Systems and methods for pairwise inference of drug-gene interaction networks

A method for determining whether a first cellular perturbation interacts with a second cellular perturbation in one of a specific cellular context and a background, in a cell based assay, the cell based assay comprising a plurality of wells across one or more plates, the method comprising, at a computer system comprising one or more processors and a memory:

• obtaining a baseline data point for a baseline state, wherein the baseline data point comprises a plurality of dimensions, in a plurality of cellular characteristics, determined across a plurality of baseline aliquots of cells representing the baseline state in corresponding wells, in the plurality of wells, wherein the baseline state comprises a first cellular context;
• obtaining a perturbation data point for a perturbation state, wherein the perturbation data point comprises the plurality of dimensions, in the plurality of cellular characteristics, determined across a plurality of perturbation aliquots of cells representing the perturbation state in corresponding wells, in the plurality of wells, wherein the perturbation state comprises a first perturbation of the first cellular context in which expression of a gene is perturbed relative to expression of the gene in the baseline state;
• obtaining a compound data point for a compound state, wherein the compound data point comprises the plurality of dimensions, in the plurality of cellular characteristics, determined across a plurality of compound aliquots of cells representing the compound state in corresponding wells, in the plurality of wells, wherein the compound state comprises a second perturbation of the first cellular context in which the first cellular context is exposed to a compound;
• obtaining a combination data point for a combination state, wherein the combination data point comprises the plurality of dimensions, in the plurality of cellular characteristics, determined across a corresponding plurality of combination aliquots of cells representing the combination state in corresponding wells, in the plurality of wells, wherein the combination state comprises a third perturbation of the first cellular context in which (i) expression of the gene is perturbed relative to expression of the gene in the baseline state and (ii) the first cellular context is exposed to the compound;
• applying a dimension reduction model, in turn, to each of the baseline data point, the perturbation data point, the compound data point, and the combination data point to respectively generate a plurality of baseline feature values for the baseline data point, a plurality of perturbation features values for the perturbation data point, a plurality of compound feature values for the compound data point, and a plurality of combination feature values for the combination data point;
• and
• determining whether a first cellular perturbation interacts with a second cellular perturbation in one of a specific cellular context and a background by using the plurality of baseline feature values, the plurality of perturbation feature values, the plurality of compound feature values, and the plurality of combination feature values to resolve whether the interaction of the first cellular perturbation with the second cellular perturbation has a threshold interaction effect on one or more cellular characteristic in the plurality of cellular characteristics.

A non-transitory computer readable storage medium having one or more computer programs embedded therein for determining whether a first cellular perturbation interacts with a second cellular perturbation in one of a specific cellular context and a background, in a cell based assay, the cell based assay comprising a plurality of wells across one or more plates, the one or more computer programs comprising instructions which, when executed by a computer system, cause the computer system to perform a method comprising:

• obtaining a baseline data point for a baseline state, wherein the baseline data point comprises a plurality of dimensions, in a plurality of cellular characteristics, determined across a plurality of baseline aliquots of cells representing the baseline state in corresponding wells, in the plurality of wells, wherein the baseline state comprises a first cellular context;
• obtaining a perturbation data point for a perturbation state, wherein the perturbation data point comprises the plurality of dimensions, in the plurality of cellular characteristics, determined across a plurality of perturbation aliquots of cells representing the perturbation state in corresponding wells, in the plurality of wells, wherein the perturbation state comprises a first perturbation of the first cellular context in which expression of a gene is perturbed relative to expression of the gene in the baseline state;
• obtaining a compound data point for a compound state, wherein the compound data point comprises the plurality of dimensions, in the plurality of cellular characteristics, determined across a plurality of compound aliquots of cells representing the compound state in corresponding wells, in the plurality of wells, wherein the compound state comprises a second perturbation of the first cellular context in which the first cellular context is exposed to a compound;
• obtaining a combination data point for a combination state, wherein the combination data point comprises the plurality of dimensions, in the plurality of cellular characteristics, determined across a corresponding plurality of combination aliquots of cells representing the combination state in corresponding wells, in the plurality of wells, wherein the combination state comprises a third perturbation of the first cellular context in which (i) expression of the gene is perturbed relative to expression of the gene in the baseline state and (ii) the first cellular context is exposed to the compound;
• applying a dimension reduction model, in turn, to each of the baseline data point, the perturbation data point, the compound data point, and the combination data point to respectively generate a plurality of baseline feature values for the baseline data point, a plurality of perturbation features values for the perturbation data point, a plurality of compound feature values for the compound data point, and a plurality of combination feature values for the combination data point;
• and
• determining whether a first cellular perturbation interacts with a second cellular perturbation in one of a specific cellular context and a background by using the plurality of baseline feature values, the plurality of perturbation feature values, the plurality of compound feature values, and the plurality of combination feature values to resolve whether the interaction of the first cellular perturbation with the second cellular perturbation has a threshold interaction effect on one or more cellular characteristic in the plurality of cellular characteristics.