Quality assurance/quality control for electrospray ionization processes

• US 7,395,160 B2
• Filed: 07/28/2003
• Issued: 07/01/2008
• Est. Priority Date: 07/29/2002
• Status: Expired due to Fees

• Current Assignee: Vermillion, Inc.
• Original Assignee: Correlogic Systems, Inc. (Aspira Women's Health, Inc.)
• Inventors: Coleman, Timothy A., Levine, Peter J., Hitt, Ben A.
• Primary Examiner(s): Clow; Lori A.
• Application Number:
  US10/628,136
• Publication Number:
  US 20040053333A1
• Time in Patent Office: 1,800 Days
• Field of Search: None
• US Class Current: 702/19
• CPC Class Codes: C40B 30/04 by measuring the ability to specifically bind a target molecule, e.g. antibody-antigen binding, receptor-ligand binding
• CPC Class Codes: G01N 33/6803 General methods of protein analysis not limited to specific proteins or families of proteins
• CPC Class Codes: G01N 33/6848 Methods of protein analysis involving mass spectrometry
• CPC Class Codes: G16B 25/00 ICT specially adapted for hybridisation; ICT specially adapted for gene or protein expression
• 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
• CPC Class Codes: Y10T 436/24 Nuclear magnetic resonance, electron spin resonance or other spin effects or mass spectrometry

Abstract

The present invention relates to a method of quality assurance/quality control for high-throughput bioassay processes. The method includes generating a bioassay process model, and then comparing spectral data based on a combination of a biochip and a test serum to the bioassay process model to determine if the test sample and the bioassay process are producing acceptable data. Alternatively, the method may include comparing spectral data based on a combination of serum and diluents used in an electrospray process to the bioassay process model. If the bioassay process and test sample fall within the model, then the spectrum produced may be further analyzed.

Claims

1. A method of determining whether mass spectral data from a test serum is acceptable for analysis in a bioassay, comprising:

selecting a diverse group of sera, the diverse group of sera having different characteristics;

diluting each serum of the diverse group of sera with a plurality of different diluents;

obtaining information associated with a mass spectrum of each of the diluted sera from the diverse group of sera using an electrospray process;

generating a control model based at least in part on the spectra obtained from the diverse group of sera, the control model including at least one centroid located in an n-dimensional space defined by n mass spectral features included in the control model;

diluting a test serum with a test diluent;

performing mass spectrometry on the test serum to obtain a test spectrum associated with the test serum;

mapping the test spectrum to the n-dimensional space; and

certifying that the test spectrum is acceptable for analysis in the bioassay if it is determined that the test spectrum maps to the n-dimensional space within an acceptable distance from said at least one centroid in the control model.

2. The method of claim 1, wherein said diluting each serum of the diverse group of sera includes diluting the sera with diluents having a predetermined diluent concentration, and said diluting a test serum with a test diluent includes diluting a test serum with a diluent having the same concentration as the diluent used to dilute each serum of the diverse group of sera.

3. The method of claim 1, wherein said diluting each serum of the diverse group of sera includes diluting the sera with diluents having a predetermined diluent concentration, and said diluting a test serum with a test diluent includes diluting a test serum with a diluent having a different concentration than the diluent used to dilute each serum of the diverse group of sera.

4. The method of claim 1, further comprising:

classifying a biological state from the spectrum based on a predetermined biological state model.

5. The method of claim 1, wherein if the test spectrum does not map to the n-dimensional space within an acceptable distance from the at least one centroid in the control model, and the test diluent is a first diluent, the method further comprising:

repeating the steps of diluting a test serum, performing, mapping, and certifying for a second diluent different from said first diluent.

6. The method of claim 1, said selecting further comprising:

selecting at least two different sera from a pool of diverse sera, the pool of diverse sera consisting of;

sera from healthy males, sera from healthy females, sera from males afflicted with a disease, sera from females afflicted with a disease, sera from persons of different races, and

sera from people of different ages.

7. The method of claim 1, wherein said generating includes:

identifying at least one cluster in common to the sera of the diverse group of sera and the plurality of different diluents; and

selecting only one cluster as the centroid of the control model.

8. The method of claim 1, wherein the obtaining information includes:

obtaining information on sera diluted with two different diluents, the diluents including at least acetonitrile and methanol.

9. The method of claim 1, wherein the test diluent is one of the plurality of different diluents.

10. The method of claim 1, wherein the test diluent is not one of the plurality of different diluents.

11. The method of claim 1, wherein said plurality of different diluents includes acetonitrile and methanol.

12. The method of claim 1, wherein said diluting each serum of the diverse group of sera includes creating a plurality of dilutions of each serum with a diluent at a plurality of concentrations.

13. The method of claim 12, wherein said plurality of concentrations ranges between 1:

250 to 1;

1000.

14. The method of claim 1, wherein said diluting a test serum includes diluting a test serum with a known diluent.

15. The method of claim 1, wherein said diluting a test serum includes diluting a test serum with one of the plurality of different diluents used to dilute the diverse group of sera.

16. The method of claim 1, wherein said diluting a test serum includes diluting a test serum with a test diluent different than any of the plurality of different diluents used to dilute the diverse group of sera.

17. A method of determining whether mass spectral data from a test serum is acceptable for analysis in a bioassay for a biological diagnostic employing a control model generated based on mass spectra obtained from sera analyzed following an electrospray process, the spectra being associated with a plurality of different sera and a plurality of different diluents, the control model including at least one centroid located in an n-dimensional space defined by n mass spectral features included in the control model, comprising:

diluting a test serum using a test diluent;

ionizing the diluted test serum using an electrospray process;

performing mass spectrometry on the ionized diluted test serum to obtain test spectral data associated with the test serum and the test diluent; and

mapping the test spectrum to the n-dimensional space; and

certifying that the test spectrum is acceptable for analysis in the bioassay if the test spectrum maps to the n-dimensional space within an acceptable distance from the centroid.

18. The method of claim 17,

wherein the bioassay determines if the test serum exhibits a particular biological state.

19. The method of claim 18, wherein the test diluent is one of acetonitrile and methanol.

20. A method of determining whether mass spectral data from a test serum is acceptable for analysis in a bioassay using sera diluted with a first diluent, comprising:

providing in an n-dimensional space defined by n mass spectral features a location of at least one centroid associated with a first diluent and that distinguishes the first diluent from at least one second diluent;

using an electrospray ionization process, ionizing a test serum diluted with the at least one second diluent to generate a test mass spectrum;

mapping the test mass spectrum to the n-dimensional space; and

certifying the spectrum for analysis in the bioassay if the spectrum maps to the n-dimensional space within an acceptable distance from the at least one centroid associated with the first diluent.

21. A method of determining whether mass spectral data from a test serum using an electrospray process is acceptable for analysis in a bioassay that generates mass spectral data from a sample that is diluted by a diluent, comprising:

providing a location in an n-dimensional space defined by n mass spectral features of at least one centroid associated with a preferred diluent concentration and composition;

providing a location in the n-dimensional space of at least one test centroid associated with a test sample;

comparing the at least one test centroid to the at least one centroid associated with a preferred diluent to determine the displacement in the n-dimensional space of the at least one test centroid;

determining a degree of error between the test centroid and the centroid associated with the preferred diluent; and

certifying to a user that the test sample is accepted for analysis if the degree of error between the test centroid and the centroid associated with the preferred diluent is acceptable.

22. The method of claim 21, wherein the bioassay determines if the test serum exhibits a particular biological state.

23. The method of claim 21, wherein the sample is serum.

24. The method of claim 21, wherein the mass spectral data is generated by an electrospray ionization technique.

25. A method of determining whether mass spectral data from a test serum using an electrospray process is acceptable for analysis in a bioassay that generates mass spectral data from a sample that is diluted by a diluent, comprising:

providing a location in an n-dimensional space defined by n mass spectral features of at least one centroid associated with a preferred diluent concentration and composition;

providing a location in the n-dimensional space of at least one test centroid associated with a test sample; and

determining the displacement in the n-dimensional space of the at least one test centroid from the at least one centroid associated with the preferred diluent; and

certifying to a user that the test sample is accepted for analysis if the displacement of the at least one test centroid from the at least one centroid associated with the preferred diluent is within an acceptable distance.

26. The method of claim 25, wherein the bioassay determines if the test serum exhibits a particular biological state.

27. The method of claim 25, wherein the sample is serum.

28. The method of claim 25, wherein the mass spectral data is generated by an electrospray ionization technique.

29. A method of determining whether mass spectral data from a test serum using an electrospray process is acceptable for analysis in a bioassay quality assurance for a biological diagnostic employing a control model generated based on mass spectral features associated with a sample that includes serum and a preferred concentration of diluent and composition of diluent, the control model including at least one centroid located in an n-dimensional space defined by n mass spectral features associated with a sample that includes serum and a preferred concentration of diluent and composition of diluent and included in the model, comprising:

performing mass spectrometry on a test sample that includes serum and a diluent having a concentration and a composition to obtain a test spectrum associated with the test sample; and

mapping the test spectrum to the n-dimensional space; and

certifying that the concentration of the diluent and the composition of the diluent are acceptable for the bioassay, if the test spectrum maps to the n-dimensional space within an acceptable distance from the at least one centroid.

30. The method of claim 29, wherein the bioassay is capable of determining if the test serum exhibits a disease state.