SynToxProfiler - User Documentation

Getting Started


What is SynToxProfiler?

SynToxProfiler: an interactive analysis tool for drug combination prioritization based on integrated synergy, toxicity and efficacy profiles (or any combination of them).

SynToxProfiler:

  • enables prioritization of drug combinations in terms of integrated synergy, efficacy and toxicity profiles.
  • supports interactive investigation of the results.
  • provides publication-quality 2D and 3D diagrams for interrelation between efficacy,toxicity and synergy of drug pairs.
  • is a free tool with an open source code available under GNU General Public License v4.0.

SynToxProfiler workflow

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SynToxProfiler ranks drug combinations based on integrated synergy, toxicity, and efficacy (STE) scores.

Synergy:

SynToxProfiler allows users to estimate synergy between drugs using either the highest single-agent (HSA) model (Berenbaum M.C,1989), Bliss independence (Bliss C.I.,1939), or Loewe additivity model (Loewe S,1953), and zero interaction efficacy (ZIP) model (Yadav, B, 2015) as implemented in the SynergyFinder R-package (Ianevski et al, 2017) from the dose-response surfaces measured in diseased cells. The estimated synergy matrix is summarized into single score as a volume under synergy matrix.

Efficacy:

The normalized volume under each provided dose-response surface (matrix) is quantified as an efficacy of combination.

Toxicity:

SynToxProfiler caclulates a toxicity scores as normalized volume under dose-response measurements in healthy cells (control) for each combination.

In case if no control measurements are provided users may calculate STE score only based on synergy and efficacy of each combination (neglecting toxicity).


How to use?

For each drug combination, SynToxProfiler expects two dose-response matrices provided in the input file (one measured in sample and another in control), please see example file. The input dose-response matrices are represented as a table where each row contains the information about one cell (well) in the dose-response matrix. The expected file extensions are either *.xlsx, comma-delimited *.csv, or comma-separated *.txt file.

SynToxProfiler input

An example of the header of input file is shown below:


The input table must comprise the following columns:
  • Drug1 – name of the first drug
  • Drug2 – name of the second drug
  • Conc1 - concentration of Drug1 (in the units given in ConcUnit column, e.g. nM)
  • Conc2 - concentration of Drug2 (in the units given in ConcUnit column, e.g. nM)
  • Response - %inhibition values (Percent inhibition values, ranging from 0% to 100%, where 0% inhibition means no drug activity)
  • ConcUnit - unit of concentrations (for Drug1 and Drug2, e.g. nM)
  • Type - sample or control (represents whether corresponding drug combination responses are measured in sample or control)

The orders of rows and columns are arbitrary. The number of drug combinations provided in the input file is unlimited. The only restriction is imposed on the size of a dose-response matrix, which should comprise at least three rows and columns, so that sensible synergy, toxicity and efficacy scores can be calculated.

In case if measurements on healthy cells (control) are not provided, the STE score can be calculated only based on synergy and efficacy of each combination (neglecting toxicity).


SynToxProfiler output

SynToxProfiler provides a barplot of top 20 drug combinations ranked by combined STE score, which are provided under the Summary tab:

Individual drug combination plots can be shown by hovering over each bar.


A combined synergy, toxicity, efficacy landscape interactive plot is provided under the Combined landscape tab. By hovering over each point, users can see heatmaps of dose-response matrices and synergy distribution for each combination:

A summary STE score scatterplot with 2 components (i) Selective efficacy and (ii) Synergy can be found under an STE score scatterplot tab. It is also possible to neglect the toxicity component of STE score, or rank drug combinations based on STE calculated for the most synergistic area of each dose-response matrix.

SynToxProfiler enables users to export the results using corresponding buttons. The ouput excel files provide a summary (STE) score as well as results of individual component ranking.

License

The SynToxProfiler code is released under the GNU General Public License, version 4. Please follow this link for details.


Using SynToxProfiler through R

A source code of SynToxProfiler is freely available at GitHub, which can be run as a standalone application through R shiny or users may modify the code based on their purposes.

Please cite SynToxProfiler using:

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