Biomarker normalization

• US 9,217,701 B2
• Filed: 02/18/2011
• Issued: 12/22/2015
• Est. Priority Date: 08/06/2002
• Status: Active Grant

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Sullivan, Benjamin
• Primary Examiner(s): Lin, Jerry
• Application Number:
  US13/031,051
• Publication Number:
  US 20110144919A1
• Time in Patent Office: 1,768 Days
• Field of Search: 702/19
• US Class Current: 1/1
• CPC Class Codes: B01L 2300/0654 Lenses; Optical fibres
• CPC Class Codes: B01L 3/502715 characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
• CPC Class Codes: G01N 13/04 Investigating osmotic effects
• CPC Class Codes: G01N 21/6486 Measuring fluorescence of biological material, e.g. DNA, RNA, cells G01N21/6428 takes precedence
• CPC Class Codes: G01N 27/07 Construction of measuring vessels; Electrodes therefor
• CPC Class Codes: G01N 27/26 by investigating electrochemical variables; by using electrolysis or electrophoresis
• CPC Class Codes: G01N 2800/162 Conjunctival disorders, e.g. conjunctivitis
• CPC Class Codes: G01N 2800/24 Immunology or allergic disorders
• CPC Class Codes: G01N 33/4836 using multielectrode arrays
• CPC Class Codes: G01N 33/487 of liquid biological material
• CPC Class Codes: G16B 40/00 ICT specially adapted for biostatistics; ICT specially adapted for bioinformatics-related machine learning or data mining, e.g. knowledge discovery or pattern finding
• CPC Class Codes: G16B 40/10 Signal processing, e.g. from mass spectrometry [MS] or from PCR

Abstract

A fluid sample is measured with a tear film measuring system that includes a processing device that receives a sample chip comprising a sample region configured to contain an aliquot volume of sample fluid, the processing device configured to perform analyses of osmolarity and of one or more biomarkers within the sample fluid, wherein the analysis of biomarkers includes normalization of biomarker concentration values.

Claims

1. A fluid measuring system comprising:

a processing device which receives a sample chip configured to contain an aliquot volume of a sample fluid,

wherein the processing device is configured to perform analyses of

(a) the osmolarity of the sample fluid, and

(b) at least one biomarker within the sample fluid selected from;

glucose, insulin, a protein, a hormone, a hormone metabolite, a nucleic acid, a lipid fraction, or any combination thereof;

wherein the analysis of the one or more biomarkers includes normalization of biomarker concentration values.

2. The fluid measuring system of claim 1, wherein the normalization of biomarker concentration values corrects for patient-specific tear homeostasis.

3. The fluid measuring system of claim 1, wherein the normalization of biomarker concentration values corrects for clinician induced tear sampling variance in connection with obtaining the sample fluid.

4. The fluid measuring system of claim 1, wherein the analyses of osmolarity and of the one or more biomarkers are performed simultaneously.

5. The fluid measuring system of claim 1, wherein the analyses of osmolarity

and of the one or more biomarkers are performed serially.

6. The fluid measuring system of claim 1, wherein the normalization of biomarker concentration values is linear.

7. The fluid measuring system of claim 1, wherein the normalization of biomarker concentration values is ratiometric.

8. The fluid measuring system of claim 1, wherein the normalization of biomarker concentration values is exponential.

9. The fluid measuring system of claim 1, wherein the normalization of biomarker concentration values is based on a calibration curve.

10. The fluid measuring system of claim 1, wherein the sample region contains a plurality of electrodes.

11. The fluid measuring system of claim 10, wherein the plurality of electrodes are constructed from a non-polarizing metal.

12. The fluid measuring system of claim 10, wherein the plurality of electrodes are coupled to a conductive polymer.

13. The fluid measuring system of claim 10, wherein the plurality of electrodes are coupled to an electrochemical transducer.

14. The fluid measuring system of claim 1, wherein the sample region contains an optical transducer.

15. The fluid measuring system of claim 1, wherein the biomarker is selected from:

an immunoglobulin, lactoferrin, tears lysozyme, a cytokine, or any combination thereof.

16. The fluid measuring system of claim 1, wherein the biomarker is selected from:

IgE, IgA, IgG, IgM, or any combination thereof.

17. The fluid measuring system of claim 1, wherein:

the processing device receives an osmolarity output signal from the sample region that indicates energy properties of the sample fluid, wherein the osmolarity output signal is correlated with the osmolarity of the sample fluid;

the processing device receives a biomarker output signal from the sample region that indicates chemical properties of the sample fluid, wherein the biomarker output signal is correlated with the biomarker concentration values of the sample fluid; and

the processing device processes the osmolarity output signal to produce an osmolarity value for the sample fluid and processes the biomarker output signal to produce a biomarker concentration values for the ample fluid.

18. The fluid measuring system of claim 17, wherein the osmolarity and biomarker output signals are multiplexed in space.

19. The fluid measuring system of claim 17, wherein the osmolarity and biomarker output signals are multiplexed in time.

20. The fluid measuring system of claim 17, wherein the osmolarity and biomarker output signals are multiplexed in frequency.

21. The fluid measuring system of claim 17, wherein the osmolarity and biomarker output signals are multiplexed in a transduction mechanism.

22. The fluid measuring system of claim 1, wherein the normalization of biomarker concentration values is multiplicative.

23. A method of measuring a sample fluid, the method comprising:

(a) receiving an output signal from a sample region of a sample chip that is configured to produce an osmolarity output signal that correlates to the osmolarity of the sample fluid;

(b) receiving an output signal from the sample region of the sample chip that is configured to produce a biomarker output signal that correlates to the concentration values for one or more biomarkers selected from;

glucose, insulin, a protein, a hormone, a hormone metabolite, a nucleic acid, a lipid fraction, or any combination thereof;

(c) processing (i) the osmolarity output signal to produce an osmolarity value for the sample fluid, and (ii) the biomarker output signal to produce a biomarker concentration value for the sample fluid; and

(d) determining an Adjusted Biomarker Level that provides normalization of biomarker concentration values.

24. The method of claim 23, wherein normalization of biomarker concentration values corrects for patient-specific tear homeostasis.

25. The method of claim 23, wherein normalization of biomarker concentration values corrects for clinician induced tear sampling variance in connection with obtaining the sample fluid.

26. The method of claim 23, wherein processing the osmolarity output signal and processing the biomarker output signal are performed simultaneously.

27. The method of claim 23, wherein processing the osmolarity output signal and processing the biomarker output signal are performed serially.

28. The method of claim 23, wherein normalization of biomarker concentration values is linear.

29. The method of claim 23, wherein normalization of biomarker concentration values is ratiometric.

30. The method of claim 23, wherein normalization of biomarker concentration values is exponential.

31. The method of claim 23, wherein normalization of biomarker concentration values is based on a calibration curve.

32. The method of claim 23, wherein the sample region contains a plurality of electrodes.

33. The method of claim 32, wherein the plurality of electrodes are constructed from a non-polarizing metal.

34. The method of claim 32, wherein the plurality of electrodes are coupled to a conductive polymer.

35. The method of claim 32, wherein the plurality of electrodes are coupled to an electrochemical transducer.

36. The method of claim 23, wherein the sample region contains an optical Transducer.

37. The method of claim 23, wherein the output signals are multiplexed in space.

38. The method of claim 23, wherein the output signals are multiplexed in time.

39. The method of claim 23, wherein the output signals are multiplexed in frequency.

40. The method of claim 23, wherein the output signals are multiplexed in transduction mechanism.

41. The method of claim 23, wherein the biomarker is selected from:

an immunoglobulin, lactoferrin, tears lysozyme, a cytokine, or any combination thereof.

42. The method of claim 23, wherein the biomarker is selected from:

IgE, IgA, IgG, IgM, or any combination thereof.