NMR clinical analyzers and related methods, systems, modules and computer program products for clinical evaluation of biosamples

• US 20050222504A1
• Filed: 03/30/2005
• Published: 10/06/2005
• Est. Priority Date: 04/01/2004
• Status: Active Grant

• Current Assignee: LipoScience, Inc. (Laboratory Corporation Of America Holdings)
• Original Assignee: LipoScience, Inc. (Laboratory Corporation Of America Holdings)
• Inventors: Morgan, David R., Matyus, Steven P., Otvos, James D., Silberman, Bruce D., Jeyarajah, Elias J., Deuel, Donald R., Markham, Stephen
• Granted Patent: US 8,013,602 B2
• Time in Patent Office: Days
• US Class Current: 600/410
• CPC Class Codes: G01R 33/307 specially adapted for moving the sample relative to the MR system, e.g. spinning mechanisms, flow cells or means for positioning the sample inside a spectrometer
• CPC Class Codes: G01R 33/465 applied to biological material, e.g. in vitro testing

Abstract

Methods, computer program products and apparatus automate clinical NMR in vitro diagnostic analyzers. The clinical analyzer can automatically electronically monitor selected parameters and automatically electronically adjust parameters to maintain the analyzer within desired operational ranges. The clinical NMR analyzers can be configured as a networked system with a plurality of clinical NMR analyzers located at different use sites; and at least one remote control system in communication with one or a plurality of clinical NMR analyzers, the at least one remote system configured to monitor selected local operating parameters associated with a respective clinical NMR analyzer.

Claims

1. A method of operating a clinical NMR in vitro diagnostic analyzer, comprising:

electronically monitoring data associated with a plurality of selected parameters of a clinical NMR analyzer;

electronically determining whether the selected parameters are within desired operational ranges based on the monitored data;

automatically adjusting operational parameters of selected components of the clinical NMR analyzer based on data obtained by the electronically determining step;

obtaining NMR signal spectra of a biosample; and

electronically generating at least one clinical measurement of the biosample based on the obtained NMR spectra.

2. A method according to claim 1, further comprising automatically calibrating selected components of the NMR analyzer based on the monitored data.

3. A method according to claim 1, further comprising automatically electronically shimming the magnetic field to a desired level of homogeneity based on the monitored data.

4. A method according to claim 2, wherein the NMR analyzer comprises a magnet with a magnet bore and a probe configured to reside in the magnet bore, and wherein the monitoring step monitors a temperature of the probe, and wherein the adjusting step comprises automatically adjusting the probe temperature to within a desired operating range.

5. A method according to claim 4, wherein the automatically adjusting selected operational parameters comprises tuning the probe to a desired operational frequency.

6. A method according to claim 2, wherein the automatically adjusting step comprises automatically electronically centering a magnetic field in an acquisition window.

7. A method according to claim 2, wherein the automatically adjusting step comprises adjusting a lock power and lock phase associated with the NMR analyzer.

8. A method according to claim 1, wherein the NMR analyzer comprises an RF source configured to generate an RF pulse to biosamples, and wherein the automatically adjusting step comprises automatically calibrating the RF source to generate about a 90-degree pulse width within a desired pulse width tolerance.

9. A method according to claim 2, further comprising automatically determining in situ an appropriate NMR analyzer-specific normalization factor to be used during the analyzing step to thereby adjust for instrument-specific sensitivity.

10. A method according to claim 1, further comprising automatically correlating the obtained NMR data with an identifier associated with a respective biosample.

11. A method according to claim 10, wherein the correlating comprises electronically relating, at the point of aspiration, the biosample to an electronic file configured to hold corresponding NMR data thereof.

12. A method according to claim 10, further comprising electronically maintaining the correlation of the obtained data before, during and after the generating step.

13. A method according to claim 1, further comprising automatically adding a desired reagent to a respective biosample prior to the obtaining step.

14. A method according to claim 1, further comprising automatically heating or cooling the biosample to be within a desired temperature range prior to the obtaining step.

15. A method according to claim 1, further comprising adding a reference analyte to the biosample prior to the obtaining step.

16. A method according to claim 1, further comprising verifying test conditions in situ temporally proximate but prior to the obtaining step by obtaining a first pre-test set of NMR spectra of the biosample or a test validation reference sample and electronically evaluating the first NMR spectra therefrom.

17. A method according to claim 16, further comprising automatically identifying when test conditions are outside an acceptable range based on the pre-test set of NMR spectra and electronically flagging, invalidating and/or discarding the NMR spectra of the biosample based on data obtained from the verifying step when test conditions are identified as being outside the acceptable range.

18. A method according to claim 1, wherein the NMR analyzer comprises a magnet with a magnet bore and an NMR probe cell configured to hold the biosample in the magnet bore during the obtaining step, wherein the monitoring step comprises determining whether a biosample in the NMR probe flow cell is stationary during the obtaining step.

19. A method according to claim 1, wherein the NMR analyzer comprises a magnet with a magnet bore and an NMR flow cell configured to hold the biosample in the magnet bore during the obtaining step, wherein the determining step comprises determining whether a biosample in the NMR flow cell is an infinite sample during the obtaining step.

20. A method according to claim 1, wherein the NMR analyzer comprises a magnet with a magnet bore and an NMR flow cell configured to hold the biosample in the magnet bore during the obtaining step, wherein the determining step comprises determining whether there are air bubbles in the biosample residing in the NMR flow cell.

21. A method according to claim 1, wherein the NMR analyzer comprises a magnet with a magnet bore and an NMR flow cell configured to hold the biosample in the magnet bore during the obtaining step, wherein the determining step comprises determining the temperature of the biosample in the NMR flow cell, and wherein the automatically adjusting step comprises adjusting parameters that bring the temperature of the biosample in the NMR flow cell into an acceptable range.

22. A method according to claim 1, wherein the determining and adjusting steps are carried out to perform at least one of the following:

(a) determine whether homogeneity of a magnetic field associated with a magnet in the NMR analzyer is within a desired operational range, and automatically shimming the homogeneity if the determined homogeneity is outside the desired operational range; and

(b) determine whether suppression of a water signal is within a desired operational range, and automatically adjusting selected operational parameters to bring the water suppression to within the desired operational range.

23. A method according to claim 1, wherein the generating step automatically electronically generates at least one diagnostic quantitative measurement of the biosample, and wherein the method further comprises automatically generating an electronic patient report of the diagnostic data measurement.

24. A method according to claim 1, further comprising determining a patient'"'"'s risk of having and/or developing CHD based on quantitative measurements from the generating step.

25. A method according to claim 1, further comprising determining a patient'"'"'s risk of having and/or developing Type II diabetes based on quantitative measurements from the generating step.

26. A method according to claim 1, further comprising electronically obtaining NMR derived measurements of lipoprotein particle sizes and concentrations of the biosample based on the generating step.

27. A method according to claim 1, further comprising electronically obtaining NMR derived measurements of VLDL, LDL and HDL subclass lipoprotein particles in a blood plasma and/or serum biosample based on the generating step.

28. A method according to claim 1, further comprising automatically determining a patient'"'"'s risk of having an insulin resistance disorder based on the generating step.

29. A method according to claim 1, further comprising determining the presence or absence of a selected species or constituent, subspecies, analyte, interference material, contaminant and/or toxin in the biosample based on the obtaining and analyzing steps.

30. A method according to claim 1, further comprising determining the concentration of a selected species or constituent, subspecies, analyte, interference material, contaminant and/or toxin in the biosample based on the obtaining and analyzing steps.

31. A method according to claim 1, further comprising automatically determining a diagnostic test to be carried out on the biosample.

32. A method according to claim 31, further comprising adjusting testing parameters based on the properties of the biosample and/or the test to be carried out.

33. A method according to claim 1, further comprising automatically executing an automated self-diagnostic quality control test at equipment startup and/or desired intervals.

34. A method according to claim 1, further comprising serially aspirating biosamples from respective sample containers into an enclosed flow path and automatically serially detecting patient identification data for each respective patient biosample at a point of aspiration into the enclosed flow path to thereby inhibit incorrect patient biosample correlation.

35. A method according to claim 34, further comprising serially aspirating biosamples from respective sample containers into an enclosed flow path and flowing the aspirated samples into a top portion of the bore and directing the sample to travel generally vertically down to an intermediate location in the magnet bore to thereby reduce flow path length.

36. A clinical NMR in vitro diagnostic analyzer, comprising:

an automated sample handler configured to automatically introduce biosamples into a magnet bore of a high-field superconducting magnet of a NMR spectroscopy instrument associated with a clinical NMR analyzer;

means for automatically obtaining NMR signal spectra of the biosamples;

means for automatically electronically sensing data associated with selected operating parameters to verify that test conditions of the NMR diagnostic analyzer are within target operating ranges; and

means for automatically electronically adjusting selected operating parameters based on the verified test conditions.

37-43. -43. (canceled)

44. A clinical NMR in vitro diagnostic analyzer, comprising:

an automated sample handler configured to automatically introduce biosamples into a magnet bore of a high-field superconducting magnet of a NMR spectroscopy instrument associated with a clinical NMR analyzer;

a control circuit in electronic communication with the NMR spectroscopy instrument; and

a plurality of electronic sensors disposed in the clinical NMR analyzer, the electronic sensors in communication with the control circuit, the electronic sensors configured to detect data associated with selected operating parameters to verify that selected conditions of the NMR diagnostic analyzer are within target operating ranges,

wherein the clinical NMR analyzer is configured to automatically electronically adjust selected operating parameters based on data provided by the electronic sensors so that the clinical NMR analyzer operates within target process limits.

45-49. -49. (canceled)

50. A computer program product for automating clinical NMR in vitro diagnostic analyzers comprising a magnet with a magnet bore, the computer program product comprising:

a computer readable storage medium having computer readable program code embodied in said medium, said computer-readable program code comprising;

computer readable program code configured to automatically run an automated self-diagnostic quality control test for the clinical NMR in vitro diagnostic analyzer; and

computer readable program code configured to automatically monitor and electronically adjust selected operating parameters of the NMR in vitro diagnostic analyzer over time during operation.

51-62. -62. (canceled)

63. A method of analyzing undiluted plasma and/or serum:

obtaining a proton NMR composite spectrum of an undiluted biosample; and

generating a spectral deconvolution of the NMR composite spectrum using a predetermined doublet region of the proton NMR spectrum for spectral referencing and/or alignment.

64-68. -68. (canceled)

69. A clinical NMR in vitro analyzer, comprising:

an automated sample handler for serially presenting respective biosamples to an input port;

an enclosed flow path configured to serially flow the respective biosamples presented by the automated sample handler, wherein the enclosed flow path includes a non-magnetic rigid generally straight flow cell;

an NMR detector in communication with an NMR flow probe, the NMR detector comprising a high-field cryogenically cooled superconducting magnet with a magnet bore having an opposing top and bottom, the flow probe configured to generally reside in the magnet bore, wherein the straight flow cell is configured and sized to extend into the magnet bore and direct the samples to serially flow from the top of the magnet bore into the magnet bore during operation; and

a processor comprising a computer readable storage medium with computer program code for obtaining and analyzing NMR signal spectra of the biosamples to determine desired quantitative and/or qualitative measurements of the respective biosamples.

70. A clinical NMR analyzer according to claim 69, wherein the generally straight flow cell is configured so that, in operation, the portion of the flow cell inside the magnet bore is straight.

71. A clinical NMR analyzer according to claim 72, wherein the enclosed flow path comprises polymeric tubing that is connected to the flow cell and resides outside the magnet bore.

72. A clinical NMR analyzer according to claim 69, wherein the analyzer is configured to automatically run a quality control status evaluation of selected operational parameters associated therewith and to automatically electronically adjust selected components based on the evaluation.

73. A networked system of clinical NMR analyzers, comprising:

a plurality of clinical NMR analyzers located at different local use sites; and

at least one remote control system in communication with the plurality of clinical NMR analyzers configured to monitor selected local operating parameters associated with each clinical NMR analyzer.

74-110. -110. (canceled)