Methods of monitoring disease states and therapies using gene expression profiles
First Claim
1. A method of determining a level of one or more disease states in a subject, said method comprising determining, for each of said disease states, one or a combination of interpolated response profiles, extracted from interpolated response curves correlated to levels of each of said disease states, for which similarity is greatest between a diagnostic profile and said determined interpolated response profiles, said diagnostic profile comprising measured amounts of a first plurality of cellular constituents in one or more cells of said subject, and wherein said interpolated response curves are the products of a method comprising(i) providing response profiles of one or more cells of one or more analogous subjects for each of said disease states wherein said response profiles comprise measured amounts of a second plurality of cellular constituents in said cells of said one or more analogous subjects at a plurality of levels for each of said disease states, said second plurality comprising at least a portion of said first plurality, and (ii) interpolating said response profiles so that a response profile may be extracted over a range of levels for each of said disease states, wherein the level of each disease state correlated to each determined interpolated response profile indicates said levels of said disease states.
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Abstract
The present invention provides methods for monitoring disease states in a subject, as well as methods for monitoring the levels of effect of therapies upon a subject having one or more disease states. The methods involve: (i) measuring abundances of cellular constituents in a cell from a subject so that a diagnostic profile is obtained, (ii) measuring abundances of cellular constituents in a cell of one or more analogous subjects so that perturbation response profiles are obtained which correlate to a particular disease or therapy, and (iii) determining the interpolated perturbation response profile or profiles which best fit the diagnostic profile according to some objective measure. In other aspects, the invention also provides a computer system capable of performing the methods of the invention, data bases comprising perturbation response profiles for one or more diseases and/or therapies, and kits for determining levels of disease states and/or therapeutic effects according to the methods of the invention.
358 Citations
56 Claims
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1. A method of determining a level of one or more disease states in a subject, said method comprising determining, for each of said disease states, one or a combination of interpolated response profiles, extracted from interpolated response curves correlated to levels of each of said disease states, for which similarity is greatest between a diagnostic profile and said determined interpolated response profiles, said diagnostic profile comprising measured amounts of a first plurality of cellular constituents in one or more cells of said subject, and wherein said interpolated response curves are the products of a method comprising
(i) providing response profiles of one or more cells of one or more analogous subjects for each of said disease states wherein said response profiles comprise measured amounts of a second plurality of cellular constituents in said cells of said one or more analogous subjects at a plurality of levels for each of said disease states, said second plurality comprising at least a portion of said first plurality, and (ii) interpolating said response profiles so that a response profile may be extracted over a range of levels for each of said disease states, wherein the level of each disease state correlated to each determined interpolated response profile indicates said levels of said disease states.
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7. A method of determining a level of effect of one or more therapies upon a subject, said method comprising determining, for each of said therapies, one or a combination of interpolated response profiles, extracted from interpolated response curves correlated to levels of effect of each of said therapies, for which similarity is greatest between a diagnostic profile and said determined interpolated response profiles, said diagnostic profile comprising measured amounts of a first plurality of cellular constituents in one or more cells of said subject, and wherein said interpolated response curves are the products of a method comprising:
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(i) providing response profiles of one or more cells of one or more analogous subjects for each of said therapies wherein said response profiles comprise measured amounts of a second plurality of cellular constituents in said cells of said one or more analogous subjects at a plurality of levels of effect for each of said therapies, said second plurality comprising at least a portion of said first plurality, and (ii) interpolating said response profiles so that a response profile may be extracted over a range of levels for each of said therapies, wherein the level of effect of each therapy correlated to each determined interpolated response profile indicates said levels of effect of said therapies. - View Dependent Claims (8, 9, 10, 11, 12, 13, 14, 15, 16, 21, 51, 52, 53, 54, 55)
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34. A computer system for determining a level of one or more disease states in a subject comprising a processor and a memory coupled to said processor, said memory encoding one or more programs, said one or more programs causing said processor to perform a method comprising determining, for each of said disease states, one or a combination of interpolated response profiles, extracted from interpolated response curves correlated to levels of each of said disease states, for which similarity is greatest between a diagnostic profile and said determined interpolated response profiles, said diagnostic profile comprising measured amounts of a first plurality of cellular constituents in one or more cells of said subject, and wherein said interpolated response curves are the products of a method comprising
(i) providing response profiles of one or more cells of one or more analogous subjects for each of said disease states wherein said response profiles comprise measured amounts of a second plurality of cellular constituents in said cells of said one or more analogous subject at a plurality of levels for each of said disease states, said second plurality comprising at least portion of said first plurality, and (ii) interpolating said response profiles so that a response profile may be extracted over a range of levels for each of said disease states, wherein the level of each disease state correlated to each determined interpolated response profile indicates said levels of said disease states.
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35. A computer system for determining a level of effect of one or more therapies upon a subject comprising a processor and a memory coupled to said processor, said memory encoding one or more programs, said one or more programs causing said processor to perform a method comprising determining, for each of said therapies, one or a combination of interpolated response profiles, extracted from interpolated response curves correlated to levels of effect of each of said therapies, for which similarity is greatest between a diagnostic profile and said determined interpolated response profiles, said diagnostic profile comprising measured amounts of a first plurality of cellular constituents in one or more cells of said subject, and wherein said interpolated response curves are the products of a method comprising:
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(i) providing response profiles of one or more cells of one or more analogous subjects for each of said therapies wherein said response profiles comprise measured amounts of a second plurality of cellular constituents in said cells of said one or more analogous subjects at a plurality of levels of effect for each of said therapies, said second plurality comprising at least a portion of said first plurality, and (ii) interpolating said response profiles so that a response profile may be extracted over a range of levels for each of said therapies, wherein the level of effect of each therapy correlated to each determined interpolated response profile indicates said levels of effect of said therapies.
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42. A kit for determining a level of a disease state in a subject comprising a solid phase containing on its surface a plurality of nucleic acids of known, different sequences, each at a known location an said solid phase, each nucleic acid capable of hybridizing to an RNA species or cDNA species derived therefrom, wherein said RNA species are known to be increased or decreased at different levels of said disease state said plurality substantially excluding nucleic acids capable of hybridizing to RNA species that are not so increased or decreased.
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43. A kit for determining a level of effect of a therapy in a subject comprising a solid phase containing on its surface a plurality of nucleic acids of known, different sequences, each at a known location on said solid phase, each nucleic acid capable of hybridizing to an RNA species or cDNA species derived therefrom, wherein said RNA species are known to be increased or decreased at different levels of said effect of said therapy, said plurality substantially excluding nucleic acids capable of hybridizing to RNA species that are not so increased or decreased.
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44. A kit for determining a level of one or more disease states in a subject comprising:
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(a) a solid phase containing on its surface a plurality of nucleic acids of known, different sequences, each at a known location on said solid phase, each nucleic acid capable of hybridizing to an RNA species or cDNA species derived therefrom, wherein said RNA species are known to be increased or decreased at different levels of said disease states, and (b) response profiles, in electronic or written form, correlated to levels of each of said disease states, wherein said response profiles comprise measured amounts of a plurality of cellular constituents in a cell or cells of one or more subjects at a plurality of levels for each of said disease states. - View Dependent Claims (46, 47)
(a) receiving a diagnostic profile of a cell of said subject, said diagnostic profile comprising measured abundances of RNA species or cDNA derived therefrom from said cell;
(b) receiving said response profiles; and
(c) determining the response profile for each of said disease states for which similarity is greatest between said diagnostic profile and a combination of said determined interpolated response profiles, wherein the level correlated to each determined response profile indicates said level of said disease states.
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45. A kit for determining a level of effect of one or more therapies in a subject comprising:
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(a) a solid phase containing on its surface a plurality of nucleic acids of known, different sequences, each at a known location on said solid phase, each nucleic acid capable of hybridizing to an RNA species or cDNA species derived therefrom, wherein said RNA species are known to be increased or decreased at different levels of said effect of therapies, and (b) response profiles, in electronic or written form, correlated to levels of effect of each of said therapies, wherein said response profiles comprise measured amounts of a plurality of cellular constituents in a cell or cells of one or more subjects at a plurality of levels of effect of each of said therapies. - View Dependent Claims (56)
(a) receiving a diagnostic profile of a cell of said subject, said diagnostic profile comprising measured abundances of RNA species or cDNA derived therefrom from said cell;
(b) receiving said response profiles; and
(c) determining the response profile for each of said therapies for which similarity is greatest between said diagnostic profile and a combination of said determined interpolated response profiles, wherein the level correlated to each determined response profile indicates said level of effect of said therapies.
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- 48. A database on computer readable medium response profiles for one or more disease states or effects of therapies wherein said database is in electronic form, wherein said response profiles comprise measurements of a plurality of cellular constituents in a cell or cells of one or more subjects at a plurality of levels for each of said disease states or effects of said therapies.
Specification