U.S. patent application number 11/009441 was filed with the patent office on 2005-07-14 for test strip qualification system.
Invention is credited to Patel, Harshad, Witt, James.
Application Number | 20050153457 11/009441 |
Document ID | / |
Family ID | 22278828 |
Filed Date | 2005-07-14 |
United States Patent
Application |
20050153457 |
Kind Code |
A1 |
Patel, Harshad ; et
al. |
July 14, 2005 |
Test strip qualification system
Abstract
In connection with a fluidic medical diagnostic device that
permits measurement of the coagulation time of blood, software,
methods and associated devices for quality control are disclosed.
The fluidic device preferably comprises a test strip with one end
having a sample port for introducing a sample and a bladder at the
other end for drawing the sample to a measurement area. A channel
carries sample from the sample port to an assay measurement area
and first and second control measurement areas. Preferably a stop
junction, between the measurement areas and bladder, halts the
sample flow for measurement. If results from measurements taken for
each control fall within a predetermined zone or defined limits,
the assay measurement is qualified. If not, an error is registered
and the test strip is counted as unfit.
Inventors: |
Patel, Harshad; (Fremont,
CA) ; Witt, James; (Sunnyvale, CA) |
Correspondence
Address: |
BOZICEVIC, FIELD & FRANCIS LLP
1900 UNIVERSITY AVENUE
SUITE 200
EAST PALO ALTO
CA
94303
US
|
Family ID: |
22278828 |
Appl. No.: |
11/009441 |
Filed: |
December 9, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11009441 |
Dec 9, 2004 |
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10712680 |
Nov 12, 2003 |
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6849456 |
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10712680 |
Nov 12, 2003 |
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10100254 |
Mar 14, 2002 |
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6682933 |
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Current U.S.
Class: |
436/169 |
Current CPC
Class: |
G01N 33/558 20130101;
Y10T 436/10 20150115; Y10T 436/2575 20150115 |
Class at
Publication: |
436/169 |
International
Class: |
G01N 031/22 |
Claims
We claim:
1.-14. (canceled)
15. A kit comprising: a test strip comprising an assay reaction
area and a control reaction area; and a meter configured for
receiving said test strip and for qualifying said test strip by
obtaining results for said control reaction area and comparing
results from said control reaction area to control qualification
criteria comprising an upper limit and a lower limit, said upper
limit being about a 1.9 International Normalized Ratio and said
lower limit being about a 0.60 International Normalized Ratio,
wherein said meter is configured to qualify said test strip if said
results fall within said upper limit and said lower limit.
16. The kit of claim 15, wherein said meter is configured to output
a message to a user indicating test strip qualification.
17. The kit of claim 15, wherein said test strip is configured to
measure prothrombin time.
18. A kit comprising: a test strip for use to measure prothrombin
time (PT) comprising an assay reaction area and a control reaction
area; and a meter configured for receiving said test strip and
qualifying said test strip by obtaining PT results for said
reaction areas and comparing results from said control reaction
area to control qualification criteria comprising an upper limit
and a lower limit, each being dependent on assay reaction area PT
results, wherein said meter is configured to qualify said test
strip if said results fall within said upper limit and said lower
limit.
19. The kit of claim 18, wherein said upper and lower limits
comprise line functions.
20. The kit of claim 18, wherein said line functions are expressed
as y=mx+b, wherein y represents an International Normalized Ratio
results obtained for said control reaction area, x represents an
International Normalized Ratio results obtained for said assay
reaction area and m.apprxeq.0.56 to 0.58 and b.apprxeq.0.90 for
said upper limit and wherein m.apprxeq.0.36 and b.apprxeq.0.37 to
0.38 for said lower limit.
21. The kit of claim 18, wherein said meter is configured to output
a message to a user indicating test strip qualification.
22. A kit comprising: a test strip for use to measure prothrombin
time (PT) comprising an assay reaction area, a first control
reaction area and a second control reaction area; and a meter
configured for receiving said test strip and qualifying said test
strip by obtaining PT results for each said reaction areas, for
comparing results from said first control reaction area to first
control qualification criteria comprising a first upper limit and a
first lower limit, said first upper limit being about a 1.9
International Normalized Ratio and said first lower limit being
about a 0.60 International Normalized Ratio, and for comparing
results from said second control reaction area to second control
qualification criteria comprising a second upper limit and a second
lower limit, each being dependent on assay reaction area PT
results, wherein said meter is configured to qualify said test
strip if said results from said first control reaction area fall
within said first upper limit and said first lower limit and if
said results from said second control reaction area fall within
said second upper limit and said second lower limit.
24. The kit of claim 23, wherein said meter is configured to output
a message to a user indicating test strip qualification.
Description
FIELD OF THE INVENTION
[0001] This invention relates to approaches for qualifying results
obtained in using analyte test strips. The invention is
particularly suited for testing the quality of test strips used for
measuring prothrombin time (PT time) with whole blood in which a
measurement area includes a composition that catalyzes the blood
clotting cascade.
BRIEF DESCRIPTION OF THE DRAWINGS
[0002] FIGS. 1-3 represent information known in the art and are
referenced in the Background of the Invention. Each of FIGS. 4A-5B
diagrammatically illustrates aspects of the present invention.
Variation of the invention from that shown in the figures is
contemplated.
[0003] FIG. 1A is a top view of a test strip as may be used in
connection with the present invention; FIG. 1B is a side view of
the test strip.
[0004] FIG. 2A is a schematic of hardware elements for a meter for
that may be used in the present invention; FIG. 2B shows an
alternative variation of an element of the meter of FIG. 2A.
[0005] FIG. 3 is a graph of data that used to determine PT
time.
[0006] FIG. 4 is a graph showing a qualification zone for an assay
second control.
BACKGROUND OF THE INVENTION
[0007] European patent application EP 0 974 840 the (840
publication), published Jan. 26, 2001, describes a device and
system that may be used with the present invention. FIG. 1
presented herein as adapted from the 840 publication shows a
parallel multi-channel test strip 2. In it, measurement areas 4, 6
and 8 are provided. Upon introducing a sample, usually whole blood,
at introduction port 10 and depressing a bladder 12 and releasing
it, a partial vacuum draws the blood though channel 14 up to shared
stop junction 16. The test strip also includes a bypass channel 18
which draws sample toward bladder 12 to alleviate negative pressure
at the stop junction order to prevent overcoming the surface
tension that pins the fluid in the measurement areas at the stop
junction.
[0008] For PT measurements, it is important to stop the flow of
sample as it reaches that point to permit reproducible "rouleaux
formation"--the stacking of red blood cells--which is an important
step in monitoring blood clotting using the present invention. The
principle of stop junction operation is described in U.S. Pat. No.
5,230,866.
[0009] A test strip body is described as preferably produced from
three layers. The elements above are formed by cutouts in
intermediate layer 20, sandwiched between a top layer 22 and bottom
layer 24. Preferably, layer 22 is double-sided adhesive tape. Stop
junction 16 is preferably formed by an additional cutout in layer
22 and/or 24, aligned with the cutout in layer 22 and sealed with
sealing layer 26 and/or 28.
[0010] Each cutout for stop junction 16 is preferably at least as
wide as channel 14. A filter may optionally be used to cover sample
port 10. The filter separates red blood cells from a whole blood
sample and/or may contain a reagent to interact with the blood to
provide additional information. A suitable filter comprises an
anisotropic membrane, preferably a polysulfone membrane of the type
available from Spectral Diagnostics, Inc., (Toronto, Canada). An
optional reflector may be on, or adjacent to, a surface or layer of
test strip 2 and positioned over the measurement areas. If a
reflector is present, the device becomes a transfiectance
device.
[0011] Typically, in producing the test strip, reagent is
bubble-jet printed onto areas 4, 6 and 8. The chemicals at each
site are disclosed in the 840 publication as: 1) thromboplastin in
area 4; 2) thromboplastin bovine eluate, and recombinant Factor
VIIa in area 6 and 3) thromboplastin and bovine eluate alone in
area 8. The composition in area 6 is selected to normalize the
clotting time of a blood sample by counteracting the. effect of an
anticoagulant, such as warfarin. The composition in area 8 is
selected to partially overcome the effect of an anticoagulent. The
bovine eluate (plasma barium citrate bovine eluate) is available
from Haemotologic-Technologies, (Burlington, Vt.); recombinant
Factor VIIa from American Diagnostica, (Greenwich, Conn.).
Thromboplastin, from Ortho Clinical Diagnostics, (Raritan,
N.J.).
[0012] After printing, a sample port is cut in untreated polyester
film such as AR1235, available from Adhesives Research, (Glen Rock,
Pa.) and then laminated, in register, to the top of the
double-sided tape after removing the release layer. A die then cuts
the stop junction through the three layers of the sandwich.
Finally, strips of single-sided adhesive tape such as MSX4841,
available from 3M, (St. Paul, Minn.) are applied to the outside of
the polyester layers to seal the stop junction.
[0013] Use of the test strip can be understood with reference to a
schematic of the elements of a meter shown in FIGS. 2A and 2B (also
adapted from the 840 publication), which contemplates an automated
meter. Alternatively, manual operation is also possible. In that
case, bladder 12 is manually depressed before sample is applied to
port 10, then released. The first step the user performs is to turn
on the meter, thereby energizing strip detector 30, sample detector
32, measurement system 34, and optional heater 36. The second step
is to insert the strip. Preferably, the strip is not transparent
over at least a part of its area, so that an inserted strip will
block the illumination by LED 38 of detector 40. (More preferably,
the intermediate layer is formed of a non-transparent material, so
that background light does not enter measurement system 34.)
Detector 40 thereby senses that a strip has been inserted and
triggers bladder actuator 42 to compress bladder 12. A meter
display 44 then directs the user to apply a sample to sample port
10 as the third and last step the user must perform to initiate the
measurement sequence. The empty sample port is reflective. When a
sample is introduced into the sample port, it absorbs light from
LED 46 and thereby reduces the light that is reflected to detector
48. That reduction in light, in turn, signals actuator 42 to
release bladder 12. The resultant suction in channel 14 draws
sample through the measurement areas to the stop junction. For each
measurement area 4, 6 and 8, a LED 50 and detector 52 pair is
provided to monitor the light transmitted through the sample as it
is clotting.
[0014] Analysis of the transmitted light as a function of time (as
described below) permits a calculation of the PT time, which is
displayed on the meter display 44 and any messages regarding test
strip fitness or reliability. Preferably, sample temperature is
maintained at about 37.degree. C. by heater 36. Each such function
is controlled by a microprocessor chip 54 controlled by software
stored in programmable, read-only memory 56.
[0015] As described above, the detector senses a sample in sample
port 10, simply by detecting a reduction in (specular) reflection
of a light signal that is emitted by 46 and detected by 48.
However, that simple system cannot easily distinguish between a
whole blood sample and some other liquid (e.g. blood serum) placed
in the sample port in error or, even, an object (e.g., a finger)
that can approach sample port 10 and cause the system to
erroneously conclude that a proper sample has been applied.
[0016] To avoid this type of error, another embodiment measures
diffuse reflection from the sample port. This embodiment appears in
FIG. 2B, which shows detector 48 positioned normal to the plane of
strip 2. With the arrangement shown here, if a whole blood sample
has been applied to sample port 10, the signal detected by 48
increases. abruptly, because of scattering in the blood sample,
then decreases, because of rouleaux formation. The detector system
32 is thus programmed to require that type of signal before causing
actuator 42 to release bladder 12. The delay of several seconds in
releasing the bladder does not substantially affect the readings
described below.
[0017] FIG. 3 depicts a typical "clot signature" curve in which
current from detector 50 is plotted as a function of time. Blood is
first detected in a measurement area at time 1. In the time
interval A, between points 1 and 2, the blood fills the measurement
area. The reduction in current during that time interval is due to
light scattered by red cells and is thus an approximate measure of
the hematocrit. At point 2, sample has filled the measurement area
and is at rest, its movement having been stopped by the stop
junction. The red cells begin to stack up like coins (rouleaux
formation). The rouleaux effect allows increasing light
transmission through the sample (and less scattering) in the time
interval between points 2 and 3. At point 3, clot formation ends
rouleaux formation and transmission through the sample reaches a
maximum. The PT time can be calculated from the interval B between
points 1 and 3 or between 2 and 3. The result is typically reported
in terms of its "INR" (i.e., International-Normalized Ratio).
Thereafter, the blood changes state from liquid to a semi-solid
gel, with a corresponding reduction in light transmission. The
reduction in current (C) between the maximum 3 and endpoint 4
correlates with fibrinogen in the sample.
[0018] Measurements made on a whole blood sample using the strip
yield a curve of the type shown in FIG. 3 for each of the
measurement areas. The data from the curves for the controls
(measurement areas 6 and 8) are used to qualify the data from the
curve for measurement area 4. The measurement of sample from area 4
is validated only when measurements on areas 6 and 8 yield results
within a predetermined range. If either or both of these control
measurements are outside the range, then a retest with another test
strip is indicated. Ageing or oxidization of reagents can
potentially yield failing Control 1 an/or Control 2 tests.
SUMMARY OF THE INVENTION
[0019] In connection with such a two-control test strip such as
described in the '840 publication, the present invention applies
certain criteria to produce a highly-accurate test strip
qualification process based on results obtained from each control.
Results from the first control (C1) are qualified if they fall
within a simple numerical range. Where results are expressed in
terms of INR, C1 readings at or between about 0.60 and 1.9 INR are
acceptable. Results from the second control (C2) are qualified if
they fall within a zone or region bounded by functions dependent
upon assay PT time. When results from the second control and assay
are expressed in terms of INR, the functions are line functions,
diverging from one another at higher assay INR values. As in the
referenced system, test strip results are qualified, or determined
to be fit or reliable, upon both C1 and C2 results falling within
the prescribed ranges.
[0020] Systems of the present invention preferably operate in
connection with a disposable test strip and hand held meter as
described above. Mathematical algorithms or functions, preferably
those described in detail below, are used to qualify test strip
data in a highly accurate manner as evidenced by exemplary results.
Such results are preferably accomplished with a hand-held meter in
a rapid fashion. The algorithms as implemented by hardware as well
as the methodology disclosed form aspects of the present
invention.
DETAILED DESCRIPTION OF THE INVENTION
[0021] In describing the invention in greater detail than provided
in the Summary above, the subject test strip qualification system
and methods for its use are described in relation to FIG. 4 and
various equations. Before the present invention is described in
such detail, however, it is to be understood that this invention is
not limited to particular variations set forth and may, of course,
vary. Various changes may be made to the invention described and
equivalents may be substituted without departing from the true.
spirit and scope of the invention. In addition, many modifications
may be made to adapt a particular situation, material, composition
of matter, process, process step or steps, to the objective, spirit
and scope of the present invention. All such modifications are
intended to be within the scope of the claims made herein.
[0022] Furthermore, where a range of values is provided, it is
understood that every intervening value, between the upper and
lower limit of that range and any other stated or intervening value
in that stated range is encompassed within the invention. The upper
and lower limits of these smaller ranges may independently be
included in the smaller ranges and is also encompassed within the
invention, subject to any specifically excluded limit in the stated
range. Where the stated range includes one or both of the limits,
ranges excluding either both of those included limits are also
included in the invention. Also, it is contemplated that any
optional feature of the inventive variations described herein may
be set forth and claimed independently, or in combination with any
one or more of the features described herein.
[0023] Unless defined otherwise, all 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. Although
any methods and materials similar or equivalent to those described
herein can also be used in the practice or testing of the present
invention, the preferred methods and materials are described. All
existing subject matter mentioned herein (e.g., publications,
patents, patent applications and hardware) is incorporated by
reference herein in its entirety. The referenced items are provided
solely for their disclosure prior to the filing date of the present
application. Nothing herein is to be construed as an admission that
the present invention is not entitled to antedate such material by
virtue of prior invention.
[0024] Also, it is noted that as used herein and in the appended
claims, the singular forms "a," "and," "said" and "the" include
plural referents unless the context clearly dictates otherwise.
Conversely, it is contemplated that the claims may be so-drafted to
require singular elements or exclude any optional element indicated
to be so here in the text or drawings. This statement is intended
to serve as antecedent basis for use of such exclusive terminology
as "solely," "only" and the like in connection with the recitation
of claim elements or the use of a "negative" claim
limitation(s).
[0025] The present invention is preferably practiced with the test
strip and procedured disclosed in connection with the '840
publication. According to the present invention, C1 includes
sufficient coagulation factors to counteract any effect of
anticoagulant--Coumadin in particular--in the blood sample to
preferably produce a PT for C1 between 0.8 and 1.9 in a
good-quality test strip. C2 differs form C1 both in the composition
(as indicated above) and quantity of coagulation factors present in
the reagent formulation. Fewer factors are added to C2 to create a
partial normalization of the effects of the anticoagulant in the
blood sample. Reaction area 6--corresponding to C1--preferably
includes recombinant tissue factor with buffers and preservatives,
bovine coagulation factors of the extrinsic pathway, and
recombinant factor VIIa protein. Reaction area 8--corresponding to
C2--preferably includes recombinant tissue factor with buffers and
preservatives, bovine coagulation factors of the extrinsic
pathway.
[0026] In qualifying test strips, measurements are preferably made
on whole blood sample at each of the three test strip measurement
areas, yielding curves of the type shown in FIG. 3 used to
determine an INR value for each well. First, whole blood sample is
drawn into each of the reaction areas so that the fluid rehydrates
the dried reagents and reacts at each site. The data obtained for
control wells 6 and and 8 are used to qualify the data from the
curve from measurement area 4 providing PT time. The test results,
including that for the controls, is preferably converted to INR
results for use in the algorithms described below and reporting
results to the user.
[0027] Based on multiple test strip lots evaluated at multiple
clinical sites, it was determined that sufficiently accurate
qualification of test strips results if the PT INR for C1 has an
upper limit of about 1.9 and a lower limit of about 0.60 (instead
of the more modest range indicated above). As for C2 qualification
results, is has been observed that C2 follows a linear or
proportional relationship with the assay results obtained. Again,
data from multiple test strip lots and clinical sites was used to
generate qualification criteria.
[0028] The qualification criteria for C2 may be represented as
lines with slightly different slopes and y-intercept values. The
slope an upper limit line 58 as seen in FIG. 4 is greater than that
of a lower limit line 60 also seen therein. The lines diverge from
one another at higher PT values, thus creating a C2 widening
qualification zone 62.
[0029] For the second control upper limit 58, when expressed in the
form y=mx+b, with m.apprxeq.0.56 to 0.58 and b.apprxeq.0.90 the
line produce provides an excellent fit to test data generated. For
the second control lower limit 60, when expressed in the form
y=mx+b, with m.apprxeq.0.36 and b.apprxeq.0.37 to 0.38 the line
produce provides an excellent fit to test data generated. By use of
the ".apprxeq." sign, it is meant equals or is about equal.
[0030] In actuality, the line equations described above may been
defined with greater precision. Two significant figures are
expressed in order to indicate that variation on such an order is
contemplated.. (The same holds true for C1 qualification criteria.)
Still, FIG. 4 is drawn with the precision to which the invention is
preferably practiced.
[0031] This being said, substantial variability in approach is
contemplated as part of the present invention. For instance, one or
more polynomial equations may be used to set the bounds, especially
for C2. Alternately, tabular data representing results within each
qualification ranges for C1 and C2, respectively, may be employed.
In any event, various qualification zones or regions are defined.
Further variation may include modifying C1 and C2 chemicals. While
altering the chemistry may affect the characteristics of the
functions defining the qualification zones, the general nature of
the present invention should not change.
[0032] In instances where C1 and C2 results are qualified, the test
strip meter display 44 shows PT time for the assay (preferably in
terms of an INR value). If either or both of these control
measurements are outside the ranges defined, another sort of
message indicating test reliability or fitness is displayed by the
test strip meter. Error messages specific to they type of failure
may be presented (i.e., messages indicative of C1, C2 or C1 and C2
failure). Alternately, a retest with another test strip may simply
be indicated.
EXAMPLES
[0033] A series of trials were conducted in connection with the
present invention as early as March 2000. These trials were of an
experimental nature, necessary to determine and/or verify the
accuracy of the test strip qualification approach taught herein.
The results of such testing gave positive indication of sufficient
accuracy in test strip accuracy achieved through use of the present
inventions. As of the filing date for this Specification, no
product according to the present invention has yet been made
available to the public.
[0034] The accuracy of the inventive methods function was first
studied in connection with subjects enrolled at three independent
institutions for evaluation against test strips as described above.
In such clinical trials, venous blood was drawn and tested on a
reference clinical laboratory device. These results were used for
absolute reference. By comparison through expanded agreement
analysis, which considers comparison of the clinical interpretation
of test results versus the ultimate laboratory reference system,
inventive system produced a 99% clinical agreement. This rate of
agreement evinces significant improvement over the approach of the
CoaguCheck meter by Roche Diagnostics (formerly Boehringer Mannheim
Corp.) that produced a published performance of 87% expanded
agreement vs. laboratory reference. A test strip error frequency of
about 0.5% was observed in connection with these clinical trials
for the present invention.
[0035] Lay person trials were also conducted on patients who tested
themselves at four defined time intervals in the home environment
with the subject test strip and meter and were than listed within
four hours using venous blood for the reference laboratory system.
The home environment/end user results were compared with the
clinical results. This trial also produced an error frequency
consistent with the first study at about 0.5%. A 0.5% error
frequency rate was observed in connection with C1 and 0.5% with C2.
Errors registered for both C1 and C2 occurred at a 0.1% frequency
rate.
[0036] In running multiple other tests for verifying test strip
accuracy, clinical accuracy of layperson end-users versus the
laboratory reference device was determined tube in 95% clinical
agreement using expanded agreement of result analysis.
[0037] Using the cumulative frequency approach, the accuracy of the
subject invention as preferably practiced in the hands of the
layperson end-user in comparison to the laboratory reference can be
stated such that 94% of the time, the end-use obtains results
within 0.5 INR units of the laboratory reference method. This shows
a significant improvement over a corresponding 90% performance
rating for results within 0.5 INR as published in connection with
Avocet Medical products.
[0038] Though the invention has been described in reference to a
single example, optionally incorporating various features, the
invention is not to be limited to what is described or indicated as
contemplated with respect to possible variation. The breadth of the
present invention is to be limited only by the literal or equitable
scope of the following claims. That being said,
* * * * *