Characterizing biological stimuli by response curves

• US 7,246,012 B2
• Filed: 07/16/2004
• Issued: 07/17/2007
• Est. Priority Date: 07/18/2003
• Status: Expired due to Fees

• Current Assignee: Cytokinetics, Inc.
• Original Assignee: Cytokinetics, Inc.
• Inventors: Vaisberg, Eugeni A., Coleman, Daniel A., Kutsyy, Vadim
• Primary Examiner(s): Brusca; John
• Assistant Examiner(s): SIMS, JASON M
• Application Number:
  US10/892,450
• Publication Number:
  US 20050137806A1
• Time in Patent Office: 1,096 Days
• Field of Search: None
• US Class Current: 702/19
• CPC Class Codes: G06F 18/24143 Distances to neighbourhood prototypes, e.g. restricted Coulomb energy networks [RCEN]
• CPC Class Codes: G06F 2218/12 Classification; Matching
• CPC Class Codes: G06V 20/698 Matching; Classification

Abstract

A method for calculating distances between stimulus response curves (e.g., dose response curves) allows classification of stimuli. The response curves show how the phenotype of one or more cells changes in response to varying levels of the stimulus. Each “point” on the curve represents quantitative phenotype or signature for cell(s) at a particular level of stimulus (e.g., dose of a therapeutic). The signatures are multivariate phenotypic representations of the cell(s). They include various features of the cell(s) obtained by image analysis. To facilitate the comparison of stimuli, distances between points on the response curves are calculated. First, the response curves may be aligned on a coordinate representing a separate distance, r, from a common point of negative control (e.g., the point where no stimulus is applied). Integration on r may be used to compute the distance between two response curves. The distance between response curves is used to classify stimuli.

Claims

1. A method of classifying a stimulus based on its associated stimulus response path in biological feature space, the method comprising:

(a) applying a stimulus to cells;

(b) imaging the cells;

(c) deriving two or more stimulus response oaths from images of the cells;

(d) aligning two or more of the stimulus response paths on a common radius, r, from a point in biological feature space where a negative control is applied;

(e) calculating a separation distance, D, between points on two of the stimulus response paths having the common radius, r, from the negative control point; and

(f) classifying the stimulus of at least one of the stimulus response paths on the basis of the calculated value of the separation distance, D, and providing that classification for a user.

2. The method of claim 1, wherein aligning the two or more stimulus response paths comprises calculating the common radius, r, as a Euclidean distance from the negative control point.

3. The method of claim 1, wherein calculating the separation distance, D, comprises calculating a value based on a spherical geometry including the points sharing the common radius, r, from the negative control point.

4. The method of claim 3, wherein the value based on a spherical geometry comprises an angle or an inner product.

5. The method of claim 1, wherein the stimulus response paths are associated with particular mechanisms of action, and wherein (f) comprises classifying the at least one of the stimulus response paths based on the mechanism of action.

6. The method of claim 1, wherein the stimulus response paths comprise points that define signatures, and wherein the signatures comprise phenotype features of a biological system exposed to stimuli.

7. The method of claim 6, wherein the signatures are obtained by applying varying levels of the stimuli to the biological system.

8. The method of claim 6, wherein the signatures are obtained by monitoring the effect of the stimulus on the biological system over time.

9. The method of claim 6, wherein the biological system is a cell line.

10. The method of claim 1, wherein the stimulus is exposure to a chemical compound.

11. A computer program product comprising a machine readable medium on which is provided program instructions for classifying a stimulus based on its associated stimulus response path in biological feature space, the instructions comprising:

(a) applying a stimulus to cells;

(b) imaging the cells;

(c) deriving two or more stimulus response paths from images of the cells;

(d) aligning two or more of the stimulus response paths on a common radius, r, from a point in biological feature space where a negative control is applied;

(e) calculating a separation distance, D, between points on two of the stimulus response paths having the common radius, r, from the negative control point; and

(f) classifying the stimulus of at least one of the stimulus response paths on the basis of the calculated value of the separation distance, D, and providing that classification for a user.

12. The computer program product of claim 11, wherein instructions for aligning the two or more stimulus response paths comprise instructions for calculating the common radius, r, as a Euclidean distance from the negative control point.

13. The computer program product of claim 11, wherein instructions for calculating the separation distance, D, comprise instructions for calculating a value based on a spherical geometry including the points sharing the common radius, r, from the negative control point.

14. The computer program product of claim 13, wherein the value based on a spherical geometry comprises an angle or an inner product.

15. The computer program product of claim 11, wherein the stimulus response paths are associated with particular mechanisms of action, and wherein (f) comprises instructions for classifying the at least one of the stimulus response paths based on the mechanism of action.

16. The computer program product of claim 11, wherein the stimulus response paths comprise points that define signatures, and wherein the signatures comprise phenotype features of a biological system exposed to stimuli.