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Drug-combination synergy analysis — quantify whether two drugs together are synergistic, additive, or antagonistic using the standard reference models (Bliss independence, HSA / highest single agent, Loewe additivity, ZIP, and the Chou-Talalay Combination Index).
Passed 17 of 19 test cases with the skill, and 15 of 19 without it.
and 3 more in the full report
5 fixed15 passed either way0 still failing2 broke
Tokens, turns and time describe resource use, not a dollar price.
One of 4 test cases the skill fixed. Same model, same prompt, with and without the skill.
When invoking the HSA interaction tool across four tested dose points, what data structure type must be supplied for single-agent and combination effects?
| Checked | Without skill | With skill |
|---|---|---|
| Specifies passing arrays or lists of fractional effect values for effects_a, effects_b, and effects_combo. | Missed | Passed |
The instructions your model reads when the skill loads.
Decide whether a two-drug combination does more than expected (synergy), exactly as expected (additivity), or less (antagonism) — and pick the right reference model for the data you have.
"Synergy" only means something relative to a null model of additivity, and the models define additivity differently — so the first decision is which model, driven by what data you measured.
| You measured… | Use model | Tool | Input |
|---|---|---|---|
| Single effects of A, B, and A+B at one dose pair | Bliss | DrugSynergy_calculate_bliss | effect_a, effect_b, effect_combination (each a fraction 0–1) |
| Effects of A, B, A+B across several dose points | HSA | DrugSynergy_calculate_hsa | effects_a, effects_b, effects_combo (arrays) |
| Single-agent dose-response curves + one combination point | Loewe | DrugSynergy_calculate_loewe | doses_a_single/effects_a_single, doses_b_single/effects_b_single, dose_a_combo, dose_b_combo, effect_combo |
| Single-agent dose-response + combo point, want Chou-Talalay CI | Combination Index | DrugSynergy_calculate_ci | same as Loewe + assumption |
| A full dose × dose viability matrix | ZIP | DrugSynergy_calculate_zip | doses_a, doses_b, viability_matrix (% , 0–100) |
Effects must be on a consistent inhibition scale. Bliss/HSA/Loewe expect fractional inhibition
0–1(0 = no effect, 1 = complete kill). If your data is % viability, convert:inhibition = 1 − viability/100. ZIP takes the viability matrix in % directly. Mixing scales is the most common error.
| Model | Null (additive) expectation | Best when |
|---|---|---|
| Bliss independence | drugs act independently: E_exp = E_a + E_b − E_a·E_b | different mechanisms; quick single-point screen |
| HSA (highest single agent) | combo should beat the better single agent: E_exp = max(E_a, E_b) | conservative "does it beat monotherapy?" question |
| Loewe additivity | a drug combined with itself = additive (dose equivalence) | same/similar mechanism; needs dose-response |
| ZIP | combines Bliss + Loewe; potency shift of one drug's curve by the other | dose-matrix screens (the SynergyFinder default) |
| Chou-Talalay CI | CI<1 synergy, =1 additive, >1 antagonism (median-effect) | classic isobologram-style analysis with dose-response |
There is no single "correct" model — state which one you used. Bliss and Loewe genuinely disagree for some combinations (that's expected, not an error); reporting two models (e.g. Bliss + HSA, or Loewe + ZIP) is good practice.
# Bliss (single dose pair, fractional inhibition)
tu run DrugSynergy_calculate_bliss '{"operation":"calculate_bliss",
"effect_a":0.4,"effect_b":0.3,"effect_combination":0.7}'
# -> expected 0.58, bliss_synergy_score 0.12, "Strong synergy"
scripts/synergy_reference.py computes the Bliss, HSA, and Loewe-style expected combination effects side-by-side from one dose pair, so you can see at a glance whether the models agree before running the full tools.
test cases passed, vs 15 / 19 without
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