ArticlePloS one2019
Statistical determination of synergy based on Bliss definition of drugs independence.
Article in PloS one, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT04516395 (Optimizing Antibiotic Dosing Regimens for the Treatment of Infection Caused by Carbapenem Resistant Enterobacteriaceae), which is not on this map. Cited by 99 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Optimizing Antibiotic Dosing Regimens for the Treatment of Infection Caused by Carbapenem Resistant Enterobacteriaceae: the Study of in Vitro Activity of Monotherapy and Combination Therapy, PK/PD Study and Treatment Outcomes
Who cites it
99 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Dietary Interventions with Polyphenols in Osteoarthritis: A Systematic Review Directed from the Preclinical Data to Randomized Clinical Studies.Nutrients · 2021Pooled it
- Oxidative Phosphorylation Is a Metabolic Vulnerability of Endocrine Therapy-Tolerant Persister Cells in ER+ Breast Cancer.Cancer research · 2025Trial
- Phage-Antibiotic-Peptide Synergy Overcomes Biofilm-Mediated Multidrug Resistance inAntibiotics (Basel, Switzerland) · 2026Article
- [Research square · 2026Article
- Common xenobiotics modulate gut microbial responses to low‑calorie sweeteners in vitro.Molecular systems biology · 2026Article
- Combination of Melittin andInternational journal of molecular sciences · 2026Article
- ATR inhibitors synergise with mitomycin C to enhance cytotoxicity in patient-derived non-muscle invasive bladder cancer organoids.British journal of cancer · 2026Article
- Sustained Intra-Articular Delivery of Triple Therapeutics Using a Phase-Transition Phospholipid-Based Gel for Effective Treatment of Gouty Arthritis.Pharmaceutical research · 2026Article
- Synergic Effect of Fluconazole and Quinoline Derivatives Combination AgainstMicroorganisms · 2026Article
- Pharmacological chromatin remodeling enhances response to estrogen therapy in ERMolecular oncology · 2026Article
- FLT3L-secreting cDC1 in situ vaccination enhances antitumor immunity and synergizes with PD-1 blockade in murine non-small cell lung cancer.Journal for immunotherapy of cancer · 2026Article
- Acute pretrauma ethanol exacerbates PTSD-like phenotype in rats and is reversed by early intranasal ketamine.Scientific reports · 2026Article
- Article
- Bromide is a surprisingly potent larvicide for Anopheles gambiae in the laboratory.Scientific reports · 2026Article
- WEE1 stabilizes MYC to promote therapeutic resistance in esophageal adenocarcinoma.Cancer letters · 2026Article
- Study on the synergistic efficacy and mechanism of CD24 silencing combined with trastuzumab in HER2-positive breast cancer.Journal of molecular histology · 2026Article
- Article
- The Use of Piperidinium Surfactants in Nematicide Formulations.Molecules (Basel, Switzerland) · 2026Article
- Metabolic Response to CDK4/6 Inhibition in ER+ Breast Cancer Creates a Therapeutic Vulnerability in Drug-Tolerant Persister Cells.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Synergistic role of CSPBP and SGS1 in sporozoite entry into Aedes aegypti salivary glands.Scientific reports · 2026Article
39 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
2 authors.
Funding
Abstract
Although synergy is a pillar of modern pharmacology, toxicology, and medicine, there is no consensus on its definition despite its nearly one hundred-year history. Moreover, methods for statistical determination of synergy that account for variation of response to treatment are underdeveloped and if exist are reduced to the traditional t-test, but do not comply with the normal distribution assumption. We offer statistical models for estimation of synergy using an established definition of Bliss drugs' independence. Although Bliss definition is well-known, it remains a theoretical concept and has never been applied for statistical determination of synergy with various forms of treatment outcome. We rigorously and consistently extend the Bliss definition to detect statistically significant synergy under various designs: (1) in vitro, when the outcome of a cell culture experiment with replicates is the proportion of surviving cells for a single dose or multiple doses, (2) dose-response methodology, (3) in vivo studies in organisms, when the outcome is a longitudinal measurement such as tumor volume, and (4) clinical studies, when the outcome of treatment is measured by survival. For each design, we developed a specific statistical model and demonstrated how to test for independence, synergy, and antagonism, and compute the associated p-value.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.