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

• US 8,013,602 B2
• Filed: 03/30/2005
• Issued: 09/06/2011
• 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
• Primary Examiner(s): Shrivastav; Brij B
• Application Number:
  US11/093,596
• Publication Number:
  US 20050222504A1
• Time in Patent Office: 2,351 Days
• Field of Search: 324300-322, 600407-445, 600/309, 600/310, 435/21
• US Class Current: 324/309
• 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 the clinical NMR analyzer, the NMR analyzer comprising a flow probe held in a magnet bore of an NMR spectrometer;

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

initiating an automated calibration procedure (i) at start-up as part of a self-diagnostic start-up procedure before authorizing or allowing evaluation of patient samples that are introduced to the flow probe held in the NMR spectrometer and (ii) when one or more of the selected parameters are determined to be outside desired operational ranges based on the determining step, wherein the calibration procedure includes delivering a calibration standard to the flow probe in the NMR spectrometer;

automatically aborting a test, alerting an operator of abnormal conditions and/or adjusting operational parameters of selected components of the clinical NMR analyzer based on data obtained by the electronically determining step;

introducing patient biosamples to the flow probe in the NMR spectrometer;

obtaining NMR signal spectra of the introduced patient biosamples; and

electronically generating at least one clinical quantitative measurement of the patient biosamples 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 2, 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.

4. A method according to claim 3, wherein the automatically adjusting selected operational parameters comprises tuning the probe to a desired operational frequency.

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

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

7. 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.

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 a point of aspiration, the biosample to an electronic file configured to hold corresponding NMR test data of a respective patient.

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;

and automatically heating or cooling the biosample to be within a desired temperature range prior to the obtaining step.

14. A method according to claim 1, further comprising electronically generating a patient retest notice if data corruption is electronically identified as being associated with a patient test.

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 1, further comprising electronically flagging, invalidating and/or discarding the NMR spectra of the biosample when test conditions are identified as being outside the acceptable range based on data from the determining step.

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

19. A method according to claim 1, further comprising an NMR flow cell configured to hold the biosample in the flow probe 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, further comprising an NMR flow cell configured to hold the biosample in the flow probe 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, further comprising an NMR flow cell configured to hold the biosample in the flow probe in the magnet bore during the obtaining step, wherein the determining step comprises determining a 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 analyzer 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 a plurality of clinical quantitative measurement of the-biosample, and wherein the method further comprises automatically generating an electronic patient report of the measurements.

24. A method according to claim 1, further comprising electronically 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 electronically 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, wherein the generating step is carried out to electronically obtain NMR derived measurements of lipoprotein particle sizes and concentrations of the biosamples.

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 electronically 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 electronically 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 electronically 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 and/or clinical quantitative measurement to be carried out on the biosample from a plurality of different pre-defined tests and/or measurements using the NMR analyzer.

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

33. A method according to claim 1, wherein the initiating step is carried out automatically at equipment startup and/or at intervals during operation.

34. A method according to claim 1, wherein the introducing, obtaining and generating steps are carried out to analyze at least 400 patient biosamples per twenty-four hours.

35. A method according to claim 1, wherein the introducing step is carried out to flowably introduce the patient biosamples to the NMR spectrometer in a high throughput rate of at least about 600 samples per 24 hours.

36. A method according to claim 34, wherein the introducing, obtaining and generating steps are carried out by the NMR analyzer to diagnostically analyze at least about 400 biosamples per twenty-four hours without requiring dedicated on-site NMR support staff to reliably operate the NMR analyzer.

37. A method according to claim 1, wherein the flow probe is a modular top loading flow probe configuration thereby allowing ease of installation and tuning, the method further comprising releasably attaching the flow probe by inserting the flow probe into a top of the magnet bore of the NMR spectrometer.

38. A method according to claim 37, wherein tuning capacitors associated with the flow probe are mounted above the flow probe, the method further comprising replacing the flow probe by removing a first modular flow probe from a top of the magnet, then inserting a second modular flow probe from the top of the magnet and attaching the flow probe to the magnet.

39. A method according to claim 1, wherein the introducing step is carried out using an automated sample handler with a sample handler interface and a sample injector interface, wherein the clinical NMR analyzer comprises an instrument automation module, the method further comprising electronically controlling the operation of the sample handler, the sample injector and the NMR spectrometer using the instrument automation module.

40. A method according to claim 39, further comprising electronically selecting what clinical quantitative measurement to be carried out for a respective biosample using the instrument automation module and a patient analytical test module, wherein the patient analytical test module includes a plurality of selectable different tests.

41. A method according to claim 39, wherein the instrument automation module comprises an LIS interface.

42. A method according to claim 1, further comprising automatically electronically invalidating, not acquiring, flagging or discarding NMR spectra for a respective biosample when test conditions are outside defined limits based on data from the determining step.

43. A method according to claim 1, further comprising electronically selecting a test format and/or sample variables of interest for a respective biosample and generating a test report for the biosample using the selected test format.

44. A method according to claim 1, wherein the NMR analyzer is configured to generate a customizable report format, one for each of a plurality of different test sites.

45. A method according to claim 1, wherein the NMR analyzer comprises a sample handler that holds containers of the respective biosamples and an enclosed flow path the directs the biosamples to flow into a flow cell held inside the flow probe in the magnet bore, and wherein the introducing step is carried out by electronically directing an aspirating member to blow out an injection port associated with the flow path after injecting a first sample into the flow path before pre-fetching a second sample to maintain liquid-air gaps between neighboring samples in the flow path.

46. A method according to claim 1, further comprising:

automatically electronically monitor NMR signal lineshapes of obtained NMR signal spectra of the biosamples;

automatically electronically scale the NMR signal spectra of the biosamples responsive to the monitored signal lineshape;

electronically center a resonance of a biosample constituent within an RF window of interest;

electronically adjust lock power and lock phase;

electronically shim the magnet to a desired level of homogeneity;

electronically monitor temperature of the flow cell probe;

electronically determine a pulse width of the RF excitation pulse used to excite the biosample in the magnet bore;

electronically monitor a normalization factor to adjust for NMR spectrometer-specific sensitivity in situ;

electronically invalidate, not acquire, flag or discard NMR spectra for a biosample when test conditions are determined to be outside defined acceptable limits;

electronically determine what type of diagnostic test to run on the biosamples being introduced;

electronically obtain NMR derived measurements of lipoprotein particle size(s) and concentrations in a blood plasma and/or serum sample as the biosample;

electronically relate the test data to respective patients; and

electronically generate respective electronic patient reports of the measurements.

47. A method according to claim 1, further comprising automatically generating a patient data file record for each biosample that includes a patient identifier, a dilution factor, the at least one clinical measurement, and an associated test date and time.

48. 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;

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

before the obtaining step, 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.

49. A method according to claim 48, further comprising flowing the aspirated samples into a flow cell associated with the flow path held in a magnet bore of the NMR analyzer and directing the sample to travel generally vertically to an intermediate location in the magnet bore inside the flow cell held in a flow probe in the magnet bore to thereby reduce flow path length.

50. A method of operating a clinical NMR in vitro analyzer in a patient biosample test laboratory without an onsite dedicated NMR support technician, the clinical analyzer comprising an NMR spectrometer with a magnet having a bore, the method comprising the steps of:

automatically introducing in vitro biosamples into a top-loaded flow probe held in the magnet bore of the NMR spectrometer;

electronically detecting data associated with selected operating parameters of the clinical NMR analyzer during normal operation;

electronically verifying that selected conditions of the clinical NMR analyzer are within target operating ranges on the basis of the detected data;

executing an automated electronic self-diagnostic quality control and/or calibration test during operation using a calibration standard introduced to the flow probe; and

electronically obtaining NMR spectra for at least 400 biosamples per twenty-four hours and generating quantitative measurements based on the obtained NMR spectra.