U.S. patent application number 17/508214 was filed with the patent office on 2022-02-10 for nmr analyzers for clinical evaluation of biosamples.
This patent application is currently assigned to LipoScience, Inc.. The applicant listed for this patent is LipoScience, Inc.. Invention is credited to Donald R. Deuel, Elias J. Jeyarajah, Stephen Markham, Steven P. Matyus, David R. Morgan, James D. Otvos, Bruce D. Silberman.
Application Number | 20220043086 17/508214 |
Document ID | / |
Family ID | 1000005917990 |
Filed Date | 2022-02-10 |
United States Patent
Application |
20220043086 |
Kind Code |
A1 |
Otvos; James D. ; et
al. |
February 10, 2022 |
NMR Analyzers for Clinical Evaluation of Biosamples
Abstract
The clinical analyzers 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.
Inventors: |
Otvos; James D.; (Cary,
NC) ; Jeyarajah; Elias J.; (Raleigh, NC) ;
Markham; Stephen; (Raleigh, NC) ; Matyus; Steven
P.; (Durham, NC) ; Morgan; David R.; (Raleigh,
NC) ; Silberman; Bruce D.; (Apex, NC) ; Deuel;
Donald R.; (Raleigh, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
LipoScience, Inc. |
Morrisville |
NC |
US |
|
|
Assignee: |
LipoScience, Inc.
Morrisville
NC
|
Family ID: |
1000005917990 |
Appl. No.: |
17/508214 |
Filed: |
October 22, 2021 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
16452007 |
Jun 25, 2019 |
11156685 |
|
|
17508214 |
|
|
|
|
14198940 |
Mar 6, 2014 |
10365339 |
|
|
16452007 |
|
|
|
|
13207594 |
Aug 11, 2011 |
8704521 |
|
|
14198940 |
|
|
|
|
11093596 |
Mar 30, 2005 |
8013602 |
|
|
13207594 |
|
|
|
|
60558516 |
Apr 1, 2004 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
G01R 33/465 20130101;
G01R 33/307 20130101 |
International
Class: |
G01R 33/465 20060101
G01R033/465; G01R 33/30 20060101 G01R033/30 |
Claims
1. 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.
2. A system according to claim 1, wherein each of the clinical NMR
analyzers includes a high field NMR superconducting magnet, and
wherein the remote system automatically obtains data corresponding
to homogeneity of the magnetic field generated by the
superconducting magnet.
3. A system according to claim 1, wherein the clinical NMR
analyzers generate and store an electronic history file of selected
operational parameters, the history file configured to be accessed
by the remote system.
4. A system according to claim 1, wherein the clinical NMR
analyzers and/or remote system are configured to automatically
monitor process variables and statistically analyze data
corresponding to measurements of the monitored process variables to
thereby perform an automated quality control analysis.
5. A system according to claim 4, wherein the clinical NMR
analyzers are configured to automatically adjust operating
equipment to keep the process variables within a predetermined
statistical variation responsive to the monitored data.
6. A system according to claim 1, wherein the clinical NMR
analyzers are configured to automatically generate an alert when an
abnormal operating condition is detected.
7. A system according to claim 1, wherein the remote system is
configured to automatically generate an alert when an abnormal
operating condition is detected.
8. A system according to claim 1, wherein the clinical NMR
analyzers are configured to generate an electronic service log that
is accessible by the remote system.
9. A system according to claim 1, wherein the clinical NMR
analyzers are configured to automatically detect temporally
relevant data of selected operational parameters at desired
intervals and generate an electronic maintenance file thereof, and
to electronically store the maintenance files for interrogation by
the remote system.
10. A system according to claim 9, wherein the selected operational
parameters include the NMR signal lineshape and/or scaling thereof
of a patient sample.
11. A system according to claim 9, wherein the maintenance file
includes respective patient sample identifiers correlated to
selected operational parameters measured at a time the NMR signal
of the patient sample was obtained.
12. A system according to claim 9, wherein an electronic
maintenance file of selected operational parameters is generated
for each sample.
13. A system according to claim 1, wherein the clinical NMR
analyzers generate an electronic log of NMR sample data
corresponding to the samples processed by the respective analyzers
over a desired interval, the log configured to be electronically
accessible by the remote system.
14. A system according to claim 1, wherein an operator at the
remote system determines when to send technical support on-site to
the clinical NMR analyzers.
15. A system according to claim 1, wherein the remote system
automatically controls selected parameters of the clinical NMR
analyzers.
16. A system according to claim 1, wherein the clinical NMR
analyzers electronically store sample data correlated to an
accession patient identifier and sample dilution factor.
17. A system according to claim 1, wherein the clinical NMR
analyzers are configured with a user interface that accepts local
user input to select a report format and/or sample variables of
interest for NMR analysis.
18. A system according to claim 1, wherein the NMR analyzers
include program code configured to generate patient reports from
each clinical NMR analyzer site, the program code including a site
identifier that is correlated to the patient reports from
respective clinical NMR analyzer sites, and wherein the computer
program code is configured to allow the report to be generated in
electronic and/or paper form.
19. A system according to claim 1, wherein the remote system is
configured to automatically obtain data regarding the number of
patient samples analyzed over a desired interval on each clinical
NMR analyzer.
20. A system according to claim 1, wherein the clinical NMR
analyzers are configured to obtain NMR derived concentration
measurements of lipoproteins in a blood plasma and/or serum
sample.
21. A system according to claim 1, wherein the clinical NMR
analyzers are configured to obtain NMR derived concentration
measurements of LDL and/or HDL subclass particles in a blood plasma
and/or serum sample.
22. A system according to claim 20, wherein the clinical NMR
analyzers are configured to determine a patient's risk of having
and/or developing CHD based on the lipoprotein measurements.
23. A system according to claim 20, wherein the clinical NMR
analyzers are configured to determine a patient's risk of having
and/or developing Type II diabetes.
24. A system according to claim 23, wherein the clinical NMR
analyzers are configured to determine a patient's risk of having an
insulin resistance disorder.
25. A system according to claim 1, wherein each clinical NMR
analyzer is configured to automatically execute a start-up
self-diagnostic and tuning/calibration routine and relay abnormal
data regarding same to the remote control system.
26. A system according to claim 1, wherein the clinical NMR
analyzers are configured to automatically monitor the NMR signal
lineshapes to determine a height and/or width thereof.
27. A system according to claim 26, wherein the clinical NMR
analyzers comprise a high field superconducting magnet, and therein
the clinical NMR analyzers automatically shim the NMR spectroscopic
magnetic field to provide increased homogeneity if the line widths
degrade.
28. A system according to claim 27, wherein the clinical NMR
analyzers are configured to automatically adjust scaling of the NMR
signal height when signal height and/or width is outside a desired
range.
29. A system according to claim 1, wherein one of the selected
operational parameters is RF excitation pulse power, and wherein
the clinical NMR analyzers are configured to automatically adjust
the RF excitation pulse power if the power is outside a desired
operating range and/or varies from pulse to pulse by more than a
predetermined amount and/or percentage.
30. A system according to claim 29, wherein the clinical NMR
analyzers are configured to invalidate NMR signal data obtained
when power variation of the RF pulses is greater than a
predetermined amount.
31. A system according to claim 1, wherein the remote system is
configured to automatically order consumables for the clinical NMR
analyzers based on monitored data.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 13/207,594 (and indirect divisional of U.S.
patent application Ser. No. 11/093,596), filed Aug. 11, 2011, which
is a first divisional of U.S. patent application Ser. No.
11/093,596, filed Mar. 30, 2005, which claims the benefit of
priority of U.S. Provisional Application Ser. No. 60/558,516, filed
Apr. 1, 2004, the contents of which are hereby incorporated by
reference as if recited in full herein.
FIELD OF THE INVENTION
[0002] The present invention relates generally to NMR systems, and
may be particularly suitable for clinical NMR in vitro diagnostic
systems capable of analyzing biosamples.
BACKGROUND OF THE INVENTION
[0003] In the past, NMR detectors have been used to provide NMR
LipoProfile.RTM. lipoprotein panel reports. The NMR detectors have
been located in a central testing facility with on-site support.
The LipoProfile.RTM. report, available from LipoScience, Inc.,
located in Raleigh, N.C, is a lipoprotein test panel that assesses
a patient's risk of coronary artery disease ("CAD") and provides
NMR-derived (quantitative analysis) lipoprotein measurement average
low-density lipoprotein (LDL) particle size as well as LDL particle
number, the latter representing the concentration or quantity (in
concentration units such as nmol/L), and the former representing
the average size of the LDL particles (in nm units) making up the
LDL in the sample. HDL and VLDL subclass measurements can also be
provided. See www.liposcience.com and U.S. Pat. No. 6,576,471 for
exemplary reports of particular lipoprotein subclass parameters;
the contents of the patent are hereby incorporated by reference as
if recited in full herein.
[0004] It is known that NMR spectroscopic evaluation techniques can
be used to concurrently obtain and measure a plurality of different
lipoprotein constituents in an in vitro blood plasma or serum
sample, as described in U.S. Pat. No. 4,933,844, entitled
Measurement of Blood Lipoprotein Constituents by Analysis of Data
Acquired from an NMR Spectrometer to Otvos and U.S. Pat. No.
5,343,389, entitled Method and Apparatus for Measuring Classes and
Subclasses of Lipoproteins, also to Otvos. See also, U.S. Pat. No.
6,617,167, entitled Method Of Determining Presence And
Concentration Of Lipoprotein X In Blood Plasma And Serum and
co-pending co-assigned U.S. Provisional Patent Application Ser. No.
60/513,795, entitled Methods, Systems and Computer Programs for
Assessing CHD Risk Using Mathematical Models that Consider In Vivo
Concentration Gradients of LDL Particle Subclasses of Discrete
Size. The contents of all the above patents and patent applications
are hereby incorporated by reference as if recited in full
herein.
[0005] As is well known to those of skill in the art, NMR detectors
include an RF amplifier, an NMR probe that includes an RF
excitation coil (such as a saddle or Helmholtz coil), a
cryogenically cooled high-field superconducting magnet and an
enclosed flow path that directs samples to flow serially, from the
bottom of the magnet bore to a predetermined analysis location in
the magnet bore. The NMR detector is typically a high-field magnet
housed in a magnetically (and/or RF) shielded housing that can
reduce the magnetic field level that is generated to within a
relatively small volume. NMR detectors are available from Varian,
Inc., having corporate headquarters in Palo Alto, Calif. and Bruker
BioSpin, Corp., located in Billerica, Mass.
[0006] In operation, to evaluate the lipoproteins in a blood plasma
and/or serum sample, the operator places the patient samples in a
sample tray and an electronic reader correlates the sample to a
patient, typically using a bar code on the sample tray. The sample
is aspirated from the sample container and directed to flow through
the flow path extending through the NMR detector. For detailed
lipoprotein analysis, the NMR detector may analyze the sample for
1-5 minutes to determine amplitudes of a plurality of NMR
spectroscopy derived signals within a chemical shift region of the
proton NMR spectrum. These signals are derived by deconvolution of
the composite signal or spectrum and are compared to predetermined
test criteria to evaluate a patient's risk of having or developing
coronary artery or heart disease.
[0007] In the past, a plurality of NMR spectrometers, all disposed
at a central testing facility, have been used to carry out
lipoprotein analysis on blood plasma samples to generate
LipoProfile.RTM. test reports. The NMR spectrometers communicate
with a local but remote computer (the computer is in a different
room from the spectrometers) to allow the remote computer to obtain
NMR spectra and analyze the NMR spectra to generate the patient
diagnostic reports with quantitative lipoprotein values.
Unfortunately, an operator manually carries out adjustments to the
equipment using a manually input quality control sample to adjust
the line width. In addition, the sample handler does not
communicate with the NMR spectrometer and is not capable of
electronically notifying the system of handling problems. The NMR
spectrometer systems are complex and typically require dedicated
on-site experienced operational oversight.
[0008] In view of the above, there remains a need for improved NMR
analyzers that may be used in high-volume quantitative clinical
applications at one or more remote locations.
SUMMARY OF EMBODIMENTS OF THE INVENTION
[0009] Certain embodiments of the present invention are directed at
providing automated NMR clinical analyzers that can be used without
requiring dedicated on-site NMR support staff and/or undue
technician support to reliably operate the NMR analyzers. The
automated NMR clinical analyzers can be configured to obtain
quantitative analysis measurements that can be used for in vitro
diagnostics. In some embodiments, the automated NMR analyzers can
be configured to meet governmental medical regulatory requirements
such as those described in applicable federal regulations,
including those in 21 CFR (such as 21 CFR 820 and 21 CFR 11) for
medical devices.
[0010] In some embodiments, the NMR analyzers can monitor and
adjust selected operating parameters "on the fly" reducing the need
for manual assistance and providing automated operation. The NMR
analyzers can include interactive sample handlers that communicate
with the NMR spectrometer and/or remote control system. The NMR
clinical analyzers can be configured to reliably run and obtain
quantified clinical measurements for diagnostic tests on high
volume throughput of biosamples while reducing the amount of
operator input or labor required to operate the automated
analyzers. The NMR analyzers can be constructed and/or configured
in such a manner as to be able to obtain PMA (pre-market approval)
and/or 510(k) approval from the United States Food and Drug Agency
("USFDA") and/or corresponding foreign agencies.
[0011] Certain embodiments are directed to methods of operating a
clinical NMR in vitro diagnostic analyzer. The methods include: (a)
electronically monitoring data associated with selected equipment
and/or environmental operational test conditions of a clinical NMR
analyzer; (b) electronically determining whether the selected test
conditions are within desired operational ranges based on the
monitored data; (c) automatically adjusting operational parameters
of selected components of the clinical NMR analyzer based on data
obtained by the electronically determining step; (d) obtaining NMR
signal spectra of a biosample; and (e) analyzing the obtained NMR
spectra to generate target clinical measurements of the
biosample.
[0012] Other embodiments are directed to clinical NMR in vitro
diagnostic analyzers. The analyzers include: (a) 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;
(b) means for automatically obtaining NMR signal spectra of the
biosamples; (c) 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 (d) means for automatically electronically
adjusting selected operating parameters based on the verified test
conditions.
[0013] Some embodiments are directed to clinical NMR in vitro
diagnostic analyzers that include: (a) 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, (b) a control
circuit in electronic communication with the NMR spectroscopy
instrument; and (c) 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. 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.
[0014] Still other embodiments are directed to computer program
products for automating clinical NMR in vitro diagnostic analyzers.
The computer program products include a computer readable storage
medium having computer readable program code embodied in said
medium. The computer-readable program code includes: (a) computer
readable program code configured to automatically run an automated
self-diagnostic quality control and/or calibration test for the
clinical NMR in vitro diagnostic analyzer; and (b) computer
readable program code configured to automatically electronically
monitor selected operating parameters of the NMR in vitro
diagnostic analyzer over time during operation.
Still other embodiments are directed to methods of analyzing
undiluted plasma and/or serum by: (a) obtaining a proton NMR
composite spectrum of an undiluted biosample; and (b) 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.
[0015] The undiluted biosample may be neat serum and the doublet
may comprise a lactate doublet generally centered at about 1.3 ppm
of the proton NMR spectrum. The undiluted sample can be serum that
comprises glucose and the doublet can be an anomeric proton signal
from glucose in the serum that is generally located at about 5.2
ppm of the NMR spectrum.
[0016] Another embodiment is directed to computer program products
for analyzing undiluted plasma and/or serum. The computer program
product includes a computer readable storage medium having computer
readable program code embodied in the medium. The computer-readable
program code can include: (a) computer readable program code
configured to obtain a proton NMR composite spectrum of an
undiluted biosample, the proton NMR composite spectrum being devoid
of a CaEDTA peak; and (b) computer readable program code configured
to generate a spectral deconvolution of the NMR composite spectrum
using a predetermined doublet region of the proton NMR spectrum for
spectral referencing and/or alignment.
[0017] Yet other embodiments are directed to clinical NMR in vitro
analyzers that include: (a) an automated sample handler for
serially presenting respective biosamples to an input port; (b) 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 straight flow
cell; (c) 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, 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 a top of
the magnet bore into the magnet bore during operation; and (d) a
processor comprising computer program code for obtaining and
analyzing NMR signal spectra of the biosamples to determine desired
quantitative measurements of the respective biosamples.
[0018] Some embodiments of the present invention are directed to a
networked system of clinical NMR analyzers. The system includes:
(a) a plurality of clinical NMR analyzers located at different use
sites; and (b) at least one remote control (service/support) system
in communication with the plurality of clinical NMR analyzers. The
at least one remote system is configured to monitor selected local
operating parameters associated with each clinical NMR
analyzer.
[0019] In some embodiments, the remote system monitors the local
NMR analyzers to inhibit down time and/or identify and correct
process variables before test data is corrupted to increase the
reliability of the equipment and quantitative test results. The
local and/or remote system can be configured to monitor
predetermined process parameter data, service histories, cryogen
use, patient test data, and the like.
[0020] In some embodiments, the local system can be configured to
monitor and identify process variation and generate an alarm that
is sent to the remote system (local and/or remote site) for
appropriate corrective action/investigation. In other embodiments,
the remote system can monitor the process variation and generate an
alert to a service/support technician at the remote site.
Combinations of the local and remote monitoring can also be used.
The remote station can reduce the technical support and/or operator
knowledge needed at each local use site thereby allowing increased
numbers of clinical analyzers to be used in field sites with
relatively economic operational costs.
[0021] The local systems may generate and store an electronic
history file of selected operational parameters. The electronic
history file can be configured to be accessed by the remote system.
The local and/or remote system may be configured to automatically
monitor process variables and statistically analyze data
corresponding to measurements of the monitored process variables to
thereby perform an automated quality control analysis (such as
maintain the parameters within a 3 sigma and/or in some
embodiments, a 6 sigma process limit). In some embodiments, the
local system can be configured to automatically adjust operating
equipment to keep the process variables within a predetermined
statistical variation responsive to the monitored data.
[0022] In some embodiments, the clinical NMR analyzers can be
configured to automatically adjust scaling of the NMR lineshape
when the height and/or width thereof is outside a desired range.
The local system can monitor RF excitation pulse power and
automatically adjust the RF excitation pulse power if the power is
outside a desired operating range and/or varies from pulse to pulse
by more than a predetermined amount and/or percentage. In
particular embodiments, the clinical NMR analyzers can be
configured to disregard NMR signal data obtained when power
variation of the RF pulses is greater than a predetermined
amount.
[0023] Other embodiments are directed to methods of generating
NMR-derived quantitative measurement data for diagnostic clinical
reports of patient biosamples. The methods include: (a)
automatically serially introducing biosamples of interest into an
NMR analyzer (which can be carried out by aspirating to an enclosed
flow path that serially flows the biosamples into the NMR analyzer)
having a NMR spectroscopy instrument with a magnet and a bore at a
plurality of different clinical sites; (b) automatically
correlating a patient identifier to a respective patient biosample;
(c) obtaining NMR derived quantitative measurements of the
biosamples for diagnostic reports; and (d) automatically monitoring
the NMR analyzers at the different clinical sites from a remote
monitoring station.
[0024] In some embodiments the methods can include configuring the
analyzer/user to decide in situ how to analyze a particular patient
biosample. The obtaining step may include determining NMR derived
concentration measurements of lipoproteins in an in vitro blood
plasma and/or serum sample.
[0025] In certain embodiments, the automated clinical NMR analyzer
is configured with modular assemblies including: an automated
sample handling assembly; an NMR spectrometer; an NMR probe; and a
sample flow path to the NMR spectrometer each configured to
releasably attach and operate with its mating modular components
thereby allowing ease of repair and/or field replacement.
[0026] The clinical NMR analyzers may be configured to
automatically run an automated self-diagnostic quality control test
at startup. The analyzer may include computer program code that is
configured to determine a patient's risk of having and/or
developing CHD based on the NMR derived quantitative measurements
of the patient's respective biosample and/or computer program code
that is configured to determine a patient's risk of having and/or
developing Type II diabetes based on the NMR derived quantitative
measurements of the patient's respective biosample.
[0027] Yet additional embodiments are directed to clinical NMR in
vitro diagnostic apparatus for obtaining data regarding lipoprotein
constituents in a biosample. The apparatus includes: (a) an
automated sample handler system comprising a plurality of in vitro
blood plasma and/or serum samples; (b) an NMR spectrometer for
serially acquiring an NMR composite spectrum of the in vitro blood
plasma or serum sample in communication with the automated handler
system; (c) at least one sample of validated control material
configured to repeatedly controllably flow into and out of the NMR
spectrometer at desired times; and (d) a processor configured to
receive data of the validated control material. The processor
includes: (a) computer program code configured to define an a
priori single basis set of spectra of validated reference control
material; (b) computer program code configured to obtain NMR
spectra of the validated control material; and (c) computer program
code configured to perform a spectral deconvolution of a CH.sub.3
region of the obtained NMR spectra of the validated control
material and comparing data associated with the spectral
deconvolution of the CH.sub.3 region with data associated with the
apriori spectra of the validated control material to determine
whether the NMR analyzer is in a suitable operational status and/or
ready for diagnostic testing operation.
[0028] As will be appreciated by those of skill in the art in light
of the present disclosure, embodiments of the present invention may
include methods, systems, apparatus and/or computer program
products or combinations thereof.
[0029] The foregoing and other objects and aspects of the present
invention are explained in detail in the specification set forth
below.
BRIEF DESCRIPTION OF THE FIGURES
[0030] FIG. 1 is a graph showing the chemical shift spectra of a
representative sample of lipoprotein constituent subclasses.
[0031] FIG. 2 is a graph illustrating NMR spectra for a composite
plasma sample and the lipoprotein subclass and protein components
thereof, with the peaks for methyl groups being illustrated.
[0032] FIG. 3A is a schematic illustration of a single basis set of
apriori data used with the CH.sub.3 region of a proton NMR spectra
of a blood plasma or serum sample according to embodiments of the
present invention.
[0033] FIG. 3B is a graph of a proton NMR spectrum of serum with a
lactate doublet useable for spectral alignment according to
embodiments of the present invention.
[0034] FIG. 3C is a graph of a proton NMR spectrum of serum with an
anomeric glucose doublet useable for spectral alignment according
to embodiments of the present invention.
[0035] FIG. 4 is a schematic illustration of a networked system of
a plurality of local clinical NMR analyzers that are in
communication with an automated remote service/support system
according to embodiments of the present invention.
[0036] FIG. 5 is a schematic illustration of an in vitro diagnostic
NMR analyzer according to embodiments of the present invention.
[0037] FIG. 6 is a schematic illustration of an automated clinical
NMR analyzer according to embodiments of the present invention.
[0038] FIG. 7 is a schematic illustration of another embodiment of
an automated clinical analyzer according to the present
invention.
[0039] FIG. 8A is a schematic of NMR analyzer software architecture
according to embodiments of the present invention.
[0040] FIG. 8B is a schematic of NMR analyzer software architecture
according to embodiments of the present invention.
[0041] FIG. 9 is a flow chart of operations that can be carried out
for an NMR analyzer start-up and/or process evaluation procedure
according to embodiments of the present invention.
[0042] FIG. 10 is a flow chart of operations that can be carried
out to run control samples of validated material through an NMR
analyzer according to embodiments of the present invention.
[0043] FIG. 11 is a flow chart of normal-run mode or operation of
an NMR analyzer according to embodiments of the present
invention.
[0044] FIG. 12 is a schematic diagram of a data processing system
according to embodiments of the present invention.
DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION
[0045] The present invention will now be described more fully
hereinafter, in which embodiments of the invention are shown. This
invention may, however, be embodied in different forms and should
not be construed as limited to the embodiments set forth herein.
Rather, these embodiments are provided so that this disclosure will
be thorough and complete, and will fully convey the scope of the
invention to those skilled in the art. In the drawings, like
numbers refer to like elements throughout, and thickness, size and
dimensions of some components, lines, or features may be
exaggerated for clarity. The order of operations and/or steps
illustrated in the figures or recited in the claims are not
intended to be limited to the order presented unless stated
otherwise. Broken lines in the figures, where used, indicate that
the feature, operation or step so indicated is optional unless
specifically stated otherwise.
[0046] It will be understood that when a feature, such as a layer,
region or substrate, is referred to as being "on" another feature
or element, it can be directly on the other feature or element or
intervening features and/or elements may also be present. In
contrast, when an element is referred to as being "directly on"
another feature or element, there are no intervening elements
present. It will also be understood that, when a feature or element
is referred to as being "connected", "attached" or "coupled" to
another feature or element, it can be directly connected, attached
or coupled to the other element or intervening elements may be
present. In contrast, when a feature or element is referred to as
being "directly connected", "directly attached" or "directly
coupled" to another element, there are no intervening elements
present. Although described or shown with respect to one
embodiment, the features so described or shown can apply to other
embodiments.
[0047] Unless otherwise defined, all terms (including technical and
scientific terms) used herein have the same meaning as commonly
understood by one of ordinary skill in the art to which this
invention belongs. It will be further understood that terms, such
as those defined in commonly used dictionaries, should be
interpreted as having a meaning that is consistent with their
meaning in the context of the relevant art and this application and
should not be interpreted in an idealized or overly formal sense
unless expressly so defined herein. As used herein, the term
"and/or" includes any and all combinations of one or more of the
associated listed items.
[0048] As used herein, the singular forms "a", "an" and "the" are
intended to include the plural forms as well, unless the context
clearly indicates otherwise. It will be further understood that the
terms "comprises" and/or "comprising," when used in this
specification, specify the presence of stated features, integers,
steps, operations, elements, and/or components, but do not preclude
the presence or addition of one or more other features, integers,
steps, operations, elements, components, and/or groups thereof.
[0049] The term "biosample" includes whole blood, plasma, serum,
urine, cerebral spinal fluid (CSF), lymph samples, stool samples,
tissues, and/or body fluids in raw form and/or in preparations. The
biosamples can be from any target subject. Subjects', according to
the present invention, can be any animal subject, and are
preferably mammalian subjects (e.g., humans, canines, felines,
bovines, caprines, ovines, equines, rodents (mice, rats, hamsters,
guinea pigs or others), porcines, primates, monkeys, and/or
lagomorphs). The animals can be laboratory animals or
non-laboratory animals, whether naturally occurring, genetically
engineered or modified, and/o whether being laboratory altered,
lifestyle and/or diet altered or drug treated animal
variations.
[0050] The term "clinical" with respect to data measurements means
qualitative and/or quantitative measurements that can be used for
therapeutic or diagnostic purposes, and typically for diagnostic
purposes and meets the appropriate regulatory guidelines for
accuracy, depending on the jurisdiction or test being performed.
The term "clinical" with respect to NMR analyzer is described above
in the Summary section of the specification.
[0051] The term "automatic" means that substantially all or all of
the operations so described can be carried out without requiring
active manual input of a human operator, and typically means that
the operation(s) can be programmatically directed and/or carried
out. The term "electronic" means that the system, operation or
device can communicate using any suitable electronic media and
typically employs programmatically controlling the communication
between a control system that may be remote and one or more local
NMR analyzers using a computer network.
[0052] The term "computer network" includes one or more local area
networks (LAN), wide area networks (WAN) and may, in certain
embodiments, include a private intranet and/or the public Internet
(also known as the World Wide Web or "the web"). The term
"networked" system means that one or a plurality of local analyzers
can communicate with at least one remote (local and/or offsite)
control system. The remote control system may be held in a local
"clean" room that is separate from the NMR clinical analyzer and
not subject to the same biohazard control requirements/concerns as
the NMR clinical analyzer.
[0053] As will be appreciated by one of skill in the art, the
present invention may be embodied as an apparatus, a method, a data
or signal processing system, and/or a computer program product.
Accordingly, the present invention may take the form of an entirely
software embodiment, or an embodiment combining software and
hardware aspects. Furthermore, certain embodiments of the present
invention may take the form of a computer program product on a
computer-usable storage medium having computer-usable program code
means embodied in the medium. Any suitable computer readable medium
may be utilized including hard disks, CD-ROMs, optical storage
devices, or magnetic storage devices.
[0054] The computer-usable or computer-readable medium may be, but
is not limited to, an electronic, magnetic, optical,
superconducting magnetic, infrared, or semiconductor system,
apparatus, device, or propagation medium. More specific examples (a
nonexhaustive list) of the computer-readable medium would include
the following: an electrical connection having one or more wires, a
portable computer diskette, a random access memory (RAM), a
read-only memory (ROM), an erasable programmable read-only memory
(EPROM or Flash memory), an optical fiber, and a portable compact
disc read-only memory (CD-ROM). Note that the computer-usable or
computer-readable medium could even be paper or another suitable
medium, upon which the program is printed, as the program can be
electronically captured, via, for instance, optical scanning of the
paper or other medium, then compiled, interpreted or otherwise
processed in a suitable manner if necessary, and then stored in a
computer memory.
[0055] Computer program code for carrying out operations of the
present invention may be written in an object oriented programming
language such as Java.RTM., Smalltalk, Python, Labview, C++, or
VisualBasic. However, the computer program code for carrying out
operations of the present invention may also be written in
conventional procedural programming languages, such as the "C"
programming language or even assembly language. The program code
may execute entirely on the user's computer, partly on the user's
computer, as a stand-alone software package, partly on the user's
computer and partly on a remote computer or entirely on the remote
computer. In the latter scenario, the remote computer may be
connected to the user's computer through a local area network (LAN)
or a wide area network (WAN), or the connection may be made to an
external computer (for example, through the Internet using an
Internet Service Provider).
[0056] The flowcharts and block diagrams of certain of the figures
herein illustrate the architecture, functionality, and operation of
possible implementations of analysis models and evaluation systems
and/or programs according to the present invention. In this regard,
each block in the flow charts or block diagrams represents a
module, segment, operation, or portion of code, which comprises one
or more executable instructions for implementing the specified
logical function(s). It should also be noted that in some
alternative implementations, the functions noted in the blocks may
occur out of the order noted in the figures. For example, two
blocks shown in succession may in fact be executed substantially
concurrently or the blocks may sometimes be executed in the reverse
order, depending upon the functionality involved.
[0057] Embodiments of the present invention may be used to analyze
any in vitro biosample. The biosample may be in liquid, solid,
and/or semi-solid form. The biosample may include tissue, blood,
biofluids, biosolids and the like. However, as noted above, the
automated clinical NMR analyzer may be particularly suitable to
analyze lipoprotein data in in vitro blood serum and/or plasma
samples. The small person-to-person variations in the lineshapes of
the lipoprotein classes are caused by the subclass heterogeneity
known to exist within each of these lipoprotein classes. FIG. 1
shows the lineshapes and chemical shifts (positions) for a number
of subclasses of lipoproteins. As shown in FIG. 1, the chemical
shifts and lineshape differences between the different subclasses
are much smaller than those between the major lipoprotein classes,
but are completely reproducible. Thus, differences among the NMR
signals from the plasma of individuals are caused by differences in
the amplitudes of the lipid resonances from the subclasses present
in the plasma, which in turn are proportional to their
concentrations in the plasma. This is illustrated in FIG. 2, in
which the NMR chemical shift spectra of a blood plasma sample is
shown. The spectral peak produced by methyl (CH.sub.3) protons 60
(shown as a solid line) is shown for the blood serum sample in FIG.
2. The spectral peak 61 (shown as a dotted line) in FIG. 2 is
produced by the arithmetic sum of the NMR signals produced by the
lipoprotein subclasses of the major classes VLDL, LDL, HDL,
proteins and chylomicrons, as illustratively shown by certain of
the subclasses in FIG. 1. It can be seen that the lineshape of the
whole plasma spectrum is dependent on the relative amounts of the
lipoprotein subclasses whose amplitudes change (sometimes
dramatically) with their relative concentrations in the plasma
sample.
[0058] Since the observed CH.sub.3 lineshapes of whole plasma
samples are closely simulated by the appropriately weighted sum of
lipid signals of their constituent lipoprotein classes, it is
possible to extract the concentrations of these constituents
present in any sample. This is accomplished by calculating the
weighting factors which give the best fit between observed blood
plasma NMR spectra and the calculated blood plasma spectra.
Generally speaking, the process of NMR lipoprotein analysis can be
carried out by the following steps: (1) acquisition of an NMR
"reference" spectrum for each of the "pure" individual constituent
lipoprotein classes and/or subclasses of plasma or serum of
interest and/or related groupings thereof; (2) acquisition of a
whole plasma or serum NMR spectrum for a sample using measurement
conditions substantially identical to those used to obtain the
reference spectra; and (3) computer deconvolution of the NMR
spectrum in terms of the constituent classes and/or subclasses (or
related groupings thereof) to give the concentration of each
lipoprotein constituent expressed as a multiple of the
concentration of the corresponding lipoprotein reference.
[0059] Although the procedure can be carried out on lipoprotein
classes, carrying out the process for subclasses of lipoproteins
can decrease the error between the calculated lineshape and the NMR
lineshape, thus increasing the accuracy of the measurement while
allowing for simultaneous determination of the subclass profile of
each class. Because the differences in subclass lineshapes and
chemical shifts are small, for certain applications, it may be
important to correctly align the reference spectrum of each
subclass with the plasma spectrum.
[0060] The alignment of these spectra can be accomplished by the
alignment of control peaks in the spectra, which are known to
respond in the same manner to environmental variables, such as
temperature and sample composition, as do the lipoprotein spectra.
As is known, one such suitable alignment peak is the peak produced
by CaEDTA found in prepared (diluted) sample mixtures, although
other EDTA peaks or suitable peak may be utilized. By alignment of
the spectra, the small-variations in the subclasses' lineshapes and
chemical shifts may be exploited to produce higher accuracy and
subclass profiles.
[0061] Further description of these methods can be found in U.S.
Pat. Nos. 4,933,844 and 5,343,389 to Otvos. The mathematics used in
the lineshape fitting process (i.e., least squares fit of an
unknown function in terms of a weighted sum of known functions) is
well known and is described in many textbooks of numerical
analysis, such as F. B. Hildebrand, Introduction to Numerical
Analysis, 2nd edition, pp. 314-326, 539-567, McGraw-Hill, 1975.
Validation Control Material and Operational Status Evaluation
[0062] In the past, as part of start-up or periodic quality
assessment, at least two types/levels of control material samples
were introduced into the NMR spectrometer and multiple NMR derived
lipoprotein parameters were assessed (compared to stored values)
for conformance to expected results for quality control review.
[0063] In some embodiments of the present invention, it is
contemplated that the multiple variables previously reviewed can be
reduced to a single variable by performing spectral deconvolution
of the CH.sub.3 region of the spectra or other suitable region for
at least one validation control material sample. The analyte NMR
lineshape can be deconvoluted using multivariate analysis with
non-negative constraints. See, e.g., Lawson, C. L., Hanson, R. J.
Solving Least Squares problems. Philadelphia, Pa.: SIAM, 1995, pp.
160-165.
[0064] The analyte spectra array consists of "m" discrete data
points denoted P.sub.i.sup.0, where i=1, 2 . . . m. The method for
fitting the validated control spectrum, P.sub.i.sup.0, with a
linear combination of n constituent spectra is based on the premise
that there are a set of coefficients, c.sub.j, corresponding to the
contributions of component j, and a coefficient, c.sub.p.sup.1,
corresponding to the imaginary portion of the sample plasma
spectrum, such that for each data point,
P.sub.i.sup.0.apprxeq.P.sub.i.sup.c, where
P i c = n j = 1 .times. c j .times. V ji + c p I .times. V i I .
EQUATION .times. .times. ( 1 ) ##EQU00001##
[0065] The best fit can be obtained by minimizing the root mean
square error in a manner analogous to that previously described in
U.S. Pat. No. 6,617,167, except that V.sub.j represents only the
single (j=1) basis set of the validated control spectra array
stored in the computer. The contents of this patent are hereby
incorporated by reference as if recited in full herein.
[0066] The correlation coefficient, r, of the fit of control
spectra of the CH.sub.3 region as a function of the stored
validated control spectra will be used along with coefficient
c.sub.j to determine the acceptability of status of the analyzer to
acquire clinical data. In certain embodiments, both r and c.sub.j
can be as chosen to be as close to 1.0 as practicable and/or
possible. Acceptable limits for deviation from 1.0 can be
established in consonant with standard clinical practices mandated
by CLIA.
[0067] The phrase "validation control material sample" refers to a
priori or known measurement values of a known reference sample, the
known sample corresponding to those types of samples that will be
undergoing evaluation using the equipment and analysis software
(whatever biotype, i.e., blood plasma or serum, urine, etc). The
spectral deconvolution of the CH.sub.3 region of the spectra of the
control material can be carried out using the single basis set of
the stored spectra of the validated known control samples. Thus, a
known validation sample can be analyzed and its associated values
can be stored as known or control values. Periodically, the
validation control sample can be reanalyzed by the NMR system to
confirm that the test values conform to the stored (expected
values). The NMR analyzer can be configured to flag or alert when
there is undue departure from predetermined norms so that the
system can be recalibrated.
[0068] The validation control sample and validation control
protocol can typically be run at start-up (each shift or daily) and
at increased intervals as needed. The increased intervals may be
based on signal degradation of the proton NMR spectrum lineshape
(width/height), when an unknown sample is quantified outside normal
bounds and/or upon other automatically detected and monitored
parameters.
Undiluted Samples
[0069] In certain embodiments, the NMR clinical analyzers 10 (FIG.
4) can be configured to analyze undiluted (neat) plasma and/or
serum. Unfortunately, a CaEDTA peak may not appear when the sample
is undiluted serum, which can impede spectral referencing for
deconvolution. Thus, in certain embodiments, as shown in FIG. 3B, a
lactate doublet 66 generally centered about 1.3 ppm in the proton
NMR spectrum of serum can be used for spectral referencing and
alignment for NMR derived quantification analysis (such as
lipoprotein quantification of serum samples). In other embodiments,
as shown in FIG. 3C, an anomeric proton signal from the glucose in
serum can appear as a doublet 67 at about 5.2 ppm and this doublet
may also be used (with or alone) as an anchor point for spectral
alignment.
Network of Clinical Analyzers
[0070] As shown in FIG. 4, certain embodiments of the invention are
directed to a networked system 18 of clinical NMR analyzers 10. The
networked system 18 includes at least one clinical NMR analyzer 10
that communicates with at least one remote system 15. Typically, a
plurality of clinical NMR analyzers 10 located at a common local
use site communicate with a respective at least one remote
service/support system 15. The at least one remote system 15 can be
configured to monitor selected local operating parameters
associated with each clinical NMR analyzer 10. In some embodiments,
each local site may include a plurality (at least two) NMR
analyzers 10, which may be configured to communicate with each
other and/or at least one remote control system 15. The at least
one remote control system 15 may be configured as a common local or
offsite control station for a plurality of different local
analyzers 10 (typically for all of the local analyzers at a use
site). The at least one remote control system 15 can be a plurality
of generally independent stations configured to communicate with
one or selected local analyzers 10. In other embodiments, the at
least one control system 15 can be a plurality of remote control
systems 15 that may be in communication with another offsite
control station 15' as optionally shown in FIG. 4. Each respective
local analyzer 10 can communicate with a common remote control
system 15 or a plurality may communicate with different control
systems and/or sites. The local analyzers 10 may also be configured
to operate independently of the others and/or not to communicate
with each other. The broken line box 15R drawn around the remote
control box in FIG. 4 illustrates that the remote control system(s)
15 can be located on-site (in the same facility) but in a room 15R
that is enclosed and away from the NMR Analyzers 10 so as to not be
under the same biohazard, laboratory access/cleanliness or
operation restrictions as the NMR clinical analyzer itself 10.
[0071] In some embodiments some of the local analyzers 10 may be
configured to communicate with each other directly or indirectly
using the control system 15, such as, but not limited to, those at
affiliated locations or a common local site. The communication can
be electronic communication such as (a) wireless, which may be
carried out using mobile communications and/or satellite systems,
(b) via an intranet, (c) via a global computer network such as the
Internet, and/or (d) use a POTS (land based "plain old telephone
system"). The system 18 may use combinations of communications
systems.
[0072] The local analyzers 10 may be controlled by the remote
system 15 in a manner that allows for interactive adjustment during
operation, such as during the NMR analysis and/or start-up or
calibration mode. As such, the operational and/or test analysis
data can be relayed to the remote control system 15 in
substantially "real-time". The NMR analyzers 10 can be configured
to interactively communicate with the remote control system 15 to
allow "smart" monitoring status. For example, the NMR analyzer 10
can automatically send a signal alerting the control system 15 when
a test is complete for a subject, allowing the control system 15 to
timely obtain the data therefrom and generate the test report using
the data.
[0073] In some particular embodiments, the system 18 can include a
data processing system, which comprises a web server. In
particular, the data processing system may be an Internet
Appliance, such as a PICOSERVER.RTM. appliance by Lightner
Engineering located in San Diego, Calif. (see also www.picoweb.net)
or other such web servers, including, but not limited to, those
available from Axis Communications, or PICOWEB, RABBIT, and the
like. The data processing system can receive commands from the
support site 15 and controls certain operational parameters of the
system 10. The data processing system can also include a TCP stack
and Ethernet NIC to provide the communication link between the
computer network 10 and the test administration site 15.
[0074] The processing system can provide information about the
local analyzers 10 to the administration site 15 as web pages which
may be predefined and stored at the local device 10. Such web pages
may also be dynamically generated to incorporate test specific
information. The web pages may be Hypertext Markup Language (HTML)
common gateway interface (CGI) web pages which allow for user input
by a client, such as a web browser, of a user at the test
administration site 15. The web pages may also be or include Java
scripts, Java applets or the like which may execute at the test
administration site so as to control operations of an
administration data processing system at the administration site
15. As will be appreciated by those of skill in the art, other
mechanisms for communicating between a web server and a client may
also be utilized. For example, other markup languages, such as
Wireless Markup Language (WML) or the like, for communicating
between the local device 10 and the administration site 15 may be
utilized.
[0075] In certain embodiments, operations of a web server and a web
client can include a web browser as the administration site 15 that
requests an initial web page from the web server of the local
device 10. Such a request may take the form of a Hypertext Transfer
Protocol (HTTP) request to the IP address of the web server of the
local device. The IP address may be pre-assigned to the local
device 10 or may be dynamically assigned when the local device 10
attaches to the network 15. Thus, the web browser may know in
advance the IP address of the local devices 10 or may be notified
of the IP address as part of a setup procedure.
[0076] When the local device 10 receives the request for the
initial web page, it sends the initial web page and a Java applet
which causes the web browser to periodically reload its current web
page. Alternatively, "push" technology could be employed by the
server to push data to the web browser when status is to be
updated. The rate at which the web page is reloaded may be based on
the type of data relayed or detected and/or the web page being
displayed. Similarly, the rate may also be based on the type of
network connection utilized such that for slower connection types
the refresh rate could be reduced. In some embodiments, the Java
applet could be generated once with the initial web page, while in
others the Java applet could be provided with each web page, and
the refresh rate could be based on the particular web page
provided. For example, a setup web page could be refreshed less
often then a test status web page (or not at all).
[0077] In any event, after the initial web page is provided to the
web browser, the web server of the local devices 10 waits for a
subsequent request, for a web page. When a request is received, it
may be determined if the request is for a response to an
operational status inquiry, such as lineshape width and/or height
of the last two samples, which is to be included in the responsive
web page. If so, then the web page may be revised to indicate the
information. In any event, it may also be determined if the request
specifies parameters for the inquiry by, for example, providing a
CGI request which reflects user input to the web browser. If so,
the parameters are set based on the CGI specifications and the web
page corresponding to the URL of the request is returned to the web
browser. If the inquiry is terminated, then operations may
terminate. Otherwise, the web server waits for the next request
from the web browser.
[0078] In some embodiments, the clinical NMR analyzers 10 include a
high field NMR superconducting magnet and the remote system
automatically obtains data regarding homogeneity of the magnetic
field generated by the superconducting magnet. The homogeneity data
can include data regarding the lineshape characteristics of
biosamples undergoing analysis (which can indicate a degradation in
homogeneity over time). In some embodiments, the local NMR analyzer
10 generates and stores an electronic history file of selected
operational parameters. The local NMR analyzers 10 can be
configured to review and generate an automatic approval of each
sample test results and/or a retest (reject) decision.
[0079] The history file can be configured to be electronically
accessible by the remote system 15. In some embodiments, the local
analyzers 10 and/or remote system 15 are configured to
automatically monitor process variables and statistically analyze
data corresponding to measurements of the monitored process
variables to thereby perform an automated quality control analysis.
In particular embodiments, the local systems 10 are configured to
automatically adjust operating equipment to keep the process
variables within a predetermined statistical variation responsive
to the monitored data. The local systems can be configured to
automatically generate an alert when an abnormal operating
condition is detected. In other embodiments, the remote system 15
is configured to automatically generate an alert when an abnormal
operating condition is detected at the local NMR analyzer site(s)
10. The local analyzers 10 can be configured to generate an
electronic service log and/or an electronic process history log
that is electronically accessible by the remote system 15.
[0080] The local analyzers 10 can be configured to automatically
detect temporally relevant data of selected operational parameters
at desired intervals and generate an electronic maintenance file
thereof, and the local NMR analyzers 10 can be configured to
electronically store their respective maintenance files for
electronic interrogation by the remote system 15. The selected
operational parameters can include the NMR signal lineshape and/or
scaling thereof of one or more patient samples. The maintenance
file may include respective patient sample identifiers correlated
to selected operational parameters measured at a time the NMR
signal of the patient sample was obtained, and may also include a
time and/or date stamp or data. The local NMR analyzers 10 can be
configured to generate an electronic maintenance file of selected
operational parameters for each sample processed. The local NMR
analyzers 10 can electronically store (at least temporarily) sample
data correlated to an accession patient identifier and/or sample
dilution factor.
[0081] In some embodiments, the local analyzer 10 can generate an
electronic log of NMR sample data that is analyzed for one or more
biosamples and the log can be configured to be accessible by the
remote system 15. In certain-embodiments, an operator or service
program at the remote system 15 determines when to send (and places
the service order for) technical support onsite to the local
clinical analyzers 10.
[0082] In particular embodiments, the remote system 15
automatically controls selected features of the local clinical NMR
analyzers 10. The local NMR analyzers 10 can be configured with a
user interface that accepts local user input to select a report
format and/or sample variables of interest for NMR analysis,
thereby allowing customizable report formats by site/region.
Patient reports generated by the analyzers 10 at each local
clinical NMR analyzer site can have a site identifier thereon and
the report can be generated in electronic and/or paper form.
[0083] To help monitor the number of tests performed, the remote
system 15 can automatically obtain data regarding the number of
patient samples analyzed over a desired interval on each clinical
NMR analyzer 10. This monitoring can allow the remote control
system to order consumables based on projected and/or actual needs
customized to a particular site.
[0084] In some embodiments, each NMR analyzer 10 can include an
electronic library of predetermined computer program functions that
refer to a NMR normalization factor used to carry out
quantification measurements. The NMR analyzers 10 can be configured
to obtain NMR derived concentration measurements of lipoproteins in
a blood plasma and/or serum sample. In some embodiments, the NMR
analyzers 10 can be configured to obtain NMR derived concentration
measurements of one or more of LDL, HDL, and/or VLDL subclass
particles in a blood plasma and/or serum sample and/or configured
to determine: (a) a patient's risk of having and/or developing CHD
based on the lipoprotein measurements; and/or (b) a patient's risk
of having and/or developing Type II diabetes or other insulin
resistance disorders.
[0085] In certain embodiments, each clinical NMR analyzer 10 can be
configured to automatically execute a start-up self-diagnostic
and/or tuning/calibration routine and relay abnormal data regarding
same to the remote control system 15. The clinical NMR analyzers 10
can be configured to automatically monitor the NMR signal
lineshapes, and/or determine a height and/or width thereof, over
time, to monitor if adjustments to equipment are indicated. For
example, the clinical NMR analyzers 10 include a high field
superconducting magnet and the clinical NMR analyzers can be
configured to automatically shim the NMR spectroscopic magnetic
field to provide increased homogeneity if the line widths degrade
beyond a desired amount.
[0086] In some embodiments, the clinical NMR analyzers 10 can be
configured to automatically adjust scaling of the NMR lineshape of
the proton NMR spectrum of the biosample when the height and/or
width thereof is outside a desired range.
[0087] In some embodiments, one of the selected operational
parameters monitored for can be RF excitation pulse power. The
clinical NMR analyzers 10 can be configured to automatically adjust
the RF excitation pulse power (increase or decrease the RF
amplifier, if the power is outside a desired operating range and/or
varies from pulse to pulse (and/or sample to sample) by more than a
predetermined amount and/or percentage. The clinical NMR analyzers
10 can be configured to disregard and/or invalidate NMR signal data
obtained when power variation of the RF pulses is greater than a
predetermined amount. In some embodiments, when large RF power
changes are detected, the analyzer 10 can be configured to
disregard, flag as error-prone and/or invalidate the sample data.
In some embodiments, increased accurate control of RF power
monitoring can be obtained by using a controlled sample introduced
into the analyzer 10 at desired intervals, such as a standard
solution containing TMA.
[0088] The networked system 18 can be configured to monitor, in
substantially real time, at least intermittently and/or at desired
intervals, certain parameters associated with the operational
status of the NMR analyzer 10 during operation. The system 18 may
go into a standby mode during non-active periods (down shifts), but
monitor for certain major parameters, such as cryogen level,
electronic circuitry over-temperature, and the like.
Automated Clinical NMR Analyzer
[0089] FIG. 5 is a schematic diagram of one example of an in vitro
diagnostic (IVD) clinical NMR analyzer 10. As shown, the analyzer
10 includes an NMR detector 50, an enclosed flow path 65, an
automated sample handier 70, and a controller/processor 80 (shown
as a CPU) with operational software 80s. The term "NMR detector"
may also be known as an NMR spectrometer as will be appreciated by
those of skill in the art. The NMR detector 50 includes a magnet,
typically a cryogenically cooled high field superconducting magnet
20, with a magnet bore 20b, a flow probe 30, and RF pulse generator
40. The term "high-field" magnet refers to magnets that are greater
than 1 Tesla, typically greater than 5 Tesla, and more typically
greater than about 9 Tesla. Magnetic fields greater than about 13
Tesla may, in some situations, generate broader lineshapes, which
in some analysis of some biosamples, may not be desirable. The flow
probe 30 is in communication with the RF pulse generator 40 and
includes an RF excite/receive circuit 30c, such as a Helmholtz
coil. However, as will be appreciated by those of skill in the art,
other excite/receive circuit configurations may also be used.
[0090] It is noted that although illustrated as a system that
serially flows biosamples using a flow cell 60, other sample
handlers 70 and biosample introduction means can be used. For
example, the biosample can be processed as it is held in a
respective tube or other sample container (not shown). In some
embodiments, each of the modular components of the NMR analyzer 10
may be sized and configured to fit within a single housing or
enclosure.
[0091] Field homogeneity of the detector 50 can be adjusted by
shimming on a sample of about 99.8% D.sub.2O until the spectral
linewidth of the HDO NMR signal is less than 0.6 Hz. The 90.degree.
RF excitation pulse width used for the D.sub.2O measurement is
typically about 6-7 microseconds. Other shimming techniques can
also be used. For example, the magnetic field can be automatically
adjusted based on the signal lineshape and/or a width or height
thereof. The NMR detector 50 may optionally include a gradient
amplifier in communication with gradient coils 41 held in the
magnet-bore 20b as is well known to those of skill in the art, and
the gradient system may also be used to help shim the magnet.
[0092] During operation, the flow probe 30 is held inside the
magnet bore 20b. The flow probe 30 is configured to locate the flow
probe RF circuitry 30c within the bore 20b to within about +/-0.5
cm of a suitably homogeneous portion of the magnetic field B.sub.0.
The flow probe 30 is also configured to receive the flow cell 60
that forms part of the biosample enclosed flow path 65. The flow
cell 60 typically includes a larger holding portion 60h that aligns
with the RF circuitry 30c of the flow probe 30. The flow cell 60 is
configured to remain in position with the holding portion 60h in
the magnet bore 20b and serially flow biosamples to the holding
portion 60h; with successive biosamples being separated by a fluid
(typically air gaps) to inhibit cross-contamination in a flowing
stream. The samples may be introduced as a train of samples, but
are more typically introduced (injected) one at a time. The
biosample is typically held in the holding portion 60h for between
about 1-5 minutes during which time a proton NMR spectrum is
obtained and electronically correlated to the sample accession
number or identifier (i.e., a patient identifier). The flow cell 60
can be formed of a non-magnetic material that does not degrade the
performance of the NMR detector 50. Typically, the flow cell 60 is
formed of a suitable grade of silicate (glass) material, however,
other magnetic-friendly non-porous materials may be used including
ceramics, polymers, and the like.
[0093] A magnetically-friendly optic viewing scope (such as a fiber
optic system) may be used to allow a user and/or the system 10 to
visually monitor conditions in the magnet bore 20b (i.e., position
of the probe, leaks or the like) (not shown). The viewing scope can
be mounted to the bore or made integral to the flow cell 60 or the
flow probe 30. Similarly, at least one leak sensor can be placed to
automatically detect fluid leakage, whether biosamples, cleansers
or cryogens. If the former, a leak sensor can be used to detect
leaks caused by flow path disruption; if the latter a gas sniffer
type sensor can be used. The gas sensor can be located away from
the probe. Cryogen level sensors can also be used to monitor the
level of the liquid (helium and/or nitrogen) to allow for automated
supply orders, identification of an increased use rate (which may
indicate a magnet problem), and the like.
[0094] In the embodiment shown, the flow cell 60 is in fluid
communication with a waste receptacle 61 at one end portion and a
sample intake 73 on the other end portion. In certain embodiments,
the analyzer 10 is configured to flow the samples from top to
bottom using a flow cell 60 that has a major portion that is
substantially straight (I.e., without bends) to reduce the length
of the flow path 60 and/or to reduce the likelihood that the bends
in a flow path will block the flow. In some embodiments, the flow
cell 60 is entirely straight. In particular embodiments, the entire
flow path 65 may be straight throughout its length (including
portions upstream and downstream of the flow cell 60, from intake
to discharge into the waste container). In other embodiments,
elastomeric, typically polymeric, conduit and/or tubing (which may
comprise TEFLON) can be used to connect the flow cell 60 to the
sample intake portion of the flow path 65 and the conduit and/or
tubing may be bent to connect to mating components as desired.
However, it the conduit/tubing extend into the magnet bore 20b,
then that part of the flow path 65 may also be configured to be
straight as discussed with respect to the flow cell 60.
[0095] In some embodiments, the flow cell 60 has an inner diameter
of between about 0.5 mm to about 0.8 mm upstream and downstream of
the holding portion 60h. The downstream portion is typically at
least about 0.8 mm to inhibit clogs in the flow system. The holding
portion 60h may have a diameter that is between about 1.0 mm-to
about 4.0 mm.
[0096] The biosamples may be configured in appropriate sample
volumes, typically, for blood plasma or serum, about 0.5 ml. For
whole plasma, a reduced sample size of about 50-300 microliters,
typically about 60-200 microliters, and more typically between
about 60-100 microliters may be desired. In some embodiments, the
sample flow rate may be between about 2-6 ml/min to flow the sample
to the holding portion 60h for the NMR data collection and
associated analysis.
[0097] Still referring to FIG. 5, the automated sample handler 70
may be configured to hold a plurality of samples 70s in suitable
sample containers 70c and present the samples 70s in their
respective container 70c to an intake member 72 that directs the
sample into the enclosed flow path 65. The sample bed 71 may hold
about 50-100 samples in containers. In some embodiments, the bed 71
may optionally be configured to provide and/or held in a
refrigerated or cooled enclosed compartment. In other embodiments,
conventional small and/or large racks of sample tubes can be used.
Typically, the intake member 72 is configured to aspirate the
sample into the flow path 65. As shown, the intake member 72
comprises a pipetter and/or needle that withdraws the desired
sample amount from the container 70c, and then directs the sample
(typically via injection through an injection port) into a conduit
73 that is in fluid communication with the flow cell 60. The
pipette may rotate about 180 degrees to access tray samples or a
lab automation system (TLA, workcell, etc.). However, other sample
transfer means may also be used. In other embodiments, the intake
member 72 can be in direct communication with the flow cell 60
without the use of an intermediate conduit 73. In particular
embodiments, the samples may be directly aspirated from a source
tube on the sample handler tray. The sample handler system 70 can
be configured to provide rapid flow cleaning and sample delivery.
In particular embodiments, the handler system 70 can be configured
to operate on about a 1-minute or less cycle (excluding NMR data
acquisition) while reducing dilution and/or carryover.
[0098] A multi-port valve (which may replace or be used with the
injection port) may be used to help reduce unwanted sample dilution
due to flow cleaning carried out between samples. In certain
embodiments, the intake member 72 includes an aspiration needle
that can be quickly dried using a non-contact means, such as forced
air or gas, rather than conventional blotter paper to inhibit
blockage of the needle. The flow cell 60 may include chromatography
connectors that connect the flow cell 60 to tubing or plumbing
associated with the flow path 65.
[0099] In some embodiments, the analyzer 10 can be configured to
direct the aspiration to blow out the injection port immediately
after injecting a first sample before pre-fetching a next sample to
maintain liquid-air gaps between neighboring samples.
[0100] The sample containers 70c can be held in beds 71 that can be
loaded and placed in queue for analysis. The samples 70s are
electronically assigned a patient identifier to allow electronic
correlation to the test results. Conventionally, the beds 71
include bar codes that are automatically read and input into the
computer as electronic records as a batch of samples, thereby
inhibiting adjusting test parameters for a particular sample. In
some embodiments, the NMR analyzer system 10 is configured so that
the point of identification of each sample is carried out
automatically at the point of aspiration. Thus, an optic or other
suitable reader can be configured to define a patient identifier to
a particular sample while the sample is being aspirated. In any
event, the system control software 81 can be configured to create
an archivable patient data file record that includes the patient
identifier (also known as an accession number) as well as a
dilution factor, the NMR-derived measurement values, test date and
time, and "common" rack identifier, where used, and other process
information that can be electronically searched as desired for
service, operational and/or audit purposes. The electronic records
can be relayed to a storage location (such as a central collection
site within each region or country) and/or stored locally.
[0101] In operation, NMR-derived quantitative measurement data for
diagnostic clinical reports of patient biosamples can be generated
by: (a) automatically serially aspirating biosamples of interest
into an enclosed flow path that serially flows the biosamples into
an NMR analyzer having a NMR spectroscopy instrument with a magnet
and a bore at a plurality of different clinical sites; (b)
automatically correlating a patient identifier to a respective
patient biosample; (c) and obtaining NMR derived quantitative
measurements of the biosamples for diagnostic reports. In some
particular embodiments, the operation may also include (d)
automatically monitoring the NMR analyzers at the different
clinical sites from a remote system.
[0102] Referring again to FIG. 5, the system 10 includes a
controller/processor 80 that is configured with computer program
code 80s that includes and/or is in communication with instrument
automation control software 81, analytical software 82, and/or
remote communication software 83. The control software 81 can
primarily direct the automated operational sequences and monitoring
protocols of the system 10 while the analytical software 82
typically includes proprietary software that carries out the
quantitative measurements of the biosamples undergoing analysis
using the NMR-spectrum thereof. For at least the analytical
software 82, the processor 80 may include a digital signal
processor capable of performing rapid Fourier transformations.
[0103] The remote communication-software 83 is configured to carry
out and/or facilitate the communication between the local
analyzer(s) and remote control system 10, 15, respectively. The
controller/processor 80 may be configured as a single processor or
a plurality of processors that communicate with each other to
provide the desired automated interfaces between the system
components.
[0104] In certain embodiments, it may be desired to maintain the
temperature of the sample undergoing NMR evaluation at a desired
temperature. For example, for blood plasma and/or serum samples, it
is typically desired to maintain the temperature of the sample at
about 48.degree. C.
[0105] In certain embodiments, the system 10 includes a plurality
of spatially distributed temperature sensors along the flow path 65
that monitor the temperature of the sample undergoing analysis (not
shown). The sample temperature can be determined at different times
in the analysis including (a) prior to the sample entering the
magnet bore 20b, (b) prior to initiating the RF pulse sequence,
and/or (c) at the time and location of discharge from the probe,
without disturbing the NMR lineshape in a manner that would impede
NMR data collection/reliability. The temperature can be monitored
during the NMR data acquisition (such as at least every 2-5
seconds). The sample can be actively cooled and/or heated during
the evaluation to maintain a substantially constant homogeneous
sample temperature without undue thermal gradients.
[0106] The system can include cooling and heating means that are
configured to provide distributed heating and/or cooling for
reducing hot spots in the sample. One type of heater is a capillary
heater that may be slipped over the outer surface of the flow cell
60. An example of a heater is described in U.S. Pat. No. 6,768,304
to Varian, Inc., the contents of which are hereby incorporated by
reference herein. It is contemplated that a longer capillary heater
can be used that extends above the flow cell 60 (where the sample
is flowed into the bore 20b from the top) and may have a length
that is sufficient to extend about a major part of the flow path
length. In some embodiments, the system 10 can include a heater
that is highly conductive with a relatively large thermal mass
(similar to a heat sink) that is above the probe 30 (where the flow
is from top to bottom), and/or above the flow cell holding portion
60h to thereby improve distributed heating while reducing the
likelihood of overheating of the sample as it travels to the probe
30. The large thermal mass may be located outside the magnet bore
20b.
[0107] In some embodiments, a circulating or forced supply of
temperature-controlled gas can be flowed into the magnet bore to
maintain the sample at a desired temperature during the NMR
analysis. The temperature of the forced air can be adjusted
relatively quickly in response to in situ measured sample
temperature(s). To reduce moisture that may be inadvertently
directed into sensitive electronics in the probe or spectrometer,
the gas can be filtered and/or dried prior to introduction into the
magnet bore 20b.
[0108] Typically, the samples are preheated from a cooled storage
temperature. The auto sample handler 70 can hold the samples while
in queue and gradually heat the sample in stages prior to the
injection/input port to provide a sample that is preheated to a
desired temperature range (such as about 45-47.9.degree. C.).
Alternatively, the sample may not be heated until it is in the flow
cell 60. In some particular embodiments, the handler 70 may also be
configured to hold the samples in a refrigerated or cooled state.
Combinations of both heating techniques may be used. Thus, the
system 10 can include thermal sensors along the path the samples
travel on/in the handler 70 and/or flow path 65 that detect the
temperature thereof and provide real-time feedback to allow the
system 10 to automatically adjust for any deviation from predicted
or norm.
[0109] In any event, the system 10 can include a sensor module that
electronically communicates with processor 80 and accepts/monitors
electronic data output from sensors regarding the status of the
sensors.
[0110] The flow path 65 may be configured with a valved flow bypass
channel (not shown) that bifurcates out of and into the flow path
65 and/or flow cell 60 to allow selected samples to be redirected
back into the flow path 65 above the magnet bore 20b after the
sample exits the probe 30 but before it reaches the waste container
61 when a data corruption event is detected (not shown). The bypass
channel could be in fluid communication with a solvent cleaner that
allows automatic flushing of the bypass channel after use. In other
embodiments, the sample(s) affected can be flushed into the waste
receptacle and the analyzer 10 and/or remote control system 15 can
generate a retest notice or order for that subject.
[0111] Modularity
[0112] In certain embodiments, as shown in FIG. 6, the automated
clinical NMR analyzer 10 can be configured with modular assemblies
including: an automated sample handling assembly 70; an NMR
spectrometer or detector 50 (with a modular NMR probe 30); and a
sample flow path 65 with flow cell 60 having a flow cell probe 30
that resides in the NMR spectrometer magnet bore 20b. Each modular
assembly component can be configured to releasably operate with its
mating modular components thereby allowing ease of repair and/or
field replacement. Further, the analyzer 10 is configured with
interface software that allows the operational interchange between
the different modular assemblies. The flow cell 60 may be
considered a part of the NMR detector 50 or the sample handler 70
for modularity purposes. Either way, the NMR analyzer 10 includes
suitable interfaces (software and/or hardware) between the
automated sample handler 70 and the NMR detector 50 so as to allow
the NMR detector module 50 and the sample handler module 70 to
cooperate to automatically serially analyze biosamples in a
high-volume throughput.
[0113] Typically, the NMR analyzer 10 can diagnostically analyze at
least about 400, and more typically at least about 600, samples per
twenty-four hours. The modular system 10 can be configured so that
it can operate in a laboratory environment by staff with little
training in NMR support functions. The system 10 may also operate
with reduced maintenance and downtime over conventional NMR
detectors and can have a simplified user interface.
[0114] In certain embodiments, the NMR detector 50 can include a
flow probe 30 that can be modularly replaced in the field and
calibrated for operation within a relatively short time upon
identification of a malfunction or contamination of the probe 30
due to flow cell leaks and the like.
[0115] The system 10 can be configured to store certain operating
values of the flow probe 30 being removed and those values can be
can be pre-calibrated to defined norms for the new or replacement
flow probe 30. In particular embodiments, the flow probe 30 can
include a memory card or chip that stores certain operational
parameter values (input upon installation and/or automatically at
desired intervals) and can be used in a replacement flow probe 30.
In other embodiments, the capacitors and/or other tunable circuit
components can be programmatically tuned by an automated tuning
routine carried out by the NMR analyzer 10 and/or control system
15.
[0116] The flow probe 30 may be configured so that tuning
capacitors are mounted underneath (where the flow probe is inserted
from the bottom into the bore) or above (where the flow probe is
inserted from the top of the magnet bore) the flow probe for easy
external access. The flow probe 30 can be a generally rigid member
that is configured to releasably mount to the magnet without the
use of permanent (solder-type) connections.
[0117] FIG. 6 illustrates one embodiment of a modular analyzer 10.
In this embodiment, the sample handler assembly 70 includes an
upstream portion 70u that provides a staging or queuing sample
handler subassembly with automated drive means and a downstream
portion 70d that includes the sample intake member (such as an
injector) 72. Each portion 70u, 70d can have a respective software
interface 70I.sub.1, 70I.sub.2 that communicates with the
instrument automation control module 81. The respective interfaces
70I.sub.1, 70I.sub.2 nay also optionally communicate with each
other. The NMR detector 50 also includes a software interface 501
that communicates with the automation control module 81. The
instrument automation control module 81 can be configured to
interface with a computer interface and/or network connection
circuit/board 50B of the NMR detector 50 (FIG. 7), monitor and/or
control sensors, detectors, and/or alarms and direct that certain
actions and/or functions be carried out when errors or undue
process parameter variations are detected, provide remote access to
the remote station 15 (FIG. 4), directly and/or via the remote
communications module 83, and support automated start-up and
automated (daily) process control monitoring.
[0118] As shown in FIG. 6, the instrument automation module 81
optionally communicates with the remote communications module 83 a
LIS ("Laboratory Information System") interface 84. The LIS
interface 84 is in communication with the LIS system 86 and a user
interface module 85 that accepts local user input into selection of
certain operating features and/or test report parameters. The LIS
interface 84 can be a common interface that communicates with other
equipment or lab programs, allowing a single common interface that
a local user can use in the clinical laboratory. The LIS interface
84 can be in communication with the analytical software module 82
that includes the test quantification analysis or evaluation
program code (and may be proprietary and/or customized to each type
of analysis performed). The data (raw and/or in report form) can be
transmitted to the laboratory's LIS. As indicated by the broken
line connections, the analytical software module 82 may optionally
communicate directly with either the instrumentation automation
module 81 and/or the remote communications module 83.
[0119] The term "module" refers to program code that is directed to
carrying out and/or directing particular operational,
communications and/or monitoring functions. The term "module" is
not meant to limit the program code to a bundled package or a
successive portion of code, as the module program code may be
distributed code within a particular processor or processors that
are in communication. As such, the module may be a stand-alone
module on a respective single processor or may be configured with
an architecture/hierarchy that plugs into other program modules on
one or more processors. Furthermore, selected ones or each module
noted in the figures may share common code or functionality with
other modules.
[0120] FIG. 7 illustrates another embodiment of the automated
clinical NMR analyzer 10. As shown, the NMR detector 50 includes an
NMR operational software module SOS with an interface 501. The NMR
software module 50S is in communication with the remote
access/communications module 83. The remote access/communications
module 83 may also be in communication with the user interface 85.
In the embodiment shown, the system 10 includes an electronic
library 82L of predetermined computer program functions that stores
common parameters, or computer program routines, such as a NMR
normalization factor, that can be accessed by a plurality of
interface components so that the common routines or values do not
have to be separately coded in each device/component. As shown, the
sample handler interface 70I, the user interface 85, and the NMR
detector 50 can access the common library (shown s "dl1") 82L
(directly to the NMR detector as shown and/or optionally via the
NMR software module 50S).
[0121] The normalization factor is used to standardize the
measurements of different NMR analyzers. Different NMR probes will
have different (typically instrument specific) sensitivities based
on the "Q" factor of the probe. Q is defined as the frequency of
the resonant circuit divided by the half power bandwidth. A
standard sample like, for example, trimethyl acetic acid (TMA) can
be run on different NMR machines and with different probes, and the
integral of the CH.sub.3 proton can be measured to standardize it
to a fixed value. The ratio between the predefined (fixed) value
and the integral under then-current conditions is termed the
"normalization factor", and this can be used to standardize
different NMR analyzers by multiplying any raw NMR intensity by the
normalization factor. An extension of the same concept allows for
adjusting for relatively small sensitivity differences from day to
day for the same probe on a particular NMR analyzer by running the
same standard sample and calculating the daily normalization factor
in a similar manner. Hence, the NMR normalization factor can be
calculated in situ for each NMR analyzer for each probe and, in
some embodiments, adjusted for each NMR analyzer at desired
intervals (such as after certain numbers of samples, upon start-up,
upon detection of a change in selected local operational
conditions).
[0122] FIG. 8A illustrates yet another embodiment of an exemplary
structure of an NMR analyzer 10. In this embodiment, system
coordination software 180 communicates with the analytical software
82, the LIS interface 84, the user interface 85, the NMR control
software 50S and the sample handler control/interface software 70I
(which can include both the upstream and downstream interfaces
70I.sub.2, 70I.sub.1, respectively as shown in FIG. 6). In this
embodiment, hardware components are controlled though the interface
software. The software can provide functionality by exposing a
collection of function calls that implement an Application
Programming Interface ("API"). The function calls can include mid-
and high-level commands. For example, in the sample handler 70,
"aspirate" or "move to safe travel height" are mid-level commands.
High-level commands generally include multiple mid-level commands
which are encompassed by a high-level command. For example, a
high-level command of "inject sample (x)" implies several mid-level
commands be carried out to achieve this function, such as a
requirement to move to a safe travel height, position over sample
(x), move down, and aspirate sample (x). Examples of API commands
that may be used for certain NMR detector functions include, but
are not limited to the following: [0123] AcquireData ([IN]
acquisition parameters, [OUT] ft data) This command provides the
parameter set defining the desired NMR experiment. The NMR performs
the experiment and returns the acquired data (perhaps an fid) to
the calling software. [0124] ApplyPhase ([IN] ft data, [IN] phase,
[OUT] ft data) [0125] AutoPhase ([IN] ft data, [OUT] ft data),
[OUT] phase) [0126] Calibrate90Pulse ([IN] starting acquisition
parameters, [OUT] ending acquisition parameters) [0127]
CalibrateTemperatureController( ) [0128] CenterField ([OUT] field
center position) [0129] ComputeFt ([IN] processing parameters, [IN]
ft data, [OUT] ft data) [0130] GradientShim ([IN] shim map, [OUT]
shim values) [0131] PhaseLockSignal ([OUT] phase) [0132] SetPhase
([IN] phase) [0133] SetTemperature ([IN] target temperature) [0134]
TuneProbe ([IN] channel, [OUT] frequency, [OUT] match value) [0135]
TuneTemperatureController( )
[0136] FIG. 8B is yet another schematic illustration of control
and/or communication architecture that can be used for the NMR
analyzer 10. As before, an instrument automation module 607 can
communicate with the NMR detector 50, the sample handler 70 and the
sample intake member 72 (which may in some embodiments be an
injector). The sample intake member 72 may share the sample handler
interface 604 and/or be controlled through the sample handler 70 in
lieu of having its own direct interface 605 with the instrument
module 607 as shown. In some embodiments, the sample intake member
72 can be configured to aspirate the sample into a flow path 65 as
discussed above. In other embodiments, the sample intake member 72
can be configured to move the sample held in a container into the
NMR detector 50. In any event, as shown, the sample handler 70 and
the NMR detector 50 each include an interface, 604, 606,
respectively.
[0137] The instrument automation module 607 can communicate with a
data acquisition quality control module 608, a LIS interface 610,
an instrument user interface 617, an NMR Analyzer ("NMRA") database
611 and an NMRA filebase 612. The system 10 can also include a test
automation module 613 that allows a selection of different
diagnostic test options using the NMR platform. TestB and TestC
modules, 615, 616, respectively, can be configured as separate
modules that can be deployed as plug in modules. The test
automation module 613 can communicate with the LIS interface 610
the instrument user interface 617, and at least indirectly, with
the instrumentation automation module 607,
Self-Diagnostic/Calibration
[0138] FIG. 9 is a flow chart of exemplary operations (blocks
201-230) that can be executed as a part of an automated
self-diagnostic, calibration, and/or tuning start-up procedure that
can help assure that the NMR analyzer 10 is ready for clinical data
output before authorizing or allowing evaluation of "real" patient
or other target samples. The start-up procedure may be
self-executing upon operator sign-in or initiation. The start-up
procedure may also be configured to run at desired intervals, after
a certain number of samples are throughput, and/or when the process
appears to be out of absolute or relative process limits.
[0139] FIG. 10 is a flow chart of exemplary operations (blocks
301-327) that can be executed as part of an automated procedure for
running quality control samples through the NMR analyzer 10
including detector 50. As before, the operations can be carried out
at start-up and/or at other desired intervals. The term "quality
control scan" refers to a scan taken of a control reference
analyte(s) and/or a biosample to assess operational
status/conditions of the analyzer 10 and/or its environment at a
desired time to assess the operational status or condition of the
analyzer 10 and/or its environment. The reference analyte is
configured to generate a reference peak in an NMR signal. The
reference analyte(s) can be provided in a calibration solution of a
plurality of different constituent chemicals. In some embodiments,
the reference analyte is Trimethylacetic acid ("TMA"). In
particular embodiments, the TMA is in a solution comprising KCl,
CaCl.sub.2, Na.sub.2EDTA and D.sub.2O. However, the reference
analyte can be any suitable analyte that can generate a reference
peak in a NMR signal. In some embodiments, the reference analyte
can comprise a molecule that can generate a relatively sharp peak
that can be used as a reference for shimming quality and/or to
identify the position of other peaks in the NMR spectrum.
Typically, the reference analyte is used qualitatively rather than
quantitatively, but may also be used quantitatively as
appropriate.
[0140] FIG. 11 is a flow chart of exemplary operations (blocks
501-526) that can be executed as part of "normal" operation and/or
active-analysis run mode for an automated procedure for running the
NMR analyzer 10.
[0141] Certain blocks, groups of blocks, and/or combinations of
blocks from any or each of FIGS. 9-11 can be used in particular
embodiments.
[0142] FIG. 12 is a block diagram of exemplary embodiments of data
processing systems that illustrate systems, methods, and computer
program products in accordance with embodiments of the invention.
The Processor 410 communicates with the memory 414 via an
address/data bus 448. The processor 410 can be any commercially
available or custom microprocessor. The memory 414 is
representative of the overall hierarchy of memory devices
containing the software and data used to implement the
functionality of the data processing system. 405. The memory 414
can include, but is not limited to, the following types of devices:
cache, ROM, PROM, EPROM, EEPROM, flash memory, SRAM, and DRAM.
[0143] As shown in FIG. 12, the memory 414 may include several
categories of software and data used in the data processing system
405: the operating system 452; the application programs 454; the
input/output (I/O) device drivers 458; an automation module 450,
which might provide capabilities such as self-adjusting
calibration, processing control, or remote communications; and data
456.
[0144] The data 456 may include NMR signal (constituent and/or
composite spectrum lineshape) data 462 which may be obtained from a
data or signal acquisition system 420. The data can include values,
other operating or process parameters of interest, such as leak
sensors, thermal sensors, pressure sensors, RF power sensors, the
number of successive irregular NMR signal scans, service histories,
maintenance files, sample history files, and the like. As will be
appreciated by those of skill in the art, the operating system 452
may be any operating system suitable for use with a data processing
system, such as OS/2, AIX or OS/390 from International Business
Machines Corporation in Armonk, N.Y., Windows CE, Windows NT,
Windows 95, Windows 98, Windows 2000, or Windows XP from Microsoft
Corporation, Redmond, Wash., Palm OS from PalmSource, Inc.,
Sunnyvale, Calif., Mac OS from Apple Computer, Inc, UNIX, FreeBSD,
or Linux, proprietary operating systems or dedicated operating
systems, for example, for embedded data processing systems.
[0145] The I/O device drivers 458 typically include software
routines accessed through the operation system 452 by the
application programs 454 to communicate with devices such as I/O
data port(s), data storage 456 and certain memory 414 components
and/or the data acquisition system 420. The application programs
454 are illustrative of the programs that implement the various
features of the data processing system 405 and preferably include
at least one application that supports operations according to
embodiments of the present invention. Finally, the data 454
represents the static and dynamic data used by the application
programs 454, the operating system 452, the I/O device drivers 458,
and other software programs that may reside in the memory 414.
[0146] While the present invention is illustrative, for example,
with reference to the automation module 450 being an application
program in FIG. 12, as will be appreciated by those of skill in the
art, other configurations may also be utilized while still
benefiting from the teachings of the present invention. For
example, the automation module 450 may also be incorporated into
the operating system 452, the I/O device drivers 458, or other such
logical division of the data processing system 405. Thus the
present invention should not be construed as limited to the
configuration of FIG. 12, which is intended to encompass any
configuration capable of carrying out the operations described
herein.
[0147] In certain embodiments, the automation module 450 may
include computer program code for communicating with a remote
control system (local or offsite). The automation module 450 can
also include program code that provides: automated multi-parameter
process monitoring and self-correction/adjustment, a log of
operational conditions that may be correlated to patient samples
(including time/date data), selectable test formats and selectable
test analysis, a log of data variability and/or service history, a
log of the number of patient samples processed (which may be parsed
over desired intervals), and archived process parameter information
for remote interrogation, diagnostics, and other data as indicated
above.
[0148] In particular embodiments, the NMR analyzer 10 can be
configured to electronically monitor (alone and/or cooperating with
a remote control system 15) a plurality of components for selected
operational variables and to carry out different testing
methodologies according to the test desired of a particular
biosample to facilitate automated function of the device
automatically whereby the NMR analyzer 10 operates without
requiring undue amounts of manual input and/or on-site service
support during normal operation. Examples of the components and
variables were discussed above and are illustrated in the figures
and can include, for example, one or more of the following: [0149]
electronically monitoring measurements of selected components and
adjusting the operational output/input so that the component(s)
operate within a desired range; [0150] electronically automatically
calibrating selected electronic components; [0151] executing an
automated calibration routine at start-up or other desired
intervals; [0152] electronically tuning the flow cell probe; [0153]
electronically centering a resonance of a sample constituent (which
may be a sample solvent) within an RF window of interest (i.e.,
centering a magnetic field in an acquisition window); [0154]
electronically adjusting lock power and lock phase; [0155]
electronically thinning the magnet to a desired level of
homogeneity; [0156] adjusting the temperature of the flow cell
probe; [0157] adjusting the temperature of the biosample; [0158]
electronically calibrating the pulse width of the RF excitation
pulse used to excite the biosample in the magnet bore; [0159]
electronically (programmatically) determining a normalization
factor to adjust for instrument-specific sensitivity in situ;
[0160] electronically correlating a biosample with a patient
identifier in situ (such as at the point of aspiration): [0161]
electronically obtaining the NMR clinical test data from the
biosample and electronically relating the test data to the patient;
[0162] electronically controlling the introduction of a reagent(s)
to the biosample prior to obtaining the NMR spectra thereof; [0163]
electronically controlling the introduction of a selected calibrant
material to the biosample prior to obtaining NMR spectra; [0164]
conditioning the biosample to a desired temperature range; [0165]
obtaining NMR spectra of the biosample using the appropriate NMR
test; [0166] obtaining NMR spectra of the biosample and/or a
control validation sample to verify test conditions separate from
obtaining NMR spectra of the biosample for clinical diagnostic
analysis; [0167] electronically invalidating, not acquiring,
flagging or discarding NMR spectra for a biosample when test
conditions are outside defined acceptable limits; [0168]
electronically verifying whether the biosample is delivered
properly to a test location in the magnet bore (such as confirming
the biosample is static or whether it constitutes an "infinite
sample" whereby the sample extends beyond the detection region so
that there are no or reduced boundary effects); [0169]
electronically determining whether the delivered biosample has air
bubbles as it resides in the NMR probe flow cell; [0170]
electronically determining the temperature of the biosample as it
resides in the flow cell (and may include automatically adjusting
the temperature of the biosample in situ if it is outside
acceptable limits); [0171] electronically determining whether the
suppression of a water signal is in a desired operational range
(and if not electronically adjusting parameters to adjust the water
suppression to be within the desired range); [0172] electronically
determining what type of diagnostic test to run on the biosample
under analysis; [0173] electronically adjusting experiment protocol
parameters based on the biosample and/or properties thereof; [0174]
electronically obtaining NMR derived measurements of lipoprotein
particle size(s) and concentrations in a blood plasma and/or serum
sample; [0175] electronically determining a patients risk of having
and/or developing CHD and/or Type II diabetes based on NMR derived
lipoprotein measurements; [0176] electronically determining an NMR
derived diagnostic data measurement of the biosample and generating
an electronic patient report of the data; [0177] electronically
obtaining NMR spectra to qualitatively determine the presence or
absence of a selected species or constituent, subspecies, analyte,
interference material, contaminant and/or toxin; and [0178]
electronically obtaining NMR spectra to quantitatively determine
the concentration a selected species or constituent, subspecies,
analyte, interference material, contaminant and/or toxin.
[0179] The foregoing is illustrative of the present invention and
is not to be construed as limiting thereof. Although a few
exemplary embodiments of this invention have been described, those
skilled in the art will readily appreciate that many modifications
are possible in the exemplary embodiments without materially
departing from the novel teachings and advantages of this
invention. Accordingly, all such modifications are intended to be
included within the scope of this invention as defined in the
claims. In the claims, means-plus-function clauses, where used, are
intended to cover the structures described herein as performing the
recited function and not only structural equivalents but also
equivalent structures. Therefore, it is to be understood that the
foregoing is illustrative of the present invention and is not to be
construed as limited to the specific embodiments disclosed, and
that modifications to the disclosed embodiments, as well as other
embodiments, are intended to be included within the scope of the
appended claims. The invention is defined by the following claims,
with equivalents of the claims to be included therein.
* * * * *
References