Method and system for evaluation of signals received from spatially modulated excitation and emission to accurately determine particle positions and distances

• US 9,164,037 B2
• Filed: 01/26/2007
• Issued: 10/20/2015
• Est. Priority Date: 01/26/2007
• Status: Expired due to Fees

• Current Assignee: Xerox Corporation (Xerox Holdings Corp.)
• Original Assignee: Palo Alto Research Center, Inc. (Xerox Holdings Corp.)
• Inventors: Bassler, Michael, Kiesel, Peter, Schmidt, Oliver
• Primary Examiner(s): DeJong, Eric S
• Application Number:
  US11/698,338
• Publication Number:
  US 20080183418A1
• Time in Patent Office: 3,189 Days
• US Class Current: 1/1
• CPC Class Codes: G01N 2015/1027 Determining speed or velocity of a particle
• CPC Class Codes: G01N 2015/1486 Counting the particles
• CPC Class Codes: G01N 21/6408 with measurement of decay time, time resolved fluorescence
• CPC Class Codes: G01N 21/6458 Fluorescence microscopy fluorescence microscopes per se G02B21/0076 and G02B21/16
• CPC Class Codes: G06F 2111/10 Numerical modelling
• CPC Class Codes: G16B 5/00 ICT specially adapted for modelling or simulations in systems biology, e.g. gene-regulatory networks, protein interaction networks or metabolic networks
• CPC Class Codes: G16H 50/20 for computer-aided diagnosis, e.g. based on medical expert systems

Abstract

A method is provided for extracting the position of a particle, e.g., a moving or stationary particle that is excited or is emitting light. The method includes, among other steps, detecting and recording a signal based on, for example, the movement of the particle, a correlation step to eliminate noise and to create a transformed signal, a matching or fitting step to match the transformed signal to a fit function and an extracting or determining step to determine the position of the particle from the fit function. In one form, at least two particle positions are detected so that the distance between the subject particles can be determined.

Claims

1. A method of operating a particle analyzer for determining a position of a particle, the method comprising:

detecting, in a detector of the particle analyzer, energy modulated by relative motion between the particle and a spatially modulated pattern including at least three first features that alternate positionally with at least three second features;

recording a time modulated signal that corresponds to the modulation of the energy, the time modulated signal including more than three transitions from an on state to an off state;

determining, by a processor of the particle analyzer, the position of the particle, comprising;

applying a correlation routine by correlating the time modulated signal to a test signal to generate a correlation signal;

applying a fit function to the correlation signal; and

,

extracting the position of the particle based on the applying of the fit function.

2. The method as set forth in claim 1 wherein two positions are detected in order to calculate the distance between both positions.

3. The method as set forth in claim 1 wherein the particle is a DNA sequencing tag and the detecting is based on an optical bar code read out.

4. The method as set forth in claim 1 wherein the particle is disposed on a bio-chip.

5. The method as set forth in claim 1 wherein the fit function is a triangle.

6. The method of claim 1, wherein detecting the particle comprises detecting based on relative motion between the particle and a spatially modulated excitation pattern.

7. The method of claim 1, wherein detecting the particle is achieved using at least one of a spatially modulated shadow mask, a spatially modulated phase mask, a micro-lens array, or a micro-mirror array.

8. The method of claim 1, wherein detecting the particle is achieved using at least one of a spatially modulated electrode array, spatially modulated magnetic field sensors, spatially modulated acoustic field sensors, or spatially modulated micro-cavities.

9. The method of claim 1, wherein detecting the particle is achieved using spatially modulated fluorescence quenching.

10. The method of claim 1, wherein the test function is a sinusoid with a periodicity of the recorded signal frequency.

11. The method of claim 1, wherein applying the fit function comprises independently varying a position of the fit function e to the time modulated signal.

12. The method of claim 1, wherein:

applying the fit function comprises applying multiple fit functions and independently varying a position of each of the multiple fit functions relative to the time modulated signal; and

determining the position of the particle comprises;

determining a position of a first particle; and

determining a position of a second particle.

13. The method of claim 1, wherein the test signal is an expected time modulated signal.

14. The method of claim 1, wherein determining the position of the particle comprises determining the position relative to an environment of the particle that includes the spatially modulated pattern or to a position of another particle.

15. A method of operating a particle analyzer to determine a position of at least one particle comprising:

detecting in a detector of the particle analyzer energy modulated by relative motion between the particle and a spatially modulated pattern including at least three first features that alternate positionally with at least three second features;

recording a time modulated signal that corresponds to the modulation of the energy, the time modulated signal including more than three transitions from an on state to an off state;

determining, in a processor of the particle analyzer, the position of the particle, comprising;

calculating a sliding integral over time on the time modulated signal;

applying a fit function to the sliding integral to obtain an estimated position of the particle;

calculating a correlation signal to eliminate noise;

calculating a derivative signal of the correlation signal;

determining a maximum and a minimum of the derivative signal based on the estimated position of the particle;

determining a zero transition of the derivative signal; and

determining a position of the particle based on the zero transition of the derivative signal.

16. The method as set forth in claim 15 wherein the fit function is a triangle.

17. The method as set forth in claim 16 further comprising determining the slope of flanks of the triangle to determine if multiple particles are present.

18. The method as set forth in claim 16 further comprising integrating the triangle to determine if multiple particles are present.

19. The method as set forth in claim 15 wherein the determining the maximum and the minimum comprises determining multiple maximums and minimums to determine the positions of multiple particles.

20. The method as set forth in claim 15 wherein the method is applied in two dimensions to determine a location of the particle.

21. The method as set forth in claim 15 further comprising the use of least squares fitting of a measured signal to determine the positions of multiple particles that are within a predetermined distance from one another.

22. The method as set forth in claim 15 wherein the energy is optical energy and the time modulated signal corresponds to modulated optical energy.

23. The method as set forth in claim 22 whereby the optical energy is light.

24. The method as set forth in claim 15 wherein:

the energy is non-optical energy the time modulated signal corresponds to modulated non-optical energy.

25. The method as set forth in claim 15 wherein the correlation signal is based on a chirp signal.

26. The method as set forth in claim 15 wherein the time modulated signal is periodic.

27. The method as set forth in claim 15 wherein the time modulated signal is based on a known signal.

28. A particle analyzer system for determining a position of a particle comprising:

a spatially modulated pattern including at least three first features alternating positionally with at least three second features;

a detector configured to detect energy modulated by relative motion between the particle and the spatially modulated pattern and;

to record a time modulated signal that corresponds to the modulation of the energy; and

a processor configured to;

apply a correlation routine to correlate the time modulated signal to a test signal to generate a correlation signal,

apply a fit function to the correlation signal, and

extract the position of the particle based on applying of the fit function.

29. The system as set forth in claim 28 wherein the particle is a DNA sequencing tag.

30. The system as set forth in claim 28 wherein the particle is disposed on a bio-chip.

31. The system as set forth in claim 28 wherein the fit function is a triangle.

32. A particle analyzer system to determine a position of at least one particle comprising:

a spatially modulated pattern including at least three first features alternating positionally with at least three second features;

a detector configured to detect energy modulated by relative motion between the particle and the spatially modulated pattern and

a to record a time modulated signal that corresponds to modulation of the energy, the time modulated signal including more than three transitions from an on state to an off state; and

a processor configured to calculate a sliding integral over time on the recorded signal, to apply a fit function to the sliding integral to obtain an estimated position of the particle, to calculate a correlation signal, to calculate a derivative signal of the correlation signal, to determine a maximum and a minimum of the derivative signal based on the estimated position of the particle, to determine a zero transition of the derivative signal, and to determine a calculated position of the particle based on the zero transition of the derivative signal.