Methods and system for multi-drug treatment discovery
First Claim
Patent Images
1. A method for screening a combination of treatments to specifically target a disease process, wherein the disease process impacts gene expression, said method comprising the steps of:
- (a) providing differential expression levels of predetermined genes of diseased tissue samples relative to at least one reference tissue for respective features of microarrays targeting the predetermined genes, wherein each feature targets a specific gene, said features being used to calculate the differential expression levels;
(b) for each of the respective features of respective microarrays for each diseased tissue sample, providing a single phenotypic/genotypic signature representing the differential expression level for each diseased tissue sample for that feature across the respective microarrays;
(c) treating the diseased tissue samples with a treatment;
(d) measuring a treatment-response value with respect to each of the diseased tissue samples as effected by the treatment;
(e) generating a single phenotypic signature representing the treatment-response values of each of the diseased tissue samples;
(f) repeating steps (c)-(e) with a different treatment at least once so that multiple phenotypic signatures have been generated for multiple treatments;
(g) performing a clustering operation based on the phenotypic/genotypic signatures of the differential expression levels and the phenotypic signatures of the treatment-response values together; and
(h) selecting treatments by identifying the treatment-response phenotypic/genotypic signatures caused by those treatments, and which are clustered with phenotypic signatures representing differential expression levels representative of the diseased tissue samples.
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Abstract
Methods, systems and recordable media for using expression data characterizing protein pathways of diseases to produce phase relationships between treatment responses of diseased tissues to treatments applied thereto and expression profiles of the diseased tissues as measured when untreated. Methods, systems and recordable media for augmenting an original or existing treatment or treatment combination with one or more treatments that cover gene activity of a disease not addressed by the original/existing treatment.
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Citations
25 Claims
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1. A method for screening a combination of treatments to specifically target a disease process, wherein the disease process impacts gene expression, said method comprising the steps of:
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(a) providing differential expression levels of predetermined genes of diseased tissue samples relative to at least one reference tissue for respective features of microarrays targeting the predetermined genes, wherein each feature targets a specific gene, said features being used to calculate the differential expression levels; (b) for each of the respective features of respective microarrays for each diseased tissue sample, providing a single phenotypic/genotypic signature representing the differential expression level for each diseased tissue sample for that feature across the respective microarrays; (c) treating the diseased tissue samples with a treatment; (d) measuring a treatment-response value with respect to each of the diseased tissue samples as effected by the treatment; (e) generating a single phenotypic signature representing the treatment-response values of each of the diseased tissue samples; (f) repeating steps (c)-(e) with a different treatment at least once so that multiple phenotypic signatures have been generated for multiple treatments; (g) performing a clustering operation based on the phenotypic/genotypic signatures of the differential expression levels and the phenotypic signatures of the treatment-response values together; and (h) selecting treatments by identifying the treatment-response phenotypic/genotypic signatures caused by those treatments, and which are clustered with phenotypic signatures representing differential expression levels representative of the diseased tissue samples. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20)
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21. A method of augmenting an original or existing single treatment or treatment combination for a disease with at least one additional treatment that covers gene activity of the disease not addressed by the original or existing treatment, said method comprising the steps of:
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(a) providing differential expression levels of predetermined genes of diseased tissue samples relative to at least one reference tissue for respective features of microarrays targeting the predetermined genes, wherein each feature targets a specific gene, said features being used to calculate the differential expression levels; (b) for each of the respective features of respective microarrays for each diseased tissue sample, providing a phenotypic/genotypic signature representing the differential expression level for each diseased tissue sample for that feature across the respective microarrays; (c) treating the diseased tissue samples with the original or existing single treatment or combination treatment; (d) measuring a treatment-response value with respect to each of the diseased tissue samples as effected by the original or existing single or combination treatment; (e) generating a phenotypic signature representing the treatment-response values of each of the diseased tissue samples as effected by the original or existing single or combination treatment; (f) treating the diseased tissue samples with a treatment that is not included in the original or existing single or combination treatment; (g) measuring a treatment-response value with respect to each of the diseased tissue samples as effected by the treatment that is not included in the original or existing single or combination treatment; (h) generating a phenotypic signature representing the treatment-response values of each of the diseased tissue samples as effected by the treatment that is not included in the original or existing single or combination treatment; (i) repeating steps (f)-(h) with a different treatment that is also not included in the original or existing single or combination treatment at least once so that multiple phenotypic signatures have been generated for multiple treatments not included in the original or existing single or combination treatment; (j) performing a clustering operation based on the phenotypic/genotypic signatures of the differential expression levels and the phenotypic signatures of the treatment-response values together; and (k) selecting at least one treatment by identifying the treatment-response phenotypic signatures caused by the at least one treatment, and which are clustered with phenotypic signatures identifying the treatment-response phenotypic signatures caused by the treatment or treatments in the original treatment, as well as with phenotypic/genotypic signatures representing differential expression levels representative of the diseased tissue samples, but separated from the phenotypic signatures identifying the treatment-response phenotypic signatures caused by the treatment or treatments in the original treatment, so as to address disease-gene activity not currently addressed by the treatment or treatments in the original or existing treatment. - View Dependent Claims (22, 23)
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24. A method for screening a combination of treatments to specifically target a disease process, wherein the disease process impacts gene expression, said method comprising the steps of:
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(a) providing differential expression levels of predetermined genes of diseased tissue samples relative to at least one reference tissue for respective features of microarrays targeting the predetermined genes used to calculate the differential expression levels; (b) for each of the respective features of respective microarrays for each diseased tissue sample, providing a single phenotypic/genotypic signature as a vector representing the differential expression level for each diseased tissue sample for that feature across the respective microarrays; (c) treating the diseased tissue samples with a treatment; (d) measuring a treatment-response value with respect to each of the diseased tissue samples as effected by the treatment; (e) generating a single phenotypic signature as a response vector representing the treatment-response values of each of the diseased tissue samples; (f) repeating steps (c)-(e) with a different treatment at least once so that multiple phenotypic signatures have been generated for multiple treatments; (g) performing a clustering operation based on the phenotypic/genotypic signatures of the differential expression levels and the phenotypic signatures of the treatment-response values together; (h) selecting treatments by identifying the treatment-response phenotypic signatures caused by those treatments, and which are clustered with phenotypic/genotypic signatures representing differential expression levels representative of the diseased tissue samples; (i) labeling the phenotypic/genotypic signatures representing the differential expression levels as “
in phase”
signatures;(j) generating “
out of phase”
signatures by inverting the “
in phase”
signatures; and(k) including the “
out of phase”
signatures with the “
in phase”
signatures and the treatment-response signatures when performing steps (g) and (h).
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25. A method of augmenting an original or existing single treatment or treatment combination for a disease with at least one additional treatment that covers gene activity of the disease not addressed by the original or existing treatment, said method comprising the steps of:
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(a) providing differential expression levels of predetermined genes of diseased tissue samples relative to at least one reference tissue for respective features of microarrays targeting the predetermined genes used to calculate the differential expression levels; (b) for each of the respective features of respective microarrays for each diseased tissue sample, providing a phenotypic/genotypic signature as a vector representing the differential expression level for each diseased tissue sample for that feature across the respective microarrays; (c) treating the diseased tissue samples with the original or existing single treatment or combination treatment; (d) measuring a treatment-response value with respect to each of the diseased tissue samples as effected by the original or existing single or combination treatment; (e) generating a phenotypic signature as a vector representing the treatment-response values of each of the diseased tissue samples as effected by the original or existing single or combination treatment; (f) treating the diseased tissue samples with a treatment that is not included in the original or existing single or combination treatment; (g) measuring a treatment-response value with respect to each of the diseased tissue samples as effected by the treatment that is not included in the original or existing single or combination treatment; (h) generating a phenotypic signature as a vector representing the treatment-response values of each of the diseased tissue samples as effected by the treatment that is not included in the original or existing single or combination treatment; (i) repeating steps (f)-(h) with a different treatment that is also not included in the original or existing single or combination treatment at least once so that multiple phenotypic signatures have been generated for multiple treatments not included in the original or existing single or combination treatment; (j) performing a clustering operation based on the phenotypic/genotypic signatures of the differential expression levels and the phenotypic signatures of the treatment-response values together; (k) selecting at least one treatment by identifying the treatment-response phenotypic signatures caused by the at least one treatment, and which are clustered with phenotypic signatures identifying the treatment-response phenotypic signatures caused by the treatment or treatments in the original treatment, as well as with phenotypic/genotypic signatures representing differential expression levels representative of the diseased tissue samples, but separated from the phenotypic signatures identifying the treatment-response phenotypic signatures caused by the treatment or treatments in the original treatment, so as to address disease-gene activity not currently addressed by the treatment or treatments in the original or existing treatment; labeling the phenotypic/genotypic signatures representing the differential expression levels as “
in phase”
signatures;generating “
out of phase”
signatures by inverting the “
in phase”
signatures; andincluding the “
out of phase”
signatures with the “
in phase”
signatures and the treatment-response signatures when performing steps (j) and (k).
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Specification