavailable) calculates an interaction index from tumor-volume measurements at the end of the study, supporting the single-day aspect. It does not report that the index fluctuates excessively or switches between synergy and antagonism on different days; it also calls the measure an interaction index, not CI. (LLM, conf=0.85)
Experimental — accuracy not yet measuredExisting methods have limited power to detect synergy in animal studies.
“Existing methods have limited power to detect synergy in animal studies.”
From Statistical Assessment of Drug Synergy from <i>In Vivo</i> Combination Studies Using Mouse Tumor Models (2023) · cites this paper as [24]
The Introduction (page unavailable) says response-surface methods are not applicable to fixed-dose combination studies and that little literature addresses joint-action assessment in tumor xenograft experiments. The Interaction Index section notes that these studies often have small samples. These passages establish methodological challenges in a specific kind of animal study, but do not establish that existing methods have limited statistical power to detect synergy. (LLM, conf=0.78)
Experimental — accuracy not yet measuredHuang and colleagues established CombPDX as a statistical framework for Bliss independence, HSA, and response additive models, with Bliss CI equivalent to Wu and colleagues and HSA and RA newly introduced.
“More recently, Huang and colleagues established CombPDX as a statistical framework for three synergy models: Bliss independence, HSA, and response additive (RA; ref. 27), their definition of Bliss CI is equivalent to that in Wu and colleagues (24), while HSA and RA were newly introduced.”
From Statistical Assessment of Drug Synergy from <i>In Vivo</i> Combination Studies Using Mouse Tumor Models (2023) · cites this paper as [24]
CI cannot be calculated after a day when most or all mice in the vehicle control group are euthanized because their tumors reach a size threshold faster than drug-treated tumors.
“or that CI cannot be calculated after a day when most or all mice in the vehicle control group are euthanized because their tumors reach certain size threshold faster than drug-treated tumors.”
From Statistical Assessment of Drug Synergy from <i>In Vivo</i> Combination Studies Using Mouse Tumor Models (2023) · cites this paper as [24]
Section 2 (Interaction Index; page unavailable) defines an index using tumor-volume measurements from a control group, but does not discuss whether it can be calculated after control mice are euthanized. Section 5 (Actual Tumor Xenograft Data Analysis; page unavailable) says mice were euthanized after two weeks of treatment, without describing a tumor-size threshold or earlier euthanasia of controls. Searches for those conditions found no supporting passage. (LLM, conf=0.76)
Experimental — accuracy not yet measured
Existing methods have trouble dealing with missing and unbalanced TV data even though mathematical interpolation is used to patch missing data with unmeasurable uncertainty.
“or have trouble dealing with missing and unbalanced TV data even though mathematical interpolation is used to patch missing data with unmeasurable uncertainty”
From Statistical Assessment of Drug Synergy from <i>In Vivo</i> Combination Studies Using Mouse Tumor Models (2023) · cites this paper as [24]
Section 2 analyzes observed tumor volumes at the end of the study, and Section 3 examines confidence-interval coverage in small samples. Searches for missing or unbalanced tumor-volume data, interpolation, and uncertainty from interpolated values found no passage addressing the claim. (LLM, conf=0.72)
Experimental — accuracy not yet measuredExisting methods impose unrealistic assumptions for tumor growth and TV data.
“These methods, however, have inherent limitations because they either impose unrealistic assumptions for tumor growth and TV data”
From Statistical Assessment of Drug Synergy from <i>In Vivo</i> Combination Studies Using Mouse Tumor Models (2023) · cites this paper as [24]
The Introduction (page unavailable) says there is little literature on assessing fixed-dose drug combinations in tumor xenograft experiments, but it does not say existing methods impose unrealistic assumptions. Searches for limitations and assumptions about tumor growth or tumor-volume data found no passage addressing that criticism. (LLM, conf=0.72)
Experimental — accuracy not yet measured
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Research works printed but not linked: 16
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Cited by
Sorted by citations
Mao, B., & Guo, S. (2023) · Cancer Research Communications · doi:10.1158/2767-9764.crc-23-0243 · Cited by 27 · see citing works
CombPDX: a unified statistical framework for evaluating drug synergism in patient-derived xenografts
Huang, L., Wang, J., Fang, B., Meric-Bernstam, F., Roth, J. A., & Ha, M. J. (2022) · Scientific Reports · doi:10.1038/s41598-022-16933-6 · Cited by 21 · see citing works
- Authors
- Wu, J., Tracey, L., & Davidoff, A. M.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Corresponding author
- Wu, Jianrong
- Venue
- Journal of Biopharmaceutical Statistics
- Publisher
- Informa UK Limited
- Published
- 2012-03-14
- Volume
- 22
- Issue
- 3
- Pages
- 535-543
- ISSN
- 1054-3406 (ISSN-L)
- 1520-5711
- PMC
- PMC4667736
- OpenAlex
- W2064062107
- Cited by
- 21
- References
- 0
- Citations by year
- 2026: 1 · 2025: 1 · 2023: 8 · 2022: 6 · 2021: 2 · 2020: 2 · 2013: 1
- FWCI
- 0.31
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Biopharmaceutical Statistics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (CA-23099, P01CA023099, CA21765, P30CA021765)
- Topics
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Social Sciences › Decision Sciences › Management Science and Operations Research › Optimal Experimental Design Methods
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- combination therapy, fixed-dose combination, tumor xenografts, interaction index, regression analysis
- MeSH terms
- Animals, Antineoplastic Combined Chemotherapy Protocols, Dose-Response Relationship, Drug, Drug Combinations, Drug Interactions, Drug Synergism, Humans, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice
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